Product, Substructure

Query Query

Results

Date

1809 reactions

2012-12-21 07h:03m:36s (EST)

O N

1. Query

H N

N

N H

O O

Search as: Product, Substructure: on all atoms, No salts, No mixtures

Copyright © 2012 Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys ® is a trademark owned and protected by Elsevier Properties SA and used under license.

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O

O

O

H N

N O

N H O N

N N O

O

Rx-ID: 1066739 View in Reaxys 1/250 Yield 89 %

Conditions & References Example Name 19 Example Title Synthesis of 2-Methyl-5-(4-nitro-phenyl)-[1,3,4]oxadiazole Synthesis of 2-Methyl-5-(4-nitro-phenyl)-[1,3,4]oxadiazole A solution of 4-nitro-benzoic acid N'-acetyl-hydrazide (200 mg, 8.9 mmol) in distilled POCl3 (4 mL) was refluxed at 110° C. under nitrogen for 6 hours. The reaction mixture was concentrated and the residue was quenched with 10percent NaOH solution. The resulting precipitate was collected by filtration to afford 160 mg (89percent) of 2-Methyl-5-(4-nitro-phenyl)-[1,3,4]oxadiazole. 1H NMR: (CDCl3): δ 8.38 (d, 2H), 8.24 (d, 2H), 2.7 (s, 3H). Stage 1: With trichlorophosphate, Time= 6h, T= 110 °C , Inert atmosphere Stage 2: With sodium hydroxide in water Patent; FOREST LABORATORIES HOLDINGS LIMITED; US2009/239848; (2009); (A1) English View in Reaxys

83 %

With trichlorophosphate Popova, N. A.; Krasovitskii, B. M.; Pivnenko, N. S.; Surov, Yu. N.; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol. 33; nb. 6; (1997); p. 712 - 717; Khimiya Geterotsiklicheskikh Soedinenii; nb. 6; (1997); p. 816 - 821 View in Reaxys With pyridine, thionyl chloride in toluene, Heating Golfier,M.; Guillerez,M.-G.; Tetrahedron Letters; (1976); p. 267 - 270 View in Reaxys

80 % Spectr.

With trifluorormethanesulfonic acid, dimethyl-dichlorosilane in acetonitrile, Time= 24h, T= 80 °C Rigo, Benoit; Cauliez, Pascal; Synthetic Communications; vol. 18; nb. 11; (1988); p. 1247 - 1252 View in Reaxys With tetrabutyl ammonium fluoride, 1,1,1,3,3,3-hexamethyl-disilazane in chlorobenzene, Time= 4h, Heating, further reagents, Yield given Rigo, Benoit; Fasseur, Dominique; Cauliez, Pascal; Couturier, Daniel; Synthetic Communications; vol. 19; nb. 13-14; (1989); p. 2321 - 2336 View in Reaxys

100 % Spectr.

With tetrabutyl ammonium fluoride, 1,1,1,3,3,3-hexamethyl-disilazane, Time= 5h, Heating Rigo, Benoit; Cauliez, Pascal; Fasseur, Dominique; Couturier, Daniel; Synthetic Communications; vol. 16; nb. 13; (1986); p. 1665 - 1670 View in Reaxys in N,N,N',N',N'',N''-hexamethylphosphoric triamide, Time= 0.0111111h, microwave irradiation Mashraqui, Sabir H.; Ghadigaonkar, Shailesh G.; Kenny, Rajesh S.; Synthetic Communications; vol. 33; nb. 14; (2003); p. 2541 - 2546 View in Reaxys Reaction Steps: 2 1: SOCl2, Py / diethyl ether 2: toluene / Heating With pyridine, thionyl chloride in diethyl ether, toluene Golfier,M.; Guillerez,M.-G.; Tetrahedron Letters; (1976); p. 267 - 270


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View in Reaxys O

O O

O

N

O

N

H N

O

N H

N N O

Rx-ID: 2192959 View in Reaxys 2/250 Yield

Conditions & References

91 %

Example Name 1 To 100 mg (0.448 mol) of N'-acetyl-2-nitrobenzohydrazide was added 3 mL of phosphorus oxychloride. The solution was heated at 100 °C for 1 h, then the excess phosphorus oxychloride was removed in vacuo. The residue was dissolved in 5 mL of water, and a white precipitate formed. This was extracted with ethyl acetate ( 1 x 5 mL), then the ethyl acetate layer was back extracted with saturated NaHCO3(^ ) (1 x 5 mL), and brine (1 x 5 mL), dried over MgSO4, filtered, and concentrated to give 84 mg (91percent) of a white crystalline solid. Stage 1: With trichlorophosphate, Time= 1h, T= 100 °C Stage 2: With sodium hydrogencarbonate in water Patent; SIRTRIS PHARMACEUTICALS, INC.; WO2009/58348; (2009); (A1) English View in Reaxys

77 %

With polyvinylpyridine polymer-supported dimethylaminopyridine, 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido{1,2a}pyrimidine in tetrahydrofuran, Time= 0.0833333h, microwave irradiation Brain, Christopher T.; Brunton, Shirley A.; Synlett; nb. 3; (2001); p. 382 - 384 View in Reaxys

33 %

With trichlorophosphate in acetonitrile, Time= 2.5h, Heating Peet, Norton P.; Sunder, Shyam; Journal of Heterocyclic Chemistry; vol. 21; (1984); p. 1807 - 1816 View in Reaxys With polyethylene glycol supported Burgess reagent in tetrahydrofuran, Time= 0.0333333h, Irradiation, microwave, 100 W, Pyrex tube, Yield given Brain, Christopher T.; Paul, Jane M.; Loong, Yvonne; Oakley, Paul J.; Tetrahedron Letters; vol. 40; nb. 16; (1999); p. 3275 - 3278 View in Reaxys

O

Br

H N Cl

N H

N N

O

O

Br Cl


Conditions & References Example Name 5 The product of preparation 4 (25.5g, 87mmol) was added to phosphorous oxychloride (90mL) and the reaction mixture heated to 110°C for 3 hours. The mixture was then allowed to cool to room temperature and was concentrated in vacuo. The residue was diluted with water (500mL) and basified with saturated sodium hydrogen carbonate solution. The aqueous mixture was extracted with ethyl acetate (2x250mL) and the organic phases were combined. These were washed with water (500mL) and brine (250mL), dried over sodium sulfate and concentrated in vacuo to afford the title product in 77percent yield, 18.2g. 1H NMR(CDCI3, 400MHz) 8: 4.80(s, 2H), 7.70 (d, 8.00 (d, MS APCI+ m/z 275 [MH] + With trichlorophosphate, Time= 3h, T= 110 °C Patent; PFIZER LIMITED; PFIZER INC.; WO2005/121152; (2005); (A1) English View in Reaxys

77 %

Example Name 6


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Preparation 6; 2-(4-Bromoprienyl)-5-(chloromethyl)-1.3.4-oxadiazole; The product of preparation 2 (25.5g, 87mmol) was added to phosphorous oxychloride (9OmL) and the mixture was heated at 1100C for 3 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water. The aqueous mixture was basified using sodium hydrogen carbonate solution and extracted with ethyl acetate (50OmL). The organic solution was washed with water (50OmL) EPO and brine (25OmL)1 dried over sodium sulfate and concentrated in vacuo to afford the title compound in 77percent yield, 18.41 g.1HNMR(400MHz, CDCI3) δ: 4.80(s, 2H), 7.70 (d, 2H), 8.80(d, 2H); Microanalysis: C9H6BrCIO requires (percent): C 39.52; H 2.21 ; N 10.24; found (percent): C 39.35; H 2.27, N 10.17. Stage 1: With trichlorophosphate, Time= 3h, T= 110 °C Stage 2: With sodium hydrogencarbonate in water Patent; PFIZER LIMITED; WO2006/100588; (2006); (A1) English View in Reaxys 70 %

With trichlorophosphate, Heating Cao, Song; Wei, Na; Zhao, Chuanmeng; Li, Lina; Huang, Qingchun; Qian, Xuhong; Journal of Agricultural and Food Chemistry; vol. 53; nb. 8; (2005); p. 3120 - 3125 View in Reaxys With trichlorophosphate, Reflux Ellis, David; Synthetic Communications; vol. 41; nb. 7; (2011); p. 963 - 975 View in Reaxys

Br

O

H N

N N

N H

O

O Br


Conditions & References With trichlorophosphate, Time= 6h, Heating Dingemans, Theo J.; Murthy, N. Sanjeeva; Samulski, Edward T.; Journal of Physical Chemistry B: Condensed Matter, Materials, Surfaces, Interfaces, and Biophysical Chemistry; vol. 105; nb. 37; (2001); p. 8845 - 8860 View in Reaxys

89 %

Example Name 1.1.iii (iii) Synthesis of O11Br; Further, 15 g (47 mmol) of the 1-benzoyl-2-(4-bromobenzoyl)hydrazine obtained by the method shown in (ii) above was put in a 200-mL three-neck flask, 100 mL of phosphoryl chloride was added therein, and the mixture was heated and stirred at 100° C. for 5 hours. After the reaction, the solid obtained by completely distilling off phosphoryl chloride was washed with water and a sodium carbonate aqueous solution in this order and collected by suction filtration. Then, the solid was recrystallized with methanol; thus, 13 g of a white solid of O11Br that was an object of Step 1 was obtained (yield: 89percent). A synthesis scheme of Step 1 described above is shown in the following scheme (a-1). With trichlorophosphate, Time= 5h, T= 100 °C Patent; Semiconductor Energy Laboratory Co., Ltd.; US2007/149784; (2007); (A1) English View in Reaxys

89 %

Example Name 1.iii; E.1 Further, 15 g (47 mmol) of 1-benzoyl-2-(4-bromobenzoyl)hydrazine obtained by the method shown in (ii) above was put in a 200-mL three-neck flask, 100 mL of phosphoryl chloride was added therein, and the mixture was heated and stirred at 100 °C for 5 hours. After the reaction, a solid obtained by completely distilling off phosphoryl chloride was washed with water and a sodium carbonate aqueous solution in this order and collected by suction filtration. Then, the solid was recrystallized with methanol; thus, 13 g of a white solid of O11Br that was an object of Step 1 was obtained (yield: 89percent). A synthetic scheme of Step 1 described above is shown in the following scheme (E-1). With trichlorophosphate, Time= 5h, T= 100 °C


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Patent; SEMICONDUCTOR ENERGY LABORATORY CO., LTD.; EP1873163; (2008); (A1) English View in Reaxys 85 %

With trichlorophosphate, Time= 5h, Inert atmosphere, Reflux Wu, Jing; Li, Hong-Yan; Kang, Ling-Chen; Li, Dong-Ping; Xu, Qiu-Lei; Zhu, Yu-Cheng; Tao, Yun-Mei; Zheng, You-Xuan; Zuo, Jing-Lin; You, Xiao-Zeng; Journal of Organometallic Chemistry; vol. 695; nb. 17; (2010); p. 2048 2056 View in Reaxys Wu, Jing; Li, Hong-Yan; Kang, Ling-Chen; Li, Dong-Ping; Zhou, Xin-Hui; Sui, Yan; Zheng, You-Xuan; Zuo, JingLin; You, Xiao-Zeng; Li, Huan-Rong; Journal of Photochemistry and Photobiology A: Chemistry; vol. 211; nb. 2-3; (2010); p. 135 - 142 View in Reaxys

85 %

With trichlorophosphate, Time= 5h, Reflux, Inert atmosphere Xu, Qiu-Lei; Li, Hong-Yan; Wang, Cheng-Cheng; Zhang, Song; Li, Tian-Yi; Jing, Yi-Ming; Zheng, You-Xuan; Huang, Wei; Zuo, Jing-Lin; You, Xiao-Zeng; Inorganica Chimica Acta; vol. 391; (2012); p. 50 - 57 View in Reaxys

33%

Example Name 1.3; B.3 A synthetic scheme of 2-(4-bromophenyl)-5-phenyl-1,3,4-oxadiazole is shown in (B-3). In a 300 mL three-necked flask were placed 19 g (60 mmol) of N'-benzoyl-4-bromobenzohydrazide and 100 mL of phosphoryl chloride. This mixture was stirred while being heated at 100° C. for 5 hours under a stream of nitrogen. After a predetermined time, the solid obtained by distilling off phosphoryl chloride from the mixture under reduced pressure was washed with a saturated aqueous sodium carbonate solution. The mixture was collected by suction filtration, and the collected solid was washed with methanol, so that 6.0 g of a white powder, which was a target substance, was obtained at a yield of 33percent. Stage 1: With trichlorophosphate, Time= 5h, T= 100 °C Stage 2: With sodium carbonate in water Patent; Semiconductor Energy Laboratory Co., Ltd.; US2009/140641; (2009); (A1) English View in Reaxys With trichlorophosphate Grekow et al.; Zhurnal Obshchei Khimii; vol. 29; (1959); p. 3054,3055; engl. Ausg. S. 3020, 3021 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys

F

O F

O

O

N

N N

HN

NH

N

N N

O

O

O

N

N N

N

N N

O


Conditions & References Example Name 97 To a solution of (R)-4-(5-(azidomethyl)-2-oxooxazolidin-3-yl)-2-fluoro-N'-(2-(pyridin-2- yl)acetyl)benzohydrazide (300mg, 0.72 mmol) in acetonitrile POCl3 (57mg, 0.36 mmol) and catalytic amount of DMAP were added and the reaction mixture was refluxed at 80 0C for overnight. Solvent was removed under reduced pressure and the residue was basified with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. Solvent was evaporated and the residue was purified by column chromatography to yield the title product 188 mg .Yield: 65percentIR (KBr, cm'1): 3070, 2924, 2094, 1629, 1492, 1409, 1209, 962, 748, 565 1HNMR (400 MHz, DMSO): δ 8.52 - 8.48 (m, IH), 8.00 (t, J= 8.5 Hz, IH), 7.82 (dt, J= 1.8Hz, 7.7 Hz, IH), 7.72 (dd, J = 2.1 Hz, 13.4 Hz, IH), 7.57 (dd, J = 2.1 Hz, 8.8 Hz, IH), 7.48 (d, J = 7.7 Hz, IH), 7.34 - 7.30 (m, IH), 4.98 -


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4.90 (m, IH), 4.54 (s, 2H), 4.20 (t, J= 9.1 Hz, IH), 3.85 (dd, J= 6.1 Hz, 9.4 Hz, IH), 3.78 - 3.70 (m, 2H) ES-MS (m/z): 396 (M++l) Stage 1: With trichlorophosphate, 4-(N,N-dimethlyamino)pyridine in acetonitrile, T= 80 °C , Heating / reflux Stage 2: With sodium carbonate in water Patent; DR. REDDY'S LABORATORIES LIMITED; DR. REDDY'S LABORATORIES, INC.; WO2008/143649; (2008); (A2) English View in Reaxys

O

O

O

H N N H

S

N

O

N

O

O

O

S

O

O



94 %

A solution of ethyl 6- { 2-[2-(4-methoxybenzoyl)hydrazino] -2-oxoethyl } - 1 -benzothiophene-2-carboxylate (78 mg, 0.19 mmol) and (methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt (113 mg, 0.47 mmol) in THF was heated to 100 0C in the microwave for 10 minutes. The reaction was filtered through a pad of silica and washed with ethyl acetate. The organics were evaporated to dryness to give 70 mg (94percent) of the title compound as a clear oil. LC/ MS (EI): cal'd 395.1 (MH+), exp 395.1 (MH+). With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in tetrahydrofuran, Time= 0.166667h, T= 100 °C , microwave irradiation Patent; MERCK and CO., INC.; ATON PHARMA, INC.; WO2006/115835; (2006); (A2) English View in Reaxys A solution of ethyl 6-{2-[2-(4-methoxybenzoyl)hydrazino]-2-oxoethyl}-l-benzothiophene-2-carboxylate (78 mg, 0.19 mmol) and (methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt (113 mg, 0.47 mmol) in THF was heated to 100 0C in the microwave for 10 minutes. The reaction was filtered through a pad of silica and washed with ethyl acetate. The organics were evaporated to dryness to give the title compound as a clear oil. LC/MS (EI): cal'd 395.1 (MH+), exp 395.1 (MH+). With Burgess Reagent in tetrahydrofuran, Time= 0.166667h, T= 100 °C , Microwave irradiation Patent; MERCK and CO., INC.; ATON PHARMA, INC.; WO2006/115845; (2006); (A1) English View in Reaxys

F F Cl

F

F F

H N O

Cl

F

H N O

N

O

NH

O

NH

N

O

N N

N N


Conditions & References Example Name 7.7h Intermediate 7h4-((1R,2S)-2-(benzyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3,3,3-trifluoropropylamino)-2chloro-3-methylbenzonitrile To a solution of triphenylphosphine (180 mg, 0.69 mmol) in DCM (10 mL) was added I2 (174 mg, 0.69 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (0.20 mL, 1.43 mmol) was added, followed by a solution of N'-((2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoyl)-4-cyanobenzohydrazide (180 mg, 0.32 mmol) in DCM (2 mL) and THF (2 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (1 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography


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to provide the title compound 4-((1R,2S)-2-(benzyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3,3,3-trifluoropropylamino)-2-chloro-3-methylbenzonitrile (170 mg, 98percent). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.98 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.097.17 (m, 5H), 6.45 (d, J=8.4 Hz, 1H), 5.22 (b, 2H), 5.01 (d, J=11.5 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.52 (m, 1H), 2.34 (s, 3H). With iodine, triethylamine, triphenylphosphine in tetrahydrofuran, dichloromethane, Time= 0.5h, T= 0 - 20 °C Patent; Radius Health, Inc.; US2012/4270; (2012); (A1) English View in Reaxys With iodine, triphenylphosphine in triethylamine Zeng, Chun-Min; Kerrigan, Sean A.; Katzenellenbogen, John A.; Slocum, Connie; Gallacher, Kyla; Shomali, Maysoun; Lyttle, C. Richard; Hattersley, Gary; Miller, Chris P.; Tetrahedron Letters; vol. 51; nb. 41; (2010); p. 5361 - 5363 View in Reaxys

O

Cl

H N Cl

N H

N N

O

O

Cl Cl


Conditions & References Example Name 33.b To a mixture of 4-chlorobenzohydrazide 5 (1 g, 5.86 mmol) and K2CO3 (0.97 g, 7.03 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.68 g, 6.08 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 4-chloroN'-(2- chloroacetyl)benzohydrazide 6 (1.2 g, 82percent) which was used for the next step without further purification. A mixture of 4-chloro-N'-(2-chloroacetyl)benzohydrazide 6 (0.6 g, 2.43 mmol) and phosphorous oxychloride (0.37 g, 2.43 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25percent acetone/hexanes to give compound 7 (0.45 g). Yield: 82percent. 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.02 (d, 2 H), 7.53 (d, 2 H), 4.78 (s, 2 H). With trichlorophosphate in acetonitrile, Time= 16h, Reflux Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys With sulfuric acid Vakula,T.R.; Srinivasan,V.R.; Indian Journal of Chemistry; vol. 11; (1973); p. 732 - 734 View in Reaxys With trichlorophosphate, Time= 3h, Heating Cao, Song; Qian, Xuhong; Song, Gonghua; Huang, Qingchun; Journal of Fluorine Chemistry; vol. 117; nb. 1; (2002); p. 63 - 66 View in Reaxys Cao, Song; Qian, Xuhong; Song, Gonghua; Chai, Bing; Jiang, Zhisheng; Journal of Agricultural and Food Chemistry; vol. 51; nb. 1; (2003); p. 152 - 155 View in Reaxys With trichlorophosphate, Heating Chai, Bing; Cao, Song; Liu, Haidong; Song, Gonghua; Qian, Xuhong; Heterocyclic Communications; vol. 8; nb. 6; (2002); p. 601 - 606 View in Reaxys


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O Cl

N

NH HN

O

N

Si HN

O HN

O N N

N

O

Si

Cl N



84%

Example Name 22.22e Intermediate 22e; 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2chloro-3-methylbenzonitrile ; To a 1 L round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (12.3 g, 47.0 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (500 mL) followed by addition of solid iodine (11.91 g, 47.0 mmol). This was allowed to stir at room temperature for a period of 10 min. then cooled to 0° C. Triethylamine (13.1 mL, 94 mmol) was then slowly added to this reaction (CAUTION: Exotherm). This mixture was allowed to stir at room temperature for an additional ten min., during which the reaction became a thick slurry. N'-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenyl-amino) butanoyl)-4-cyanobenzohydrazide (12.35 g, 23.5 mmol) was taken up in methylene chloride (200 mL) and slowly added to the heavily stirred reaction mixture. After a period of 10 min, TLC (1:1 EtOAc:hexanes) showed product formation and no starting material. The reaction was then quenched by slow addition of 10percent Na2S2O3/H2O (500 mL). The organic layer was then isolated and washed with additional 10percent sodium thiosulfate/water (1.x.200 mL), brine (1.x.200 mL), then dried (Na2SO4). The solution was then filtered and concentrated under reduced pressure to reveal a brown oil/solid. This was purified via silica gel chromatography eluted with 25percent EtOAc/hexanes to provide the title compound as a white solid (9.98 g, 84percent):. 1H NMR (400 MHz, CDCl3, δ in ppm) (AA'XX', J=8.8 Hz, 2H), 7.79 (AA'XX', J=8.8 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 5.35 (d, J=8.8 Hz, 1H), 4.82 (dd, J=2.0, 8.7 Hz, 1H), 3.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H), -0.22 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 20 °C , Inert atmosphere Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys With iodine, 5,15,10,20-tetraphenylporphyrin, triethylamine Miller, Chris P.; Shomali, Maysoun; Lyttle, C. Richard; O'dea, Louis St. L.; Herendeen, Hillary; Gallacher, Kyla; Paquin, Dottie; Hattersley, Gary; Compton, Dennis R.; Sahoo, Bishwabhusan; Kerrigan, Sean A.; Burge, Matthew S.; Nickels, Michael; Green, Jennifer L.; Katzenellenbogen, John A.; Tchesnokov, Alexei; Medicinal Chemistry letters; vol. 2; nb. 2; (2011); p. 124 - 129 View in Reaxys

O H N N H

N N

O

O


Conditions & References Example Title 4.2.2. 2-Isopropyl-5-phenyl-1,3,4-oxadiazole N'-(Isobutyryl)benzohydrazide (1.24 g, 6 mmol), TsCl (3.43 g, 18 mmol), and diisopropylethylamine (1.55 g 12 mmol) were dissolved in acetonitrile (60 ml), the resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 12 h, then it was poured into a 14percent NH3 aqueous solution. The resulting mixture was stirred at room temperature for 15-30 min, then extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous Na2SO4, and concentrated in vacuum to afford the crude product, which was then purified by column chromatography on silica gel with petroleum ether/ethyl acetate (10:1, v/v) to give 2-isopropyl-5-phenyl-1,3,4oxadiazole as colorless oil in 68percent yield. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.06-8.02 (m, 2H), 7.53-7.49 (m, 3H), 3.31-3.24 (m, 1H), 1.46 (d, J=9.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ (ppm): 170.8, 164.6, 131.4, 128.9, 126.7, 124.1, 26.4, 20.1; HRMS calcd for C11H13N2O [M+1]: 189.1028, found 189.1030.


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With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, Time= 12h, T= 20 °C , Inert atmosphere Chen, Xiaofeng; Liu, Rui; Xu, Yuan; Zou, Gang; Tetrahedron; vol. 68; nb. 24; (2012); p. 4813 - 4819 View in Reaxys

Si O

O H N

O

O

N H O

N

Si

N



100 %

Example Name 9.D 9D: 2-[4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl]-5-(4-isobutylphenyl)-1,3,4-oxadiazole 4-(tert-Butyl-dimethyl-silanyloxymethyl)-benzoic acid N'-(4-isobutyl-benzoyl)-hydrazide (0.513 g, 1.16 mmol) was added to a solution of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.39 g, 5.82 mmol), DMF (2 mL) and THF (23 mL) and stirred at 110° C. for 16 hours in a sealed vial. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (3.x.), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.50 g, 100percent yield) as a crude white solid. With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in tetrahydrofuran, N,N-dimethyl-formamide, Time= 16h, T= 110 °C Patent; Pfizer Inc; US2007/270438; (2007); (A1) English View in Reaxys

N

O H N N H

N

O trans trans

trans trans

O trans trans

O trans trans O

O

O



91 %

Example Name 2 A mixture of trans-methyl 4-[(2- benzoylhydrazino) carbonyl] cyclohexanecarboxylate (0.71 g, 2.35 mmol), phosphorus oxychloride (1.65 mL, 2.35 mmol) and CH3CN(20 mL) was stirred at 800C for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with AcOEt, and the mixture was washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. The residue was purified by chromatography on silica (hexanes/AcOEt 2/1) to give trans- methyl 4- (5-phenyl-l, 3, 4-oxadiazol-2-yl) cyclohexanecarboxylate (0.61 g, 91percent) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.55-1.79 (4H, m) , 2.18 (2H, dd, J = 3.2, 13.6 Hz), 2.30 (2H, dd, J = 3.2, 13.6 Hz), 2.41 (IH, m) , 2.97 (IH, m) , 3.71 (3H, s), 7.46-7.56 (3H, m) , 8.00-8.08 (2H, m) ; m/z (APCI pos) 287.1 (100percent) [M+H] . Stage 1: With trichlorophosphate in acetonitrile, Time= 4h, T= 80 °C Stage 2: With sodium hydrogencarbonate in water, ethyl acetate, T= 18 - 25 °C Patent; TAKEDA PHARMACEUTICAL COMPANY LIMITED; WO2008/11130; (2008); (A2) English View in Reaxys

F

F

O

F O

N

O O

O H N

N N H

O

O O O

O N

F

N

O

F

F

Rx-ID: 10909307 View in Reaxys 13/250


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Yield


85 %

The title compound was prepared from (S)-t-buy\\- 2,2,4-trimethyl-4-(2-(4- (octyloxy^enzoytyhydrazinecarbonytyoxazolidine-S-carboxylate using published procedure (Tet. Letters, 2006, 47, 105-108) in 85percent yield. MS (ESI, M-I-H +) = 556.1; 1H NMR (400 MHz, CDCl ) δ 8.22 (d, IH, J= 1.6 Hz), 8.14 (d, IH, J= 8.8 Hz), 8.10 (dd, IH, J= 8.8 Hz, J= 1.6 3 Hz), 4.22 (d, IH, J= 8.8 Hz), 4.12 (t, 2H, J= 6.0 Hz), 4.01 (m, IH)5 1.94 (s, 3H), 1.85 (m, 2H), 1.76 (s, 3H), 1.72 (s, 3H), 1.51-1.46 (m, 4H), 1.22 (m, 7H), 1.25 (s, 6H), 0.89 (t, 3H, J= 7.2 Hz). With trichloroacetonitrile, triphenylphosphine in acetonitrile, Time= 0.333333h, T= 120 °C , Microwave irradiation Patent; PRAECIS PHARMACEUTICALS INCORPORATED; WO2008/16692; (2008); (A2) English View in Reaxys

O H N N H

O O

I

N I

N

O

O

N

O

N

O



99 %

Example Name 2 To a suspension of the diacylhydrazide (23) prepared in the previous step, PPh3 (1.71 g, 6.54 mmol) and /-Pr2NEt (2.30 mL, 12.97 mmol) in CH3CN (50 mL) at room temperature was added hexachloroethane (1.41 g, 5.97 mmol). The reaction was stirred at room temperature for 1.5 hours and then the solvent was removed in vacuo and the residue was partitioned with ethyl acetate/H2O. The layers were separated, the aqueous phase was re-extracted with ethyl acetate (2x) and the combined organic layers were washed (H2O, brine) and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by column chromatography (hexane:ethyl acetate, 3: 1) to give (S)-tert-bvAy\\ 2-(5-(4iodophenyl)-l,3,4-oxadiazol- 2-yl)pyrrolidine-l-carboxylate 24 (1.89 g, 99percent) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (A of app AB quartet, d, J=8.4 Hz, 2H), 7.74 (A of app AB quartet, d, J=8.4 Hz, 2H), 5.02 - 5.06 (m, IH), 3.47 - 3.53 (m, IH), 3.36 - 3.41 (m, IH), 2.26 - 2.32 (m, IH), 1.91 - 2.09 (m, 3H), 1.37 (s, 4H), 1.17 (s, 5H). LCMS: Anal. Calcd. for Ci7H20IN3O3: 441; found: 442 (M+H)+. With 1,2,2-trichloro-1,1,2-trichloro-ethane, N-ethyl-N,N-diisopropylamine, triphenylphosphine in acetonitrile, Time= 1.5h, T= 20 °C Patent; BRISTOL-MYERS SQUIBB COMPANY; WO2008/144380; (2008); (A1) English View in Reaxys

O

H N Cl

O

O N H

N

O

N

O N

O N

Cl

O

O

O


Conditions & References Example Name 26.C N'-(Chloroacetyl)-3-(methyloxy)-4-nitrobenzohydrazide (1.00 g, 3.48 mmol) and Burgess' reagent (0.994 g, 4.17 mmol) in THF (15 mL) was heated to 120° C. for 20 minutes in the microwave. The reaction was complete by TLC. Purification by flash chromatography provided the title compound (0.802 g, 2.93 mmol, 85percent). 1H NMR (400 MHz, DMSOd6) δ ppm 4.04 (s, 3H), 5.16 (s, 2H), 7.72 (dd, J=8.4, 1.8 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H). With Burgess Reagent in tetrahydrofuran, Time= 0.333333h, T= 120 °C , microwave irradiation Patent; Kuntz, Kevin; Uehling, David Edward; Waterson, Alex Gregory; Emmitte, Kyle Allen; Stevens, Kirk; Shotwell, John Brad; Smith, Stephon Cornell; Nailor, Kristen E.; Salovich, James M.; Wilson, Brian John; Cheung, Mui; Mook, Robert Anthony; Baum, Erich W.; Moorthy, Ganesh; US2008/300242; (2008); (A1) English View in Reaxys


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O

Cl

N

NH HN

Br

O

Si

HN

O HN

O

Br

N

N

O

Si

Cl N



89%

Example Name 56.56c Intermediate 56c; 4-((1R,2S)-1-(5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2chloro-3-methylbenzonitrile; To a solution of triphenylphosphine (4.23 g, 16.1 mmol) in DCM (200 mL) was added 12 (4.1 g, 16.2 mmol) at 0° C. After 12 was dissolved completely, Et3N (4.5 mL, 32.3 mmol) was added, followed by a solution of 4-bromo-N'-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (4.68 g, 8.1 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for additional 15 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (400 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography to provide the title compound (4.03 g, 89percent), which was used directly in the next step With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

Cl

N

NH HN

I

O

Si

HN

O HN

I

O N

N

O

Si

Cl N

Rx-ID: 28712598 View in Reaxys 17/250 Yield 88%

Conditions & References Example Name 57.57c Intermediate 57c; 4-((1R,2S)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-iodophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2chloro-3-methylbenzonitrile; To a solution of triphenylphosphine (7.2 g, 27.5 mmol) in DCM (300 mL) was added 12 (7.0 g, 27.5 mmol) at 0° C. After 12 was dissolved completely, Et3N (7.7 mL, 55.2 mmol) was added, followed by a solution of N'-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-iodobenzohydrazide (8.6 g, 13.7 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for an additional 60 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (500 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4 and filtered. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (7.3 g, 88percent). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.06 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.56 (d, J=8.8 Hz, 1H), 5.00 (dd, J=2.0, 8.8 Hz, 1H), 4.74 (m, 1H), 2.59 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.28 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys


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O

F F

NH O

HN

S

O

O

F N

Si O

HN

HN

O O

S F

O

N

N

O Si

F F N



94%

Example Name 59.59c Intermediate 59c; 4-((1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-(methylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzonitrile; A solution of N'-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-(methylsulfonyl)benzohydrazide (5.29 g, 8.80 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (4.64 g, 17.7 mmol), iodine (4.48 g, 17.6 mmol) and Et3N (4.9 mL, 35.2 mmol). The reaction mixture was warmed to room temperature, stirred for 20 minutes and quenched with 10percent sodium thiosulfate (100 mL). The organic extract was washed with 10percent sodium thiosulfate (100 mL), H2O (100 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a pink foam, which was purified by flash chromatography over silica gel (50percent EtOAc in hexanes) to provide the title compound (4.81 g, 94percent), which was used directly in the next step. With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N

O

S

NH HN

O

N

Si

HN

Si O

O HN O

N N

S N N


Conditions & References Example Name 60.60d Intermediate 60d; 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile; To a solution of triphenylphosphine (275 mg, 1.43 mmol) in DCM (24 mL) was added 12 (363 mg, 1.43 mmol) at 0° C. After 12 was dissolved completely, Et3N (0.40 mL, 2.87 mmol) was added, followed by a solution of N'-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4cyanobenzohydrazide (380 mg, 0.71 mmol) in DCM (12 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (360 mg, 98percent). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.73 (d, J=5.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.89 (d, J=8.6 Hz, 1H), 5.12 (m, 1H), 4.74 (m, 1H), 1.61 (d, J=6.2 Hz, 3H), 1.05 (s, 9H), 0.26 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys


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O NH

Cl

HN N

N

O

HN

HN Si

O

O

Si O

N

N

Cl

N

N



98%

Example Name 79.79d Intermediate 79d; (R)-4-(3-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2chloro-3-methylbenzonitrile; To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (1 g, 3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (60 mL) followed by addition of solid iodine (688 mg, 2.71 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (1 mL, 7.24 mmol). (R)-N'-(4-(tertbutyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-cyanobenzohydrazide (950 mg, 1.81 mmol) was taken up in methylene chloride (15 mL) and slowly added to the stirred reaction mixture. After a period of 30 min, the solid polymer was filtered out and washed with additional methylene chloride (50 mL). The organic filtrate was then washed with 10percent sodium thiosulfate/water (2.x.25 mL), brine (1.x.30 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown solid (1.03 g). Purification by flash column chromatography [EtOAc-hexanes (1:2) as eluent] afforded the title compound as a white crystalline solid (900 mg, 98percent). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.19 (d, J=9 Hz, 2H), 8.00 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 6.05 (d, J=9 Hz, 1H), 5.4 (m, 1H), 4.00-3.95 (m, 1H), 3.94-3.89 (m, 1H), 2.57-2.40 (m, 2H), 2.38 (s, 3H), 0.88 (s, 9H), 0.04 (s, 3H) and 0.00 (s, 3H). With triphenylphosphine polymer bound, iodine, benzotriazol-1-ol, triethylamine in dichloromethane, T= 20 °C , Inert atmosphere Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O Cl

Cl

N

NH HN

O

O

Si

Si Cl

O HN HO

HN O N

N

O

Si

Cl N


Conditions & References Example Name 30.30c Intermediate 30c; 4-((1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-(5-(3-chloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile; To a 25 mL round bottom flask was added polymer supported triphenylphosphine (687 mg, 2.06 mmol, 2.0 equiv., approx. 3 mmol/g) and 10.3 mL of methylene chloride. The reaction was cooled to 0° C. using an ice-water bath and then iodine (523 mg, 2.06 mmol, 2.0 equiv.) was added followed by TEA (0.57 mL, 4.12 mmol, 4.0 equiv.). After stirring for 5 min, 4-(tert-butyldimethylsilyloxy)-N-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-3-chloro benzohydrazide (688 mg, 1.03 mmol, 1.0 equiv.) was added. The reaction was allowed to stir at room temperature for 2 h. The mixture was filtered over Celite.(R). in a ground glass fritted funnel and the solids rinsed with methylene chloride several times. The organics were washed with 10percent Na2S2O3 (3.x.10 mL) followed by a wash with brine (1.x.10 mL). The solution was dried over Na2SO4 and was concentrated in vacuo to yield a brown oil. The product was purified via automated flash chromatography (0-->30percent EtOAc/hexanes-->100percent EtOAc, 40g of silica gel) to provide the desired product as a yellow oil (586 mg, 88percent yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.92 (d, J=2.14 Hz, 1H), 7.80 (dd, J=1.95, 8.4 Hz, 1H), 7.50 (d, J=8.79 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.79 Hz, 1H), 5.79 (d, J=9.18 Hz, 1H), 5.02 (dd, J=6.65,


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9.19 Hz, 1H), 4.65 (m, 1H), 2.34 (s, 3H), 1.41 (d, J=6.05 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H); LRMS (ESI-) exact mass calcd for C25H30Cl2N4O3Si [M]+ 533.5, found 534.2. With polymer supported triphenylphosphine, iodine, triethylamine in dichloromethane, Time= 2h, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

F F

NH HN

O

N

F N

Si O

HN

HN O N

F

N

N

O Si

F F N



87%

Example Name 44.44d Intermediate 44d; 4-((1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propyl-amino)-2-(trifluoromethyl)benzonitrile; A solution of N'-((2R,3R)-3-(tert-butyldimethylsilyl-oxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (944 mg, 1.73 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (907 mg, 3.46 mmol), iodine (878 mg, 3.46 mmol) and Et3N (0.96 mL, 6.92 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min and quenched with sat. aq. sodium thiosulfate (200 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-30percent EtOAc in hexanes) to provide the title compound as a light yellow oil (790 mg, 87percent): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.19 (dd, J=2.5, 8.8 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 5.19 (dd, J=7.2, 9.0 Hz, 1H), 4.55 (dq, J=6.1, 7.2 Hz, 1H), 1.47 (d, J=6.1 Hz, 3H), 0.74 (s, 9H), 0.09 (s, 3H), -0.07 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

F F

NH HN

O

N

F N

Si O

HN

HN O N

F

N

N

F

O Si

F N


Conditions & References Example Name 45.45d Intermediate 45d; 4-((1R,2S)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propyl-amino)-2-(trifluoromethyl)benzonitrile; A solution of N'-((2R,3S)-3-(tert-butyldimethyl-silyloxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (1.05 g, 1.92 mmol) in CH2Cl2 (40 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.01 g, 3.85 mmol), iodine (980 mg, 3.85 mmol) and Et3N (1.1 mL, 7.70 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min and quenched with sat. aq. sodium thiosulfate (200 mL). The solution was extracted with CH2Cl2 (150 mL). The organic extract was washed with sat. aq. sodium thiosulfate (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a light brown solid, which was purified by flash chromatography over silica gel (50percent EtOAc in hexanes) to provide the title compound as a light yellow oil (900 mg, 89percent): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.8 Hz, 2H), 8.02 (dm, J=8.8 Hz, 2H),


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7.72 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.17 (dd, J=2.3, 8.6 Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 5.36 (dd, J=3.3, 9.4 Hz, 1H), 4.73 (dq, J=3.1, 6.1 Hz, 1H), 1.45 (d, J=6.3 Hz, 3H), 0.78 (s, 9H), 0.07 (s, 3H), -0.13 (s, 3H With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

Cl

N

O NH

Cl

HN

HN

O

N

Si

N

O

O

N

N H

N

N

O

Si



100%

Example Name 46.46d Intermediate 46d; 4-((1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propyl-amino)-2-chlorobenzonitrile; A solution of N'-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyanophenylamino)butanoyl)-4-cyanobenzohydrazide (1.02 g, 1.98 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.04 g, 3.97 mmol), iodine (1.01 g, 3.97 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 25 min and quenched with sat. aq. sodium thiosulfate (300 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (2.x.150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20percent EtOAc in hexanes) to provide the title compound as a light yellow oil (984 mg, 100percent): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.3, 8.8 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 5.10 (dd, J=7.2, 9.2 Hz, 1H), 4.52 (dq, J=6.1, 7.2 Hz, 1H), 1.45 (d, J=6.1 Hz, 3H), 0.75 (s, 9H), 0.09 (s, 3H), -0.07 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O H N

N

N

I N H

I

O

O



99 %

Example Name 55.2 N'-Cyclopropanecarbonyl-3-iodobenzoic hydrazide (535 mg, 1.62 mmol) obtained in Step 1 was suspended in acetonitrile (20 mL), and the mixture was stirred at 60°C for 6 hours after adding triphenylphosphine (850 mg, 3.24 mmol), carbon tetrachloride (0.63 mL, 6.48 mmol), and triethylamine (0.45 mL, 3.24 mmol). The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give 2-cyclopropyl-5-(3iodophenyl)-1,3,4-oxadiazole (499 mg, 99percent). ESI-MS: m/z 313 [M + H]+. With tetrachloromethane, triethylamine, triphenylphosphine in acetonitrile, Time= 6h, T= 60 °C Patent; Kyowa Hakko Kirin Co., Ltd.; EP2163554; (2010); (A1) English View in Reaxys O H N O

I

I N H

N

N O



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2012-12-21 07:05:37

Yield


92 %

Example Name 52.3 3-Iodo-N'-propionylbenzohydrazide (382 mg, 1.20 mmol) obtained in Step 2 was dissolved in acetonitrile (21 mL), and the mixture was stirred at 60°C for 2 hours after adding triphenylphosphine (629 mg, 2.40 mmol), carbon tetrachloride (0.46 mL, 4.80 mmol), and triethylamine (0.33 mL, 1.54 mmol). After concentrating the mixture under reduced pressure, the residue was purified by silica gel column chromatography to give 2-ethyl-5-(3-iodophenyl)-1,3,4-oxadiazole (331 mg, 92percent). ESI-MS: m/z 301 [M + H]+. With tetrachloromethane, triethylamine, triphenylphosphine in acetonitrile, Time= 2h, T= 60 °C Patent; Kyowa Hakko Kirin Co., Ltd.; EP2163554; (2010); (A1) English View in Reaxys O

I

H N

O

I O

N H

N

N



95 %

Example Name 115.2 N'-Acetyl-2-iodobenzohydrazide (1.23 g, 4.05 mmol) obtained in Step 1 was dissolved in acetonitrile (40 mL), and the mixture was stirred at 60°C for 1.5 hours after adding triphenylphosphine (2.12 g, 8.09 mmol), carbon tetrachloride (1.56 mL, 16.2 mmol), and triethylamine (0.593 mL, 8,09 mmol). The mixture was concentrated, and diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 2-(2-iodophenyl)-5-methyl-1,3,4-oxazole (1.10 g, 95percent). ESI-MS: m/z 287 [M + H]+. With tetrachloromethane, triethylamine, triphenylphosphine in acetonitrile, Time= 1.5h, T= 60 °C Patent; Kyowa Hakko Kirin Co., Ltd.; EP2163554; (2010); (A1) English View in Reaxys

O

O N

S N

O

N OH

N

H N

N

O N H

O

N

S

N H

O

O

N N N H


Conditions & References Example Name 62.2 (S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid-N'-(2S)acetoxypropionyl hydrazide (1.04 g, 2.09 mmol) obtained in Step 1 was dissolved in acetonitrile (21 mL)), and the mixture was stirred at 60°C for 1 hour after adding triphenylphosphine (1.09 g, 4.17 mmol), carbon tetrachloride (0.81 mL, 8.34 mmol), and triethylamine (0.58 mL, 4.17 mmol). The mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 mL). After adding a 10percent aqueous sodium hydroxide solution (5 mL), the mixture was stirred at room temperature for 20 minutes. Thereafter, a saturated aqueous ammonium chloride solution and chloroform were added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was then purified by silica gel column chromatography to give (S)-5-[3-(5-(1S)-hydroxyethyl)-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a, 4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (871 mg, 95percent). ESI-MS: m/z 439 [M + H]+. Stage 1: With tetrachloromethane, triethylamine, triphenylphosphine in acetonitrile, Time= 1h, T= 60 °C Stage 2: With water, sodium hydroxide in ethanol, Time= 0.333333h, T= 20 °C Patent; Kyowa Hakko Kirin Co., Ltd.; EP2163554; (2010); (A1) English View in Reaxys


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Cl

O

N

Si Cl

NH

O

N

O NH

N

O

O

N N

N

N

N



86 %

Example Name 1.7 To a solution of trinhenylphosphine (293 mg, 1.12 mmol) in DCM (20 mL) was added I2 (283 mg, 1.12 mmol) at 0 0C. After I2 was dissolved completely, Et3N (0.31 mL, 2.23 mmol) was added, followed by a solution of N'-((2i?, 3S)-3-(tertbutyldimethylsilyloxy)-2-(4-chloro-5-cyano-lH-indol-l-yl)butanoyl)-4- cyanobenzohydrazide (300 mg, 0.56 mmol) in DCM (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min.. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound \\-((\\R, 25)-2-(tert- butyldimethylsilyloxy)l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4-chloro- lH-indole-5-carbonitrile (250.0 mg, 86percent). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.46 (d, J= 8.6 Hz, 2H), 8.15 (d, J = 8.6 Hz, 2H), 8.13 (d, J= 3.2 Hz, IH), 7.82 (d, J = 8.6 Hz, IH), 7.76 (d, J= 8.6 Hz, IH), 7.18 (d, J= 3.2 Hz, IH), 6.05 (d, J- 5.9 Hz, IH), 5.15 (m, IH), 1.59 (d, J= 6.0 Hz, 3H), 1.04 (s, 9H), 0.36 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, Time= 0.166667h, T= 0 - 20 °C Patent; RADIUS HEALTH, INC.; MILLER, Chris, P.; WO2010/118287; (2010); (A1) English View in Reaxys

Si Cl

O

N

Si Cl

NH

O

N

O N

NH O

O

N N

N

N

N


Conditions & References Example Name 3.17 To a solution of triphenylphosphine (108 mg, 0.41 mmol) in DCM (8 mL) was added I2 (104 mg, 0.41 mmol) at 0 0C. After I2 was dissolved completely, Et3N (0.12 mL, 0.86 mmol) was added, followed by a solution of N'-((2S, 35)-3 -(tertbutyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l-yl)butanoyl)-4- cyanobenzohydrazide (1 10 mg, 0.20 mmol) in DCM (4 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 5 min.. The reaction was quenched with saturated sodium thiosulfate (5 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to give the title compound 1-((1(S1, 25)-2-(tert- butyldimethylsilyloxy)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4- chloroindoline-5-carbonitrile (100 mg, 96percent). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.28 (d, J= 8.4 Hz, 2H), 7.97 (d, J- 8.4 Hz, 2H), 7.55 (d, J= 8.2 Hz, IH), 6.70 (d, J = 8.2 Hz, IH), 4.90 (d, J= 9.3 Hz, IH ), 4.72 (m, IH), 4.08 (m, IH), 3.96 (m, IH), 3.26 (m, 2H), 1.55 (d, J= 6.1 Hz, 3H), 0.84 (s, 9H), 0.23 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, Time= 0.0833333h, T= 0 - 20 °C Patent; RADIUS HEALTH, INC.; MILLER, Chris, P.; WO2010/118287; (2010); (A1) English View in Reaxys


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Si O

N

Cl

Si O

N

Cl

NH O NH

N

O

O

N N

N

N

N



~ 100 %

Example Name 3.16 To a solution of triphenylphosphine (400 mg, 1.53 mmol) in DCM (20 mL) was added I2 (387 mg, 1.52 mmol) at 0 0C. After I2 was dissolved completely, Et3N (0.43 mL, 3.09 mmol) was added, followed by a solution of N'-((2i?, 3S)-3-(tertbutyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l-yl)butanoyl)-4- cyanobenzohydrazide (410 mg, 0.76 mmol) in DCM (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min.. The reaction was quenched with saturated sodium thiosulfate (5 mL) and diluted with DCM (200 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to give the title compound l-((\\R, 25)-2-(tert- butyldimethylsilyloxy)- 1 -(5 -(4cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)propyl)-4- chloroindoline-5-carbonitrile (395 mg, -100percent). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.26 (d, J= 8.2 Hz, 2H), 7.95 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.4 Hz, IH), 6.49 (d, J= 8.4 Hz, IH), 4.98 (d, J= 5.9 Hz, IH ), 4.82 (m, IH), 4.06-4.20 (m, 2H), 3.22-3.31 (m, 2H), 1.48 (d, J= 6.0 Hz, 3H), 0.87 (s, 9H), 0.21 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, Time= 0.166667h, T= 0 - 20 °C Patent; RADIUS HEALTH, INC.; MILLER, Chris, P.; WO2010/118287; (2010); (A1) English View in Reaxys

O NH

Cl

HN N

N

O OH

HN

HN O N

Cl

N

N

OH

N


Conditions & References Example Name 6 Example 6(R)-2-chloro-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile To a solution of triphenylphosphine (1.70 g, 6.48 mmol) in DCM (50 mL) was added I2 (1.63 g, 6.42 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (1.8 mL, 12.9 mmol) was added, followed by a solution of (R)N'-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-cyanobenzohydrazide (1.37 g, 3.22 mmol) in DCM (10 mL) and THF (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (10 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (R)-2-chloro-4(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile (1.18 g, 90percent). 1H NMR (400 MHz, Acetone-d6, 8 in ppm) 8.19 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.71 (d, J=9.0 Hz, 1H), 5.14 (d, J=9.0 Hz, 1H), 4.67 (s, 1H), 2.39 (s, 3H), 1.53 (s, 3H), 1.36 (s, 3H). With iodine, triethylamine, triphenylphosphine in tetrahydrofuran, dichloromethane, Time= 0.5h, T= 0 - 20 °C Patent; Radius Health, Inc.; US2012/4270; (2012); (A1) English View in Reaxys


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O

O

NH 2

H N O

N H O

O

NH 2

N N

O HO


Conditions & References Example Name 1.7.6 3-[5-(l-Amino-2-phenylcyclohexyl)-l,3,4-oxadiazol-2-yl]benzoic acid: To an ice- chilled solution of methyl 3-({2-[(l-amino-2- phenylcyclohexyl)carbonyl]hydrazino}carbonyl)benzoate (161 mg, 0.41 mmol) in CH2C12 (2 mL) were added DBU (0.304 mL, 2.04 mmol) and 2-chloro-l,3-dimethylimidazolium chloride ( 206 mg, 1.22 mmol). The reaction mixture was allowed to warm to room temperature. After stirring overnight at ambient temperature, the mixture was partitioned between EtOAc and H20, the organic layer was washed with sat. NaHC03 aq. and brine, dried over MgS04 and concentrated in vacuo. The residue (100 mg) was dissolved in dioxane (1 mL) and ethylene glycol (lmL), CsOH.H20 (226 mg, 1.35 mmol) was added to the solution. The mixture was stirred for 2 h at 150°C. After cooling to ambient temperature, 1M aq. HC1 was added and then the mixture was extracted with EtOAc, washed with brine, dried over MgS04 and concentrated in vacuo to give 3-[5-(l-amino-2-phenylcyclohexyl)-l,3,4- oxadiazol-2-yl]benzoic acid (186 mg, 126percent), which was used for the next step without further purification. MS (ESI) m/z: 364 [M + H]+. Stage 1: With 2-chloro-1,3-dimethylimidazolinium chloride, 1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane, T= 20 °C Stage 2: With caesium hydroxide monohydrate in 1,4-dioxane, ethylene glycol, Time= 2h, T= 150 °C Stage 3: With hydrogenchloride in 1,4-dioxane, water, ethylene glycol Patent; COMENTIS, INC.; ASTELLAS PHARMA INC.; BILCER, Geoffrey, M.; DEVASAMUDRAM, Thippeswamy; LILLY, John, C.; ANKALA, Sudha, V.; MOSKALEV, Nikolai, V.; LIU, Chunfeng; INOUE, Makoto; KAWAKAMI, Shimpei; MUNAKATA, Ryosuke; HAMAJIMA, Toshihiro; WO2012/54510; (2012); (A1) English View in Reaxys

O

N N

HN

NH

O

O


Conditions & References Example Title 2-(4-methylphenyl)-5-(4-tert-Butylphenyl)-1,3,4-oxadiazole: (12.4 g, 33.9 mmol) of 1-(4'-Methylbenzoyl)-2-(4'-tertbutylbenzoyl)-hydrazine was dispersed in 80mL of POCl3 atroom temperature. The mixture was refluxed for 10 h at 80 °C. After cooling, the reaction mixture was poured carefully into 500mL of ice water under stirring. The precipitate was collected by filtration, washed with water and dried under vacuum. The crude product was purified by recrystallization from methanol to give a white solid. Yield: 81percent. With trichlorophosphate, Time= 10h, T= 80 °C With trichlorophosphate, Heating, Cyclization Chung, Sung-Jae; Kim, Kyoung-Soo; Li, Tzu-Chau; He, Guang S.; Swiatkiewicz, Jacek; Prasad, Paras N.; Journal of Physical Chemistry B: Condensed Matter, Materials, Surfaces, Interfaces, & Biophysical Chemistry; vol. 103; nb. 49; (1999); p. 10741 - 10745 View in Reaxys With trichlorophosphate, Heating Cha, Soon Wook; Jin, Jung-Il; Journal of Materials Chemistry; vol. 13; nb. 3; (2003); p. 479 - 484 View in Reaxys


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Lin, Tzu-Chau; He, Guang S.; Prasad, Paras N.; Tan, Loon-Seng; Journal of Materials Chemistry; vol. 14; nb. 6; (2004); p. 982 - 991 View in Reaxys

O

H N

O

OH N H

N N

HO O

Cl

Cl



79 %

Example Name 40 EXAMPLE 405-[5-(4-Chloro-benzyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol; To a solution of 3-hydroxy-4-methyl-benzoic acid N'-[2-(4-chloro-phenyl)-acetyl]-hydrazide (0.91 g, 2.85 mmol) (from Example 39 supra) in acetonitrile (20 mL) was added diisopropylethylamine (3.0 mL, 17.1 mmol) and triphenylphosphine (1.50 g, 5.70 mmol). After stirring 5 minutes, hexachloroethane (1.01 g, 4.28 mmol) (Aldrich) was added and the mixture was allowed to stir for 2 days at room temperature. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1.x.). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 20percent ethyl acetate in hexanes to 5-[5-(4-chloro-benzyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol. (Yield 0.68 g, 79percent). Stage 1: With N-ethyl-N,N-diisopropylamine, triphenylphosphine in acetonitrile, Time= 0.0833333h Stage 2: With 1,2,2-trichloro-1,1,2-trichloro-ethane in acetonitrile, Time= 48h, T= 20 °C Patent; Chen, Yi; Luk, Kin-Chun; Rossman, Pamela Loreen; So, Sung-Sau; US2008/9515; (2008); (A1) English View in Reaxys

O

NH

O

NH

N O

N

N N O

N

O

O

F

N

F O

O

O


Conditions & References Example Name 106 To a solution of 318 (20 mg, 0.037 mmol) dissolved in methylene chloride (0.400 mL, 0.1M) was added 2-Chloro-1,3dimethyl-2-imidazolinium hexafluorophosphate (15 mg, 0.055) and triethylamine (15 μL, 0.11 mmol). The reaction was stirred under nitrogen atmosphere for 1 day at room temperature then 2 days at 40° C. at which point the reaction was complete. The mixture was purified by chromatography on silica gel (9/1-ethyl acetate/hexane) to afford the desired 1,3,4-oxadiazole 319 (15 mg, 78percent): 300 MHz 1H NMR (CDCl3) (ppm) 9.09 (s, 1H), 8.93 (s, 1H), 7.575 (m, 2H), 7.23 (m, 2H), 7.04 (dd, 2H), 6.829 (d, 2H), 5.832 (s, 2H), 4.78 (s, 2H), 4.24 (s, 2H), 3.77 (s, 3H), 3.27 (s, 3H), 2.67 (s, 3H); MS: 525 (M+1). With 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate, triethylamine in dichloromethane, Time= 72h, T= 20 - 40 °C Patent; Cai, Zhenhong R.; Jabri, Salman Y.; Jin, Haolun; Lansdown, Rachael A.; Metobo, Samuel E.; Mish, Michael R.; Pastor, Richard M.; US2008/58315; (2008); (A1) English View in Reaxys


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HN

NH

F F

NH

O

N

F

O

O O HN

N

F

N

F F

N O

O

F

F

F

F F

F



79.6 %

Example Name 2 ; In a 300 ml three-necked flask were placed 2.8 g of the intermediate, 65 ml of phosphoryl chloride, and 120 ml of 1,4-dioxane. The solution in the three-necked flask was heated to 110°C in a silicone oil bath, and allowed to react for 9 hours at around this temperature. After the termination of the reaction, precipitates were laid in the bottom. The precipitates were separated and re-dissolved in 150 ml of toluene. The obtained was filtered. The filtrate was concentrated and dried up. 1.12 g of light yellow crystals with a melting point of 288°C was obtained. The yield was 79.6percent. An NMR spectrum chart and an IR spectrum chart of the obtained crystals are respectively shown in Figure 8 and Figure 9. These data confirmed that the crystals produced in this example were the blue light-emitting compound represented by formula (22). With trichlorophosphate in 1,4-dioxane, Time= 9h, T= 110 °C Patent; HIROSE ENGINEERING CO., LTD.; EP1607392; (2005); (A1) English View in Reaxys

F F N

F O

O

O H N

O

N H

N

HN

F

N H

F

O

N

O

N

O

F



78 %

Example Name 66; 22 00364] tert-Butyl (R)-4-(5-(isoquinolin-6-yl)-l,3,4-oxadiazol-2-yl)-l-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate: tertButyl (( 1 R)-4-(2-(6- isoquinolinylcarbonyl)hydrazino)-4-oxo-l-(4-(trifluoromethyl)benzyl)butyl)carbamate (0.080 g, 0.15 mmol) and triphenylphosphine (0.070 mL, 0.30 mmol), and 0.5 mL CCl4 were heated under nitrogen in 10 mL THF at 5O0C for 20 hours. 0.2 mL DDEA was added, and the reaction mixture was heated at reflux 4 hours. The reaction mixture was filtered and the solid was washed with THF. The filtrate was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate (3 x). The solvent was evaporated, and the residue was purified by chromatography on silica gel (60 percent EtOAc in hexane) to provide the product as a white solid (0.06 g, 78 percent). LCMS (API-ES) m/ z: 513 (M+H*). Stage 1: With tetrachloromethane, triphenylphosphine in tetrahydrofuran, Time= 20h, T= 50 °C Stage 2: With N-ethyl-N,N-diisopropylamine in tetrahydrofuran, Time= 4h, Heating / reflux Patent; AMGEN INC.; WO2009/11880; (2009); (A2) English View in Reaxys

O

F F

NH HN

O

N

F N

Si O

HN

HN O N

F

N

N

F

O Si

F N



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Yield


84%

Example Name 31.31e Intermediate 31e; 4-((1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3methyl-2-(trifluoromethyl)benzonitrile; Triphenylphosphine (590 mg, 2.25 mmol) was dissolved in 25 mL of DCM followed by addition of 12 (571 mg, 2.25 mmol) and TEA (456 mg, 4.50 mmol) at 0° C. N'-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (630 mg, 1.13 mmol) in 25 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extract with EtOAc. The crude mixture was chromatographed to give the product (510 mg, 84percent) 1H NMR (400 MHz, acetone-d6, δ in ppm): 8.23 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 5.94 (d, J=9 Hz, 1H), 5.19 (m, 1H), 4.74 (m, 1H), 2.39 (m, 3H), 1.48 (d, J=6 Hz, 3H), 0.81 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

Si

O

O H N

O N H

N

O

O

Si

N



56 %

Example Name 74.3 To a stirred solution of 4-((/ert-butyldimethylsilyloxy)methyl)-ΛT- octanoylbenzohydrazide (4.02 g, 9.89 mmol), triphenylphosphine (4.07 g, 15.52 mmol), and triethylamine (1.57 g, 15.52 mmol) in dichloromethane (100 mL) was added carbon tetrachloride (7.60 g, 49.43 mmol). The reaction mixture was heated to reflux. After 6 hours, the reaction mixture was allowed to cool to room temperature and stirring continued. After 18 hours, the reaction mixture was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and brine. The organic phase was dried (magnesium sulfate), filtered, and concentrated to provide a sticky white solid. Flash chromatography using an Isco Combiflash unit (12O g SiO2 column, 10-25percent ethyl acetate/hexanes) afforded 2.14 g (56percent) of 2-{4-((tert- butyldimethylsilyloy)methyl)phenyl)-5-heptyl-1,3,4-oxadiazole as a white solid: 1H NMR (CDCl3) δ 7.99 (d, J= 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 4.80 (s, 2H), 2.91 (t, J= 7.6 Hz, 2H), 1.89-1.79 (m, 2H), 1.47-1.24 (m, 8H), 0.95 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H), 0.11 (s, 6H) ppm. With tetrachloromethane, triethylamine, triphenylphosphine in dichloromethane, T= 20 °C , Reflux Patent; GENZYME CORPORATION; XIANG, Yibin; HIRTH, Bradford; KANE, John, L.; LIAO, Junkai; NOSON, Kevin; YEE, Christopher; WO2010/33701; (2010); (A2) English View in Reaxys With tetrachloromethane, triethylamine, triphenylphosphine in dichloromethane, Reflux Xiang, Yibin; Hirth, Bradford; Kane Jr., John L.; Liao, Junkai; Noson, Kevin D.; Yee, Christopher; Asmussen, Gary; Klaus, Christine; Booker, Michael; Fitzgerald, Maria; Bioorganic and Medicinal Chemistry Letters; vol. 20; nb. 15; (2010); p. 4550 - 4554 View in Reaxys

O N

HN

N H

O

N

NH

O

O

N

N

N

NH

O

N N

N

N

N

H H


Conditions & References Example Name 20


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Compound 19 (136 mg, 0.320 mmol) obtained in Example 19 was dissolved in acetonitrile (2.1 mL), and the mixture was stirred for 1 hour under microwave (CEM; Discover, 300 watts, 150°C) irradiation after adding trichloroacetonitrile (0.0646 mL, 0.640 mmol) and triphenylphosphine-supported resin (Triphenylphosphine, polymer-supported; 3.08 mmol P/G, 320 mg, 0.960 mmol). The resin was separated by filtration, and the filtrate was collected, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (Compound 20) (108 mg, 83percent). ESI-MS: m/z 406 [M + H]+. 1H NMR (DMSO-d3) δ(ppm): 1.15 (t, J = 6.97 Hz, 3H), 1.62 (m, 1H), 1.79 (m, 1H), 1.94 (m, 1H), 2.18 (m, 1H), 2.59 (s, 3H), 3.36 (m, 2H, overlapped with DMSO), 3.70 (m, 2H), 3.88 (m, 2H), 4.03 (m, 1H), 7.24 (brs, 1H), 7.53 (dt, J = 1.47, 8.43 Hz, 1H), 7.63 (t, J = 8.07 Hz, 1H), 7.86 (dt, J = 1.47, 7.52 Hz, 1H), 7.89 (t, J = 1.65 Hz, 1H), 8.50 (s, 1H) With trichloroacetonitrile in acetonitrile, Time= 1h, T= 150 °C , microwave irradiation Patent; Kyowa Hakko Kirin Co., Ltd.; EP2163554; (2010); (A1) English View in Reaxys O

Br Br

HN N

N NH

N

N

O

O

N

NH 2

N

NH 2


Conditions & References Example Name 14.N.2 Step 2: 5-bromo-3-(5-phenyl-l,3,4-oxadiazol-2-yl)pyrazin-2-amine [00398] Polyphosphonic acid (25 niL of 84 percentw/ v, 256.1 mmol) was heated to 100 0C and treated with 3-amino-N'-benzoyl-6-bromo-pyrazine-2-carbohydrazide (6.82 g, 20.29 mmol) in portions. Analysis after 1 hour showed SM remaining therefore further polyphosphonic acid was added (25 mL of 84 percentw/v, 256.1 mmol). The reaction was heated for a total of 3 hours and then allowed to cool. Water was added and the mixture allowed to stir to obtain a precipitate which was filtered and dried under vacuum (5.02g, 78percent Yield). MS (ES+) 317.86 With polyphosphonic acid, Time= 3h, T= 100 °C Patent; VERTEX PHARMACEUTICALS INCORPORATED; CHARRIER, Jean-damien; DURRANT, Steven; KAY, David; O'DONNELL, Michael; KNEGTEL, Ronald; MACCORMICK, Somhairle; PINDER, Joanne; VIRANI, Anisa; YOUNG, Stephen; BINCH, Hayley; CLEVELAND, Thomas; FANNING, Lev, T.d.; HURLEY, Dennis; JOSHI, Pramod; SHETH, Urvi; SILINA, Alina; WO2010/54398; (2010); (A1) English View in Reaxys

62 %

Example Name 8.H.2 Step 2 : 5-Bromo-3-(5-phenyl-l,3,4-oxadiazol-2-yl)pyrazin-2-amine [00159] Polyphosphoric acid (314 g) was heated to 100°C and treated portionwise with 3- amino-N'-benzoyl-6-bromopyrazine-2-carbohydrazide (22.5 g, 66.94 mmol) over a period of 20 minutes. The reaction was allowed to stir at 1 10-120 °C for 6 hours and then allowed to cool and treated with ice/water and stirred. The resultant solid was filtered and washed with water. It was taken into EtOAc, washed with water and adjusted to pH 1 1 ( aOH solution) and then washed with brine, dried (MgSC^) and concentrated in vacuo to give the desired product (13.25g, 62percent Yield). XH NMR (400.0 MHz, DMSO) δ 7.69 (3H, m), 7.86 (2H, br s), 8.16 (2H, m), 8.50 (1H, s) ppm; MS (ES+) 319.89. Stage 1:, Time= 6.33333h, T= 100 - 120 °C Stage 2: With sodium hydroxide in water, ethyl acetate, pH= 11 Patent; VERTEX PHARMACEUTICALS INCORPORATED; CHARRIER, Jean-Damien; DURRANT, Steven, John; KNEGTEL, Ronald, Marcellus, Alphonsus; O'DONNELL, Michael; REAPER, Philip, Michael; WO2011/143419; (2011); (A1) English View in Reaxys


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O NH

Cl

HN

N

O

F OH

HN

HN O

F

OH N

N

Cl N



81 %

Example Name 5 Example 5(R)-2-chloro-4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile To a solution of triphenylphosphine (5.35 g, 20.4 mmol) in DCM (100 mL) was added I2 (5.18 g, 20.4 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (5.7 mL, 40.9 mmol) was added, followed by a solution of (R)N'-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (4.27 g, 10.2 mmol) in DCM (20 mL) and THF (20 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (20 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (R)-2-chloro-4(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile (3.31 g, 81percent). 1H NMR (400 MHz, Acetone-d , δ in ppm) 8.06 (dd, J=5.3, 9.0 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.33 (t, J=9.0 Hz, 2H), 6 6.79 (d, J=8.6 Hz, 1H), 5.70 (d, J=8.7 Hz, 1H), 5.09 (d, J=8.7 Hz, 1H), 2.39 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H). With iodine, triethylamine, triphenylphosphine in tetrahydrofuran, dichloromethane, Time= 0.5h, T= 0 - 20 °C Patent; Radius Health, Inc.; US2012/4270; (2012); (A1) English View in Reaxys

F

N O O

O NH HN

N Cl

O

N

O N O

Cl

O

F


Conditions & References Example Name 13.13c A mixture of N'-[5-chloro-2-(4-fluorophenyl)pentanoyl]-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (177 mg, 0.385 mmol), carbon tetrachloride (0.0740 mL, 0.770 mmol) and triphenylphosphine (404 mg, 1.54 mmol) in acetonitrile (3.8 mL) was stirred at 80°C for 2 hr. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 - 50/50) to give the title compound as a pale yellow oil (138 mg, 81percent). 1H NMR (CDCl3) δ: 1.73 - 1.96 (2 H, m), 2.21 - 2.35 (1 H, m), 2.40 - 2.59 (4 H, m), 3.58 (2 H, t, J=6.6 Hz), 4.04 (3 H, s), 4.28 (1 H, t, J=7.9 Hz), 7.01 - 7.12 (2 H, m), 7.30 - 7.39 (2 H, m), 7.41 - 7.74 (3 H, m), 7.82 (1 H, d, J=7.9 Hz). With tetrachloromethane, triphenylphosphine in acetonitrile, Time= 2h, T= 80 °C Patent; Takeda Pharmaceutical Company Limited; EP2455380; (2012); (A1) English View in Reaxys


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N

F

F

O

F

O O NH HN

N

O

O

N

Cl

Cl

N O

O

F F

F



81 %

Example Name 14.14c A mixture of N'-{5-chloro-2-[3-(trifluoromethyl)phenyl]pentanoyl}-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (198 mg, 0.388 mmol), carbon tetrachloride (0.0744 mL, 0.776 mmol) and triphenylphosphine (407 mg, 1.55 mmol) in acetonitrile (3.9 mL) was stirred at 80°C for 2 hr. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 - 50/50) to give the title compound as a pale yellow oil (138 mg, 81percent). 1H NMR (CDCl3) δ: 1.74 - 1.97 (2 H, m), 2.20 - 2.36 (1 H, m), 2.40 - 2.59 (4 H, m), 3.58 (2 H, t, J=6.6 Hz), 4.04 (3 H, s), 4.28 (1 H, t, J=7.9 Hz), 7.01 - 7.12 (2 H, m), 7.31 - 7.40 (2 H, m), 7.41 - 7.73 (3 H, m), 7.82 (1 H, d, J=7.9 Hz). With tetrachloromethane, triphenylphosphine in acetonitrile, Time= 2h, T= 80 °C Patent; Takeda Pharmaceutical Company Limited; EP2455380; (2012); (A1) English View in Reaxys O

O H N

O

N N H

O

N O

O

O


Conditions & References Example Name 108.B Thionyl chloride (0.34 mL, 4.7 mmol) was added to the mixture of methyl 4-(2-benzoylhydrazino)-4-oxobutanoate (900 mg, 4 mmol), Pyridine (0.87 mL, 0.011 mol) in tetrahydrofuran (20 mL) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated. The residue was mixed with toluene (20 mL) and refluxed overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to yield the desired product (600 mg, 72percent). LCMS calculated for C12H13N2O3 (M+H): 233.1; found: 233.1. With pyridine, thionyl chloride in tetrahydrofuran, toluene, Time= 3h, T= 20 °C , Heating / reflux Patent; Incyte Corporation; US2008/45554; (2008); (A1) English View in Reaxys


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O

O

O

O

NH O

NH O

Cl

N

O O

NH

N

HN O

Cl



66 %

Example Name 19.19C To a stirred slurry of 19B (590 mg, 1.3 mmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (940 mg, 2.9 mmol) in acetonitrile at 0° C. was added triphenylphosphine (760 mg, 2.9 mmol). Then TEA (0.8 ml, 5.8 mmol) was added over 1 min. After 30 min the yellow slurry formed was warmed to rt. After additional 2 h of stirring the red solution formed was concentrated. The residue was dissolved in EtOAc filtered and washed the filtrate with brine, dried, filtered and concentrated. Purification by flash chromatography on silica gel (1:10 Ether/CH2Cl2 as eluant) gave 19C (370 mg, 66percent). With 1,2-dibromo-1,1,2,2-tetrachloroethane, triethylamine, triphenylphosphine in acetonitrile, Time= 2.51667h, T= 0 20 °C Patent; Ewing, William R.; Li, Jun; Sulsky, Richard B.; Hernandez, Andres S.; US2006/79562; (2006); (A1) English View in Reaxys

N

N

O N

S

O

O H N

N

O N

O

S

O

N

N H S

O N N

S


Conditions & References Example Name 106.2 Example Title Step 2: Preparation of 2-methyl-5-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)-3,4-dihydro-2H-benzo[b] [1,4]thiazin-6-yl)-1,3,4-oxadiazole Step 2: Preparation of 2-methyl-5-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-1,3,4-oxadiazole To a solution of N'-acetyl-4-(1-methyl-1H-imidazol-4-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbohydrazide (25 mg, 63 μmol) in THF (1 mL) was added DBU (14 mg, 95 μmol) and Burgess reagent (75 mg, 316 μmol). The reaction vial was capped subjected to microwave irradiation (150° C., 10 min). LCMS analysis of the reaction mixture indicated that the starting material had been consumed. The reaction was diluted with saturated aqueous NaHCO3 (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (2 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with a gradient elution of hexanes with 10-60percent EtOAc to provide 2-methyl-5-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-1,3,4-oxadiazole (16 mg, 42 μmol, 67percent yield). LCMS (+ESI) m/z=377.8 [M+H]+; 1H-NMR (CDCl3) δ 8.05 (m, 2H), 7.9 (d, 2H), 7.8 (d, 2H), 7.4-7.5 (m, 3H), 7.25 (d, 1H), 7.1 (dd, 1H), 6.75 (d, 1H), 3.5 (t, 2H), 3.1 (t, 2H). With 1,8-diazabicyclo[5.4.0]undec-7-ene in tetrahydrofuran, Time= 0.166667h, T= 150 °C , Microwave irradiation Patent; CARA THERAPEUTICS, INC.; US2009/75973; (2009); (A1) English View in Reaxys


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O

Cl

N

NH O

HN

N

O

O

Si O

HN

HN O O

N O

N

N

O

Si

Cl N



67%

Example Name 69.69c Intermediate 69c; 4-((1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2chloro-3-methylbenzonitrile; A solution of N'-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-nitrobenzohydrazide (8.5 g, 15.57 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (8.17 g, 31.13 mmol), iodine (7.90 g, 31.13 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 50 minutes and quenched with sat. aq. sodium thiosulfate (400 mL). The solution was extracted with CH2Cl2 (250 mL). The organic extract was washed with sat. aq. sodium thiosulfate (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-40percent EtOAc in hexanes) to provide the title compound as a light yellow solid (5.5 g, 67percent): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 11H), 5.11 (d, J=9.2 Hz, 11H), 4.87 (dd, J=3.9, 8.8 Hz, 1H), 4.46 (dq, J=3.7, 6.3 Hz, 1H), 2.34 (s, 3H), 1.31 (d, J=6.3 Hz, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

Cl

NH O

Si O

HN

N

H N

O

O

Si O

HN

N

N

O

N

Cl

N N

O

O


Conditions & References Example Name 77.77c Intermediate 77c; 4-(1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2chloro-3-methylbenzonitrile; N'-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-nitrobenzohydrazide (1.4 g, 2.56 mmol) was placed in a 100 mL round bottomed flask and CH2Cl2 (40 mL) was added, followed by 12 (650 mg, 5.12 mmol), Ph3P (1.34 g, 5.12 mmol), and Et3N (1.43 mL, 10.24 mmol). The reaction mixture was allowed to stir at room temperature for 20 min, whereupon it was filtered and the filtrate washed with CH2Cl2 (50 mL). The organic layer was washed with 10percent aq. Na2S2O3 (100 mL) (.x.2) and the aqueous layer extracted with CH2Cl2 (3.x.100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to provide a yellow oil. Purification by flash column chromatography [EtOAc-hexanes (1:1.5) as eluent] afforded the title compound as a white solid (750 mg, 72percent). 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.62 (d, J=8.8 Hz, 2H), 8.47 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 5.72 (d, J=8.9 Hz, I H), 5.48 (dd, J=1.8, 8.9 Hz, 1H), 5.01-4.92 (m, 1H), 2.59 (s, 3H), 1.66 (d, J=7.4 Hz, 3H), 1.02 (s, 9H), 0.28 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, Time= 0.333333h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys


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O Cl

O Si

N

NH HN

O Si

Si

O

HN

O HN

O N

N

O Si

Cl N



68%

Example Name 7.7c Intermediate 7c; ((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethylsilyloxy)phenyl)-1,3,4-oxadiazol-2yl)propylamino)-2-chloro-3-methylbenzonitrile; To a 25 mL round bottom flask equipped with a magnetic stir bar and septum was added triphenylphosphine (polymer bound, 3.0 mmol/g loading) (100 mg, 0.3 mmol) under an atmosphere of nitrogen. To this was added methylene chloride (3 mL) followed by addition of solid iodine (76 mg, 0.30 mmol). This was allowed to stir at room temperature for a period of 10 min followed by slow addition of triethylamine (0.17 mL, 1.2 mmol). This mixture was allowed to stir at room temperature for an additional ten min. 3-(tert-butyldimethylsilyloxy)-N'((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (95 mg, 0.15 mmol) was taken up in methylene chloride (5 mL) and slowly added to the heavily stirred reaction mixture. After a period of 20 min, the solid polymer was filtered out and washed with additional methylene chloride (20 mL). The organic filtrate was then washed with 10percent sodium thiosulfate/water (2.x.10 mL), brine (1.x.20 mL) and dried (Na2SO4). The solution was then filtered and concentrated under reduced to reveal a brown oil/solid, which was purified via silica gel chromatography eluted with 20percent EtOAc/hexanes to provide the title compound as a white solid (63 mg, 68percent): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.52 (m, 1H), 7.38 (m, 1H), 7.33 (m, 2H), 6.99 (m, 1H), 6.46 (d, J=8.6 Hz, 1H), 5.37 (d, J=8.8 Hz, 1H), 4.80 (dd, J=1.8, 8.8 Hz, 1H), 4.54 (m, 1H), 2.37 (s, 3H), 1.42 (d, J=6.2 Hz, 3H), 0.98 (s, 9H), 0.86 (s, 9H), 0.19 (s, 6H), 0.06 (s, 3H), -0.20 (s, 3H). With polymer bound triphenylphosphine, iodine, triethylamine in dichloromethane, T= 20 °C , Inert atmosphere Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

O

H N

O

N H

O Br

O Br

N

N


Conditions & References 2-(4-Bromo-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazole. N'-Acetyl-4~bromo-2- methoxybenzohydrazide (720 mg, 2.51 mmol) and Burgess' Reagent (896 mg, 3.76 mmol) were dissolved in 10 ml of THF and stirred in the microwave at 120 0C for 30 minutes. The reaction was diluted with brine and extracted three times with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a yellow oil. Chromatography on silica gel (0-50percent EtOAc/DCM) gave a yellow solid (465 mg, 1.73 mmol, 69percent). 1H NMR (500 MHz, CDCl3) δ 7.74-7.77 (m, 1H), 7.18-7.23 (m, 2H), 3.94-3.97 (m, 3H), 2.59- 2.62 (m, 3H);MS (EI) [M+1]+ calc'd 269.0, found 268.9. With Burgess' reagent in tetrahydrofuran, Time= 0.5h, T= 120 °C , Irradiation Patent; MERCK SHARP andamp; DOHME CORP.; FISCHER, Christian; METHOT, Joey; ZHOU, Hua; SCHELL, Adam, J.; MUNOZ, Benito; RIVKIN, Alexey, A.; AHEARN, Sean, P.; CHICHETTI, Stephanie; MACCOSS, Rachel, N.; KATTAR, Sam, D.; CHRISTOPHER, Matthew; LI, Chaomin; ROSENAU, Andrew; BROWN, William Colby; WO2010/71741; (2010); (A1) English View in Reaxys


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O

N

Cl

Si O

N

Cl

NH O NH

N

O

O

N N

N

N

N



73 %

Example Name 1.8 To a solution of triphenylphosphine (78 mg, 0.30 mmol) in DCM (6 mL) was added I2 (75 mg, 0.30 mmol) at 0 0C. After I2 was dissolved completely, Et3N (0.082 mL, 0.59 mmol) was added, followed by a solution of N'-((25', 35)-3-(tertbutyldimethylsilyloxy)-2-(4-chloro-5-cyano-lH-indol-l-yl)butanoyl)-4- cyanobenzohydrazide (79 mg, 0.15 mmol) in DCM (3 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 5 min.. The reaction was quenched with saturated sodium thiosulfate (2 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound 1-((I1S, 25)-2-(tert- butyldimethylsilyloxy)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4-chloro- lH-indole-5-carbonitrile (55.5 mg, 73percent). 1U NMR (400 MHz, CDCl3, δ in ppm) 8.24 (d, J= 8.6 Hz, 2H), 7.90 (d, J= 8.6 Hz, 2H), 7.76 (d, J= 3.5 Hz, IH), 7.65 (d, J = 8.6 Hz, IH), 7.59 (d, J= 8.6 Hz, IH), 6.90 (d, J= 3.5 Hz, IH), 5.68 (d, J= 8.6 Hz, IH), 4.89 (m, IH), 1.19 (d, J= 6.0 Hz, 3H), 0.83 (s, 9H), 0.18 (s, 3H), 0.00 (s, 3H). With iodine, triethylamine, triphenylphosphine in dichloromethane, Time= 0.0833333h, T= 0 - 20 °C Patent; RADIUS HEALTH, INC.; MILLER, Chris, P.; WO2010/118287; (2010); (A1) English View in Reaxys O O

S S

N

N

N N

N

N

N

N

N N

O N

NH O

N

HN O


Conditions & References Example Name 56 Synthesis 56S-CMethylthiomethyO-δ-CS-phenyl-I .S^-oxadiazol^-yOimidazoIδ.i-dKI^.S.δltetrazin- 4(3H)-oneN'-benzoyl-3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5, 1 -d][1 ,2,3,5]tetrazine-8- carbohydrazide (0.47 mmol, 170 mg, 1 eq.) and 1-methoxy-N-triethylammoniosulfonyl- methanimidate (Burgess Reagent) (1.61 mmol, 383 mg, 3.4 eq.) were dissolved in THF (8 ml_). Microwave energy was applied to the solution for 5 minutes, keeping reaction temperature at 600C. The reaction mixture was poured into ice/water and the formed solid was filtered and washed with water, acetonitrile and ether, and dried under vacuum to give the title compound. Yield 71percent. δH (DMSOd6) 8.90 (1 H, bs), 7.92 (2H, bs), 7.49 (3H, bs), 5.29 (2H, bs), 2.09 (3H, bs). With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 60 °C , Microwave irradiation Patent; PHARMINOX LIMITED; HUMMERSONE, Marc, Geoffery; STEVENS, Malcolm, Francis, Graham; COUSIN, David; WO2010/149968; (2010); (A1) English View in Reaxys


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N

S

N O

O

O O

NH HN

NH O

O

O N

S N

N

O

N

H N

O

O O



71 %

Example Name 1.7.9 tert-Butyl l-methoxy-2-(5-(3-(methyl((4-methylthiazol-2- yl)methyl)carbamoyl)phenyl)-l,3,4-oxadiazol-2-yl)-3-phenylpropan-2-ylcarbamate: 2-Benzyl-3-methoxy-l-[2-(3-{methyl[(4-methylthiazol-2- yl)methyl]carbamoyl}benzoyl)hydrazinyl]-l-oxopropan-2-ylcarbamate (130 mg, 0.22 mmol) was dissolved in CH2CI2 (2.6 mL) then to the solution was added Burgess reagent (156 mg, 0.655 mmol). The mixture was heated under microwave conditions (130°C, 20 min) then the reaction was diluted with CHC13, washed with water and brine then dried over MgS04 and evaporated. The crude material was purified with silica gel column chromatography to afford tert-butyl l-methoxy-2-[5-(3-{methyl[(4-methylthiazol-2-yl)methyl]carbamoyl}phenyl)- l,3,4-oxadiazol-2-yl]-3-phenylpropan-2-ylcarbamate as a colorless oil (90 mg, 71percent). MS (ESI) m/z: 600.2 [M + Na]+. With Burgess Reagent in dichloromethane, Time= 0.333333h, T= 130 °C , Microwave irradiation Patent; COMENTIS, INC.; ASTELLAS PHARMA INC.; BILCER, Geoffrey, M.; DEVASAMUDRAM, Thippeswamy; LILLY, John, C.; ANKALA, Sudha, V.; MOSKALEV, Nikolai, V.; LIU, Chunfeng; INOUE, Makoto; KAWAKAMI, Shimpei; MUNAKATA, Ryosuke; HAMAJIMA, Toshihiro; WO2012/54510; (2012); (A1) English View in Reaxys

N

E

HN O

O

O

S

N

O

O

NH

S

O

O

N

E

N


Conditions & References Example Name 72.b b) Benzoic acid N'-{2-[4-((E)-2-cyano-ethenesulfonyl)-phenyl]-2-methyl-propionyl}- hydrazide (324 mg, 0.815 mmol) was dissolved in 1,4-Dioxane (12.0 mL) and Phosphoryl chloride (0.500 mL, 5.36 mmol) was added and the mixture was heated at 90 °C for 2h, then cooled to room temperature and diluted with Ethyl acetate (50 mL). The mixture was washed with satd. NaHC03 (25 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in DCM and applied to an ISCO cartridge (5g) and purified (ISCO 24g, 0-50percent> Ethyl acetate :hexanes) to afford a foam after concentration of product containing fractions. This foam was dissolved in MeCN and water, and then lyophilized to give (E)-3-{4-[l-Methyl-l-(5-phenyl-[l,3,4]oxadiazol-2- yl)-ethyl]-benzenesulfonyl}acrylonitrile as a white solid (223 mg, 72percent). LCMS (ESI): m/z = 380 (M+H)+; 1H-NMR (DMSO-d6, 400 MHz) δ 8.22 (d, 1H, J = 15.7 Hz), 7.97 (m, 2H), 7.90 (d, 2H, J = 8.7 Hz), 7.70 (d, 2H, J = 8.7 Hz), 7.55-7.65 (m, 3H), 6.91 (d, 1H, J = 15.7 Hz), 1.86 (s, 6H); 13C-NMR (DMSO-d6, 100 MHz) δ 170.5, 164.5, 151.6, 149.0, 136.2, 132.0, 129.4, 128.6, 127.5, 126.6, 123.3, 114.5, 112.3, 40.2, 27.1


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With trichlorophosphate in 1,4-dioxane, Time= 2h, T= 90 °C Patent; CEPHALON, INC.; UNIVERSITY OF HAWAII; UNIVERSITY OF UTAH RESEARCH FOUNDATION; DORSEY, Bruce; KUWADA, Scott K.; THEROFF, Jay P.; ZIFICSAK, Craig A.; WO2012/116151; (2012); (A2) English View in Reaxys

O

O N

O HN

NH

N O

O


Conditions & References With trichlorophosphate, Time= 7h, T= 120 °C Chiu, Yi-Hong; Liu, Jui-Hsiang; Journal of Polymer Science, Part A: Polymer Chemistry; vol. 48; nb. 15; (2010); p. 3368 - 3374 View in Reaxys

88 %

With zirconium tetrachloride in dichloromethane, Time= 2.5h, T= 20 °C Sharma, G. V. M.; Begum, Asra; Rakesh; Krishna, Palakodety Radha; Synthetic Communications; vol. 34; nb. 13; (2004); p. 2387 - 2392 View in Reaxys

87 %

With trichlorophosphate, Time= 24h, T= 80 °C Lee, Yuh-Zheng; Chen, Xiwen; Chen, Show-An; Wei, Pei-Kuen; Fann, Wun-Shain; Journal of the American Chemical Society; vol. 123; nb. 10; (2001); p. 2296 - 2307 View in Reaxys

80.7 %

With thionyl chloride, Time= 2h, Heating Jacobsen, Noel W.; Philippides, Athena E.; Australian Journal of Chemistry; vol. 39; nb. 11; (1986); p. 1911 - 1914 View in Reaxys With trichlorophosphate, Time= 0.5h, Heating Popova, N. A.; Yushko, E. G.; Krasovitskii, B. M.; Minkin, V. I.; Lyubarskaya, A. E.; Gol'dberg, M. L.; Chemistry of Heterocyclic Compounds (New York, NY, United States); (1983); p. 22 - 28; Khimiya Geterotsiklicheskikh Soedinenii; vol. 19; nb. 1; (1983); p. 26 - 32 View in Reaxys With trichlorophosphate Grekow et al.; Zhurnal Obshchei Khimii; vol. 29; (1959); p. 3054,3055; engl. Ausg. S. 3020, 3021 View in Reaxys in N,N,N',N',N'',N''-hexamethylphosphoric triamide, Time= 0.0111111h, microwave irradiation Mashraqui, Sabir H.; Ghadigaonkar, Shailesh G.; Kenny, Rajesh S.; Synthetic Communications; vol. 33; nb. 14; (2003); p. 2541 - 2546 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654


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View in Reaxys

O O

H N N H

N N O


Conditions & References With Ph3P*CCl4, triethylamine in dichloromethane, 1.) room temperature, 30 min, 2.) reflux, 3 h Mazurkiewicz, R.; Grymel, M.; Polish Journal of Chemistry; vol. 71; nb. 1; (1997); p. 77 - 82 View in Reaxys

92 %

With acetic acid, [Et2NSF2]BF4 in 1,2-dichloro-ethane, Time= 12h, T= 90 °C , Inert atmosphere Pouliot, Marie-France; Angers, Laetitia; Hamel, Jean-Denys; Paquin, Jean-Francois; Organic and Biomolecular Chemistry; vol. 10; nb. 5; (2012); p. 988 - 993 View in Reaxys

83 %

With phosphorus pentoxide, Time= 22h, T= 110 °C Carlsen, Per H. J.; Joergensen, Kare B.; Journal of Heterocyclic Chemistry; vol. 31; nb. 4; (1994); p. 805 - 808 View in Reaxys

77 %

With methanesulfonic acid, (S)-pyrophosphoric acid, Time= 4h, T= 70 °C Rigo, Benoit; Couturier, Daniel; Journal of Heterocyclic Chemistry; vol. 23; (1986); p. 253 - 254 View in Reaxys

72 %

With trichlorophosphate, Time= 1h, Heating Popova, N. A.; Krasovitskii, B. M.; Pivnenko, N. S.; Surov, Yu. N.; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol. 33; nb. 6; (1997); p. 712 - 717; Khimiya Geterotsiklicheskikh Soedinenii; nb. 6; (1997); p. 816 - 821 View in Reaxys

72 %

With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, T= -10 - 0 °C , Cyclization Liras, Spiros; Allen, Martin P.; Segelstein, Barb E.; Synthetic Communications; vol. 30; nb. 3; (2000); p. 437 - 444 View in Reaxys

30%

Example Name b Example Title (b) (b) 4-(2-Hydroxyethyl)-3-methyl-5-phenyl-4H-1,2,4-triazole 60percent Perchloric acid (12 ml) was added to a stirred suspension of 1-acetyl-2-benzoyl hydrazine (31 g, 0.174 mole) in acetic anhydride (150 ml) over 45 minutes at 5°+-5° C. The solution was brought to ambient temperature over 1 hour, then filtered. The precipitate was dissolved in water (200 ml), solid sodium carbonate added to pH 9 and the product extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated to an oil. Chromatography gave 2-methyl-5-phenyl-1,3,4-oxadiazole as a gum (9 g, 30percent). With perchloric acid, sodium carbonate in water, acetic anhydride Patent; Pfizer Inc.; US4859686; (1989); (A1) English View in Reaxys With trichlorophosphate Stolle; Chemische Berichte; vol. 45; (1912); p. 289 View in Reaxys With pyridine, thionyl chloride in toluene, Heating


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Golfier,M.; Guillerez,M.-G.; Tetrahedron Letters; (1976); p. 267 - 270 View in Reaxys 80 % Spectr.

With trifluorormethanesulfonic acid, dimethyl-dichlorosilane in acetonitrile, Time= 24h, T= 80 °C Rigo, Benoit; Cauliez, Pascal; Synthetic Communications; vol. 18; nb. 11; (1988); p. 1247 - 1252 View in Reaxys With sodium iodide in acetonitrile, Time= 24h, further reagents, Yield given Rigo, Benoit; Fasseur, Dominique; Cauliez, Pascal; Couturier, Daniel; Synthetic Communications; vol. 19; nb. 13-14; (1989); p. 2321 - 2336 View in Reaxys

100 % Spectr.

With tetrabutyl ammonium fluoride, 1,1,1,3,3,3-hexamethyl-disilazane, Time= 9h, Heating Rigo, Benoit; Cauliez, Pascal; Fasseur, Dominique; Couturier, Daniel; Synthetic Communications; vol. 16; nb. 13; (1986); p. 1665 - 1670 View in Reaxys With polyethylene glycol supported Burgess reagent in tetrahydrofuran, Time= 0.0333333h, Irradiation, microwave, 100 W, Pyrex tube, Yield given Brain, Christopher T.; Paul, Jane M.; Loong, Yvonne; Oakley, Paul J.; Tetrahedron Letters; vol. 40; nb. 16; (1999); p. 3275 - 3278 View in Reaxys With polymer bound phosphazene base P-BEMP, p-toluenesulfonyl chloride in tetrahydrofuran, Time= 4h, Heating Brain, Christopher T.; Brunton, Shirley A.; Synlett; nb. 3; (2001); p. 382 - 384 View in Reaxys Reaction Steps: 2 1: SOCl2, Py / diethyl ether 2: toluene / Heating With pyridine, thionyl chloride in diethyl ether, toluene Golfier,M.; Guillerez,M.-G.; Tetrahedron Letters; (1976); p. 267 - 270 View in Reaxys

O

H N

N N

N H

O

O


Conditions & References With trifluoromethylsulfonic anhydride, triphenyl-phosphine oxide in dichloromethane, T= 0 - 20 °C Bostroem, Jonas; Hogner, Anders; Llinas, Antonio; Wellner, Eric; Plowright, Alleyn T.; Journal of Medicinal Chemistry; vol. 55; nb. 5; (2012); p. 1817 - 1830 View in Reaxys T= 350 °C Gilbert; Journal of the American Chemical Society; vol. 49; (1927); p. 290 View in Reaxys With trichlorophosphate Grekow,A.P.; Schvaika,O.P.; J. Gen. Chem. USSR (Engl. Transl.); vol. 30; (1960); p. 3802 - 3806,3763 - 3766 View in Reaxys With PPA, Time= 2h, T= 130 °C


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Park, Yong-Dae; Kim, Jeum-Jong; Chung, Hyun-A; Kweon, Deok-Heon; Cho, Su-Dong; Lee, Sang-Gyeong; Yoon, Yong-Jin; Synthesis; nb. 4; (2003); p. 560 - 564 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys

N

O

H N

N O

N H O



100 %

With DMEG, triethylamine in dichloromethane, Time= 21h, T= 20 °C , Dehydration, Cyclization Isobe, Toshio; Ishikawa, Tsutomu; Journal of Organic Chemistry; vol. 64; nb. 19; (1999); p. 6989 - 6992 View in Reaxys

78 %

With pyridine, thionyl chloride, Time= 2h, Heating Javaid, Khalid; Smith, David M.; Journal of Chemical Research, Miniprint; nb. 4; (1984); p. 985 - 997 View in Reaxys

78 %

With trichlorophosphate, Time= 12h, Heating Zhang, Yanguang; Hu, Yufeng; Li, Hongchao; Wang, Lixiang; Jing, Xiabin; Wang, Fosong; Ma, Dongge; Journal of Materials Chemistry; vol. 13; nb. 4; (2003); p. 773 - 777 View in Reaxys T= 280 - 300 °C Stolle; Stevens; Journal fuer Praktische Chemie (Leipzig); vol. 69; (1904); p. 378 View in Reaxys With trichlorophosphate, Time= 7h, Heating Zhang, Junxiang; Cui, Yiping; Wang, Mingliang; Xu, Chunxiang; Zhong, Yuan; Liu, Juzheng; Chemistry Letters; nb. 8; (2001); p. 824 - 825 View in Reaxys

N O

N

HN

O

NH O

N

N


Conditions & References With trichlorophosphate, T= 100 °C


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Shin, Ming-Hsiang; Wong, Fung Fuh; Lin, Chun-Min; Chen, Wen-Yi; Yeh, Mou-Yung; Heteroatom Chemistry; vol. 18; nb. 3; (2007); p. 212 - 219 View in Reaxys 78 %

With trifluoromethylsulfonic anhydride, triphenyl-phosphine oxide in dichloromethane, T= 0 - 20 °C Bostroem, Jonas; Hogner, Anders; Llinas, Antonio; Wellner, Eric; Plowright, Alleyn T.; Journal of Medicinal Chemistry; vol. 55; nb. 5; (2012); p. 1817 - 1830 View in Reaxys (i) POCl3, (ii) H2O, Multistep reaction Grekov,A.P.; Nesynov,E.P.; J. Gen. Chem. USSR (Engl. Transl.); vol. 30; nb. 10; (1960); p. 3240 - 3243,3209 - 3211 View in Reaxys With polyethylene glycol supported Burgess reagent in tetrahydrofuran, Time= 0.0333333h, Irradiation, microwave, 100 W, Pyrex tube, Yield given Brain, Christopher T.; Paul, Jane M.; Loong, Yvonne; Oakley, Paul J.; Tetrahedron Letters; vol. 40; nb. 16; (1999); p. 3275 - 3278 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys

F F O O

O

F

O

O

O HN

NH

HN

N

N

O

O

HN

O

O

F O O

O

F F


Conditions & References Example Name 38 The acetic acid (S)-2-tert-butoxycarbonylamino-1- [N'- (4-trifluoromethoxy-benzoyl)- hydrazinocarbonyl]-butyl ester obtained above was split into 5 portions, which were separately reacted as follows: acetic acid (S)-2-tert-butoxycarbonylamino-1- [N'- (4-trifluoromethoxy-benzoyl)-hydrazinocarbonyl]- butyl ester (0.21 mmol, 0.1 g) was dissolved in THF (5 ml) and the solution filled into a Smith Microwave synthesizer reaction vessel. 2-tert-Butylimino-2-diethylamino-1, 3dimethylperhydro-1, 2,3- diazaphosphorine on polystyrene (1.05 mmol, 0.456 g, 2.3 mmol/g loading) and the p-Toluenesulfonic chloride (0.25 mmol, 0.048 g) were added and the reaction mixture heated at 150°C for 10 min (fixed hold time) in the microwave synthesizer. The combined reaction mixtures were filtered under suction and the resin washed with 300 ml ethyl acetate. The combined filtrates were concentrated under reduced pressure. The crude product purified via flash chromatography (Biotage Horizon, 25M column, crude product loaded on caplet, 17 ml/min flow rate, 12 mt/ fraction, 120 ml gradient from 0percent ethyl acetate in heptane to 30 percent ethyl acetate in heptane, 240 ml 30 percent ethyl acetate in heptane, 60 ml gradient 30-50 percent ethyl acetate in heptane, 300 ml 50 percent ethyl acetate in heptane) to give acetic acid (S)-2-tert- butoxycarbonylamino-1-r5- (4-trifluoromethoxy-phenyl)-1, 3, 4-oxadiazol-2yl1-but l ester (0. 28 g, 58 percent) MS: m/z= 460 (M+H+) With p-toluenesulfonyl chloride in tetrahydrofuran Solid phase= Polystyrene, Time= 0.166667h, T= 150 °C Patent; AVENTIS PHARMACEUTICALS INC.; WO2005/40142; (2005); (A1) English View in Reaxys


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O

O

O

H N N H

O

N O

N

O

O

N

O

O

N

O N

N

N N

O



57 %

Example Name 44.b Example Title [0144] Step b. 3- {5- [5-CYCLOHEXYL-L- (3, 3-DIMETHYL-2-OXO-BUTYL)-2-OXO-1, 2- DIHYDRO-3H-1, 3, 4-BENZOTRIAZEPIN-3-YHNETHYL]- [1, 3,4] OXADIAZOL-2-YL}-BENZOIC acid methyl ester. A solution of the 3-(N'-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1, 2-dihydro-3H- 1, 3, 4-BENZOTRIAZEPIN-3-YL]-ACETYL}-HYDRAZINOCARBONYL)-BENZOIC acid methyl ester (Example 44, step a) (94mg, 0.16mmol), triphenylphosphine (64mg, 0. 24MMOL) and 1,8- diazabicyclo [5.4. 0] UNDEC-7-ENE (75mg, 0. 49 mmol) in CCl4MeCN (1: 1/2ML) was stirred at room temperature for 5H. A further quantity of triphenylphosphine (43mg, 0. 16MMOL) was added after 3h. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (EtOAc-hexane (1: 1) ) to afford the product as a off-white solid (52mg, 57percent). 1H NMR (CDC13) 8. 62 (1H, s), 8.19 (2H, m), 7.56 (1H, t), 7.39-7. 35 (2H, M), 7.19 (1H, t), 6.97 (1H, d), 5.05 (1H, br d), 4.85 (1H, br d), 4.68 (2H, s), 3.96 (3H, s), 2.70 (1H, m), 1. 80-1. 60 (6H, br), 1.25 (13H, m). With 1,8-diazabicyclo[5.4.0]undec-7-ene, triphenylphosphine in tetrachloromethane, acetonitrile, Time= 5h, T= 20 °C Patent; JOHNSON and JOHNSON; WO2004/101533; (2004); (A1) English View in Reaxys

O H N

O N

N H

N N

N

O

N N O O


Conditions & References Example Name 27.2 A solution of (8S)-/V-acetyl-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8- c(|imidazole-5-carbohydrazide (step 1 , 580 mg, 1.48 mmol) in phosphorusoxy chloride (4.8 ml) was heated at 50 °C for 1 h. The reaction mixture was poured on a mixture of ice-water (50 ml) and dichloromethane (50 ml) and a pH-value of 8 was adjusted by addition of 6 N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 20 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue (530 mg of a yellow oil) was purified by column chromatography [50 g of silica gel, eluant: dichloromethane / methanol = 50:1 (v/v)]. Evaporation of the corresponding fractions afforded a solid residue (240 mg), which was washed with diethylether (10 ml). The title compound was isolated in 42 percent yield (230 mg of a colourless solid). - m. p. 190-192 °C1H NMR (DMSOd6, 300 MHz): δ = 2.01 (mc, 1 H), 2.32 (mc, 1 H), 2.40 (s, 3 H), 2.52 (s, 3 H), 2.60 (s, 3 H), 3.25 (mc, 2 H), 3.76 (s, 3 H), 5.37 (dd, 1 H), 7.27 (mc, 3 H), 7.49 (mc, 1 H), 7.62 (s, 1 H). Stage 1: With trichlorophosphate, Time= 1h, T= 50 °C Stage 2: With sodium hydroxide in dichloromethane, water, T= 0 °C , pH= 8 Patent; NYCOMED GMBH; WO2008/95912; (2008); (A2) English View in Reaxys

42 %

With trichlorophosphate, Time= 1h, T= 50 °C Palmer, Andreas M.; Chiesa, Vittoria; Schmid, Anja; Muench, Gabriela; Grobbel, Burkhard; Zimmermann, Peter J.; Brehm, Christof; Buhr, Wilm; Simon, Wolfgang-Alexander; Kromer, Wolfgang; Postius, Stefan; Volz, Juergen; Hess, Dietmar; Journal of Medicinal Chemistry; vol. 53; nb. 9; (2010); p. 3645 - 3674


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O NH

Cl

HN N

N

O

HN

HN

O

Si O

O

Si N

Cl

N

N

N



59%

Example Name 58.58d Intermediate 58d; (R)-4-(2-(tert-Butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)ethylamino)-2chloro-3-methylbenzonitrile; Polymer supported triphenylphosphine (1.5 g, 4.46 mmol) was dilluted in 200 mL of DCM followed by addition of 12 (1.13 g, 4.46 mmol) and TEA (1.67 mL, 18.8 mmol) at 0° C. (R)-N-(3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino) propanoyl)-4-cyanobenzohydrazide (1.52 g, 2.97 mmol) in 200 ml DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to come to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3.x.40 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) to provide the title compound (0.860 g, 59percent). The crude material was used directly in the next step. With polymer supported triphenylphosphine, iodine, triethylamine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O O NH

Cl

HN

N

O OH

HN

O

HN O N

Cl

N

OH

N


Conditions & References Example Name 6 Example 6 2-Chloro-4-((1R,2S)-2-hydroxy-1-(5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile To a 100 mL round bottom flask was added N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-methoxybenzohydrazide (Intermediate 6a) (441 mg, 1.1 mmol) was added THF (90 mL) and stirred at room temperature. PS-BEMP (1.45 g, 3.2 mmol base) was added to the solution followed by slow addition of p-TSCl (208 mg, 1.1 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off, washed with methanol (100 mL), and the resulting solution was concentrated to obtain the crude material. The crude material was chromatographed on silica gel with hexanes:EtOAc (2:8) to get the purified product (232 mg, 55percent). 1H NMR (400 MHz, d -acetone, δ in ppm) 7.42 (m, 1H), 7.33 (m, 3H), 7.01 (m, 1H), 6.50 (d, J=8.7 Hz, 1H), 5.37 (d, 6 J=8.5 Hz, 1H), 4.72 (m, 1H), 4.62 (m, 1H), 3.94 (br s, 1H), 3.80 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.4 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English


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O O

O

N

O

O

N

F

N

HN

NH HN

S

F

O

O

O

NH

O

S N



60 %

Example Name 50 Example Title 2-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-oxadiazole (Example 50) 2-(3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}phenyl)-5-methyl-1,3,4-oxadiazole N'-Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzohydrazide (45 mg, 0.086 mmol) synthesised in Example (49a) was dissolved in acetonitrile (3.0 mL), and (methoxycarbonysulfamoyl)triethylammonium hydroxide (50 mg, 0.210 mmol) and triethylamine (0.05 mL, 0.359 mmol) were added, followed by stirring at 100°C for 1 day under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80percent-100percent) to afford the desired compound (26 mg, yield 60percent) as a colorless liquid. 1H-NMR (CDCl , 400 MHz): δ 1.34 (3H, d, J=6.3 Hz), 2.63 (3H, s), 3.42 (3H, s), 3.50 (1H, dd, J=10.2, 4.3 Hz), 3.60 3 (1H, dd, J=10.2, 5.9 Hz), 4.54-4.62 (1H, m), 6.50-6.55 (2H, m), 6.72 (1H, dd, J=3.5, 2.0 Hz), 6.86 (1H, s), 6.99 (1H, s), 7.12-7.19 (2H, m), 7.67 (1H, d, J=3.1 Hz), 7.78 (1H, d, J=9.0 Hz), 7.87 (1H, dd, J=10.8, 1.4 Hz), 9.94 (1H, br s). MS (ESI) m/z: 507.14909 (M+H)+. With Burgess Reagent, triethylamine in acetonitrile, Time= 24h, T= 100 °C , Inert atmosphere Patent; Daiichi Sankyo Company, Limited; EP2239253; (2010); (A1) English View in Reaxys

O HN

O

HN

O O

N

O

N

O

O

N

O O

NH

F

O

N

O NH

F


Conditions & References Example Name 75.3 p-Toluenesulfonyl chloride (420 mg, 0.874 mmol) and triethylamine (0.244 ml, 1.75 mmol) were added to a methylene chloride solution (15 ml) of benzyl {(1S)-1-[(4-{2-[(2-acetylhydrazino)carbonyl]-4-fluorophenoxy}piperidin-1-yl)carbonyl]-2-methylpropyl}carbamate (420 mg, 0.795 mmol), under nitrogen stream, and stirring was carried out at room temperature overnight. Under ice cooling, the reaction solution was poured into a 2N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate, the extract was washed sequentially with water and saline, and then the resulting organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated and the resulting residue was purified by a medium-pressure preparative liquid chromatograph (manufactured by Biotage, Inc., 25+M) to afford benzyl [(1S)-1-({4-[4-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]piperidin-1-yl}carbonyl)-2-methylpropyl]carbamate (227 mg, yield 56percent) as a colorless amorphous substance. 1H-NMR (CDCl3, 400 MHz) δ: 7.69-7.63 (1H, m), 7.36-7.31 (5H, m), 7.19-7.16 (1H, m), 7.00 (1H, dd, J=8.6 Hz, 4.3 Hz), 5.60 (1H, d, J=8.6 Hz), 5.09 (2H, s), 4.72-4.67 (1H, m), 4.56 (1H, dd, J=8.6 Hz, 5.7 Hz), 4.07-3.49 (4H, m), 2.60 (3H, s), 1.97-1.91 (5H, m), 0.99 (3H, t, J=6.6 Hz), 0.89 (3H, t, J=6.6 Hz).


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With triethylamine, p-toluenesulfonyl chloride in dichloromethane, T= 20 °C , Inert atmosphere Patent; Daiichi Sankyo Company, Limited; EP2258697; (2010); (A1) English View in Reaxys

O

O

H N O

O

N H

N N

O I

I



87 %

With trichlorophosphate, T= 100 °C Zhang, Yadong; Zuniga, Carlos; Kim, Sung-Jin; Cai, Dengke; Barlow, Stephen; Salman, Seyhan; Coropceanu, Veaceslav; Bredas, Jean-Luc; Kippelen, Bernard; Marder, Seth; Chemistry of Materials; vol. 23; nb. 17; (2011); p. 4002 - 4015 View in Reaxys

86.8 %

Example Name 1 N'-(4-iodobenzoyl)-3-methoxybenzohydrazide (7.0 g, 17.67 mmol) was suspended in POCl3 (40.0 ml) and heating was started. The reaction was kept at 100 0C. During heating white solid of starting materials dissolved into a clear solution and the reaction was monitor by thin layer chromatography. After 1 h, the reaction mixture was brought to room temperature and was carefully dropped into ice-water (500.0 ml). White solid precipitated out was collected by filtration and washed with water. After dry, the crude product was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate in 25 : 1 ratio. After evaporating solvent the white solid was recrystallized from acetone/ water and finally dried under vacuum. Pure product was obtained as white solid in 5.8 g (86.8percent) yield. 1H NMR (400 MHz, CDCl3, δ): 7.86 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.67 (dt, Ji = 8.0 Hz, J2 =1.2 Hz, 1 H), 7.63 (m, 1 H), 7.42 (t, J = 8 Hz, 1 H), 7.07 (m, 1 H), 3.88 (s, 3 H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.66, 164.00, 159.92, 138.32, 130.23, 128.21, 124.73, 123.26, 119.29, 118.26, 111.56, 98.60, 55.52. With trichlorophosphate, Time= 1h, T= 100 °C Patent; GEORGIA TECH RESEARCH CORPORATION; ZHANG, Yadong; ZUNIGA, Carlos; DESHAYES, Gaelle; LEROY, Julie; BARLOW, Stephen; MARDER, Seth, R.; KIM, Sung-Jin; KIPPELEN, Bernard; WO2010/149620; (2010); (A1) English View in Reaxys

O

O

O

O

N

O

O O

H N O

N H

N H O

O

N

O N H

N

N

Rx-ID: 31610050 View in Reaxys 70/250 Yield 60.2 %

Conditions & References Example Name 122.122B Into a 150mL pressure vessel was charged a solution of 122A (0.57 g, 1.506 mmol) in anhydrous THF (30 mL), and Burgess reagent (1.077 g, 4.52 mmol) was added. The vessel was sealed under Ar, and the mixture was heated in a 75 °C oil bath with stirring behind a blast shield for 2 hrs. Reaction was cooled to room temperature, vented and then left standing at room temperature overnight. Reaction mixture was transferred to a round bottom flask with the aid of a little MeOH and evaporated to dryness. Residue was purified by silica gel chromatography to provide the oxadiazole product (0.327 g, 0.907 mmol, 60.2 percent yield) MS (ESI) m/z 383.3 (M+Na)+ 305.3 (M+H- tBu)+. With Burgess Reagent in tetrahydrofuran, T= 20 - 75 °C , Inert atmosphere


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Patent; BRISTOL-MYERS SQUIBB COMPANY; CORTE, James, R.; FANG, Tianan; DECICCO, Carl, P.; PINTO, Donald, J., P.; ROSSI, Karen, A.; HU, Zilun; JEON, Yoon; QUAN, Mimi, L.; SMALLHEER, Joanne, M.; WANG, Yufeng; YANG, Wu; WO2011/100401; (2011); (A1) English View in Reaxys

O

O O

N

Br

O

N

H N

Br N H N

O

O N

O

N

NH 2

N

NH 2



63 %

Example Name 5.E.2 Step 2: tert-Butyl N-[[4-[5-(2-amino-5-bromo-3-pyridyl)-l,3,4-oxadiazol-2- yl]phenyl]methyl]-N-methyl-carbamate[00152] tert-Butyl N-[[4-[[(2-amino-5-bromo-pyridine-3-carbonyl)amino]carbamoyl] phenyl]methyl]-N-methyl-carbamate (992.3 mg, 2.074 mmol) was dissolved in dry MeCN (15 mL) and cooled in an ice bath under a nitrogen atomosphere. DIPEA (804.2 mg, 1.084 mL, 6.222 mmol) was added via syringe followed by dibromo(triphenyl)phosphorane (1.185 g, 2.696 mmol) portionwise and the reaction allowed to warm to ambient temperature over 15 hours. A further portion of MeCN (15 mL) and dibromo(triphenyl)phosphorane (437.7 mg, 1.037 mmol) were added and the reaction mixture stirred at ambient temperature for a 10 minutes. The precipiate was isolated by filtration and the filtrate concentrated in vacuo. The filtrate was re-dissolved in MeCN (15 mL) and cooled to 0 °C. DIPEA (804.2 mg, 1.084 mL, 6.222 mmol) was added followed by dibromo(triphenyl)phosphorane (437.7 mg, 1.037 mmol) and the reaction mixture stirred at 0 °C for 30 minutes. The reaction mixture was concentrated in vacuo and the resultant residue purified by column chromatography (ISCO Companion.(TM)., 40 g column, 0-50percent EtO Ac/Petroleum ether) and the product containing fractions concentrated in vacuo. The residue was combined with the previously obtained precipitate to give the sub-title product as a white solid (682 mg, 63percent Yield corrected for residual OPPh3). 3/4 NMR (400.0 MHz, DMSO) δ 1.39 - 1.46 (d, 9H), 4.48 (d, J = 10.5 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 8.22 (d, J = 8.2 Hz, 2H), 8.32 (d, J = 2.4 Hz, 1H) and 8.49 (d, J = 2.4 Hz, 1H) ppm; MS (ES+) 462.1. With N-ethyl-N,N-diisopropylamine, dibromotriphenyl-phosphorane in acetonitrile, Time= 15.6667h, T= 20 °C , Inert atmosphere, Cooling with ice Patent; VERTEX PHARMACEUTICALS INCORPORATED; DAMIEN-CHARRIER, Jean; DURRANT, Steven, John; KNEGTEL, Ronald, Marcellus Alphonsus; REAPER, Philip, Michael; WO2011/143422; (2011); (A1) English View in Reaxys

O

F

NH HN

F

O

F N

F OH

HN

HN F

F

O OH

F

N

N

F N


Conditions & References Example Name 2 Example 2(R)-4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methyl-2-(trifluoromethyl)benzonitrile Triphenylphosphine (766 mg, 2.92 mmol) was dissolved in DCM (100 mL) followed by addition of I2 (741 mg, 2.92 mmol) and TEA (0.81 mL, 5.84 mmol) at 0° C. (R)-N'-(2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (660 mg, 1.46 mmol) in DCM (20 mL) and THF (10 mL) was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred for 30 min. The reaction mixture was then concentrated to furnish a yellow solid (781 mg). The crude material was chromatographed with EtOAc:Hexanes (2:1) to furnish the title compound as a white solid (361 mg, 57percent). 1H NMR (500 MHz, Acetone d6, δ in ppm): 7.97-7.94 (m, 2H), 7.49 (d, J=9 Hz, 1H), 7.19-7.14 (m, 2H), 6.81 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.72 (d, J=9 Hz, 1H), 2.35 (s, 3H), 1.50 (s, 3H) and 1.35. With iodine, triethylamine, triphenylphosphine in tetrahydrofuran, dichloromethane, Time= 0.5h, T= 0 °C


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Patent; Radius Health, Inc.; US2012/4270; (2012); (A1) English View in Reaxys

O

F

NH HN N

F

O

F N

OH

HN

HN O

F

OH

N

F

N

N

F N


Conditions & References Example Name 3 Example 3(R)-4-(1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methyl-2-(trifluoromethyl)benzonitrile Triphenylphosphine (766 mg, 2.92 mmol) was dissolved in DCM (100 mL) followed by addition of I2 (741 mg, 2.92 mmol) and TEA (0.81 mL, 5.84 mmol) at 0° C. (R)-N'-(2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (660 mg, 1.46 mmol) in DCM (20 mL) and THF (10 mL) was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred for 30 min. The reaction mixture was then concentrated to furnish a yellow solid (781 mg). The crude material was chromatographed with EtOAc:Hexanes (2:1) to furnish the title compound as a white solid (361 mg, 57percent). 1H NMR (500 MHz, Acetone d6, δ in ppm): 8.08 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.70-7.64 (m, 1H), 7.02-6.95 (m, 1H), 6.64 (d, J=8 Hz, 1H), 4.14 (d, J=9 Hz, 1H), 2.38 (br s, 1H), 1.48 (s, 3H) and 1.44 (s, 3H). With iodine, triethylamine, triphenylphosphine in tetrahydrofuran, dichloromethane, Time= 0.5h, T= 0 °C Patent; Radius Health, Inc.; US2012/4270; (2012); (A1) English View in Reaxys

O

H N

O

N H

N N O


Conditions & References Example Title 5.1.1. 2-(Biphenyl-4-yl)-5-ethyl-1,3,4-oxadiazole (7) Propionyl chloride (4.37 g, 47.2 mmol) at 0 °C was added to a solution of biphenyl-4-carboxylic hydrazide (6, 10.0 g, 47.2 mmol) and triethylamine (4.96 g, 49.1 mmol) in N,N-dimethylformamide (DMF) (200 mL), and the mixture was stirred at room temperature for 2 h before being concentrated in vacuo. EtOAc and water was then added, and the mixture was further stirred for 10 min. The precipitate was collected by filtration and washed with water and EtOAc, and the wet solid was dried in vacuo to give N'-propionylbiphenyl-4-carbohydrazide (8.20 g, 65percent) as a colorless powder. A solution of N'-propionylbiphenyl-4-carbohydrazide (11.5 g, 42.9 mmol) in phosphorus oxychloride (50 mL) was stirred at 100 °C for 1 h. After cooling at room temperature, the mixture was concentrated in vacuo, and the residue was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo, while the residue was purified using column chromatography on silica gel (hexane/EtOAc = 3/1) to give 7 (8.21 g, 97percent) as a white solid. 1H NMR (DMSO-d6) δ 1.46 (3H, t, J = 7.5 Hz), 2.98 (2H, q, J = 7.5 Hz), 7.35-7.52 (3H, m), 7.61-7.66 (2H, m), 7.71 (2H, dt, J = 2.0, 8.6 Hz), 8.10 (2H, dt, J = 1.8, 8.6 Hz); MS (FAB) m/z 251 [M+H]+. With trichlorophosphate, Time= 1h, T= 100 °C Sugane, Takashi; Tobe, Takahiko; Hamaguchi, Wataru; Shimada, Itsuro; Maeno, Kyoichi; Miyata, Junji; Suzuki, Takeshi; Tsukamoto, Shin-Ichi; Kimizuka, Tetsuya; Morita, Takuma; Sakamoto, Shuichi; Bioorganic and Medicinal Chemistry; vol. 20; nb. 1; (2012); p. 34 - 41 View in Reaxys


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O

O

O

O

NH

NH

N

N

O

O

O

N

HN

O

N

NH O

Br

Br



64 %

Example Name 62 To a suspension of methyl (2S,5S)-2-(2-(4-bromobenzoyl)hydrazinecarbonyl)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-5-yl carbamate (1.65 g, 3.29 mmol), PPh3 (1.29 g, 4.94 mmol) and N,N'-diisopropylethylamine (1.72 mL, 9.87 mmol) in acetonitrile (25 mL) at room temperature was added hexachloroethane (1.09 g, 4.61 mmol). The mixture was stirred at room temperature overnight. Solvent was then removed by evaporation. The residue was purified by column chromatography (0-60percent EtOAc in hexane) to give methyl (25,55)-2-(5-(4bromophenyl)-1,3,4-oxadiazol-2-yl)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-5-ylcarbamate (1.02 g, 64percent): ESI-LRMS m/e calcd for C22H19BrN4O4 [M+]484, found 485 [M+H+]. With N-ethyl-N,N-diisopropylamine in 1,2,2-trichloro-1,1,2-trichloro-ethane, acetonitrile, T= 20 °C Patent; Alam, Muzaffar; Berthel, Steven Joseph; Brinkman, John A.; Hawley, Ronald Charles; Li, Hongju; Palmer, Wylie Solang; Pietranico-Cole, Sherrie; Sarabu, Ramakanth; Smith, Mark; So, Sung-Sau; Yi, Lin; Zhai, Yansheng; Zhang, Qiang; Zhao, Shu-Hai; US2012/230951; (2012); (A1) English View in Reaxys

Cl

O

H N

N N

N H

O

O Cl


Conditions & References With acetic acid, [Et2NSF2]BF4 in 1,2-dichloro-ethane, Time= 12h, T= 90 °C , Inert atmosphere Pouliot, Marie-France; Angers, Laetitia; Hamel, Jean-Denys; Paquin, Jean-Francois; Organic and Biomolecular Chemistry; vol. 10; nb. 5; (2012); p. 988 - 993 View in Reaxys

74 %

With zirconium tetrachloride in dichloromethane, Time= 3h, T= 20 °C Sharma, G. V. M.; Begum, Asra; Rakesh; Krishna, Palakodety Radha; Synthetic Communications; vol. 34; nb. 13; (2004); p. 2387 - 2392 View in Reaxys

68 %

With trifluoromethylsulfonic anhydride, triphenyl-phosphine oxide in dichloromethane, T= 0 - 20 °C Bostroem, Jonas; Hogner, Anders; Llinas, Antonio; Wellner, Eric; Plowright, Alleyn T.; Journal of Medicinal Chemistry; vol. 55; nb. 5; (2012); p. 1817 - 1830 View in Reaxys With trichlorophosphate Grekow et al.; Zhurnal Obshchei Khimii; vol. 29; (1959); p. 3054,3055; engl. Ausg. S. 3020, 3021 View in Reaxys With PPA, Time= 2h, T= 130 °C


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Park, Yong-Dae; Kim, Jeum-Jong; Chung, Hyun-A; Kweon, Deok-Heon; Cho, Su-Dong; Lee, Sang-Gyeong; Yoon, Yong-Jin; Synthesis; nb. 4; (2003); p. 560 - 564 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys

O H N Cl

N H

N N

O

O Cl



80 %

With trichlorophosphate in acetonitrile, Time= 4h, T= 80 °C Balsells, Jaume; DiMichele, Lisa; Liu, Jinchu; Kubryk, Michele; Hansen, Karl; Armstrong, Joseph D.; Organic Letters; vol. 7; nb. 6; (2005); p. 1039 - 1042 View in Reaxys With sulfuric acid Vakula,T.R.; Srinivasan,V.R.; Indian Journal of Chemistry; vol. 11; (1973); p. 732 - 734 View in Reaxys With trichlorophosphate, Time= 3h, Heating Cao, Song; Qian, Xuhong; Song, Gonghua; Huang, Qingchun; Journal of Fluorine Chemistry; vol. 117; nb. 1; (2002); p. 63 - 66 View in Reaxys Cao, Song; Qian, Xuhong; Song, Gonghua; Chai, Bing; Jiang, Zhisheng; Journal of Agricultural and Food Chemistry; vol. 51; nb. 1; (2003); p. 152 - 155 View in Reaxys With trichlorophosphate, Heating Chai, Bing; Cao, Song; Liu, Haidong; Song, Gonghua; Qian, Xuhong; Heterocyclic Communications; vol. 8; nb. 6; (2002); p. 601 - 606 View in Reaxys

O

H N O

N H

O N

N


Conditions & References With acetic acid, [Et2NSF2]BF4 in 1,2-dichloro-ethane, Time= 12h, T= 90 °C , Inert atmosphere Pouliot, Marie-France; Angers, Laetitia; Hamel, Jean-Denys; Paquin, Jean-Francois; Organic and Biomolecular Chemistry; vol. 10; nb. 5; (2012); p. 988 - 993 View in Reaxys

71 %

With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, T= -10 - 20 °C , Cyclization


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Liras, Spiros; Allen, Martin P.; Segelstein, Barb E.; Synthetic Communications; vol. 30; nb. 3; (2000); p. 437 - 444 View in Reaxys 96 % Spectr.

With trifluorormethanesulfonic acid, dimethyl-dichlorosilane in acetonitrile, Time= 24h, T= 80 °C Rigo, Benoit; Cauliez, Pascal; Synthetic Communications; vol. 18; nb. 11; (1988); p. 1247 - 1252 View in Reaxys With trifluorormethanesulfonic acid, dimethyl-dichlorosilane in acetonitrile, Time= 24h, T= 80 °C , further reagent, Yield given Rigo, Benoit; Fasseur, Dominique; Cauliez, Pascal; Couturier, Daniel; Synthetic Communications; vol. 19; nb. 13-14; (1989); p. 2321 - 2336 View in Reaxys

85 % Spectr.

With tetrabutyl ammonium fluoride, 1,1,1,3,3,3-hexamethyl-disilazane, Time= 5h, Heating Rigo, Benoit; Cauliez, Pascal; Fasseur, Dominique; Couturier, Daniel; Synthetic Communications; vol. 16; nb. 13; (1986); p. 1665 - 1670 View in Reaxys With carbon tetrabromide, triphenylphosphine in dichloromethane, T= 0 °C Rajapakse, Hemaka A.; Zhu, Hong; Young, Mary Beth; Mott, Bryan T.; Tetrahedron Letters; vol. 47; nb. 28; (2006); p. 4827 - 4830 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys

O

Cl

Cl

Cl

H N Cl

N H

N N

O

O

Cl Cl


Conditions & References With trichlorophosphate, Heating Cao, Song; Wei, Na; Zhao, Chuanmeng; Li, Lina; Huang, Qingchun; Qian, Xuhong; Journal of Agricultural and Food Chemistry; vol. 53; nb. 8; (2005); p. 3120 - 3125 View in Reaxys

79 %

Example Name 34.a To a suspension of 2,4-dichlorobenzohydrazide 8 (451 mg, 2.2 mmol) in 20 mL of acetonitrile was added chloroacetyl chloride (260 mg, 2.3 mmol) followed by NaOH (100 mg, 2.3 mmol). The mixture was stirred at ambient temperature for 4 hours. The solid was collected by filtration, washed with water and dried to give 545 mg (88percent) of compound 9 which was used for the next step without further purification. To a suspension of compound 9 (270 mg, 0.96 mmol) in 30 mL of acetonitrile was added 300 mg OfPOCl3. The mixture was heated at reflux for 5 hours. After removal of the solvent, the residue was purified by column (1 :1 of hexane/ethyl acetate) to give 200 mg of compound 10. Yield: 79percent. 1H-NMR (300 MHz, CHLOROFORM-d) δ (ppm): 7.97 (d, IH), 7.60 (d, IH), 7.42 (dd, IH), 4.56 (s, 2H). With trichlorophosphate in acetonitrile, Time= 5h, Reflux Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys


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F

N H N N H

O

N

F

O H H N

S O N H F

F

O

O

H H N

O O

S N H

F F

F

F

racemate

racemate



51 %

Example Name 1.2 Burgess'reagent (183 mg) was added to a solution of the diacyl hydrazide from Step 1 (138 mg) in THF (2 mL) in a microwave reaction tube. The mixture was irradiated in a microwave for 600 s at 120°C. The mixture was washed into a flask using ethyl acetate and was then concentrated in vacuo. The product was purified by chromatography on silica eluting with 2 to 3 to 5percent MeOH in dichloromethane. The white solid obtained was triturated with diethyl ether to give 68 mg (51percent yield) of the title compound. 8 (1H, 400MHz, CDCl3) 1.31-1. 39 (2H, m), 1.75-1. 79 (2H, m), 2.51-2. 54 (2H, m), 2.77-2. 88 (2H, m), 3.29 (1H, d, J=5.6 Hz), 3.33 (1H, d, J=5.6 Hz), 3.46 (2H, s), 3.70 (2H, q, J = 8.7 Hz), 4.87 (1H, br s), 7.21-7. 29 (3H, m), 7.86-7. 89 (2H, m), 8.13-8. 17 (2H, m). With Burgess Reagent in tetrahydrofuran, Time= 0.166667h, T= 120 °C , Irradiation in microwave Patent; MERCK SHARP and DOHME LIMITED; WO2003/93252; (2003); (A1) English View in Reaxys

N N Cl O

O

H N N H

Cl

O

Cl

Cl


Conditions & References Example Name 5.E Example Title Synthesis of 2,5-Dichloro-N'-[(9,9-dioctyl-9H-fluoren-2-yl)carbonyl]benzohydrazide Part E Synthesis of 2-(2,5-Dichlorophenyl)-5-(9,9-dioctyl-9H-fluoren-2-yl)-1,3,4-oxadiazole (13) 2,5-Dichloro-N'-[(9,9-dioctyl-9H-fluoren-2-yl)carbonyl]benzohydrazide (20.0 g, 32.17 mmole) and phosphorus oxychloride (91 mL) were refluxed for 8 hrs. The reaction was distilled until about half the volume remained. The pot fraction was cooled and poured onto an ice/water mixture with constant stirring. The sticky paste that formed was extracted into hexane and the hexane extract dried and concentrated. Column chromatography (5percent ethyl acetate in hexane) gave 14.98 g (77percent yield) of the desired compound as an oil. With trichlorophosphate, Time= 8h, Heating / reflux Patent; 3M Innovative Properties Company; US7094902; (2006); (B2) English View in Reaxys

77%

Example Name 5.E Example Title Synthesis of 2-(2,5-Dichlorophenyl)-5-(9,9-dioctyl-9H-fluoren-2-yl)-1,3,4-oxadiazole Part E: Synthesis of 2-(2,5-Dichlorophenyl)-5-(9,9-dioctyl-9H-fluoren-2-yl)-1,3,4-oxadiazole 2,5-Dichloro-N'-[(9,9-dioctyl-9H-fluoren-2-yl)carbonyl]benzohydrazide (20.0 g, 32.17 mmole) and phosphorus oxychloride (91 mL) were refluxed for 8 hrs. The reaction was distilled until about half the volume remained. The pot fraction was cooled and poured onto an ice/water mixture with constant stirring.


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The sticky paste that formed was extracted into hexane and the hexane extract dried and concentrated. Column chromatography (5percent ethyl acetate in hexane) gave 14.98 g (77percent yield) of the desired compound as an oil. With trichlorophosphate in hexane, ethyl acetate Patent; 3M Innovative Properties Company; US7271406; (2007); (B2) English View in Reaxys

O

O

O

N O

O N

O H N

O

NH O

N O

O F

N

O

F F

F N

F

F

N


Conditions & References Example Name 48b Example 48. b) A suspension of 2-trifluoromethyl-nicotinic acid N'-(3,4-dimethoxy-5-nitro-benzoyl)- hydrazide (0.60 g, 1.44 mmol) in phosphorus oxychloride (10 mL) was stirred at 130 °C for three hours, becoming a pale yellow solution. The mixture was allowed to cool to room temperature and then poured onto ice-water (200 mL). The white precipitate was filtered off, washed with water and dried to give 3-[5-(3,4-dimethoxy-5-nitro-phenyl)- [1,3, 4] oxadiazol-2-yl] -2trifluoromethyl-pyridine, 0.48 g (84percent). With trichlorophosphate, Time= 3h, T= 130 °C Patent; PORTELA and CA. S.A.; WO2007/13830; (2007); (A1) English View in Reaxys

84 %

Example Name 1.b A suspension of 2-trifluoromethyl-nicotinic acid N'-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide (0.60 g, 1.44 mmol) in phosphorus oxychloride (10 mL) was stirred at 130° C. for three hours, becoming a pale yellow solution. The mixture was allowed to cool to room temperature and then poured onto ice-water (200 mL). The white precipitate was filtered off, washed with water and dried to give 2-(3,4-dimethoxy-5-nitrophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-oxadiazole, 0.48 g (84percent). With trichlorophosphate, Time= 3h, T= 130 °C Patent; Learmonth, David Alexander; Kiss, Laszlo Erno; Palma, Pedro Nuno Leal; Ferreira, Humberto Dos Santos; Silva, Patricio Manuel Vieira Soares da; US2010/168113; (2010); (A1) English View in Reaxys

O N

N

NH HN

O O N

N N

N


Conditions & References Example Name 7 Example 7; 3-(5-Pyridine-3-yl-[1 ,3,41oxadiazol-2-yl)-benzonitrile (Compound 7.1 ); 3-Cyano-benzoic acid-λ/'-(pyridine-3-carbonyl)-hydrazide (1 .2 g, 4.5 mmole) in 25 ml of dichloromethane and 0.8 ml (9.5 mmole) of pyridine under a nitrogen atmosphere was cooled to -100C, 2.8 g (9.9 mmole) of thfluoromethanesulfonic anhydride was added droop wise. The reaction mixture was stirred at -100C for one hour, then at 0°C of one hour and at room temperature overnight. The reaction mixture was added 100 ml of10percent (aq.) sodium bicarbonate and 100 ml of dichloromethane. The organic phase was washed with 50 ml brine, dried with sodium sulfate and evaporated to an oil. The crude product was purified by column chromatography. Yield 0.6 g (2.4 mmole, 54percent); Mp. 170-1740C.


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Stage 1: With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, T= -10 - 20 °C Stage 2: With water, sodium hydrogencarbonate in dichloromethane Patent; NeuroSearch A/S; WO2008/49864; (2008); (A1) English View in Reaxys

O

H N

N

N H

N N H

N N

N

O

N

O

N

N

N

N

NH



50 %

Example Name 22 Example Title (PT-200) Compound A (735 mg, 1.7276 mmol) was dissolved in POCl3 (6.0 ml, 65.27 mmol) and heated at 100° C. overnight. In 15 h LCMS showed the disappearance of A and formation of B as the major component (81percent, tr 5.2 m). The mixture was cooled to room temperature, and the majority of the liquid was removed in vacuo. Ethyl acetate (30 ml) added, and the mixture was then poured into 2M Na2CO3 (30 ml) at 0° C. and stirred for 30 min. A grey suspension formed between the aqueous and organic phases. An insoluble solid was recovered by filtration and was washed with H2O (100 ml), cold EtOAc (10 ml), and then dried in vacuo to afford a grey solid B (350 mg, 50percent). LCMS m/z 408.2 (M+H). 1H-NMR (DMSO-D ) matched the desired structure. 6 Analytical HPLC >97percent purity. The filtrate was extracted with EtOAc (2*50 ml), and the combined organic phase was washed with 30percent NH4Cl (2*40 ml), brined (60 ml), dried over Na2SO4, and concentrated to give brown gel-like solid (ca. 320 mg, including 90percent of B). Stage 1: With trichlorophosphate, T= 100 °C , Neat (no solvent) Stage 2: With sodium carbonate in water, ethyl acetate, Time= 0.5h, T= 0 °C Patent; Abelman, Matthew; Jiang, Robert; Zablocki, Jeff; US2009/12103; (2009); (A1) English View in Reaxys N

O H N N H O

N

N

N

O

N

O

N

O

O

O

HN

HN

O

O


Conditions & References Example Name 3.5d To a solution of the bis-acy\\ hydrazide (113 mg, 0.207 mmol) in DCM (2 niL) was added pyridine (0.042 mL, 0.518 mmol). The solution was cooled to -10 0C (ice bath with NaCl), then triflic anhydride (0.077 mL, 0.456 mmol) was added (solution turned bright orange) and the mixture was gradually warmed to rt overnight. The reaction was quenched by the addition of sat. NaHCO3 (30 mL) and extract with DCM (3 x 30 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (100percent EtOAc) provided 53 mg (0.100 mmol, 48percent) of pure oxadiazole (RE5- 3c). With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, T= -10 - 20 °C Patent; MERCK FROSST CANADA LTD.; BERTHELETTE, Carl; BOYD, Michael; BURCH, Jason; DUFRESNE, Claude; FARAND, Julie; HAN, Yongxin; STURINO, Claudio, F.; WO2010/34110; (2010); (A1) English View in Reaxys


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O N H N

O

O H N

O

N H O

N

O

O

N H N

N Cl

N

N

Cl



49 %

Example Name 5.5 Phosphorus oxychloride (0.38 ml_, 3.84 mmol) was added to a solution of Λ/-{2-[2-(3-chlorobenzoyl)hydrazino]-2-oxoethyl}-3- methoxy-4-(4-methyl-1 /-/-imidazol-1-yl)benzamide) (73 mg, 0.16 mmol) in acetonitrile (3 ml_), and the mixture was heated at 100 0C for 2 hours. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution, and concentrated under reduced pressure. Chromatography on silica (Eluant: 10percent methanol in dichloromethane) afforded the title compound as a gray solid. Yield: 33 mg, 0.078 mmol, 49percent. LCMS m/z 424.5, 426.5 (M+1 ). 1H NMR (400 MHz, CD3OD) δ 2.25 (d, J=1.0 Hz, 3H), 3.96 (s, 3H), 4.92 (s, 2H), 7.15 (m, 1 H), 7.49 (d, J=8.2 Hz, 1 H), 7.57 (dd, J=8.0, 7.7 Hz, 1 H), 7.60-7.64 (m, 2H), 7.74 (d, J=1.8 Hz, 1 H), 7.89 (d, J=1.4 Hz, 1 H), 7.98 (ddd, J=7.7, 1.4, 1.4 Hz, 1 H), 8.05 (dd, J=1.8, 1.8 Hz, 1 H). With trichlorophosphate in acetonitrile, Time= 2h, T= 100 °C , Inert atmosphere Patent; PFIZER INC.; ALLEN, Martin, Patrick; AM ENDE, Christopher, William; BRODNEY, Michael, Aaron; DOUNAY, Amy, Beth; JOHNSON, Douglas, Scott; PETTERSSON, Martin, Youngjin; SCHWARZ, Jacob, Bradley; TRAN, Tuan, Phong; WO2010/100606; (2010); (A1) English View in Reaxys

O NH Cl

HN

O

N

Si N

O

NH

HN O

O

Si

N N

Cl N

N


Conditions & References Example Name 4.4d Intermediate 4d4-((1R,2S)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino-2chloro-3-propylbenzonitrile Triphenylphosphine (0.710 g, 2.71 mmol) was dissolved in 10 mL of DCM followed by addition of I2 (0.687 g, 2.71 mmol) and TEA (0.75 mL, 5.41 mmol) at -15° C. N'-((2R,3S)-3-(tert-Butyldimethylsilyloxy)-2(3-chloro-4-cyano-2-propylphenylamino)butanoyl)-4-cyanobenzohydrazide (intermediate 1119-C) (0.750 g, 1.35 mmol) in 20 ml DCM and 10 mL THF was added to the pre-cooled solution mixture of the PPh3/I2/TEA system and stirred. The temperature was allowed to warm to room temperature and stirred overnight. The reaction was quenched with citric acid (0.260 g) and Na2SO3 (0.170 g) in 50 mL of water and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3.x.20 mL) and the combined organic extracts were washed with sat. aq. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting brown solid was purified by flash chromatography (SiO2, [EtOAc-hexanes (20percent:80percent)-->EtOAc-hexanes (50percent:50percent) as eluent]) to provide the title compound with other minor impurities (0.344 g, 47percent). 1H NMR (400 MHz, Acetone d6, δ in ppm): 8.20 (d, J=8.0 Hz, 2H), 8.01 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 1H), 5.32 (dd, J=2.0, 8.0 Hz, 1H), 4.78 (m, 1H), 2.87 (t, J=8.0 Hz, 2H), 1.73 (m, 2H), 1.50 (d, J=4.0 Hz, 3H), 1.11 (t, J=8.0 Hz, 3H), 0.84 (s, 9H), 0.10 (s, 3H), -0.20 (s, 3H). With iodine, triethylamine, triphenylphosphine in tetrahydrofuran, dichloromethane, T= -15 - 20 °C , Inert atmosphere Patent; Radius Health, Inc.; US2012/4270; (2012); (A1) English View in Reaxys


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F F

N F

O O

O

N

NH HN

O

N Cl

O

Cl N O

O

F F F


Conditions & References Example Name 15.15c A mixture of N'-{5-chloro-2-[4-(trifluoromethyl)phenyl]pentanoyl}-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (223 mg, 0.437 mmol), carbon tetrachloride (0.0841 mL, 0.875 mmol) and triphenylphosphine (459 mg, 1.75 mmol) in acetonitrile (4.3 mL) was stirred at 80°C for 2 hr. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 - 50/50) to give the title compound as a pale yellow oil (110 mg, 50percent). 1H NMR (CDCl3) δ: 1.75 - 1.98 (2 H, m), 2.24 - 2.40 (1 H, m), 2.46 - 2.61 (4 H, m), 3.59 (2 H, t, J=6.6 Hz), 4.02 - 4.07 (3 H, m), 4.37 (1 H, t, J=7.9 Hz), 7.44 - 7.71 (7 H, m), 7.82 (1 H, d, J=8.3 Hz). With tetrachloromethane, triphenylphosphine in acetonitrile, Time= 2h, T= 80 °C Patent; Takeda Pharmaceutical Company Limited; EP2455380; (2012); (A1) English View in Reaxys

O O

H N N H O

O

O O N

O N


Conditions & References Example Title 4.2.2. 2,5-Bis(6-(dodecyloxy)naphthalen-2-yl)-1,3,4-oxadiazole (1a-12) General procedure: The mixture of 6-(dodecyloxy)-N'-(6-(dodecyloxy)-2-naphthoyl)-2-naphthohydride (1.0 g, 1.41 mmol) and phosphoryl chloride was gently refluxed for 8 h under nitrogen atmosphere. Water was slowly added, and the solution was stirred with dilute aqueous NaOH (1.0 M) added for 4 h. The resulting yellow-green solids were collected. The products isolated as white solids were obtained after three times recrystallization from hot THF. Yield 72percent. Stage 1: With trichlorophosphate, Time= 8h, Inert atmosphere, Reflux Stage 2: With sodium hydroxide in water, Time= 4h, Inert atmosphere Kuo, Hsiu-Ming; Li, Sih-Yeh; Lai, Chung K.; Sheu, Hwo-Shuenn; Tetrahedron; vol. 68; nb. 36; (2012); p. 7331 7337 View in Reaxys


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O O

H N N H O

O

O O N

O N



O O

H N N H O

O

O O N

O N



O O

H N N H O

O


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O O N

O N


Conditions & References Example Title 4.2.2. 2,5-Bis(6-(dodecyloxy)naphthalen-2-yl)-1,3,4-oxadiazole (1a-12) The mixture of 6-(dodecyloxy)-N'-(6-(dodecyloxy)-2-naphthoyl)-2-naphthohydride (1.0 g, 1.41 mmol) and phosphoryl chloride was gently refluxed for 8 h under nitrogen atmosphere. Water was slowly added, and the solution was stirred with dilute aqueous NaOH (1.0 M) added for 4 h. The resulting yellow-green solids were collected. The products isolated as white solids were obtained after three times recrystallization from hot THF. Yield 72percent. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, -CH3, 6H, J=6.3 Hz), 1.24-1.50 (m, -CH2, 36H), 1.79-1.89 (m, -CH2, 4H), 4.08 (t, -OCH2, 4H, J=6.3 Hz), 7.14 (s, Ar-H, 2H), 7.15-7.22 (m, Ar-H, 2H), 7.84 (t, Ar-H, 4H, J=9.9 Hz), 8.16 (d, Ar-H, 2H, J=8.7 Hz), 8.55 (s, ArH, 2H). MS (FAB): calcd for M+: C46H62N2O3: 691.00. Found: 691.2. Anal. Calcd for C46H62N2O3: C, 79.96; H, 9.04. Found: C, 79.61; H, 9.01. Stage 1: With trichlorophosphate, Time= 8h, Inert atmosphere, Reflux Stage 2: With sodium hydroxide in water, Time= 4h, Inert atmosphere Kuo, Hsiu-Ming; Li, Sih-Yeh; Lai, Chung K.; Sheu, Hwo-Shuenn; Tetrahedron; vol. 68; nb. 36; (2012); p. 7331 7337 View in Reaxys

O O

H N N H O

O

O O N

O N




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O O

H N N H O

O

O O N

O N



72 %

Example Title 4.2.2. 2,5-Bis(6-(dodecyloxy)naphthalen-2-yl)-1,3,4-oxadiazole (1a-12) General procedure: The mixture of 6-(dodecyloxy)-N'-(6-(dodecyloxy)-2-naphthoyl)-2-naphthohydride (1.0 g, 1.41 mmol) and phosphoryl chloride was gently refluxed for 8 h under nitrogen atmosphere. Water was slowly added, and the solution was stirred with dilute aqueous NaOH (1.0 M) added for 4 h. The resulting yellow-green solids were collected. The products isolated as white solids were obtained after three times recrystallization from hot THF. Yield 72percent. Stage 1: With trichlorophosphate, Time= 8h, Inert atmosphere, Reflux Stage 2: With sodium hydroxide in water, Time= 4h, Inert atmosphere Kuo, Hsiu-Ming; Li, Sih-Yeh; Lai, Chung K.; Sheu, Hwo-Shuenn; Tetrahedron; vol. 68; nb. 36; (2012); p. 7331 7337 View in Reaxys

N

O N HN

NH

N N O

O


Conditions & References With trifluoromethylsulfonic anhydride, triphenyl-phosphine oxide in dichloromethane, T= 0 - 20 °C Bostroem, Jonas; Hogner, Anders; Llinas, Antonio; Wellner, Eric; Plowright, Alleyn T.; Journal of Medicinal Chemistry; vol. 55; nb. 5; (2012); p. 1817 - 1830 View in Reaxys With trichlorophosphate Grekow,A.P.; Schvaika,O.P.; J. Gen. Chem. USSR (Engl. Transl.); vol. 30; (1960); p. 3802 - 3806,3763 - 3766 View in Reaxys With trichlorophosphate, Time= 0.5h, Heating Popova, N. A.; Yushko, E. G.; Krasovitskii, B. M.; Minkin, V. I.; Lyubarskaya, A. E.; Gol'dberg, M. L.; Chemistry of Heterocyclic Compounds (New York, NY, United States); (1983); p. 22 - 28; Khimiya Geterotsiklicheskikh Soedinenii; vol. 19; nb. 1; (1983); p. 26 - 32 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys


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O

O

O

O

S

O

O S

O

O O O O

N

O

HN

O

NH

N O

O



88 %

Example Name 32.B Example Title Part B. The product from Part A (2.1 g, 3.75 mmol) was heated to reflux in toluene (25 mL) with p-toluenesulfonic acid (100 mg) for 4 hr. The reaction was concentrated in vacuo. Recrystalization from hot methanol provided 1.6 g (88percent) of the free acid of the oxadiazole as a white solid. ESMS m/z=487 [M+Na]+. With toluene-4-sulfonic acid in toluene, Time= 4h, Heating / reflux Patent; Freskos, John N.; Fobian, Yvette M.; Barta, Thomas E.; Becker, Daniel P.; Bedell, Louis J.; Boehm, Terri L.; Carroll, Jeffery N.; DeCrescenzo, Gary A.; Hockerman, Susan L.; Kassab, Darren J.; Kolodziej, Steve A.; McDonald, Joseph; Mischke, Deborah A.; Norton, Monica B.; Rico, Joseph G.; Talley, John J.; Villamil, Clara I.; Wang, Lijuan Jane; US2004/10019; (2004); (A1) English View in Reaxys

F

O N F

F O

N F

N

O

H N

N

N H

O

O


Conditions & References Example Name 58(B) 58 (B) (4-Fluoro-phenyl)- {3-[5-(4-fluoro-phenyl)-[1, 3, 4] oxadiazol-2-yl]- piperidin-1-yl}-methanone; A mixture of 4fluoro-benzoic acid N'-[(S)-1-(4-fluoro-benzoyl)-piperidine-3- carbonyl]-hydrazide (100 mg, 0.26 mmol), 4-toluenesulphonyl chloride (60 mg, 0.31 mmol), solid supported 2-tert-Butylimino-2-diethylamino-1, 3-dimethyl-perhydro- 1,3, 2diaza-phosphorine (PS-BEMP, ex Fluka, 586 mg, 1.3 mmol, loading 2.2 mmol/g) in dry tetrahydrofuran (6 mL) was irradiated by microwaves under the following conditions: MW cycle: t=l min, P=100 W, cooling time= 2 min. After 5 MW cycles, the resin was filtered off and washed repeatedly with dichloromethane. The solvent was evaporated under reduced pressure to give a crude solid that was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 1: 1). The title compound was obtained as a white solid (82 mg). Yield: 85percent ; LCMS (Tr): 6.75 min (Method A); MS (ES+) gave m/z: 370.1. 1H-NMR (CDC13,300 K, 300 MHz), 8 (ppm): 8.02 (m, 2H); 7.41 (m, 2H) ; 7.31-6. 93 (m, 4H); 4.96-3. 37 (m, 3H); 3.22 (m, 2H), 2.32 (m, 1H) ; 2.20-1. 63 (m, 3H). With C20H35N3PPol, p-toluenesulfonyl chloride in tetrahydrofuran Solid phase= Polystyrene, Time= 0.0333333h Patent; ADDEX PHARMACEUTICALS SA; WO2005/44797; (2005); (A1) English View in Reaxys


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O N O

O

O

O O O

N

N H

O NH

N

O

O

N

O

O N

O

O

N

N

O

N



92 %

Example Name 1 This compound was synthesized according to a modified literature procedure.29 4-Nitro-benzoic acid N'- 14-[5-(3,4,5tris-dodecyloxy-phenyl)- [1,3,4]oxadiazol-2-yl]-benzoyl}-hydrazide BK2_23 (3.25 g, 3.31 mmol) was heated in 140 ml of POCl3 at 120 °C overnight. Excess POCl3 was distilled off till around 25 ml are left (the complete distillation of POCl3 lead to tarr and no product was detected, experiment BK2_5). The solution was then poured slowly over 1 L of icewater (excess POC13 reacts with water). The greenish solid was filtered off and was recrystallized from CHC13/ethanol to yield 2.92 g (92 percent) of greenish solid. 1H (300 MHz, CDCl3) No. 8.44- 8.34 (m, 4H), 8.32 (s, 4H), 7.33 (s, 2H), 4.10-4.058 (t, J= 12.6 Hz, 4H), 4.06-4.02 (t, J= 12 Hz, 2H), 1.89-1.80 (pentet, J= 7.8 Hz, 4H), 1.78-1.71 (pentet, J= 6.9 Hz, 2H), 1.54- 1.43 (m, 6H), 1.39-1.19 (m, 48H), 0.88-0.84 (t, J= 6 Hz, 9H). 1 3C (CDCI3, 75 MHz) (at) 165.16, 164.51, 163.17, 163.11, 153.52, 149.56, 141.61, 128.96,127.85, 127.62,127.49, 127.11,125.72,124.40,117.91,105.49,73.66, 69.44, 32.00, 30.42,29.78, 29.73,29.66, 29.40, 29.45, 29.40, 26.18, 22.78,14.22 ppm. MALDI-TOF MS (M) : m/z 964.5; calcd for C58H85N5O7, 964.3. With water, trichlorophosphate, T= 120 °C Patent; GEORGIA TECH RESEARCH CORPORATION; WO2005/123737; (2005); (A2) English View in Reaxys

N O

O

N H

H H N

O

N

H N

O

S

S N

N

H

H F F

N

O

H H N

O

O

N

F F

F

F racemate

racemate


Conditions & References Example Name 2.3


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Burgess'reagent (85 mg) was added to a solution of the diacyl hydrazide (62 mg) in THF (1 mL). The mixture was irradiadiated in a microwave for 300s at 1200C. The reaction mixture was washed out of the reaction tube using ethyl acetate, and concentrated. Chromatography on silica eluting with 2percent methanol in dichloromethane was followed by trituration with diethyl ether to give the title compound (25 mg, 42percent) and some slightly impure material (20 mg). 8 (1H, 400MHz, CDCl3) 1.32-1. 35 (2H, m), 1.74- 1.78 (2H, m), 2.49-2. 52 (2H, m), 2.77-2. 89 (2H, m), 3.25-3. 33 (2H, m), 3.45 (2H, s), 3.69 (2H, q, J = 8.7 Hz), 4.70 (1H, s), 7.25-7. 28 (1H, m), 7.46-7. 49 (1H, m), 7.89-7. 93 (1H, m), 7.97-7. 99 (2H, m), 8.33 (1H, d, J = 8.2 Hz), 8.82 (1H, d, J = 4.3 Hz); MS (ES+) 506 ( [MH] +). With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 120 °C , Irradiation in microwave Patent; MERCK SHARP and DOHME LIMITED; WO2003/93252; (2003); (A1) English View in Reaxys Br

O

H N Br

N H

N N O

O


Conditions & References Example Name 4.1.iii (iii) Synthesis of mO11Br Further, 7.1 g (22 mmol) of 1-benzoyl-2-(3-bromobenzoyl)hydrazine obtained by the method shown in (ii) above was put in a 300-mL three-neck flask, 100 mL of phosphoryl chloride was added therein, and the mixture was heated and stirred at 100° C. for 5 hours so as to be reacted. After the reaction, a solid was obtained by completely distilling off the phosphoryl chloride in the flask. The obtained solid was washed with water and a sodium carbonate aqueous solution in this order and collected by suction filtration. Then, the collected solid was recrystallized with methanol; thus, 4.9 g of a white solid that was an object was obtained (yield: 73percent). A synthesis scheme of Step 1 described above is shown in the following scheme (a-4). With trichlorophosphate, Time= 5h, T= 100 °C Patent; Semiconductor Energy Laboratory Co., Ltd.; US2007/149784; (2007); (A1) English View in Reaxys

73 %

Example Name 1.1.iii (iii) Synthesis of mO11Br; Furthermore, 7.1 grams (22 mmol) of the 1-benzoyl-2-(3-bromobenzoyl)hydrazine obtained by the method described in (ii) above were placed into a 300-mL, three-neck flask; 100 mL of phosphoryl chloride was added thereto; the mixture was heated and stirred at 100°C for 5 hours; and the contents of the flask were reacted together. After the reaction was completed, when the phosphoryl chloride in the flask was completely distilled away, a solid was obtained. The obtained solid was washed first with water and then with an aqueous solution of sodium carbonate, and an obtained solid was removed by suction filtration. When the removed solid was recrystallized by methanol, 4.9 grams of a white-colored solid, which was the objective of the synthesis process, were obtained at a yield of 73percent. The synthesis scheme of the present Step 1 described above is shown in Scheme (a-1), which is given below Stage 1: With trichlorophosphate, Time= 5h, T= 100 °C Stage 2: With water, sodium carbonate Patent; SEMICONDUCTOR ENERGY LABORATORY CO., LTD.; EP1972625; (2008); (A1) English View in Reaxys


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O O

O O O

O N

HN

N N

O

O

N

N

NH

N

O


Conditions & References Example Name 1.5 Step 5: Methyl 4 -(5-(4-(5-(4-tert-Butylphenyl)-1.3.4-oxadiazol-2-yl)phenyl)-1.3.4- oxadiazol-2-yl)-benzoate (YZ -1-207): Methyl 4-(2-(4-(5-(4-tert-butylphenyl)-l,3,4-oxadiazol-2-yl)benzoyl)- hydrazinecarbonyl)benzoate (2.5 g, 5.05 mmol) and POCl 3 (50 ml) were taken into a 100 mL round bottom flask. The reaction was kept at 100 0C. During the heating (about 30 min) the starting material solid disappeared. After 2 hours of the reaction, the solid appeared due to the insolubility of product in POCl 3. After 7 hours at 100 0C, the reaction mixture was allowed to cool down to room temperature and was slowly dropped into ice -water (200.0 ml). The white solid formed was collected by filtration, dried under vacuum and gave 2.2 g (91.7 percent) in yield. The purification and characterization were difficult due to the very low solubility of this compound in common organic solvents. With trichlorophosphate, Time= 7h, T= 100 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

N

O H N O N

N

O N

N

N

O

O

N H

O

O


Conditions & References Example Name 8.2 Step 2 : 2 -(4 -tert-Butylphenyl) -5 -(3 -(5 -(3 -methoxyphenyl) - 1.3.4 -oxadiazol -2- yl)phenyl)-1.3.4-oxadiazole (YZI-249):3-(5-(4-tert-Butylphenyl)-l,3,4-oxadiazol-2-yl)-N'-(3-methyoxy- benzoyl)benzohydrazine (1.75 g, 3.72 mmol) was added in POCl 3 (15.0 ml). The reaction was heated to 90 0C and kept at this temperature for 4 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice -water (300.0 ml). The white solid formed was collected by vacuum filtration. The crude product was dried and purified by a silica gel column using dichlorom ethane/ethyl acetate, ratio (9 : 1), as the eluent. After the removal of the solvents, a pure white solid product was obtained in 1.18 g (70.2 percent) yield. 1H NMR (400 MHz, CDCl 3) δ: 8.86 (t, 1 H, J= 1.6 Hz), 8.34 (dt, 2 H, J1 = 7.6 Hz, J2 = 1.6 Hz), 8.11 (d, 2 H, J= 8.4 Hz), 7.73 (m, 3 H), 7.57 (d, 2 H, J= 8.4 Hz), 7.47 (t, 1 H, J= 7.6 Hz), 7.32 (dd, 1 H, J1 = 7.6 Hz, J2 = 1.6 Hz), 3.93 (s, 3 H, OCH 3), 1.39 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl 3) δ: 165.11, 164.94, 163.62, 163.34, 159.95, 155.64 , 130.26, 129.97, 129.74, 126.89, 126.10, 125.10, 124.92, 124.90, 124.65, 120.70, 119.42, 118.42, 111.60, 55.56, 35.10, 31.08 ppm. MS-EI (m/z): [M]+ calcd for C28H24N4O4 452.2, found 452.2. With trichlorophosphate, Time= 4h, T= 90 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

70.2 %

Example Name 4.2 3-(5-(4-tert-Butylphenyl)-l,3,4- oxadiazol-2-yl)-N'-(3-methyoxy-benzoyl)benzohydrazine (1.75 g, 3.72 mmol) was added in POCl3 (15.0 ml). The reaction was heated to 90 0C and kept at this temperature for 4 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice-water (300.0 ml). The white solid formed was collected by vacuum filtration. The crude product was dried and purified by a silica gel column using dichloromethane/ ethyl acetate, ratio (9 : 1), as the eluent. After the removal of the solvents, a pure white solid product was obtained in 1.18 g (70.2 percent) yield. 1H NMR (400 MHz, CDCl3) δ: 8.86 (t, 1 H, J= 1.6 Hz), 8.34 (dt, 2 H, J1 = 7.6 Hz, J2 = 1.6 Hz), 8.11 (d, 2 H, J= 8.4 Hz), 7.73 (m, 3 H), 7.57 (d, 2 H, J= 8.4 Hz), 7.47 (t, 1 H, J= 7.6 Hz), 7.32 (dd, I H, J1 = 7.6 Hz, J2 = 1.6 Hz), 3.93 (s, 3 H, OCH3), 1.39 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl3) δ: 165.11, 164.94, 163.62, 163.34, 159.95, 155.64, 130.26, 129.97, 129.74, 126.89, 126.10, 125.10, 124.92, 124.90, 124.65, 120.70, 119.42, 118.42, 111.60, 55.56, 35.10, 31.08 ppm. MS-EI (m/z): [M]+ calcd for C28H24N4O4 452.2, found 452.2.


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With trichlorophosphate, Time= 4h, T= 90 °C Patent; GEORGIA TECH RESEARCH CORPORATION; ZHANG, Yadong; ZUNIGA, Carlos; DESHAYES, Gaelle; LEROY, Julie; BARLOW, Stephen; MARDER, Seth, R.; KIM, Sung-Jin; KIPPELEN, Bernard; WO2010/149620; (2010); (A1) English View in Reaxys

O

O

NH

O

O

O HN

O O

O

O

O

O

O

N

N O



89.1 %

Example Name 9.4 Step 4: Methyl 4-(5-(3A5-tris(hexyloxy)phenyl)-l,3,4-oxadiazol-2-yl)benzoate (YZ-2-751): Methyl 4-(2-(3,4,5-tris(hexyloxy)benzoyl)hydrazinecarbonyl)benzoate (14.0 g,23.38 mmol) was added to POCl 3 (60.0 ml). The reaction was heated to 80 0C, and kept at this temperature for 4 h. After cooling, the reaction mixture was slowly added to ice water (1500.0 ml). The crude product was collected as yellow solid, and purified by silica gel column using ethyl acetate/ hexane (2 : 8) as eluent. Pure product was obtained in 12.1 g (89.1percent).1H-NMR (500 MHz, CDCl 3) δ: 8.23 (d, 2 H, J= 8.5 Hz), 8.20 (d, 2 H, J= 8.5 Hz), 7.33 (s, 2 H), 4.09 (t, 4 H, 2 x OCH 2, J= 6.5 Hz), 4.05 (t, 2 H, OCH 2, J= 6.5 Hz), 3.97 (s, 3 H, OCH3), 1.86 (m, 4 H, 2 x CH 2), 1.77 (m, 2 H, CH 2), 1.52 (m, 6 H, 3 x CH2), 1.37 (m, 12 H, 6 x CH 2), 0.92 (m, 9 H, 3 x CH3) ppm. 13C-NMR (126 MHz, CDCI3) δ: 166.14, 165.21, 163.61, 153.60, 141.52, 132.67, 130.22, 127.73, 126.78, 118.14, 105.44, 73.62, 69.36, 52.49, 31.70, 31.53, 30.26, 29.24, 25.73, 25.70, 22.68, 22.62, 14.08, 14.03 ppm. With trichlorophosphate, Time= 4h, T= 80 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

O O

O N N

O

O

O

O

O HN

NH

O

O

O

N

O N

O

O

N

O

N


Conditions & References Example Name 9.7 Step 7:Methyl 4 -(5-(4-(5-(3 ,4,5 -tris(hexyloxy)phenyl -1,3 ,4-oxadiazol-2-yl)phenyl)- 1 ,3,4-oxadiazol-2-yl)benzoate : Methyl 4 -(2-(4-(5-(3,4,5 -tris(hexyloxy)phenyl) - l,3,4-oxadiazol-2-yl)benzoyl)hydrazinecarbonyl)benzoate (4.7 g, 6.32 mmol) was added to POCl 3 (60.0 ml). The reaction was heated to 80 0C, and kept at this temperature for 4 h. After


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cooling, the reaction mixture was slowly added to ice water (400.0 ml). The crude product was collected as yellow solid, and purified by silica gel column using ethyl acetate/hexane (2 : 8) as eluent. Pure product was obtained in 4.12 g (89.8percent) . 1H-NMR (400 MHz, CDCl 3): δ 8.33 (s, 4 H), 8.25 (d, 2 H, J= 8.4 Hz), 8.23 (d, 2 H, J= 8.4 Hz), 7.34 (s, 2 H), 4.08 (m, 6 H, 3 x OCH 2), 3.98 (s, 3 H, OCH3), 1.86 - 1.73 (m, 6 H, 3 x CH 2), 1.51 (m, 6 H, 3 x CH 2), 1.37 (m, 12 H, 6 x CH 2), 0.92 (m, 9 H, 3 x CH3) ppm. 13C-NMR (100 MHz, CDCl 3) δ: 166.01, 165.24, 164.25, 164.16, 163.41, 153.63, 141.62, 133.06, 130.33, 127.58, 127.50, 127.32, 126.95, 126.90, 126.14, 118.06, 105.48, 73.62, 69.39, 52.53, 31.71, 31.54, 30.26, 29.25, 25.73, 25.69, 22.66, 22.60, 14 .07, 14.02 ppm. With trichlorophosphate, Time= 4h, T= 80 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys O O

N O

N

O O O HN

NH

O


Conditions & References Example Name 1.2 Step 2: Methyl 4 -(5-(4-tert-butylphenyl)-l?3?4-oxadiazol-2-yl)benzoate (YZ -1-187): Methyl 4-(2-(4-tert-butylbenzoyl)hydrazinecarbonyl)benzoate (2.46 g, 6.94 mmol) was suspended in POCl 3 (20.0 ml) and heating was started. The reaction was kept at 85 0C. During heating, the white solid starting mated als dissolved into a clear solution and the reaction was monitored by thin layer chromatography. After 4 hours, the reaction mixture was brought to room temperature and was carefully dropped into ice -water (200 ml). The white solid precipitated out was c ollected by filtration and dried under vacuum to give 2.1 g (90.1 percent) of white powder.1H NMR (400 MHz, CDCl 3) δ: 8.22 (s, 2 H), 8.21 (s, 2 H), 8.08 (d, 2 H, J= 8.4 Hz), 7.56 (d, 2 H, J= 8.4 Hz), 3.98 (s, 3 H5 OCH 3), 1.38 (s, 9 H, 3 x CH3) ppm. 13C NMR(100 MHz, CDCl3) δ: 166.13, 165.16, 163.60, 155.73, 132.70, 130.25, 127.71,126.90, 126.79, 126.13, 120.71, 52.48, 35.13, 31.09 ppm. With trichlorophosphate, Time= 4h, T= 85 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

N

O O O HN

N

O

HN

O

NH

NH

O

O O

N

N


Conditions & References Example Name 11.5 Step 5: 5,5'-(2-methoxy-l,4-phenylene)bis(2 -(4-tert-butylphenyl)l,3,4 -oxadiazole) (SKP-I-ODZ-27):N'1, N'4-Bis(4-tertbutylbenzoyl)-2-methoxyterephthalohydrazide (2.0 g, 3.68 mmol) was suspended in 75 mL Of POCl3 and the reaction was refluxed at 96 0C for 8 hours. During the reaction the solid SKP -I-ODZ-25 were completely dissolved in POCl3. After cooling down to room temperature the mixture was poured into 250 mL of ice -water mixture. The light yellow solid formed was collected by filtration and dried under vacuum. The yield of the reaction is 1.75 g (94 percent). MS -EI (m/ z): [M]+ calcd for C3iH32N4O3 508, found 508. 1H NMR (400 MHz, CDCl 3) δ: 8.22 (d, 1 H, J= 8.0 Hz), 8.08 - 8.11 (m, 4 H), 7.89 (s, 1 H), 7.83 (dd, 1 H, J1 = 1.6 Hz, J2 = 8.0 Hz, 1 H), 7.56 - 7.59 (m, 4 H), 4.14 (s, 3 H), 1.39 (s, 9 H), 1.38 (s, 9 H) ppm. 13C NMR (75.5 MHz, CDCl 3) δ: 165.15, 164.78, 163.50, 162.32, 158.05, 155.70, 155.41, 131.03, 127.77, 126.88, 126.86, 126.10, 126.02, 120.9 4, 120.67, 118.95, 115.90, 109.99, 56.44, 35.09, 35.07, 31.07 ppm. Anal. Calcd for C3iH32N4O3: C, 73.21; H, 6.34; N, 11.02. Found: C, 72.53; H, 6.49; N, 10.91. With trichlorophosphate, Time= 8h, T= 96 °C


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Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

O

Cl

N

NH Si

O

HN

O

Si O

HN

Si O

HN

O N

N

O Si

Cl N



44%

Example Name 49.49d Intermediate 49d; 4-((1R,2S)-2-(tert-Butyldimethylsilyloxy)-1-(5-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-1,3,4oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile; Polymer supported triphenylphosphine (6.22 g, 23.7 mmol) was dilluted in 200 mL of DCM followed by addition of I2 (6.02 g, 23.7 mmol) and TEA (8.81 mL, 63.2 mmol) at 0° C. N'-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-((tert-butyldimethylsilyloxy)methyl)benzohydrazide (10.2 g, 15.8 mmol) in 200 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to warm to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3.x.40 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) [EtOAc-hexanes (1:2), then 100percent EtOAc as eluent] to provide the title compound (4.35 g, 44percent). 1H NMR (500 MHz, acetone d6, 6 in ppm): 8.16 (d, J=8 Hz, 2H), 7.75 (d, J=9 Hz, 2H), 7.64 (d, J=9 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 5.73 (d, J=9 Hz, 1H), 5.41 (d, J=9 Hz, 1H), 5.03 (s, 2H), 4.97-4.88 (m, 1H), 2.22 (s, 3H), 1.63 (d, J=6 Hz, 3H), 1.11 (s, 9H), 1.06 (s, 9H), 0.30 (s, 3H), 0.28 (s, 3H). With polymer supported triphenylphosphine, iodine, triethylamine in dichloromethane, T= 0 - 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O

S NH HN

O

HN N

OH

OH

HN

O

N N

S N

N


Conditions & References Example Name 61 Example 61; 4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile; To a solution of 4-cyano-N'-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.95 g, 2.26 mmol) in THF (150 mL) was added PS-BEMP (3.1 g, 6.82 mmol, 2.2 mmol/g) and p-TsCl (470 mg, 2.46 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH (400 mL). The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-1(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (401 mg, 44percent). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.14 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.83 (d, J=5.6 Hz, 1H), 7.68 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.18 (dd, J=6.5, 8.8 Hz, 1H), 4.72 (b, 1H), 4.61 (m, 1H), 1.50 (d, J=6.2 Hz, 3H).


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With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 2h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O

S NH HN

O

F

HN

OH

HN

OH O

N N

S N

F



43 %

Example Name 64 Example 64; 4-((1R,2R)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile; To a solution of N'-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.41 g, 0.99 mmol) in THF (80 mL) was added PS-BEMP (1.36 g, 2.99 mmol, 2.2 mmol/g) and p-TsCl (191 mg, 1.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (170 mg, 43percent). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.84 (d, J=5.6 Hz, 1H), 7.71 (d, J=5.6 Hz, 1H), 7.64 (d, J=8.2 Hz, 11H), 7.32 (t, J=8.8 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.13 (dd, J=6.4, 8.8 Hz, 1H), 4.66 (d, J=6.1 Hz, 1H), 4.57 (m, 1H), 1.48 (d, J=6.2 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 15h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O

S

NH HN

O OH

HN

HN OH O

N N

S N


Conditions & References Example Name 65 Example 65; 4-((1R,2R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile; To a solution of N'-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.56 g, 1.42 mmol) in THF (120 mL) was added PS-BEMP (1.94 g, 4.27 mmol, -2.2 mmol/g) and p-TsCl (275 mg, 1.44 mmol) at room temperature. The mixture was stirred at room temperature for 18 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2R)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (229 mg, 43percent). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.98 (m, 2H), 7.85 (d, J=5.5 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.517.57 (m, 3H), 6.87 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 5.14 (dd, J=6.5, 8.8 Hz, 1H), 4.66 (d, J=6.0 Hz, 1H), 4.58 (m, 1H), 1.49 (d, J=6.2 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 18h, T= 20 °C


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Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH

Cl

HN

N

O

O OH

HN

HN O

O

N

N

Cl

OH

N



41 %

Example Name 2 Example 2 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile The crude material from the reaction immediately preceding (Intermediate 2a) N'-((2R,3S)-2-(3-chloro-4-cyano-2methylphenylamino)-3-hydroxybutanoyl)-4-methoxy benzohydrazide (330 mg, 0.79 mmol) was added to THF (40 mL) and stirred at room temperature. PS-BEMP (1.08 g, 2.37 mmol base) was added to the solution followed by slow addition of p-TSCl (166 mg, 0.87 mmol). The reaction mixture was stirred for 3 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed on silica gel with Hex:EtOAc (6:4) to get the purified product (130 mg, 41percent). 1H NMR (500 MHz, Acetone-d , δ in ppm) 7.93 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 6.87 (d, 6 J=9 Hz, 1H), 5.68 (d, J=9 Hz, 1H), 5.07 (m, 1H), 4.79 (m, 1H), 4.60 (m, 1H), 3.89 (s, 3H), 2.40 (s, 3H), 1.40 (d, J=6 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

O N

N

N H O N

N

N

H N

O

O

OH

N

Cl


Conditions & References Example Name 49.B To compound 49b (255mg, 0.77mmol) was added POCI3 (2OmL) and the solution was stirred and heated to 1050C for 16h. Allowed to cool, concentrated under vacuum, added H2O (10OmL), stirred for 30min, filtered solid and dried to yield compound 49c (245mg, 96percent). With trichlorophosphate, Time= 16h, T= 105 °C Patent; SCHERING CORPORATION; WO2009/111442; (2009); (A1) English View in Reaxys

O HN O

NH

N O

N

O O



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Yield


85 %

Example Name 35 A solution of N'-acetyl-1-benzofuran-5-carbohydrazide (20.7 g, 36.2 mmol) and p-toluenesulfonyl chloride (36.2 g, 190 mmol) in pyridine (200 ml,) was stirred under an argon atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed water, 2 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from tetrahydrofuran to give the title compound (16.0 g, yield 84percent) as colorless crystals.melting point 159-160° C.1H NMR (CDCl3) δ 2.63 (3H, s), 6.86 (1H, dd, J=0.9, 2.3 Hz), 7.61 (1H, td, J=0.8, 8.7 Hz), 7.71 (1H, d, J=2.3 Hz), 8.01 (1H, dd, J=1.7, 8:7 Hz), 8.30 (1H, dd, J=0.6, 1.7 Hz).Elemental analysis (for C11H8N2O2)Calculated (percent): C, 66.00; H, 4.03; N, 13.99.Found (percent): C, 66.07; H, 4.00; N, 13.99. With pyridine, p-toluenesulfonyl chloride, Time= 16h, T= 80 °C , Reflux, Inert atmosphere Patent; Itoh, Fumio; US2010/69381; (2010); (A1) English View in Reaxys

Cl O

H N Cl

O

Cl N H

N N

O

Cl Cl

Cl



92 %

Example Name 42.b To a mixture of 3,5-dichlorobenzohydrazide 5 (0.5 g, 2.4 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 3,5-dichloro-N'-(2- chloroacetyl)benzohydrazide 6 (0.63 g, 92percent) which was used for the next step without further purification. A mixture of 3,5-dichloro-N'-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25percent acetone/hexanes to give compound 7 (0.52 g). Yield: 88percent. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.91 (s, 2 H), 7.53 (s, 1 H), 4.78 (s, 2 H). With trichlorophosphate in acetonitrile, Time= 16h, Reflux Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys Cl

O H N

Cl

N

O

N H

N

O

Br

Br


Conditions & References Example Name 59.c Compound 4 (2.1 g, 6.8 mmol, crude) was suspended in POCl3 (6 ml), and then the reaction mixture was heated to 1100C for 5 hours. The mixture was allowed to cool to ambient temperature and quenched by adding water, then the mixture was extracted with EA. The EA layer was concentrated to give a residue which was purified by column chromatography eluting with (DCM: MeOH=50: 1) to give light grey solid compound 5 (1.7g). Yield: 87percent. 1HNMR (400 MHz, CDCl3): δ (ppm): 8.23 (IH, S, Ar-H), 7.91 (IH, d, Ar-H), 7.38 (IH, d, Ar- H), 4.78 (2H, s, -CH2-), 2.48 (3H, s, CH3-). With trichlorophosphate, Time= 5h, T= 110 °C


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Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys

O

O

H N O

I N H

O

N N

O I

I

I



71 %

With trichlorophosphate, T= 100 °C Zhang, Yadong; Zuniga, Carlos; Kim, Sung-Jin; Cai, Dengke; Barlow, Stephen; Salman, Seyhan; Coropceanu, Veaceslav; Bredas, Jean-Luc; Kippelen, Bernard; Marder, Seth; Chemistry of Materials; vol. 23; nb. 17; (2011); p. 4002 - 4015 View in Reaxys

70.8 %

Example Name 1 3,5-Diiodo-N'-(3-methoxybenzoyl)benzohydrazide (5.0 g, 9.58 mmol) was suspended in POCl3 (50.0 ml) and heating was started. During heating white solid of starting materials dissolved into a clear solution (13O0C). The reaction was kept at 100 0C and the reaction was monitor by thin layer chromatography. After 5 h, the reaction mixture was brought to room temperature and was carefully dropped into ice-water (1000.0 ml). White solid precipitated out was collected by filtration and washed with water. After dried, the crude product was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate in 9.5 : 0.5 ratio. After evaporating solvent the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 3.4 g (70.8 percent) yield. 1H NMR (400 MHz, CDCl3, δ): 8.43 (dd, Ji = 1.6 Hz, J2 = 0.8 Hz, 2 H), 8.23 (t, J = 1.6 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.66 (m, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.12 (dd, Ji = 8.0 Hz, J2 = 2.4 Hz, 1 H), 3.92 (s, 3 H, OCH3). 13C

NMR (100 MHz, CDCl3, δ): 165.06, 161.67, 159.98, 148.05, 134.63, 130.31, 126.95, 124.44, 119.44, 118.56,

111.66, 94.98, 55.59. With trichlorophosphate, Time= 5h, T= 100 °C Patent; GEORGIA TECH RESEARCH CORPORATION; ZHANG, Yadong; ZUNIGA, Carlos; DESHAYES, Gaelle; LEROY, Julie; BARLOW, Stephen; MARDER, Seth, R.; KIM, Sung-Jin; KIPPELEN, Bernard; WO2010/149620; (2010); (A1) English View in Reaxys

O NH HN O

O O

N

N

O O

O


Conditions & References Example Name 6.B 6B. Ethyl 5-p-tolyl-1,3,4-oxadiazole-2-carboxylate 6A (8.1 g, 32.4 mmol) was dissolved in toluene (200 ml) and pyridine (2.6 mL, 32.4 mmol). Thionyl chloride (9.6 g, 81 mmol) was added and the reaction was refluxed for 8 h. The solvent was evaporated and the residue was partitioned between DCM and aqueous NaHCO3 (sat.). The organic phase was further washed with 0.1 M HCl and aqueous NaHCO3 (sat.), filtered through a phase separator and the solvent was removed by evaporation.


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There was obtained 7.0 g (93percent) of 6B as an off white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (t, 3H), 2.44 (s, 3H), 4.54 (q, 2H), 7.34 (d, 2H), 8.04 (d, 2H). With pyridine, thionyl chloride in toluene, Time= 8h, Reflux Patent; AstraZeneca AB; US2012/10189; (2012); (A1) English View in Reaxys

N O O

O O N

NH HN

Cl

O

N

Cl

Cl O

N O

O Cl



91 %

Example Name 18.18c A mixture of N'-[2-(benzyloxy)-5-chloropentanoyl]-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (374 mg, 0.792 mmol), carbon tetrachloride (0.152 mL, 1.58 mmol) and triphenylphosphine (831 mg, 3.17 mmol) in acetonitrile (7.9 mL) was heated under reflux for 2 hr and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=0/100 - 50/50) to give the title compound as a yellow oil (327 mg, 91percent). 1H NMR (CDCl3) δ: 1.77 - 1.97 (1 H, m), 2.01 - 2.37 (3 H, m), 2.57 (3 H, s), 3.57 (2 H, t, J=6.2 Hz), 4.07 (3 H, s), 4.53 (1 H, d, J=11.8 Hz), 4.66 (1 H, d, J=11.8 Hz), 4.72 - 4.83 (1 H, m), 7.27 - 7.37 (5 H, m), 7.54 (1 H, s), 7.63 - 7.73 (2 H, m), 7.86 (1 H, d, J=8.2 Hz). MS(ESI):454 [M+H]+. With tetrachloromethane, triphenylphosphine in acetonitrile, Time= 2h, Reflux Patent; Takeda Pharmaceutical Company Limited; EP2455380; (2012); (A1) English View in Reaxys

F

F

N

O

H N

N O

N H O F

F


Conditions & References With DMEG, triethylamine in dichloromethane, Time= 20h, T= 20 °C , Dehydration, Cyclization Isobe, Toshio; Ishikawa, Tsutomu; Journal of Organic Chemistry; vol. 64; nb. 19; (1999); p. 6989 - 6992 View in Reaxys

78 %

With zirconium tetrachloride in dichloromethane, Time= 2.7h, T= 20 °C Sharma, G. V. M.; Begum, Asra; Rakesh; Krishna, Palakodety Radha; Synthetic Communications; vol. 34; nb. 13; (2004); p. 2387 - 2392 View in Reaxys With trichlorophosphate


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Hayes et al.; Journal of the American Chemical Society; vol. 77; (1955); p. 1850 View in Reaxys Rogers et al.; U.S. Atomic Energy Comm. LA-1639; 26 View in Reaxys

O H N

N

N H

N O

O



82 %

With acetic acid, [Et2NSF2]BF4 in 1,2-dichloro-ethane, Time= 12h, T= 90 °C , Inert atmosphere Pouliot, Marie-France; Angers, Laetitia; Hamel, Jean-Denys; Paquin, Jean-Francois; Organic and Biomolecular Chemistry; vol. 10; nb. 5; (2012); p. 988 - 993 View in Reaxys

70 %

With trifluoromethylsulfonic anhydride, triphenyl-phosphine oxide in dichloromethane, T= 0 - 20 °C Bostroem, Jonas; Hogner, Anders; Llinas, Antonio; Wellner, Eric; Plowright, Alleyn T.; Journal of Medicinal Chemistry; vol. 55; nb. 5; (2012); p. 1817 - 1830 View in Reaxys With trichlorophosphate, Time= 6h, Heating, or acetic anhydride, Yield given Hamad, M. M.; Archiv der Pharmazie (Weinheim, Germany); vol. 323; nb. 9; (1990); p. 595 - 599 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys

N O H N O

H N

N H HN

O

O

N H N

O HN

O

O

O O

O

O


Conditions & References Example Name 293.2 Step 2: (S)-tert-butyl 5-(benzyloxycarbonylamino)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pentylcarbamate (340) The reaction was done following the procedure of S. Borg et al. (J. Org. Chem. 1995 60 3112-3120). To a solution of 339 (0.400 g, 0.802 mmol) in THF (5 mL), cooled to 0° C. and under nitrogen was added thionyl chloride (0.081 mL, 1.04 mmol) followed by pyridine (0.16 mL, 2.00 mmol). The reaction was stirred at 0° C. for 2 hours. It was then filtered and the filtrate concentrated and the resulting oil was suspended in toluene (5 mL) and then heated to reflux for 1.5 hours. The toluene was then removed by evaporation under reduced pressure and the residue purified twice by silica gel chromatography (Biotage 25M, 20 to 50percent ethyl acetate in hexanes) to give 340 (110 mg, 29percent) as a clear gum that was about 75percent pure by proton NMR. LRMS (ESI): (calc) 480.2 (found) 481.2 (MH)+. With pyridine, thionyl chloride in tetrahydrofuran, Time= 2h, T= 0 °C Patent; METHYLGENE INC.; US2007/293530; (2007); (A1) English View in Reaxys


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O

H N N H

OH

OH

O Cl

O Cl

N

N



28 %

Example Name 45 EXAMPLE 455-[5-(4-Chloro-phenyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol To a solution of 3-hydroxy-4-methyl-benzoic acid N'-(4-chloro-benzoyl)-hydrazide (1.28 g, 4.20 mmol) (from Example 44 supra) in acetonitrile (20 mL) was added diisopropylethylamine (4.4 mL, 25.2 mmol) and triphenylphosphine (2.21 g, 8.40 mmol). After stirring 5 minutes, hexachloroethane (1.49 g, 6.30 mmol) (Aldrich) was added and the mixture was allowed to stir for 1 day at room temperature. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1.x.). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 0-60percent ethyl acetate in hexanes to give 5-[5-(4-chloro-phenyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol. (Yield 0.34 g, 28percent). Stage 1: With N-ethyl-N,N-diisopropylamine, triphenylphosphine in acetonitrile, Time= 0.0833333h Stage 2: With 1,2,2-trichloro-1,1,2-trichloro-ethane in acetonitrile, Time= 24h, T= 20 °C Patent; Chen, Yi; Luk, Kin-Chun; Rossman, Pamela Loreen; So, Sung-Sau; US2008/9515; (2008); (A1) English View in Reaxys F O

O

H N

N

N N H

N

O N

O

O F



33 %

Example Name 38.4 Example Title Process 4 (256 mg, 0.976 mmol) was added to a solution of bromine in dichloromethane (0.1 M, 9.76 ml, 0.976 mmol) under icecooling, and the mixture was stirred for 30 minutes under ice-cooling and for 30 minutes at room temperature. Triethylamine (257 mg, 2.55 mmol) was added to the reaction mixture under ice-cooling and the whole was stirred for 10 minutes. After compound 105 (300 mg, 0.850 mmol) was added to the mixture, the whole was stirred for 2 hours at room temperature and quenched with water and extracted with chloroform. The organic layer was washed with water and dried over sodium sulfate. A crude product obtained by evaporation under reduced pressure was subjected. to silica gel column chromatography. The fractions containing desired compound eluted with ethyl acetate were concentrated under reduced to give compound 106 (94 mg, 33 percent) as colorless crystals. M.p.: 119 - 120 C NMR (DMSOd6) ?: 4.12 (3H, s), 4.43 (2H, s), 7.23 (2H, m), 7.49 (2H, m), 7.50 (1H, d, J = 8.7 Hz), 7.68 (1H, dd, J = 8.4, 4.2 Hz), 7.88 (1H, d, J = 8.7 Hz), 8.48 (1H, dd, J = 8.7, 1.8 Hz), 9.02 (1H, dd, J = 4.2, 1.8 Hz). With bromine, triethylamine, triphenylphosphine in dichloromethane, Time= 3.16667h, T= 0 - 20 °C Patent; SHIONOGI and CO., LTD.; EP1375486; (2004); (A1) English View in Reaxys

O

O

O NH

N

HN

O S N

F

O

O

H N

N

F

N

O

O

N H

O

O

H N N H

S N N

F

O

F

F

F



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Yield


29 %

Example Name 1j.2 Step 2 (S)-tert-butyl 1-((4-(5-(5-(2-methoxyphenyl)-1 ,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)- 1 H-pyrazol-1 -yl)thiophen-2-yl)methylamino)-1-oxopropan-2-ylcarbamate (17); [0193] A solution of compound 16 (73mg, 0 120 mmol) in DMF (1 OmL) and DIC (0 1 mL, 0 642 mmol) was heated to 100 degrees for 13 hours The reaction was concentrated down to a brown gum and then applied onto a 12M Biotage column and eluted with 0-5percent methanol and dichloromethane to give 72mg of a semi-purified compound This material was further purified by preparative HPLC (C18 Aquasil 20x250mm, 40-85percent methanol in water in 45 minutes at 10mL/min) to give compound 17 (20 3mg, 29percent) as a white crust LRMS (ESI) calc 592 2, found 493 2 (MH-BoC)+, 593 3 (MH)+ With diisopropyl-carbodiimide in N,N-dimethyl-formamide, Time= 13h, T= 100 °C Patent; METHYLGENE INC.; WO2008/104077; (2008); (A1) English View in Reaxys

O

O O

O

N

O

H N

F

N N

N H

F

N

O

O



29 %

Example Name 215.2 Crude N'-acetyl-4-((S)-1 -((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1 ,3-oxazinan-3- yl)ethyl)benzohydrazide (5mg, 0.0114mmol) was mixed with Burgess reagent (~4 mg, excess), dry THF (1 mL) and put into Microwave Oven, heated to 180 0C for 10 min. at 100W. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2 x 3 mL), concentrated and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1 -(4-(5methyl-1 ,3,4-oxadiazol-2- yl)phenyl)ethyl)-1 ,3-oxazinan-2-one (1.4mg, 29percent). LC-MS Method 1 tR = 1.61 , min, m/z = 422; 1H NMR (CDCI3) 7.77(d, 2H), 7.26(m, 3H), 7.01 (m, 3H), 5.70(m, 2H), 5.07(dd, 2H), 2.98(m, 1H), 2.62(s, 3H), 1.55(d, 3H). With Burgess Reagent in tetrahydrofuran, Time= 0.166667h, T= 180 °C , microwave irradiation (100W) Patent; VITAE PHARMACEUTICALS, INC.; WO2009/17664; (2009); (A1) English View in Reaxys O

O

H N N H

O

N

N O

O

O O


Conditions & References Example Name 3.2 Step 2: Methyl 3 -(5-(4-tert-butylphenyl)-1.3.4-oxadiazol-2-yl)benzoate (YZ -1-225):Methyl 3 -(2-(4-tert-butylbenzoyl)hydrazinecarbonyl)benzoate (9.5 g, 26.81 mmol) was suspended in POCl 3 (50.0 ml). The reaction was heated to 90 0C and kept at this temperature for 2 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice -water (300.0 ml). The brown color solid formed was collected by vacuum filtration. The crude product was dried and purified by silica gel column using dichloromethane/ethyl acetate (9.5 : 0.5) as the eluent. After the removal of the solvents, a pure white solid product was obtained in 7.4 g (82.2percent) yield by recrystallization from acetone/water. 1H NMR (400 MHz, CDCl3) δ: 8.77 (t, 1 H, J = 1.2 Hz), 8.36 (dt, 1 H, J1 = 7.6 Hz, J2 = 1.2 Hz), 8.22 (dt, 1 H, J1 = 7.6 Hz, J2 = 1.2 Hz), 8.09 (d, 2 H, J= 8.8 Hz), 7.64 (t, 1 H, J= 7.6 Hz),7.56 (d, 2 H, J= 8.8 Hz), 4.00 (s, 3 H, OCH 3), 1.38 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl3) δ: 166.05, 164.97, 163.56, 155.54, 132.43, 131.17, 131.00, 129.30, 127.82, 126.84, 126.07, 124.44, 120.82, 52.48, 35.09. 31.08 ppm. With trichlorophosphate, Time= 2h, T= 90 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English


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View in Reaxys

O

O

NH

O

O HN

O O

O O

O O

O

O N

N

O



79.6 %

Example Name 10.4 Step 4: Methyl 4-(5-(3.4.5-tris(dodecyloxy)phenyl)-1.3.4-oxadiazol-2-yl)benzoate:Methyl 4 -(2 -(3,4,5 -tris(dodecyloxy)benzoyl)hydrazinecarbonyl)b enzoate (10.0 g, 11.75 mmol) was added to POCl 3 (60.0 ml). The reaction was heated to 80 0C, and kept at this temperature for 5 h. After cooling, the reaction mixture was slowly added to ice water (800.0 ml). The crude product was collected as yellow solid , and purified by silica gel column using ethyl acetate/ hexane (2 : 8) as eluent. Pure product was obtained in 7.8 g (79.6percent).1H-NMR (400 MHz, CDCl 3) δ: 8.21 (ss, 4 H), 7.33 (s, 2 H), 4.07 (m, 6 H, 3 x OCH2), 3.98 (s, 3 H, OCH 3), 1.90 - 1.73 (m, 6 H, 3 x C H2), 1.50 (m, 6 H, 3 x CH2), 1.27 (m, 48 H, 24 x CH 2), 0.88 (m, 9 H, 3 x CH 3) ppm. With trichlorophosphate, Time= 5h, T= 80 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

O Cl NH

Cl

HN

N

O

Cl OH

HN

Cl Cl

HN O N

Cl

N

OH

N


Conditions & References Example Name 55 Example 55 2-Chloro-4-((1R,2S)-1-(5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile To a solution of 3,4-dichloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)benzohydrazide (1.35 g, 2.9 mmol) in anhydrous THF (100 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (4.0 g) followed by p-TSCl (621 mg, 3.2 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction and the residue washed with acetone (50 mL) followed by MeOH (50 mL).


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The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (1:12)] to give the desired product (324 mg, 25percent). 1H NMR (500 MHz, acetone-d , δ in ppm) 8.07 (d, J=2.1 Hz, 1H), 7.81 (dd, J=2.1 Hz, 8.3 Hz, 1H), 7.59 (d, J=8.3 Hz, 6 1H), 7.43 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 5.22 (d, J=8.3 Hz, 1H), 4.75 (dd, J=2.8 Hz, 8.2 Hz, 1H), 4.66-4.59 (m, 1H), 2.77 (d, J=3.6 Hz, 1H), 2.35 (s, 3H), 1.43 (d, J=6.3 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O

S NH HN

O

F

HN

OH

HN

OH O

N N

S N

F



27 %

Example Name 62 Example 62; 4-((1R,2S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile ; To a solution of N'-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.53 g, 1.29 mmol) in THF (90 mL) was added PS-BEMP (1.76 g, 3.87 mmol, 2.2 mmol/g) and p-TsCl (265 mg, 1.39 mmol) at room temperature. The mixture was stirred at room temperature for 8 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzo[b]thiophene-7-carbonitrile (139 mg, 27percent) and the dehydration product 4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (8 mg, 2percent). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.03 (dd, J=5.3, 8.8 Hz, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.32 (t, J=8.8 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.20 (dd, J=4.7, 8.4 Hz, 1H), 4.78 (b, 1H), 4.63 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.11 (dd, J=5.3, 8.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.6 Hz, 2H), 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 8h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O

S

NH HN

O OH

HN

HN OH O

N N

S N


Conditions & References Example Name 63 Example 63; 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile; To a solution of N'-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.69 g, 1.75 mmol) in THF (100 mL) were added PS-BEMP (2.39 g, 5.27 mmol, 2.2 mmol/g) and p-TsCl (353 mg, 1.85 mmol) at


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room temperature. The mixture was stirred at room temperature for 14 h, then methanol (5 mL) was added to quench the reaction. The resin was filtered and washed with MeOH. The combined filtrate was concentrated to give a residue, which was purified by flash chromatography to afford the title compound 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (167 mg, 25percent) as a foam and the dehydration product 4-(1-(5-phenyl-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzo[b]thiophene-7-carbonitrile (33 mg, 5percent). Title compound: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.98 (m, 2H), 7.88 (d, J=5.7 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.517.57 (m, 3H), 6.85 (d, J=8.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.22 (dd, J=4.7, 8.4 Hz, 1H), 4.80 (b, 1H), 4.65 (m, 1H), 1.42 (d, J=6.4 Hz, 3H). Dehydration product: 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.05 (m, 2H), 7.95 (d, J=5.6 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.557.62 (m, 4H), 7.01 (q, J=7.1 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 1.93 (d, J=7.1 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 14h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH

Cl

HN

N

O

N OH

HN

N

N

O

HN O

Z

N

N

Cl

OH

N H

Cl

N



37 %, 20 % Example Name 11 Example 11; 2-chloro-3-ethyl-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzonitrile; To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 11c) (195 mg, 0.486 mmol) in anhydrous THF (20 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (667 mg, 2.2 mmol base/g) followed by para-toluene sulfonyl chloride (p-TSCl) (111 mg, 0.583 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction and the residue washed with acetone (200 mL) followed by methanol (200 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-hexanes (3:2)] to give two fractions. The firsteluted material was identified by 1H NMR spectroscopy as (Z)-2-chloro-3-ethyl-4-(1-(5-phenyl-1,3,4-oxadiazol-2yl)prop-1-enylamino)benzonitrile (34 mg, 20percent) 1H NMR (500 MHz, CDCl3, δ in ppm) 8.04 (d, J=8 Hz, 2H), 7.57-7.6 (m, 4H), 7.39 (d, J=8 Hz, 1H), 6.79 (q, J=7 Hz, 1H), 6.5 (d, J=7 Hz, 1H), 5.82 (s, 1H), 2.93 (q, J=7 Hz, 2H), 1.83 (d, J=6 Hz, 3H), 1.38 (t, J=7 Hz, 3H).The second-eluted material was the desired 2-chloro-3-ethyl-4-((1R,2S)-2-hydroxy-1-(5phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzonitrile (69 mg, 37percent). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.82 (d, J=8 Hz, 2H), 7.47-7.50 (m, 1H), 7.39-7.41 (m, 2H) 7.32-7.37 (m, 1H), 6.58 (d, J=8 Hz, 1H), 5.44 (d, J=8 Hz, 1H), 4.78 (d, J=8 Hz, 1H), 4.60-4.62 (m, 1H), 3.94 (m, 1H), 2.83 (q, J=7 Hz, 2H), 1.42 (d, J=6 Hz, 3H), 1.22 (t, J=7 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O NH HN

O OH

HN

OH

HN

O

N N

N



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Yield


28%

Example Name 13 Example 13 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-1-naphthonitrile The crude material of N'-((2R,3S)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 13b) (602 mg, 1.5501 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (2.11 g, 4.65 mol base) was added to the solution followed by slow addition of p-TSCl (355 mg, 1.8601 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the product (160 mg, 28percent). 1H NMR (500 MHz, CDCl , δ in ppm) 8.11 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 3 1H), 7.62 (t, J=9 Hz, 1H), 7.52 (t, J=9 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.36 (t, J=9 Hz, 2H), 6.64 (d, J=9 Hz, 1H), 6.20 (d, J=9 Hz, 1H), 4.93 (dd, J=5.0, 9.0 Hz, 1H), 4.70 (m, 1H), 4.06 (d, J=5 Hz, 1H), 1.47 (d, J=6 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH

Cl

HN

N

O OH

HN

HN O N

Cl

N

OH

N



28%

Example Name 14 Example 14 (R)-2-chloro-4-(2-hydroxy-2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile The crude material of (R)-N'-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 14b) (218 mg, 0.54 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (742 mg, 1.63 mmol base) was added to the solution, followed by slow addition of p-TSCl (114 mg, 0.60 mmol). The reaction mixture was stirred for 1.5 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to give the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the title compound (75 mg, 28percent): 1H NMR (500 MHz, CDCl3, δ in ppm) 7.94 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 2H), 7.34 (d, J=9 Hz, 1H), 6.56 (d, J=9 Hz, 1H), 5.45 (d, J=9 Hz, 1H), 4.71 (d, J=9 Hz, 1H), 3.12 (s, 1H), 2.37 (s, 3H), 1.50 (s, 3H), 1.37 (s, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH O

Cl

HN

N

O

S O

OH

HN

HN

O S O

Cl

O N

N

OH

N



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Yield


25%

Example Name 25 Example 25 2-chloro-4-((1R,2R)-2-hydroxy-1-(5-(4-(methylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile To a 250 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N'-((2R,3R)-2-(3-chloro-4cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)-4-(methylsulphonyl)benzohydrazide (855 mg, 1.8 mmol) followed by a addition of anhydrous THF (200 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (350 mg, 1.8 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading, 2.51 g, 5.5 mmol). This mixture was allowed to stir at room temperature for 6.5 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a red solid. This was purified via silica gel chromatography eluted with 70percent EtOAc/hexanes to yield product as a white solid (209 mg, 25percent). 1H NMR (400 MHz, acetone-d , δ in ppm) 8.25 (AA'XX', J=8.4 Hz, 2H), 8.13 (AA'XX', J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 6 1H), 6.90 (d, J=8.8 Hz, 1H), 5.90 (d, J=9.0 Hz, 1H), 5.11 (dd, J=5.6, 8.9 Hz, 1H), 4.70 (d, J=6.0 Hz, 1H), 4.55 (m, 1H), 3.19 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.2 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 6.5h, T= 20 °C , Inert atmosphere Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

N

H N N H

N

O

N

H N

O

N H

N

O

O


Conditions & References Example Name 11 Synthesis of Λ/-(4-(5-phenyl-1 ,3,4-oxadiazol-2-yl)pyridin-2-yl)benzamide To a solution of Λ/-(4-(2-benzoylhydrazinecarbonyl)pyridin-2-yl)benzamide (0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added (methoxycarbonylsulfamoyl)- triethylammonium hydroxide (0.35 g, 0.63 mmol) at ambient temperature. The resulting solution was refluxed for 7 hours and concentrated in vacuo to dryness. The residue was purified by column chromatography to give Λ/-(4(5-phenyl-1 ,3,4-oxadiazol-2-yl)pyridin-2- yl)benzamide (0.03 g 32percent): mp 151-155 0C; 1H NMR (300 MHz, CDCI3) δ 9.03-9.00 (m, 2H), 8.41 (br s, 1 H), 8.19-7.97 (m, 2H), 7.97-7.94 (m, 2H), 7.84-7.83 (m, 1 H), 7.61-7.48 (m, 6H); 13C NMR (75 MHz, CDCI3) δ 168.1 , 167.6, 164.9, 154.7, 151.1 , 135.9, 135.4, 134.7, 134.3, 131.3, 131.1 , 129.4, 127.3, 125.4, 119.0, 112.9; MS (ES+) m/z 343.5 (M + 1 ). With Burgess Reagent in tetrahydrofuran, Time= 7h, T= 20 °C , Reflux Patent; NOVARTIS AG; XENON PHARMACEUTICALS INC.; WO2009/156484; (2009); (A2) English View in Reaxys S

S O

N

N

N

F F HN

NH

F

N F

O

F F

O


Conditions & References Example Name 5 A solution of N'-[3-[3-(trifluoromethyl)phenyl]propionyl]benzothiazole-6-carbohydrazide (433 mg, 1.10 mmol) and ptoluenesulfonyl chloride (419 mg, 2.20 mmol) in pyridine (5 mL) was stirred under an argon atmosphere at 80° C. for 16 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 0.1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl


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acetate to give the title compound (308 mg, yield 75percent) as colorless crystals.melting point 126-127° C.1H NMR (CDCl3) δ 3.24-3.35 (4H, m), 7.42-7.55 (4H, m), 8.17 (1H, dd, J=1.7, 8.7 Hz), 8.25 (1H, dd, J=0.6, 8.7 Hz), 8.64 (1H, dd, J=0.6, 1.7 Hz), 9.14 (1H, s).Elemental analysis (for C18H12F3N3OS)Calculated (percent): C, 57.59; H, 3.22; N, 11.19.Found (percent): C, 57.59; H, 3.12; N, 11.29. With pyridine, toluene-4-sulfonic acid, Time= 16h, T= 80 °C , Inert atmosphere Patent; Itoh, Fumio; US2010/69381; (2010); (A1) English View in Reaxys

N HN N

O

H N

F

N H

N

HN

F

F O

N

F

F F

O



34 %

Example Name 12 A solution of N'-[3-[3-(trifluoromethyl)phenyl]propionyl]-1H-indazole-5-carbohydrazide (320 mg, 0.850 mmol) and ptoluenesulfonyl chloride (486 mg, 2.55 mmol) in pyridine (3 mL) was stirred under an argon atmosphere at 80° C. for 24 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.A mixture of the obtained residue, 1 M aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (10 mL) and ethanol (5 mL) was heated under reflux for 30 min. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1-0/1), and recrystallized from ethanol/water to give the title compound (103 mg, yield 34percent) as colorless crystals.melting point 175-176° C.1H NMR (CDCl3) δ 3.23-3.34 (4H, m), 7.42-7.55 (4H, m), 7.62 (1H, td, J=0.9, 8.9 Hz), 8.09 (1H, dd, J=1.5, 8.9 Hz), 8.20 (1H, d, J=1.1 Hz), 8.41 (1H, dd, J=0.8, 1.5 Hz), 10.40 (1H, brs).Elemental analysis (for C18H13F3N2O)Calculated (percent): C, 60.34; H, 3.66; N, 15.64.Found (percent): C, 60.35; H, 3.66; N, 15.61. Stage 1: With pyridine, p-toluenesulfonyl chloride, Time= 24h, T= 80 °C , Inert atmosphere Stage 2: With sodium hydroxide in tetrahydrofuran, ethanol, water, Time= 0.5h, Reflux Patent; Itoh, Fumio; US2010/69381; (2010); (A1) English View in Reaxys Cl

O H N Cl

Cl

Cl N H

N N

O Cl

O Cl


Conditions & References Example Name 43.a To a mixture of 3,4-dichlorobenzohydrazide 8 (0.5 mg, 2.43 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours.The solid was collected, washed with H2O and ether, and dried to afford 3,4-dichloro-N'-(2- chloroacetyl)benzohydrazide 9 (0.59 g, 85percent) which was used for the next step without further purification. A mixture of compound 9 (0.5.9 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated.The residue was subjected to flush column chromatography eluting with 10-25percent acetone/hexanes to give compound 10 (0.43 g). Yield: 78percent.1H-NMR (300 MHz, CDCl3) δ (ppm): 7.88 (s, 1 H), 7.12 (d, 2 H), 4.78 (s, 2 H). With trichlorophosphate in acetonitrile, Time= 16h, Reflux Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys


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Cl

HN O

O

NH O

Cl

N N

N

N



78 %

Example Name 56.c Compound 4 (Ig, 4.2mmol) was suspended in POCl3 (6ml) and the reaction mixture was heated to 11O0C for 2.5 hours. The mixture was allowed to cool to ambient temperature and quenched by adding water, then it was extracted with EA and the EA layer was concentrated and purified by chromatography eluting with (DCM: MeOH=20: 1) to give compound 5 as a white solid(719mg). Yield: 78percent.1HNMR (400 MHz, DMSO-d6): δ (ppm): 8.19-8.18 (2H, dd, Ph-H), 8.10-8.08 (2H, dd, Ph-H),5.17 (2H, s, -CH2-). With trichlorophosphate, Time= 2.5h, T= 110 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys

O

O

O

O H N N H O

O

O

O O O

O

N N


Conditions & References Example Name 2.1 To a stirring mixture of Methyl 3-(4-(2-acetylhydrazinecarbonyl)phenoxy)-5- (benzyloxy)benzoate (Intermediate 10) (32 g, 73.7 mmol, 1 equiv.) in toluene in a single necked round bottomed flask fitted with reflux condenser and anhydrous CaCl2 guard tube, thonyl chloride (10.5g, 88.4 mmol, 1.2 equiv.) was added carefully. The reaction mixture was refluxed until the reaction was complete. After completion, the reaction mixture was poured onto ice and extracted twice with ethyl acetate. The combined organic extracts was washed with brine and dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to give the title compound as yellow solid product (30 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 2.61 (s, 3 H), 3.90 (s, 3 H), 5.09 (s, 2 H), 6.88 (t, J = 2.4 Hz, 1 H), 7.08 (d, J= 8.8 Hz, 2 H), 7.33 (s, 1 H), 7.43-7.34 (m, 5 H), 7.49 (s, 1 H), 8.00 (d, J = 8.8 Hz, 2 H); ESI-MS m/z (relative intensities): 417.18 (M+H)+ (100 percent), 439.17 (M+Na)+ (80 percent); UPLC Purity: 93.98 percent, Rettime: 5.218 min. With thionyl chloride, calcium chloride in toluene, Reflux Patent; CADILA HEALTHCARE LIMITED; KHARUL, Rajendra; WO2010/150280; (2010); (A1) English View in Reaxys Example Name 8 To a stirring solution of Methyl 3-[4-(2-acetylhydrazinecarbonyl) phenoxy]-5- (benzyloxy)benzoate (32 g) (Intermediate 9) in dry toluene was added thionyl chloride (10.5 g) drop wise at room temperature under nitrogen atmosphere. The reaction was refluxed and monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc. All organic layers were combined and washed with saturated sodium bicarbonate solution, water, and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude pale


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yellow solid (30 g). The crude compound was purified by solvent trituration.1H NMR (CDCl3, 400 MHz) δ ppm: 2.61 (s, 3 H), 3.90 (s, 3 H), 5.09 (s, 2 H), 6.87- 6.88 (m, 1 H), 7.08 (d, J = 8.8 Hz, 2 H), 7.32-7.33 (m, 1 H), 7.34-7.43 (m, 5 H), 7.48- 7.49 (m, 1 H), 8.00 (d, J = 8.8 Hz, 2 H); ESI MS m/z (relative intensities): 417.18, (M+H)+, (100 percent), 439.17 (M+Na)+ (80 percent) UPLC Purity: 93.98 percent, Ret.time: 5.218 min. With thionyl chloride in toluene, T= 20 °C , Inert atmosphere, Reflux Patent; CADILA HEALTHCARE LIMITED; KHARUL, Rajendra; JAIN, Mukul, R.; PATEL, Pankaj, R.; WO2011/13141; (2011); (A2) English View in Reaxys Example Name 13 Example Title Methyl 3-(benzyloxy)-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate Methyl 3-(benzyloxy)-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate To a stirring solution of Methyl 3-[4-(2-acetylhydrazinecarbonyl)phenoxy]-5-(benzyloxy)benzoate (32 g) (Intermediate 9) in dry toluene was added thionyl chloride (10.5 g) drop wise at room temperature under nitrogen atmosphere. The reaction was refluxed and monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc. All organic layers were combined and washed with saturated sodium bicarbonate solution, water, and brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude pale yellow solid (30 g). The crude compound was purified by solvent trituration. 1H NMR (CDCl , 400 MHz) δ ppm: 2.61 (s, 3H), 3.90 (s, 3H), 5.09 (s, 2H), 6.87-6.88 (m, 1H), 7.08 (d, J=8.8 Hz, 2H), 3 7.32-7.33 (m, 1H), 7.34-7.43 (m, 5H), 7.48-7.49 (m, 1H), 8.00 (d, J=8.8 Hz, 2H); ESI MS m/z (relative intensities): 417.18, (M+H)+, (100percent), 439.17 (M+Na)+ (80percent) UPLC Purity: 93.98percent, Ret.time: 5.218 min. Stage 1: With thionyl chloride in toluene, Reflux, Inert atmosphere Stage 2: With sodium hydrogencarbonate in ethyl acetate, toluene Patent; CADILA HEALTHCARE LIMITED; US2012/184544; (2012); (A1) English View in Reaxys

O

O

H N O

I N H

O

N N

O

I


Conditions & References Example Name 1 3-Iodo-N'-(3-methoxybenzoyl)benzohydrazide (11.0 g, 27.77 mmol) was suspended in POCl3 (60.0 ml) and heating was started. During heating white solid of starting materials dissolved into a clear solution. The reaction was kept at 100 0C and the reaction was monitor by thin layer chromatography. After 2 h, the reaction mixture was brought to room temperature and was carefully dropped into ice-water (1000.0 ml). White solid precipitated out was collected by filtration and washed with water. After dried, the crude product was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate in 9.5:0.5 ratio. After evaporating solvent the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 6.4 g (61.0 percent) yield. 1H NMR (400 MHz, CDCl , δ): 8.47 (t, J = 1.6 Hz, 2 H), 8.12 (dt, Ji = 8.0 Hz, J = 1.6 Hz, 1 H), 7.88 (m, 1 H), 7.70 (dt, 3 2 Ji = 8.0 Hz, J2 = 1.6 Hz, 1 H), 7.67 (m, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.10 (m, 1 H), 3.92 (s, 3 H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 164.79, 163.07, 159.94, 140.58, 135.46, 130.68, 130.26, 126.03, 125.68, 124.69, 119.36, 118.36, 111.59, 94.39, 55.56. With trichlorophosphate, Time= 2h, T= 100 °C Patent; GEORGIA TECH RESEARCH CORPORATION; ZHANG, Yadong; ZUNIGA, Carlos; DESHAYES, Gaelle; LEROY, Julie; BARLOW, Stephen; MARDER, Seth, R.; KIM, Sung-Jin; KIPPELEN, Bernard; WO2010/149620; (2010); (A1) English View in Reaxys


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61 %

With trichlorophosphate, Time= 2h, T= 100 °C Zhang, Yadong; Zuniga, Carlos; Kim, Sung-Jin; Cai, Dengke; Barlow, Stephen; Salman, Seyhan; Coropceanu, Veaceslav; Bredas, Jean-Luc; Kippelen, Bernard; Marder, Seth; Chemistry of Materials; vol. 23; nb. 17; (2011); p. 4002 - 4015 View in Reaxys

O O

O

N

O

N O

N

O

O

N

N

O

O HN

O

NH O O

O

O H N O O

O N H

O

N

N

O

O

N

O

O


Conditions & References Example Name 14 Synthesis Example 14; 5,5'-(2,5-bis(hexyloxy)-1,4-phenylene)bis(2-(3-(4-nitrophenoxy)phenyl)-1,3,4-oxadiazole); 2.7 g of 2,5-bis(hexyloxy)-N'1,N'4-bis(3-(4-nitrophenoxy)benzoyl)terephthalohydrazide (3.1 mmol) prepared in Synthesis Example 13 was dissolved in 20 ml of phosphorus oxychloride (POCl3), heated to 90° C. and then reacted for 12 hours. The resultant product was cooled to room temperature, followed by adding excess iced water, neutralizing with sodium hydroxide, filtering and performing silica gel column chromatography (developed with a solution having ethylacetate:nhexane mixed in a ratio of 1:1) to yield a product having Formula 37 (0.9 g, Yield 30percent). 1H NMR (300 MHz, CDCl3) analytical results of the product were as follows:1H NMR (300 MHz, CDCl3): [ppm] 0.82-0.91 (m, 6H), 1.25-1.51 (m, 16H), 4.16 (m, 4H), 7.05 (d, 4H), 7.31 (d, 2H), 7.61 (t, 2H), 7.83 (s, 2H), 7.89 (s, 2H), 8.04 (s, 2H), 8.25 (d, 4H). Stage 1: With trichlorophosphate, Time= 12h, T= 90 °C Stage 2: With sodium hydroxide in water, Cooling with ice Patent; SNU RandDB FOUNDATION; DONGWOO FINE-CHEM CO. LTD; US2012/46472; (2012); (A1) English View in Reaxys

O N

N HN

NH

Br Br

O

O

Rx-ID: 32895255 View in Reaxys 143/250 Yield Ca. 79 %

Conditions & References With trichlorophosphate, Time= 6h, T= 90 °C Lin, Tzu-Chau; Lee, Ying-Hsuan; Hu, Chia-Ling; Li, Yu-Kai; Huang, Yu-Jhen; European Journal of Organic Chemistry; nb. 9; (2012); p. 1737 - 1745 View in Reaxys

Ca. 79 %

Example Title 5.3.16. 2-(7-Bromo-9,9-dihexyl-9H-fluoren-2-yl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole (21)


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Two-step reaction: (i) To a mixture of compound 20 (2.25 g; 4.7 mmol) in THF (60 mL) was added 4-tert-butylbenzoyl chloride (1.03 g; 5.2mmole), pyridine (3 mL). The resulting solution was then heated and stirred for 12 h. After cooling to the room temperature, the solvent was removed and the crude solid product was collected and recrystallized from hexane. The purified product was obtained as white powder with yield of 90.3percent (2.72 g). 1H NMR (300 MHz, CDCl3, tentative assignment based on calculated values) δ: 10.16-10.14 (d, J=5.4 Hz, 1H, NH on the carbohydrazide unit), 9.81-9.79 (d, J=5.4 Hz, 1H, NH on the carbohydrazide unit), 7.96-7.92 (m, 2H, ArH on the fluorene unit), 7.85-7.82 (d, J=8.1 Hz, 2H, ArH on the phenyl group), 7.69-7.66 (d, J=8.1 Hz, 1H, ArH on the fluorene unit), 7.57-7.54 (d, J=8.4 Hz, 1H, ArH on the fluorene unit), 7.48-7.45 (m, 2H, ArH on the fluorene unit), 7.44-7.42 (d, J=8.1 Hz, 2H, ArH on the phenyl group), 1.95-1.89 (m, 4H, -CH2CH2CH2CH2CH2CH3), 1.32 (s, 9H, CH3 on the tert-butyl group), 1.11-0.93 (m, 12H, -CH2CH2CH2CH2CH2CH3), 0.74-0.68 (t, J=6.9 Hz, 6H, -CH2CH2CH2CH2CH2CH3), 0.50 (m, 4H, CH2CH2CH2CH2CH2CH3); 13C NMR (75 MHz, CDCl3, tentative assignment based on calculated values) δ:164.73 (sp2-carbon on the carbohydrazide unit), 164.36 (sp2-carbon on the carbohydrazide unit), 156.09 (aromatic carbon on the fluorene unit), 153.77 (aromatic carbon on the phenyl group), 150.87 (aromatic carbon on the fluorene unit), 144.26 (aromatic carbon on the fluorene unit), 138.80 (aromatic carbon on the fluorene unit), 130.22 (aromatic carbon on the phenyl group), 130.14 (aromatic carbon on the fluorene unit), 128.44 (aromatic carbon on the fluorene unit), 127.17 (aromatic carbon on the phenyl group), 126.91 (aromatic carbon on the fluorene unit), 126.33 (aromatic carbon on the fluorene unit), 125.70 (aromatic carbon on the phenyl group), 122.43 (aromatic carbon on the fluorene unit), 121.84 (aromatic carbon on the fluorene unit), 121.79 (aromatic carbon on the fluorene unit), 119.84 (aromatic carbon on the fluorene unit), 55.72 (sp3-carbon on the fluorene unit), 40.12 (carbon on the alkyl chain), 35.02 (4° carbon on the tertbutyl group), 31.45 (carbon on the alkyl chain), 31.09 (1° carbon on the tert-butyl group), 29.52 (carbon on the alkyl chain), 23.70 (carbon on the alkyl chain), 22.52 (carbon on the alkyl chain), 13.93 (carbon on the alkyl chain); HRMS (m/z): HRMS (m/z): [M+H]+ calcd for C37H47BrN2O2, 631.6853, found [({79}Br)M+H]+=631.2908; [({81}Br)M+H] +=633.2892.

(ii) The compound from the previous step was suspended in POCl3 (45 mL) and heated to reflux for 6 h.

After cooling to the room temperature, 50 mL of ice water was added to the reaction mixture. After filtration, the crude solid product was collected and recrystallized from methanol. The purified product was obtained as white powder with yield of .similar.79percent (2.09 g). Mp: 99.8-103.3. IR (KBr, cm-1): 3066 (C(sp2)-H stretching absorption), 2954, 2928, 2856 (C(sp3)-H stretching absorptions), 1614, 1468 (stretching absorptions of benzene rings), 1581 (CN stretching absorption), 1461 (CH2 bending absorption), 1364 (CH3 bending absorption), 1300 (Ar-N stretching absorption), 1268 (C-O-C stretching absorption). 1H NMR (300 MHz, CDCl3, tentative assignment based on calculated values) δ: 8.14-8.12 (m, 2H, ArH on the fluorene unit), 8.11-8.09 (d, J=8.1 Hz, 2H, ArH on the phenyl group), 7.80-7.78 (d, J=8.1 Hz, 1H, ArH on the fluorene unit), 7.62-7.52 (m, 3H, ArH on the fluorene unit), 7.50-7.47 (d, J=8.1 Hz, 2H, ArH on the phenyl group), 2.13-1.94 (m, 4H, -CH2CH2CH2CH2CH2CH3), 1.37 (s, 9H, CH3 on the tert-butyl group), 1.14-1.05 (m, 12H, -CH2CH2CH2CH2CH2CH3), 0.77-0.72 (t, J=7.2 Hz, 6H, -CH2CH2CH2CH2CH2CH3), 0.65-0.60 (m, 4H, CH2CH2CH2CH2CH2CH3); 13C NMR (75 MHz, CDCl3, tentative assignment based on calculated values) δ: 164.76 (aromatic carbon on the oxadiazole group), 164.49 (aromatic carbon on the oxadiazole group), 155.18 (aromatic carbon on the fluorene unit), 153.47 (aromatic carbon on the fluorene unit), 151.13 (aromatic carbon on the phenyl group), 143.43 (aromatic carbon on the fluorene unit), 138.80 (aromatic carbon on the fluorene unit), 130.23 (aromatic carbon on the fluorene unit), 126.70 (aromatic carbon on the phenyl group), 126.24 (aromatic carbon on the fluorene unit), 126.02 (aromatic carbon on the fluorene unit), 125.94 (aromatic carbon on the phenyl group), 122.72 (aromatic carbon on the phenyl group), 122.35 (aromatic carbon on the fluorene unit), 121.65 (aromatic carbon on the fluorene unit), 121.19 (aromatic carbon on the fluorene unit), 121.07 (aromatic carbon on the fluorene unit), 120.20 (aromatic carbon on the fluorene unit), 55.69 (sp3-carbon on the fluorene unit), 40.12 (carbon on the alkyl chain), 34.97 (4° carbon on the tert-butyl group), 31.37 (carbon on the alkyl chain), 31.02 (1° carbon on the tert-butyl group), 29.46 (carbon on the alkyl chain), 23.63 (carbon on the alkyl chain), 22.44 (carbon on the alkyl chain), 13.87 (carbon on the alkyl chain); HRMS (m/z): HRMS (m/z): [M+H]+ calcd for C37H45BrN2O, 612.2715, found [(79Br)M+H]+=612.2719; [(81Br)M+H] +=614.2722.

With trichlorophosphate, Time= 6h, Reflux Lin, Tzu-Chau; Lee, Ying-Hsuan; Huang, Bor-Rong; Hu, Chia-Ling; Li, Yu-Kai; Tetrahedron; vol. 68; nb. 25; (2012); p. 4935 - 4949 View in Reaxys


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N

N N

O H N

N O

H N N H

O

N N

O

O

O

O O

O

O

NH

O



76 %

Example Name 1.9.6 To a solution of 83 (80 mg, 0.12 mmoles) in dichloromethane (5 mL) was added Burgess' reagent (85 mg, 0.35 mmoles) and refluxed for 5h. The reaction mix was then cooled to room temperature, diluted with CHC13 and washed successively with satd. aq.NaHC03 and brine, dried, concentrated and purified on silica gel (1percent MeOH/99percent CHC13) to obtain 60 mg (76percent) of 84. With Burgess Reagent in dichloromethane, Time= 5h, Reflux Patent; COMENTIS, INC.; ASTELLAS PHARMA INC.; BILCER, Geoffrey, M.; DEVASAMUDRAM, Thippeswamy; LILLY, John, C.; ANKALA, Sudha, V.; MOSKALEV, Nikolai, V.; LIU, Chunfeng; INOUE, Makoto; KAWAKAMI, Shimpei; MUNAKATA, Ryosuke; HAMAJIMA, Toshihiro; WO2012/54510; (2012); (A1) English View in Reaxys

O

O O O

H N

O

O NH

N H O

O

O

N N O

O

O O NH


Conditions & References Example Name 1.7.4 Burgess' Reagent (0.1426 g, 0.61 mmol, 2.5 eq) was added to a stirred solution of 7.4.63 (0.1256 g, 0.25 mmol, 1 eq) in anhydrous 1,2-dichloroethane (5 ml) under Ar. The solution was heated to reflux overnight. After cooling to room temperature the reaction was diluted with CH2C12. The organic layer was washed with saturated aqueous NaHC03 (xl), brine (xl), and dried over Na2S04. The inorganics were filtered off, and the solvent was removed via rotary evaporation. Purification via flash chromatography on silica gel yielded 0.0984 g (0.2 mmol, 80percent) of 7.4.64. With Burgess Reagent in 1,2-dichloro-ethane, Inert atmosphere, Reflux Patent; COMENTIS, INC.; ASTELLAS PHARMA INC.; BILCER, Geoffrey, M.; DEVASAMUDRAM, Thippeswamy; LILLY, John, C.; ANKALA, Sudha, V.; MOSKALEV, Nikolai, V.; LIU, Chunfeng; INOUE, Makoto; KAWAKAMI, Shimpei; MUNAKATA, Ryosuke; HAMAJIMA, Toshihiro; WO2012/54510; (2012); (A1) English View in Reaxys


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I

I N

O NH

HN

O N

O

N

N



77 %

Example Name 5 Suspend 4-cyano-benzoic acid N'-[2-(3-iodo-phenyl)-acetyl]-hydrazide (0.50 g, 1.23 mmol) in phosphorous oxychloride (2.00 mL, 21.0 mmol) and heat at 110 °C for 1 h, resulting in complete dissolution. Cool the mixture to room temperature, pour into ice water and stir until all of the ice melts resulting in a solid precipitate. Collect the formed solid by filtration, wash with H20 and dry on the filter pad to provide 0.37 g 77percent yield of 4-[5-(3-iodo-benzyl)-[l,3,4]oxadiazol-2-yl]benzonitrile as a powder. With trichlorophosphate, Time= 1h, T= 110 °C Patent; BOEHRINGER INGELHEIM INTERNATIONAL GMBH; KIRRANE, JR., Thomas Martin; MARSHALL, Daniel Richard; SIBLEY, Robert; SNOW, Roger John; SOLEYMANZADEH, Fariba; SORCEK, Ronald John; WO2012/54367; (2012); (A1) English View in Reaxys F F

F F

F

O

O F O O

Cl

O

N

O N

S O

N

N

E

Cl

S

H N

O

N

N

N H

N

N

O

N

E

N

O

N

N



30 %

Example Name 16.h N'-[(E)-3-[4-(2-chloro-4-trifluoromethoxyphenyl)-5-(5-methylsulfonyl-2-pyridyl)-l,2,4-triazol- 3-yl]prop-2-enoyl]-2-methoxy-pyridine-4-carbohydrazide was dissolved into dichloromethane (10 mL), and triphenylphosphine (0.19 g, 0.736 mmol), carbon tetrabromide (0.24 g, 0.736 mmol) and triethylamine (0.18 mL, 1.30 mmol) was added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1 :3) to give 2-(4-(2-chloro-4-trifluoromethoxyphenyl)-5- ((E)-2-(5-(2-methoxypyridin-4yl)-l,3,4-oxadiazol-2-yl)vinyl)-4H-l,2,4-triazol-3-yl)-5- (methylsulfonyl)pyridine as a yellow solid. Yield: 0.07 g, 30percent. 1 H-NMR (300 Hz, CDC1 ) δ (ppm): 8.78 (d, 1 H), 8.62 (d, 1 H), 8.20 (d, 2 H), 7.78-7.62 (m, 3 H), 7.58-7.32 (m, 4 H), 3 7.12 (d, 1 H), 3.09 (s, 3 H).MS: 614.2 (MH+).HPLC: 96percent With carbon tetrabromide, triethylamine, triphenylphosphine in dichloromethane, Time= 2h, T= 20 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Daniel; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; VORONKOV, Andrey Edward; GOLDING, Louise; WO2012/76898; (2012); (A1) English View in Reaxys

F F O

Cl

F

O

N

N N

Cl F

O

F

N HN

NH

N

N F

N

N

N

E

N N

O N

O



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Yield


30 %

Example Name 17.f 4-Cyano-benzoic acid N'-(3- {4-(2-chloro-phenyl)-5-[5-(2,2,2-trifiuoro-ethoxy)-pyridin-2-yl]-4H- [l,2,4]triazol-3-yl}acryloyl)-hydrazide was dissolved in dichloromethane (10 mL) and triphenylphosphine (0.19 g, 0.736 mmol), carbon tetrabromide (0.24 g, 0.736 mmol) and triethylamine (0.18 niL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1 :3) to give 4-[5-(2-{4-(2-Chloro-phenyl)-5-[5-(2,2,2-trifluoro-ethoxy)- pyridin-2-yl]-4H-[l,2,4]triazol-3-yl}vinyl)-[l,3,4]oxadiazol-2-yl]-benzonitrile as a yellow solid. Yield: 0.07 g, 30percent.1 H-NMR (300 Hz, CDC13) δ (ppm): 8.38 (dd, 1 H), 8.20 (d, 2 H), 8.00 (dd, 1H), 7.80 (d, 2 H), 7.58-7.32 (m, 6 H), 7.18 (d, 1 H), 4.40 (q, 2 H). MS: 550.3 (MH+). HPLC: 96percent With carbon tetrabromide, triethylamine, triphenylphosphine in dichloromethane, Time= 2h, T= 20 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Daniel; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; VORONKOV, Andrey Edward; GOLDING, Louise; WO2012/76898; (2012); (A1) English View in Reaxys

Br

O O

N

O

H N

O

O O

N H

N

O

N N

Br



75.8 %

Example Name 31 (S)-tert-butyl2-(5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate To a suspension of (S)-tert-butyl 2-(2-(4-bromobenzoyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (13.8 g, 33.5 mmol), PPh3 (13.2 g, 50.2 mmol) and N,N'-diisopropylethylamine (17.5 mL, 100 mmol) in acetonitrile (250 mL) at room temperature was added hexachloroethane (11.1 g, 46.9 mmol). The mixture was stirred at room temperature overnight. Solvent was then removed by evaporation. The residue was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (0-80percent EtOAc in hexane) to give (S)-tert-butyl 2-(5-(4bromophenyl)-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate, (10 g, 75.8percent): ESI-LRMS m/e calcd for C17H20BrN3O3 [M+]395, found 396 [M+H+]. With N-ethyl-N,N-diisopropylamine, triphenylphosphine in 1,2,2-trichloro-1,1,2-trichloro-ethane, acetonitrile Patent; Alam, Muzaffar; Berthel, Steven Joseph; Brinkman, John A.; Hawley, Ronald Charles; Li, Hongju; Palmer, Wylie Solang; Pietranico-Cole, Sherrie; Sarabu, Ramakanth; Smith, Mark; So, Sung-Sau; Yi, Lin; Zhai, Yansheng; Zhang, Qiang; Zhao, Shu-Hai; US2012/230951; (2012); (A1) English View in Reaxys

O NH

O

HN O

O N

O

N


Conditions & References With polymer bound phosphazene base P-BEMP, p-toluenesulfonyl chloride in tetrahydrofuran, Time= 0.0833333h, microwave irradiation Brain, Christopher T.; Brunton, Shirley A.; Synlett; nb. 3; (2001); p. 382 - 384 View in Reaxys


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86 %

With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, T= -10 - 20 °C , Cyclization Liras, Spiros; Allen, Martin P.; Segelstein, Barb E.; Synthetic Communications; vol. 30; nb. 3; (2000); p. 437 - 444 View in Reaxys

43 %

With trichlorophosphate, Time= 0.5h, Heating Karakhanov, R. A.; Kelarev, V. I.; Koshelev, V. N.; Morozova, G. V.; Dibi, Ammar; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol. 31; nb. 2; (1995); p. 208 - 218; Khimiya Geterotsiklicheskikh Soedinenii; nb. 2; (1995); p. 238 - 249 View in Reaxys With trichlorophosphate Hayes et al.; Journal of the American Chemical Society; vol. 77; (1955); p. 1850 View in Reaxys Rogers et al.; U.S. Atomic Energy Comm.; LA-1639 17, 26 View in Reaxys With polyethylene glycol supported Burgess reagent in tetrahydrofuran, Time= 0.0333333h, Irradiation, microwave, 200 W, Pyrex tube, Yield given Brain, Christopher T.; Paul, Jane M.; Loong, Yvonne; Oakley, Paul J.; Tetrahedron Letters; vol. 40; nb. 16; (1999); p. 3275 - 3278 View in Reaxys With PPA, Time= 2h, T= 130 °C Park, Yong-Dae; Kim, Jeum-Jong; Chung, Hyun-A; Kweon, Deok-Heon; Cho, Su-Dong; Lee, Sang-Gyeong; Yoon, Yong-Jin; Synthesis; nb. 4; (2003); p. 560 - 564 View in Reaxys in N,N,N',N',N'',N''-hexamethylphosphoric triamide, Time= 0.0111111h, microwave irradiation Mashraqui, Sabir H.; Ghadigaonkar, Shailesh G.; Kenny, Rajesh S.; Synthetic Communications; vol. 33; nb. 14; (2003); p. 2541 - 2546 View in Reaxys

O NH N

Cl

HN

N

N

O OH

HN

HN N N

O N

Cl

N

OH

N


Conditions & References Example Name 53 Example 53 4-((1R,2S)-1-(5-(4-(1H-Pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-chloro-3-methylbenzonitrile To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(1H-pyrazol-1-yl)benzohydrazide (164 mg, 0.36 mmol) in anhydrous THF (12 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (495 mg, 1.09 mmol) followed by p-TSCl (83 mg, 0.44 mmol) and the mixture was stirred for 70 min. The mixture was filtered under suction and the residue washed with acetone (2*50 mL) followed by MeOH (2*50 mL). The filtrate was concentrated under reduced pressure to provide a off white solid, which was purified by flash chromatography over silica gel (25-50percent EtOAc in hexanes) to provided 4-((1R,2S)-1-(5-(4-(1H-pyrazol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-2-chloro-3-methylbenzonitrile as a yellow oil (24 mg, 15percent): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.46 (d, J=2.5 Hz, 1H), 8.11 (dm, J=9.2 Hz, 2H), 8.06 (dm, J=9.0 Hz, 2H), 7.77


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(d, J=1.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.57 (dd, J=1.8, 2.5 Hz, 1H), 5.70 (d, J=8.6 Hz, 1H), 5.12 (dd, J=3.5, 8.6 Hz, 1H), 4.86 (br s, 1H), 4.69-4.60 (m, 1H), 2.41 (s, 3H), 1.42 (d, J=6.5 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1.16667h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH

Cl

HN

N

O

Cl OH

HN

HN Cl

O N

N

Cl

OH

N



18%

Example Name 4 Example 4 2-Chloro-4-((1R,2S)-1-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile To a 500 mL round bottom flask was added 4-chloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 4a) (880 mg, 2.09 mmol, 1.0 equiv.) and anhydrous THF (209 mL). After being flushed with nitrogen, p-toluenesulfonic acid (439 mg, 2.3 mmol, 1.1 equiv.) was added and the solution was stirred for 10 min at room temperature. Then PS-BEMP (2.85 g, 6.27 mmol, 3.0 equiv.) was added. The reaction was stirred at room temperature for 8 h. The contents of the flask were filtered over Celite.(R). in a ground glass fritted funnel and the Celite.(R). was rinsed with several portions of acetone. The solvent was removed in vacuo to yield a yellow solid. The product was purified via flash chromatography (0-->50percent EtOAc/hexanes, 110g of silica gel; TLC Rf=0.51, 100percent EtOAc, vanillin stain) to provide the desired product as an off-white solid (150 mg, 18percent). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.01 (d, J=8.79 Hz, 2H), 7.62 (d, J=8.79 Hz, 2H), 7.49 (d, J=8.54 Hz, 1H), 6.86 (d, J=8.54 Hz, 1H), 5.68 (br. d, J=8.31 Hz, 1H), 5.12 (dd, J=3.91, 8.55 Hz, 1H), 4.82 (br. d, J=5.29 Hz, 1H), 4.62 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.35 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H16Cl2N4O2 [M]+ 403.26, found 403.4. Stage 1: With toluene-4-sulfonic acid in tetrahydrofuran, Time= 0.166667h, T= 20 °C , Inert atmosphere Stage 2: With PS-BEMP in tetrahydrofuran, Time= 8h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH

Cl

HN N

N

O OH

HN

HN O N

Cl

N

N

OH

N


Conditions & References Example Name 23 Example 23 2-chloro-4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile


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To a 250 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N'-((2R,3R)-2-(3-chloro-4cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.6871 g, 2.4 mmol) followed by addition of anhydrous THF (200 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (318 mg, 1.7 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading, 2.29 g, 5.0 mmol). This mixture was allowed to stir at room temperature for a period of 16 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a yellow solid. This was purified via silica gel chromatography eluted with 50percent EtOAc/hexanes to provide product as a white solid (138 mg, 21percent). 1H NMR (500 MHz, acetone-d , δ in ppm) 8.19 (AA'XX', J=8.4 Hz, 2H), 7.98 (AA'XX', J=8.5 Hz, 2H), 7.48 (d, J=8.6 Hz, 6 1H), 6.89 (d, J=8.7 Hz, 1H), 5.89 (d, J=8.8 Hz, 1H), 5.11 (dd, J=5.6, 8.8 Hz, 1H), 4.71 (d, J=5.9 Hz, 1H), 4.55 (m, 1H), 2.36 (s, 3H), 1.43 (d, J=6.3 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 16h, T= 20 °C , Inert atmosphere Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH O

Cl

HN

N

O

S O

OH

HN

HN

O S O

Cl

O N

N

OH

N


Conditions & References Example Name 24 Example 24 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-(methylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile To a 500 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N'-((2R,3S)-2-(3-chloro-4cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)-4-(methylsulphonyl)benzohydrazide (1.12 mg, 2.4 mmol) followed by a addition of anhydrous THF (250 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (461 mg, 2.4 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading, 3.30 g, 7.3 mmol). This mixture was allowed to stir at room temperature for a period of 16 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a red solid. This was purified via silica gel chromatography eluted with 80percent EtOAc/hexanes to yield product as a white solid (247 mg, 23percent). 1H NMR (500 MHz, acetone-d , δ in ppm) 8.23 (AA'XX', J=8.7 Hz, 2H), 8.12 (AA'XX', J=8.6 Hz, 2H), 7.47 (d, J=8.7 Hz, 6 1H), 6.87 (d, J=8.8 Hz, 1H), 5.70 (d, J=8.7 Hz, 1H), 5.17 (dd, J=3.6, 8.5 Hz, 1H), 4.86 (br s, 1H), 4.66 (m, 1H), 3.20 (s, 3H), 2.40 (s, 3H), 1.43 (d, J=6.3 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 16h, T= 20 °C , Inert atmosphere Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys


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O NH

Cl

HN N

N

O OH

HN

HN O N

Cl

N

N

OH

N



15 %

Example Name 47 Example 47 2-Chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-ethylbenzonitrile To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (310 mg, 0.73 mmol) in anhydrous THF (20 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (1.0 g) followed by p-TSCl (167 mg, 0.88 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction and the residue washed with acetone (200 mL) followed by MeOH (200 mL). The filtrate was concentrated and subjected to flash column chromatography [EtOAc-hexanes (2:1)]. The fourth fraction was the desired 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-ethylbenzonitrile (45 mg, 15percent).). 1H NMR (500 MHz, acetone-d , δ in ppm) 8.20 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.86 6 (d, J=8.6 Hz, 1H), 5.79 (d, J=8.3 Hz, 1H), 5.18 (dd, J=3.3 Hz, 8.3 Hz, 1H), 4.85 (d, J=5.1 Hz, 1H), 4.68-4.60 (m, 1H), 2.98-2.88 (m, 2H), 1.43 (d, J=6.4 Hz, 3H) and 1.2 (t, J=7.6 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O NH

Cl

HN N

N

O OH

HN

HN O N

Cl

N

N

OH

N


Conditions & References Example Name 54 Example 54 2-Chloro-4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-ethylbenzonitrile To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (310 mg, 0.73 mmol) in anhydrous THF (20 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (1.0 g) followed by p-TSCl (167 mg, 0.88 mmol) and the mixture was stirred for 1 h. The mixture was filtered and the residue washed with acetone (200 mL) followed by MeOH (200 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (1:12)] to give two fractions. The second-eluted material was the desired product (50 mg, 17percent): 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.20 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 5.99 (d, J=8.7 Hz, 1H), 5.12 (dd, J=4.5 Hz, 8.7 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.57-4.49 (m, 1H), 2.97-2.82 (m, 2H), 1.41 (d, J=6.4 Hz, 3H), 1.20 (t, J=7.6 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English


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View in Reaxys

O H N

N

N

N

F

N H

O

O F N



67%

Example Name 1.1.1 Step 1 110 mg of N'-phenylacetyl-3-cyano-4-fluorobenzohydrazide are stirred for 1 hour at 90° C. in 1.5 ml of phosphorus oxide trichloride. After cooling, the clear solution is poured into water, and the precipitated solid is filtered off with suction and dried, giving 69 mg of 5-(5-benzyl-1,3,4-oxadiazol-2-yl)-2-fluorobenzonitrile (67percent); MS-FAB (M+H+)=280.4; Rf (polar method): 2.15 min. With trichlorophosphate, Time= 1h, T= 90 °C Patent; Klein, Markus; Beier, Norbert; US2010/63115; (2010); (A1) English View in Reaxys Cl O H N

Cl

N

O

N H

N

O

Br

Br



71 %

Example Name 58.c Compound 4 (1.2 g, 3.9 mmol) was suspended in POCl3 (5 ml), and then the reaction mixture was heated to 1100C for 5 hours. The mixture was allowed to cool to ambient temperature and quenched by adding water, then the mixture was extracted with EA. The EA layer was concentrated to give a residue which was purified by recrystallization (DCM: PE) to give compound 5 as a light grey solid (800 mg). Yield: 71percent.1HNMR (400 MHz, CDCl3): δ (ppm): 7.83 (IH, d, Ar-H), 7.59 (IH, s, Ar-H), 7.27 (IH, m, Ar-H), 4.80 (2H, s, -CH2-), 2.41 (3H, s, CH3-). With trichlorophosphate, Time= 5h, T= 110 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys

N

O O

O

H N O O

N H

N

O

N O

NH

O

O


Conditions & References Example Title 4.1.7. Synthesis of 2-(3-cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (14) To a suspension of diacylhydrazine 13 (0.5 mmol) in dry benzene (5 mL) was added freshly distilled thionyl chloride (1 mL). The mixture was refluxed until a homogeneous solution was formed. After completion of the reaction, the mixture was evaporated to dryness under reduced pressure and the crude residual solid obtained was percolated through a short bed of silica gel column using ethyl acetate-hexane (1:1) to afford pure 14. Light cream solid, Yield 38percent, m.p. 138-139 °C. 1H NMR (CDCl3, 400 MHz): δH = 9.37 (1H, s(br)), 7.56-7.53 (2H, m), 6.92 (1H, d, J = 8.24 Hz), 4.89-4.86 (1H, m), 3.91 (3H, s), 3.53-3.51 (1H, m), 3.40-3.35 (1H, m), 3.23-3.20 (1H, m), 2.86-2.84 (3H, m), 2.44-2.30 (3H, m), 2.05-1.82 (6H, m), 1.65-1.62 (2H, m). MS (ESI, m/z): 344.1 (M + H)+.


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With thionyl chloride in benzene, Reflux Kumar, Dalip; Patel, Gautam; Chavers, Angela K.; Chang, Kuei-Hua; Shah, Kavita; European Journal of Medicinal Chemistry; vol. 46; nb. 7; (2011); p. 3085 - 3092 View in Reaxys

H 2N

O

N

N

H N N H

Br

NH 2 O

Br

O

N

N


Conditions & References Example Name 2.B.2 Step 2 : 5-Bromo-3-(5-phenyl-l,3,4-oxadiazol-2-yl)pyridin-2-amine[00144] Polyphosphonic acid (4.006 mL of 84 percentw/v, 41.04 mmol) was heated to 100°C and treated with 2-amino-N'-benzoyl-5-bromonicotinohydrazide (673 mg, 1.626 mmol) in portions over a period of 25 minutes. The reaction mixture was allowed to stir for 2 hours at 1 10 °C and then allowed to cool to ambient temperature. Water was added and the mixture basified (using 1M NaOH) and extracted with DCM (x3). The organic layer was separated, washed with brine, dried (MgS04), filtered and concentrated in vacuo to give the product as a white solid (372 mg, 72percent Yield). XH NMR (400.0MHz, DMSO) δ 7.54 (s, 2H), 7.62 - 7.68 (m, 3H), 8.22 - 8.25 (m, 2H), 8.32 (d, J = 2.5 Hz, 1H) and 8.50 (d, J = 2.5 Hz, 1H) ppm; MS (ES+) 318.86. Stage 1:, Time= 2.41667h, T= 100 °C Stage 2: With sodium hydroxide Patent; VERTEX PHARMACEUTICALS INCORPORATED; DAMIEN-CHARRIER, Jean; DURRANT, Steven, John; KNEGTEL, Ronald, Marcellus Alphonsus; REAPER, Philip, Michael; WO2011/143422; (2011); (A1) English View in Reaxys

O O

N N

O HN

O

NH

O O

O


Conditions & References With zirconium tetrachloride in dichloromethane, Time= 2.5h, T= 20 °C Sharma, G. V. M.; Begum, Asra; Rakesh; Krishna, Palakodety Radha; Synthetic Communications; vol. 34; nb. 13; (2004); p. 2387 - 2392 View in Reaxys

74 %

With trichlorophosphate in toluene, Time= 2h, Reflux Cioanca, Elena-Raluca; Elena, Luiza Epure; Carlescu, Irina; Lisa, Gabriela; Wilson, Daniela; Hurduc, Nicolae; Scutaru, Dan; Molecular Crystals and Liquid Crystals; vol. 537; (2011); p. 51 - 63 View in Reaxys

73.82 %

With trichlorophosphate in toluene, Time= 2h, T= 80 °C Apreutesei, Daniela; Mehl, Georg H.; Revue Roumaine de Chimie; vol. 53; nb. 7; (2008); p. 527 - 533 View in Reaxys

71 %

With thionyl chloride, Time= 2h, Heating Singh, Shiv P.; Batra, Hitesh; Sharma, Pawan K.; Journal of Chemical Research, Synopses; nb. 12; (1997); p. 468 - 469 View in Reaxys T= 260 °C


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Stolle; Bambach; Journal fuer Praktische Chemie (Leipzig); vol. 74; (1906); p. 13 Anm. 2 View in Reaxys With phosphorus pentachloride, T= 135 °C Stolle; Bambach; Journal fuer Praktische Chemie (Leipzig); vol. 74; (1906); p. 13 Anm. 2 View in Reaxys With thionyl chloride Stolle; Bambach; Journal fuer Praktische Chemie (Leipzig); vol. 74; (1906); p. 13 Anm. 2 View in Reaxys With trichlorophosphate, Time= 0.5h, Heating Popova, N. A.; Yushko, E. G.; Krasovitskii, B. M.; Minkin, V. I.; Lyubarskaya, A. E.; Gol'dberg, M. L.; Chemistry of Heterocyclic Compounds (New York, NY, United States); (1983); p. 22 - 28; Khimiya Geterotsiklicheskikh Soedinenii; vol. 19; nb. 1; (1983); p. 26 - 32 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys

O

H N Cl

O

N H

N

O

N

O

O Cl


Conditions & References With trichlorophosphate, Time= 5h Hogale, M. B.; Shelar, A. R.; Kachare, D. S.; Salunkhe, V. K.; Journal of the Indian Chemical Society; vol. 64; nb. 5; (1987); p. 314 - 316 View in Reaxys With trichlorophosphate, Time= 3h, Heating Cao, Song; Qian, Xuhong; Song, Gonghua; Huang, Qingchun; Journal of Fluorine Chemistry; vol. 117; nb. 1; (2002); p. 63 - 66 View in Reaxys Cao, Song; Qian, Xuhong; Song, Gonghua; Chai, Bing; Jiang, Zhisheng; Journal of Agricultural and Food Chemistry; vol. 51; nb. 1; (2003); p. 152 - 155 View in Reaxys With trichlorophosphate, Heating Chai, Bing; Cao, Song; Liu, Haidong; Song, Gonghua; Qian, Xuhong; Heterocyclic Communications; vol. 8; nb. 6; (2002); p. 601 - 606 View in Reaxys Example Name 46 Preparation 46; 2-Chloromethyl-5-(4-methoxy-phenvl)-r1. 3s41Oxadiazole; The product of preparation 38 (72.6g, 300mmol) was added to phosphorous oxychloride (200mL) and the reaction mixture heated to 110C for 5 hours. The mixture was then allowed to cool to room temperature and was concentrated in vacuo. The residue was taken up in ethyl acetate (500mL) and water (500mL) and treated with a saturated sodium hydrogen carbonate solution. The phases were separated and the aqueous layer was extracted with ethyl acetate (2x200mL). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to yield the title product, 53. 0g.'H NMR (CDCI3, 400MHz) 6 : 3.88 (s, 3H), 4.76 (s, 2H), 7.01 (d, 2H), 8.01 (d, 2H). MS APCI+ m/z 225 [MH] + With trichlorophosphate, Time= 5h, T= 110 °C


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Patent; PFIZER LIMITED; PFIZER INC.; WO2005/82866; (2005); (A2) English View in Reaxys

O

N

O

H N

O

N H

N O

O

O

S

O

S

N

N

N

O

N

O

Cl

Cl


Conditions & References Example Name 87.B Step B : Methyl 3-{[(l /?5-1-(2-chlorophenyl)ethyl]oxy}-5-[-(5-methyl-1 ,3,4- oxadsazol~2-y.)-1 //-benzimidazol-1-yl]-2tliiophenecarboxylateA 5.0 mL microwave vial was charged with 1.00 ml of THF, 286 mg (1,20 mmo.) of methoxycarboπylsυlfamoyi}triethy.ammonium hydroxide inner salt, and 154 mg (0.301 mmol) of methyl 5-{5~[{2-acetyihydrazino)carbonyi]-1 H- benzimidazol-1 -y.}-3-{[(1 R)A -(2-chtorophenyl)ethyi]oxy}~2-thiopheπe carboxylate. The reaction was heated in the microwave at 1500C for 10 mm. The crude was adsorbed onto silica gef and chrornatographed to give 139 mg of a tars solid as the title compound. MS (APCI): 495 [M+H]\\ With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in tetrahydrofuran, Time= 0.166667h, T= 150 °C , Microwave irradiation Patent; SMITHKLINE BEECHAM CORPORATION; WO2007/143456; (2007); (A2) English View in Reaxys Example Name 87.B Step B: Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H -benzimidazol-1-yl]-2-thiophenecarboxylate A 5.0 ml microwave vial was charged with 1.00 ml of THF, 286 mg (1.20 mmol) of methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt, and 154 mg (0.301 mmol) of methyl 5-{5-[(2-acetylhydrazino)carbonyl]-1H-benzimidazol-1-yl}-3-{[(1R)-1-(2-chlarophenyl)ethyl]oxy}-2-thiophene carboxylate. The reaction was heated in the microwave at 150° C. for 10 min. The crude was adsorbed onto silica gel and chromatographed to give 139 mg of a tan solid as the title compound, MS (APCl): 495 [M+H]+. With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in tetrahydrofuran, Time= 0.166667h, T= 150 °C , Microwave irradiation Patent; Kuntz, Kevin; Emmitte, Kyle Allen; Rheault, Tara Renae; Smith, Stephon; Hornberger, Keith; Dickson, Hamilton; Cheung, Mui; US2008/300247; (2008); (A1) English View in Reaxys

O

O

H N N H

S

O O

S

O N

N


Conditions & References Example Name 21.b b) A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N'-(5-isobutyl-thiophene-2- carbonyl)-hydrazide (1.40 g, 3.62 mmol) and Burgess reagent (1.12 g, 4.71 mmol) in THF (15 ml_) is stirred at 1100C for 3 min under microwave irradiation. The mixture is diluted with diethyl ether, washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(5-isobutyl-thiophen-2- yl)-[1 ,3,4]oxadiazole (1.02 g) as a colourless oil; LC-MS: tR = 1.21 min, [M+1]+ = 369.15 With Burgess Reagent in tetrahydrofuran, Time= 0.05h, T= 110 °C , Microwave irradiation Patent; ACTELION PHARMACEUTICALS LTD; WO2008/29306; (2008); (A2) English


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View in Reaxys Example Name 21.b b) A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N'-(5-isobutyl-thiophene-2-carbonyl)-hydrazide (1.40 g, 3.62 mmol) and Burgess reagent (1.12 g, 4.71 mmol) in THF (15 mL) is stirred at 110° C. for 3 min under microwave irradiation. The mixture is diluted with diethyl ether, washed with water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazole (1.02 g) as a colourless oil; LC-MS: tR=1.21 min, [M+1]+=369.15. With Burgess Reagent in tetrahydrofuran, Time= 0.05h, T= 110 °C , Microwave irradiation Patent; Actelion Pharmaceuticals Ltd.; US2010/48648; (2010); (A1) English View in Reaxys O NH

N

O

N

HN N

O

N

O

O


Conditions & References Example Name 28.b b) A solution of 6-isobut.yl-5-methyl-nicot.inic acid N'-(4-allyloxy-3,5-dimethyl-benzoyl)- hydrazide (89 mg, 0.224 mmol) and Burgess reagent (162 mg, 0.68 mmol) in THF (4 mL) is heated in a microwave oven at 1100C for 6 min. The mixture is diluted with EA (15 mL) and washed with 1 M aq. NaH2PO4 (5 mL), 1 M aq. NaOH (5 mL) and water (5 mL). The org. phase is dried (MgSO4), filtered and evaporated to provide crude 5-[5-(4-allyloxy-3,5- dimethyl-phenyl)-[1 ,3,4]oxadiazol-2-yl]-2-isobutyl-3-methyl-pyridine (80 mg); LC-MS: tR = 1.07 min, [M+1]+ = 378.3. With Burgess Reagent in tetrahydrofuran, Time= 0.1h, T= 110 °C , Microwave Patent; ACTELION PHARMACEUTICALS LTD; WO2008/29370; (2008); (A1) English View in Reaxys Example Name 28.b b) A solution of 6-isobutyl-5-methyl-nicotinic acid N'-(4-allyloxy-3,5-dimethyl-benzoyl)-hydrazide (89 mg, 0.224 mmol) and Burgess reagent (162 mg, 0.68 mmol) in THF (4 mL) is heated in a microwave oven at 110° C. for 6 min. The mixture is diluted with EA (15 mL) and washed with 1M aq. NaH2PO4 (5 mL), 1M aq. NaOH (5 mL) and water (5 mL). The org. phase is dried (MgSO4), filtered and evaporated to provide crude 5-[5-(4-allyloxy-3,5-dimethyl-phenyl)[1,3,4]oxadiazol-2-yl]-2-isobutyl-3-methyl-pyridine (80 mg); LC-MS: tR=1.07 min, [M+1]+=378.3. With Burgess Reagent in tetrahydrofuran, Time= 0.1h, T= 110 °C , Microwave irradiation Patent; ACTELION PHARMACEUTICALS LTD.; US2010/168005; (2010); (A1) English View in Reaxys

O

N N

NH

HN

O

O O O

O NH

O O O

N H

O

O


Conditions & References Stage 1: With 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate, triethylamine in dichloromethane Stage 2: in toluene, T= 80 °C


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Glossop, Melanie S.; Bazin, Richard J.; Dack, Kevin N.; Fox, David N. A.; MacDonald, Graeme A.; Mills, Mark; Owen, Dafydd R.; Phillips, Chris; Reeves, Keith A.; Ringer, Tracy J.; Strang, Ross S.; Watson, Christine A. L.; Bioorganic and Medicinal Chemistry Letters; vol. 21; nb. 11; (2011); p. 3404 - 3406 View in Reaxys Example Name 33 Example Title Preparation 33; (2S)-2-Benzyloxycarbonylamino-3-(5-phenyl-[1.3.4]oxadiazol-2-yl)-propionic acid ethyl ester The amide of preparation 15 (650mg, 1. 6MMOL) was dissolved in DICHLOROMETHANE (10mL) and the reaction mixture treated with 2-CHLORO-1, 3-dimethyl-4, 5-dihydro-3H- IMIDAZOL-1-IUM TETRAFLUOROBORATE (657MG, 2. 4MMOL) and triethylamine (445L, 3. 2MMOL). The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (100: 0 to 50: 50). The collected product was dissolved in toluene and heated at 80C for 8 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in DICHLOROMETHANE (1 OML) before being washed with 2M hydrochloric acid (5mL) and saturated sodium hydrogencarbonate solution (5mL). The reaction mixture was then dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (90: 10 to 80: 20) to yield the title product, 12mg ;APOS;HNMR (CDCI3, 400MHZ) : 1.25 (t, 3H), 3.49 (m, 2H), 4.22 (m, 2H), 4.87 (m, 1 H), 5. 16 (m, 2H), 5.87 (m, 1 H), 7.32 (m, 5H), 7.51 (m, 3H), 7.99 (m, 2H); MS ES+ m/z 813 [M2Na] +. With 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate, triethylamine in dichloromethane, Time= 18h, T= 20 °C Patent; PFIZER LIMITED; PFIZER INC.; WO2004/56787; (2004); (A1) English View in Reaxys

N O

N

O

O

H N

O

N H

N

N O

O

O

O O

O O



57 %

Example Name B2a 0.24 g (0.49 mmol) of4- [2- (N'- {3- [5- (4-Methoxy-phenyl)-oxazol-2-yl]- [BENZOYL}-HYDRAZINO)-2-OXO-ETHYL]BENZOIC] acid methyl ester from Preparation [8] was dissolved in about 10 mL of poly phosphoric acid. The mixture was stirred at 90-100 [°C] for 1 hour before allowing to cool to room temperature. Water was added and the product was extracted with 1: 1: 1 [ETOAC/THF/ET20] (2x). The extracts were combined and washed with saturated aqueous NaCl solution then dried [MGS04. SLURRIED] solid product in hot EtOAc and filtered. Dried in vacuum oven overnight at [70 °C] to obtain 0.13 g (57percent) desired product. MS: m/z (APCI, AP+) 468 [[M] +] NMR: [DMSO LH otilde;] (ppm) 3.80 (3H, s); 3.3. 83 (3H, s); 7.04-7. 07 (2H, m); 7.54-7. 56 (2H, m); 7.57-7. 79 (4H, m); 7.91-7. 96 (2H, m); 8. 05-8. 08 [(1H,] m); 8.25-8. 27 [(1H,] m); 8.52-8. 53 (1H, M). With PPA, Time= 1h, T= 90 - 100 °C Patent; WARNER-LAMBERT COMPANY LLC; WO2004/14366; (2004); (A1) English View in Reaxys N

O

N

O HN

NH

N O

N N

N

O

O


Conditions & References Example Name 3 With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in toluene, Time= 1h, T= 60 °C Patent; AVENTIS PHARMA DEUTSCHLAND GMBH; WO2005/70925; (2005); (A1) German


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View in Reaxys Example Name 3.B Example Title Dimethyl-(1-{4-[5-(4-phenoxyphenyl)[1,3,4]oxadiazol-2-yl]phenyl}pyrrolidin-3-yl)amine A mixture of N'-[4-(3-dimethylaminopyrrolidin-1-yl)benzoyl]-4-phenoxybenzohydrazide (178 mg), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess' reagent) (96 mg) and 5 ml of toluene was stirred at 60° C. for 1 h. After the reaction was complete, the reaction mixture was filtered, and the filtrate was washed twice with ethyl acetate. The combined organic phases were subsequently washed with 5percent strength sodium carbonate solution and then dried over Chromabond XTR. Volatiles were removed and the residue was purified by preparative HPLC. The product with the molecular weight of 426.21 (C26H26N4O2) was obtained in this way; MS (ESI): 427.21 (M+H+). With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in toluene, Time= 1h, T= 60 °C Patent; Aventis Pharma Deutschland GmbH; US2005/176710; (2005); (A1) English View in Reaxys

Cl O

Cl

O

O

HN

O

NH

N

N

O



60 %

Example Name 139 Preparation 139; 2- (3-Chloro-4-ethoxv-phenyl)-5-methvl-f1. 3, 41oxadiazole; A mixture of the product of preparation 127 (2g, 7mmol) and phosphorus oxychloride (15mL) was heated at 110°C for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a foam in 60percent yield, 1g 1H NMR (400MHz, CDCI3) 8 : 1.52 (t, 3H), 2.61 (s, 3H), 4.20 (q, 2H), 7.01 (d, 1H), 7.92 (dd, 1 H), 8.04 (d, 1 H) ; LRMS ESI m/z 239 [M+H] + With trichlorophosphate, Time= 2h, T= 110 °C Patent; PFIZER LIMITED; PFIZER INC.; WO2005/82866; (2005); (A2) English View in Reaxys

O Cl

O HN

NH

Cl

O

O

O

Cl N

Cl N


Conditions & References Example Name 1.E Example Title Synthesis of 2,5-Dichloro-N'-[4-(octyloxy)benzoyl]benzohydrazide Part E Synthesis of 2-(2,5-Dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (2) Into a 250 ml flask fitted with a mechanical stirrer and thermometer was introduced 30 g (0.0686 mol) 2,5-dichloro-N'[4-(octyloxy)benzoyl]benzohydrazide and 181 ml phosphorus oxychloride. This was refluxed and stirred for 8 hrs. About 100 ml of phosphorus oxychloride was distilled off under reduced pressure. The cooled residue was poured onto water and crushed ice with manual stirring and allowed to stand until the ice had melted. The precipitated white solid was collected by filtration, dried and recrystallized from ethanol. There was obtained 25.7 g (89percent yield, mp 86° C.) of 2-(2,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (2). The structure was confirmed unambiguously by 1D and 2D NMR techniques and gave the following: 1H-NMR (500 MHz, CDCl3) 0.89 (3H, t), 1.31 (8H, m), 1.46 (2H, q), 1.79 (2H, q), 6.97 (2H, d), 7.38 (1H, dd), 7.44 (1H, d), 8.01 (2H, d), 8.06 (1H, d); 13C-NMR (500 MHz, CDCl3) 13.90 (C-28), 22.44, 25.79, 28.91, 29.01, 29.13, 31.59, 68.08 (C-21),


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114.78 (C14 and C-16), 115.37 (C-12), 124.27 (C-6), 128.58 (C-13 and C-17), 130.23 (C-11), 130.87 (C-7), 131.75, 132.20, 132.87 (C-10), 161.03, 161.98 (C-15), 164.95 (C-5). With trichlorophosphate, Time= 8h, Heating / reflux Patent; 3M Innovative Properties Company; US7094902; (2006); (B2) English View in Reaxys 89%

Example Name 1.E Example Title Synthesis of 2-(2,5-Dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole Part E: Synthesis of 2-(2,5-Dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole Into a 250 ml flask fitted with a mechanical stirrer and thermometer was introduced 30 g (0.0686 mol) 2,5-dichlor-N'[4-(octyloxy)benzoyl]benzohydrazide and 181 ml phosphorus oxychloride. This was refluxed and stirred for 8 hrs. About 100 ml of phosphorus oxychloride was distilled off under reduced pressure. The cooled residue was poured onto water and crushed ice with manual stirring and allowed to stand until the ice had melted. The precipitated white solid was collected by filtration, dried and recrystallized from ethanol. There was obtained 25.7 g (89percent yield, mp 86° C.) of 2-(2,5-dichlorophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole. The structure was confirmed unambiguously by 1D and 2D NMR techniques and gave the following: 1H-NMR (500 MHz, CDCl3) 0.89 (3H, t), 1.31 (8H, m), 1.46 (2H, q), 1.79 (2H, q), 6.97 (2H, d), 7.38 (1H, dd), 7.44 (1H, d), 8.01 (2H, d), 8.06 (1H, d); 13C-NMR (500 MHz, CDCl3) 13.90, 22.44, 25.79, 28.91, 29.01, 29.13, 31.59, 68.08, 114.78, 115.37, 124.27, 128.58, 130.23, 130.87, 131.75, 132.20, 132.87, 161.03, 161.98, 164.95. With trichlorophosphate Patent; 3M Innovative Properties Company; US7271406; (2007); (B2) English View in Reaxys O H N

N

O

NH O

HN

N

N

N

N

O

N O

Cl

Cl

N H


Conditions & References Example Name 68.2 Step 2. A mixture of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N'-acetyl- hydrazide (0.2 g, 0.55 mmol), and Burgess reagent (0.39 g, 1.65 mmol) in THF (6 mL) is placed in a microwave reactor. After 5 min at 1300C5 the mixture is concentrated in a rotavap, and subjected to a chromatography eluting withl?percent MeOH in CH2Cl2 to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-{2- r4-(5-methyl-|"1.3.41oxadiazol-2-yl)-phenyll-ethyl}-amine (160 mg). LCMS: R? = 2.29 minutes; MS: 346 (M+H). With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 130 °C , Microwave heating Patent; AVENTIS PHARMACEUTICALS INC.; WO2006/44732; (2006); (A2) English View in Reaxys Example Name 68.2 A mixture of 4-[2-(6-ctoeoro-2-methoxy-pyrimidin-4-ylamino)-ethyl] -benzoic acid N'-acetyl- hydrazide (0.2 g, 0.55 mmol), and Burgess reagent (0.39 g, 1.65 mmol) in THF (6 mL) is placed in a microwave reactor. After 5 min at 130°C, the mixture is concentrated in a rotavap, and subjected to a chromatography eluting withl 0percent MeOH in CH2CU to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-{2- r4-f5-methyl-ri.3.41oxadiazol-2-ylVphenyll-ethvU-amine (160 mg). LCMS: Rτ = 2.29 minutes; MS: 346 (M+H). With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 130 °C , Microwave Patent; SANOFI-AVENTIS U.S. LLC; WO2008/39882; (2008); (A1) English View in Reaxys


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F

F

O O O

NH

O

S

N

N H

N

S

O

O O


Conditions & References Example Name B A solution of ethyl 6-[2-(2-benzoylhydrazino)-l-fluoro-2- oxoethyl]-l-benzothiophene-2-carboxylate (51 mg, 0.13 mmol) in THF (2.0 mL) was treated with Burgess reagent (45 mg, 0.19 mmol). The reaction vessel was sealed and heated to 12O0C in the microwave reactor for 20 minutes. The reaction was evaporated in vacuo and purified by flash chromatography (10-40percent ethyl acetate/hexanes) to give ethyl 6-[fluoro(5-phenyl-l,3>4-oxadiazol-2- yl)methyl]-l-benzothiophene-2-carboxylate as a white solid. ESMS calcd 383.1 (M+ + H), found 383.0 (M+ + H). To a solution of ethyl 6[fluoro(5-phenyl-l,3,4-oxadiazol-2-yl)methyl]-l-benzothiophene-2- carboxylate in THF (2.5 mL) was added IM sodium hydroxide (5.0 mL, 5.0 mmol) and the resulting solution was stirred at ambient temperature for 1 hour. The reaction was partitioned between ethyl acetate and IM HCl solution. The organics were dried over sodium sulfate, filtered and evaporated to give 6-[fluoro(5-phenyl-l,3,4-oxadiazol-2-yl)methyl]-l-benzothiophene-2-carboxylic acid as a white solid. ESIMS calcd 355.1 (M+ + H), found 355.0 (M+ + H). With Burgess Reagent in tetrahydrofuran, Time= 0.333333h, T= 120 °C , Microwave irradiation, Sealed vessel Patent; MERCK and CO., INC.; ATON PHARMA, INC.; WO2006/115845; (2006); (A1) English View in Reaxys Example Name B 6-[Fluoro-(5-phenyl-[l,3,4]oxadiazol-2-yl)-methyl]- benzo[b]thiophene-2-carboxylic acid. A solution of ethyl 6-[2-(2-benzoylhydrazino)-l-fluoro-2- oxoethyl]-l-benzothiophene-2-carboxylate (51 mg, 0.13 mmol) in THF (2.0 mL) was treated with Burgess reagent (45 mg, 0.19 mmol). The reaction vessel was sealed and heated to 1200C in the microwave reactor for 20 minutes. The reaction was evaporated in vacuo and purified by flash chromatography (10-40percent ethyl acetate/hexanes) to give ethyl 6-[fluoro(5-phenyl-l,3,4-oxadiazol-2- yl)methyl]-l-benzothiophene-2-carboxylate as a white solid. ESIMS calcd 383.1 (M+ + H), found 383.0 (M+ + H). With Burgess Reagent in tetrahydrofuran, Time= 0.333333h, T= 120 °C , Microwave Patent; MERCK and CO., INC.; WO2007/87129; (2007); (A2) English View in Reaxys

O

O

O

O

HN O

NH O

HN N

O

O

HN

HN N

F

N

O

N

HN N

F

O F

N

O F


Conditions & References Example Name B2 To a solution of tert-buty\\ {3-[(4-{l,l-difluoro-2-[2-(2- methoxybenzoyl)hydrazino]-2-oxoethyl}benzoyl)amino]-l -phenyl-1 J-pyrazol-4-yl}carbamate (0.05 g, 0.08 mmol) in TΗF (2 mL) was added Burgess reagent (38 mg? 0.16 mmol) and the reaction was sealed and heated to 1000C for 10 minutes under microwave irradiation. The reaction was evaporated to dryness and purified by reverse phase chromatography (5/95 acetonitrile/water to 95/5 acetonitrile/water) to give tertbutyl {3-[(4-{difluoro[5-(2-methoxyphenyl)-l,3,4-oxadiazol-2-yl]methyl}benzoyl)amino]-l-phenyl- lH-pyrazol-4-yl} carbamate as a white solid. ESIMS calcd 603.2 (M+ + Η),.found 603.2 (M+ + H). With Burgess Reagent in tetrahydrofuran, Time= 0.166667h, T= 100 °C , Microwave Patent; MERCK and CO., INC.; WO2007/87129; (2007); (A2) English View in Reaxys


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Example Name 50.H To a solution of tert-butyl {3-[(4-{l,l-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2- oxoethyl}benzoyl)amino]-l-phenyl-lHpyrazol-4-yl}carbamate (0.05g, 0.08 mmol) in TηF (2 mL) was added Burgess reagent (38mg, 0.16 mmol) and the reaction was sealed and heated to 100 0C for 10 minutes under microwave irradiation. The reaction was evaporated to dryness and purified by reverse phase chromatography (5/95 acetonitrile/water to 95/5 acetonitrile/water) to give tert-buty\\ {3-[(4- { difluoro [5-(2-methoxyphenyl)- 1 ,3 ,4~oxadiazol-2-yl]methyl}benzoyl)arnino] - 1 -phenyl- lHpyrazol-4- yl} carbamate as a white solid. ESDVIS calcd 603.2 (M+ + η), found 603.2 (M+ + η). With Burgess reagent in tetrahydrofuran, Time= 0.166667h, T= 100 °C , Microwave irradiation Patent; MERCK and CO., INC.; WO2007/55941; (2007); (A2) English View in Reaxys

O

O

O N

O N

O

O O H N

O

N

O

N H

O

N

O



56 %

Example Name 5b Example 5 b) A suspension of the solid obtained above (0.288 g, 1.017 mmol) in phosphorus oxychloride (7 mL) was stirred at 120 °C for two hours, then allowed to cool to room temperature. The solution was then poured onto ice-water (200 mL), causing formation of a white precipitate. Extracted with dichloromethane, and the organic extracts were washed with water and brine, then dried ,filtered and evaporated to leave a white solid. Recrystallisation from dichloromethane/petroleum ether gave 2-(3,4-dimethoxy-5-nitro- phenyl)-5-methyl-[1,3,4]oxadiazole as white crystals (0.151 g, 56percent). With trichlorophosphate, Time= 2h, T= 120 °C Patent; PORTELA and CA. S.A.; WO2007/13830; (2007); (A1) English View in Reaxys

O O

N

NH O

HN

N N

O

O

N

N N


Conditions & References Example Name 81.a To a solution of 2-diethylamino-6-methyl-isonicotinic acid (1.50 g, 6.13 mmol) and DIPEA (2.38 g, 18.4 mmol) in DCM (25 ml_), TBTU (2.16 g, 6.74 mmol) is added. The mixture is stirred at rt for 10 min before a solution of 4-benzyloxy-3ethyl-5-methyl-benzoic acid hydrazide (3.32 g, 6.13 mmol) in DMF (10 ml.) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM and washed with sat. aq. NaHCψ3-solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with a gradient of EA in heptane to give 4benzyloxy-3-ethyl-5-methyl- benzoic acid N'-(2-diethylamino-6-methyl-pyridine-4-carbonyl)-hydrazide (2.1 g) as a gum; LC-MS: tR = 0.88 min, [M+1]+ = not detectable. This material (2.10 g, 4.42 mmol) is dissolved in THF (40 ml.) and Burgess reagent (1.16 g, 4.87 mmol) is added. The mixture is stirred at 1 100C for 5 min under microwave irradiation. The mixture is cooled to rt, diluted with diethyl ether and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give {4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1 ,3,4]oxadiazol-2-yl]-6-methyl-pyridin- 2-yl}-diethyl-amine (1.03 g) as a pale yellow gum; LC-MS: tR = 0.99 min, [M+1]+ = 457.27. With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 110 °C , Microwave irradiation


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Patent; ACTELION PHARMACEUTICALS LTD; WO2008/114157; (2008); (A1) English View in Reaxys Example Name 81.a a) To a solution of 2-diethylamino-6-methyl-isonicotinic acid (1.50 g, 6.13 mmol) and DIPEA (2.38 g, 18.4 mmol) in DCM (25 mL), TBTU (2.16 g, 6.74 mmol) is added. The mixture is stirred at rt for 10 min before a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (3.32 g, 6.13 mmol) in DMF (10 mL) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM and washed with sat. aq. NaHCO3-solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with a gradient of EA in heptane to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N'-(2-diethylamino-6-methyl-pyridine-4-carbonyl)-hydrazide (2.1 g) as a gum; LC-MS: tR=0.88 min, [M+1]+=not detectable. This material (2.10 g, 4.42 mmol) is dissolved in THF (40 mL) and Burgess reagent (1.16 g, 4.87 mmol) is added. The mixture is stirred at 110° C. for 5 min under microwave irradiation. The mixture is cooled to rt, diluted with diethyl ether and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give {-4-[5(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridin-2-yl}-diethyl-amine (1.03 g) as a pale yellow gum; LC-MS: tR=0.99 min, [M+1]+=457.27. With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 110 °C , Microwave irradiation Patent; Bolli, Martin; Mathys, Boris; Mueller, Claus; Nayler, Oliver; Steiner, Beat; Velker, Jorg; US2010/87417; (2010); (A1) English View in Reaxys

S F

O

N NH

HN

O

S O

O S

O

N

N

F

O

N O

S


Conditions & References Example Name 104 Example Title Preparation of 2-(4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-5-phenyl-1,3,4oxadiazole Example 104 Preparation of 2-(4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-5-phenyl-1,3,4-oxadiazole To a solution of Example 78 (20 mg, 42 μmol) in THF (1 mL) was added DBU (10 mg, 64 μmol) and Burgess reagent (50.5 mg, 212 μmol). The reaction vial was capped subjected to microwave irradiation (150° C., 5 min). Analysis of the reaction mixture indicated the presence of starting material, so additional burgess reagent (10.1 mg, 42 μmol) was added and the reaction mixture was resubjected to microwave irradiation (150° C., 10 min). LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction was diluted with saturated aqueous sodium bicarbonate (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The combined were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography using a gradient elution of hexanes with 10-60percent EtOAc to provide 2-(4-(4-fluorophenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-5-phenyl-1,3,4-oxadiazole (1 mg, 2.2 μmol, 5percent yield). LCMS (+ESI) m/z=454.5 [M+H]+; 1H-NMR (CDCl3) δ 8.0-8.1 (m, 5H), 7.4-7.5 (m, 5H), 7.25 (d, 1H), 7.00 (dd, 1H), 6.76 (d, 1H), 3.53 (t, 2H), 3.08 (t, 2H). With Burgess Reagent, 1,8-diazabicyclo[5.4.0]undec-7-ene in tetrahydrofuran, Time= 0.25h, T= 150 °C , Microwave irradiation Patent; CARA THERAPEUTICS, INC.; US2009/75973; (2009); (A1) English View in Reaxys


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Cl

O

O N

HN

NH

O

O

N O

N

O O

N

O

Cl

O


Conditions & References Example Name 6 A suspension of ethyl 3-(2-{[3-chloro-5-(4-morpholinyl)phenyl]carbonyl}hydrazino)-3- oxopropanoate (D5, 0.76 g, 2.06 mmol) and(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent) (0.91 g, 3.80 mmol) in dichloromethane (5 ml.) was heated at 1000C in the microwave at high absorption for 10 minutes. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was then washed with dichloromethane and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil which was used without further purification.LC/MS (ES+ve): [M+H]+ at m/ z 352, 354 (Ci6H18CIN3O4 requires [M+H]+ at m/z 352, 354). With Burgess Reagent in dichloromethane, Time= 0.166667h, T= 100 °C , Microwave irradition Patent; GLAXO GROUP LIMITED; WO2009/819; (2008); (A1) English View in Reaxys With Burgess Reagent in dichloromethane, T= 100 °C , Microwave irradiation Nichols, Paula L.; Brand, Jonathan; D'Angeli, Mathilde; Farge, Jennifer; Hutchings, Rio; Kilford, Ian; Li, Ho Y.; MacPherson, David; Nimmo, Fiona; Sehmi, Sanjeet; Shuker, Nicola; Skidmore, John; Stott, Michael; Sweeting, Jennifer; Tajuddin, Hasmi; Takle, Andrew K.; Trani, Giancarlo; Ward, Robert; Wilson, David M.; Witty, David; Briggs, Michael; Goldsmith, Paul; Garland, Stephen L.; Wall, Ian D.; Sanderson, Francis Dominic; Bioorganic and Medicinal Chemistry Letters; vol. 20; nb. 4; (2010); p. 1368 - 1372 View in Reaxys

O

H N

O

Br

Br N H

O

O

N

O

N O

O

Cl

Cl


Conditions & References Example Name 25; 31 Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate (D24, 13 g, 35.8 mmol) was suspended in dichloromethane (45 ml_). Burgess reagent (8.52 g, 35.8 mmol) was added. The reaction mixture was split into 3 portions and stirred for 20 minutes each at 100 0C in the microwave. All 3 reactions were then combined and partitioned between dichloromethane and water, and further extracted with dichloromethane (x2). The organic layer was washed with water (x2), dried over magnesium sulfate and concentrated under reduced pressure. Material insoluble in methanol was removed by filtration. The filtrate was concentrated and purified by column chromatography, eluting with ethyl acetate/iso-hexane (0-100percent ethyl acetate over 18 column volumes). Product containing fractions were evaporated and dried under high vacuum to leave the title compound as a thick yellow liquid. 1H NMR δ (MeOH-d4): 1.29 (3H, t), 4.24 (2H, q), 4.87 (assumed 2H, overlapping with water signal), 7.87 (1 H, m), 8.04 (1 H, m), 8.14 (1 H, m).; Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate (D30, 4 g,11.0 mmol) was split into 2x2g reactions.Ethyl 3-{2-[(3-bromo-5-chlorophenyl)carbonyl]hydrazino}-3-oxopropanoate (D30, 2 g,5.50 mmol) and Burgess reagent (1.311 g, 5.50 mmol) were stirred in dichloromethane (10 ml.) for 20 minutes at 1000C in the microwave. The reaction mixtures were combined, water was added and extracted with dichloromethane (x2).The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The mixture was purified by column chromatography, eluting with0-50percent ethyl acetate in hexane to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 345, 347, 349 (Ci2H10BrCIN2O3 requires [M+H]+ at m/z 345, 347, 349). With Burgess Reagent in dichloromethane, Time= 0.333333h, T= 100 °C , Microwave irradition Patent; GLAXO GROUP LIMITED; WO2009/819; (2008); (A1) English View in Reaxys With Burgess Reagent in dichloromethane, T= 100 °C , Microwave irradiation


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Nichols, Paula L.; Brand, Jonathan; D'Angeli, Mathilde; Farge, Jennifer; Hutchings, Rio; Kilford, Ian; Li, Ho Y.; MacPherson, David; Nimmo, Fiona; Sehmi, Sanjeet; Shuker, Nicola; Skidmore, John; Stott, Michael; Sweeting, Jennifer; Tajuddin, Hasmi; Takle, Andrew K.; Trani, Giancarlo; Ward, Robert; Wilson, David M.; Witty, David; Briggs, Michael; Goldsmith, Paul; Garland, Stephen L.; Wall, Ian D.; Sanderson, Francis Dominic; Bioorganic and Medicinal Chemistry Letters; vol. 20; nb. 4; (2010); p. 1368 - 1372 View in Reaxys

O O N

O

O O

O

N

N

NH O

N

N

O

N

HN O



63.6 %

Example Name 3.5 Step 5: Methyl 4-(5-(3-(5-(4-tert-butylphenyl)-1.3.4-oxadiazol-2-yl)phenyl)-1.3.4- oxadiazol-2-yl)benzoate (YZ -1-245):Methyl 4-(2-(3-(5-(4-tert-butylphenyl)-l,3,4-oxadiazol-2-yl)benzoyl)- hydrazinecarbonyl)benzoate (2.4 g, 4.81 mmol) was added in POCl 3 (30.0 ml). The reaction was heated to 90 0C and kept at this temperature for 7.5 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice-water (300.0 ml). The white solid formed was collected by vacuum filtration. The crude product was dried and purified by silica gel column using dichloromethane/ethyl acetate (9 : 1) as the eluent. After the removal of solvents, a pure white solid product was obtained in 1.47 g (63.6 percent) yield by recrystallization from dichloromethane/methanol.1H NMR (400 MHz, CDCl 3) δ: 8.89 (t, 1 H, J= 1.2 Hz), 8.37 (dd, 2 H, J1 = 8.0 Hz, J2 = 1.2 Hz), 8.27 (d, 2 H, J= 8.8 Hz), 8.24 (d, 2 H, J= 8.8 Hz), 8.11 (d, 2 H, J = 8.8 Hz), 7.76 (t, 1 H, J= 8.0 Hz), 7.59 (d, 2 H, J= 8.8 Hz), 3.99 (s, 3 H, OCH 3), 1.39 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl 3) δ: 166.06, 165.18, 164.26, 163.30, 155.73, 133.04, 130.34, 130.09, 130.00, 129.78, 127.35, 127.01, 126.92, 126.15, 125.23, 125.06, 124.71, 120.70, 52.53, 35.13, 31.10 ppm. MS-EI (m/z): [M]+ calcd for C28H24N4O4 480.2, found 480.2. With trichlorophosphate, Time= 7.5h, T= 90 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

N

O

N

N

O

O

N O

O O N

N

HN

NH

O


Conditions & References Example Name 5.2 Step 2: 2-(4-tert-Butylphenyl)-5-(4-(5-(3-methoxyphenyl)-1.3.4-oxadizol-2- yl)phenyl)-1.3.4-oxadiazole (YZ-I-251):N'(4 -(5 -(4 -tert-Butylphenyl) - 1 ,3 ,4 -oxadiazol-2-yl)benzoyl)-3 - methoxybenzohydrazine (2 .5 g, 5.31 mmol) was added in POCl 3 (25.0 ml). The reaction was heated to 90 0C and kept at this temperature for 4 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice -water (300.0 ml). The yellow color solid for med was collected by vacuum filtration. The crude material was dried and purified by silica gel column using dichloromethane/ethyl acetate, ratio (9 : 1), as the eluent. After removal of the solvents, a pure product as white solid was obtained in 1.43 g ( 59.6percent) yield by recrystallization from THF/methanol.1H NMR (400 MHz, CDCl 3) δ: 8.32 (s, 4 H), 8.08 (d, 2 H, J= 8.8 Hz), 7.72 (dt, 1 H, J1 = 8.0 Hz, J2 = 1.2 Hz), 7.69 (dd, 1 H, J1 = 2.4 Hz, J2 = 1.2 Hz), 7.57 (d, 2 H, J = 8.8 Hz), 7.46 (t, I H, J= 8.0 Hz), 7.12 (ddq, 1 H, J1 = 8.0 Hz, J2 = 2.4 Hz, J3 = 1.2 Hz), 3.92 (s, 3 H, OCH3), 1.39 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl 3) δ: 165.12, 164.94, 163.71, 163.45, 159.97, 155.70, 130.28, 127.47, 127.42, 126.87, 126.70, 126.40, 126.13, 124.65, 120.71, 119.38, 118.39, 111.67, 55.54, 35.12, 31.08 ppm. MS-FAB (m/z): [M] + calcd for C H N O 452.2, found 452.2. 28 24 4 4 With trichlorophosphate, Time= 4h, T= 90 °C


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Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

O

O N

O

O

O

O

N

N

NH O

N

N

O

N

HN O



60.9 %

Example Name 7.2 Step 2 : 4 -(5 -(3 -(5 -(4 -tert-Butylphenyl) - 1.3.4 -oxadiazol -2 -yPphenyl) - 1.3.4 - oxadiazol-2-yl)phenyl acetate (YZ -1-247):4-(2-(3-(5-(4-tert-butylphenyl)-l,3,4-oxadiazol-2-yl)-benzoyl)- hydrazinecarbonyl)phenyl acetate (2.1 g, 4.21 mmol) was added in POCl 3 (30.0 ml) . The reaction was heated to 90 0C and kept at this temperature for 3 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice-water (300.0 ml). The white solid formed was collected by vacuum filtration. The crude product was dried and purified by silica gel column using dichloromethane/ethyl acetate, ratio (8.5 : 1.5), as t he eluent. After the removal of the solvents, a pure white solid product was obtained in 1.23 g (60.9 percent) yield. 1H NMR (400 MHz, CDCl 3) δ: 8.86 (t, 1 H, J= 1.6 Hz), 8.34 (m, 2 H), 8.22 (d, 2 H, J= 8.8 Hz), 8.12 (d, 2 H, J= 8.8 Hz), 7.74 (t, 1 H, J= 7.6 Hz), 7.58 (d, 2 H, J= 8.8 Hz), 7.32 (d, 2 H, J= 8.8 Hz), 2.36 (s, 3 H, CH 3), 1.39 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl 3) δ: 169.16, 165.41, 164.63, 163.96, 163.63, 162.04, 155.95, 153.71, 130.30, 130.07, 129.95, 128.75, 127.18, 126.41, 125.43, 125.22, 125.16, 122.82, 121.45, 120.99, 35.40, 31.36, 21.43 ppm. MS -EI (m/z): [M] + calcd for C28H24N4O4480.2, found 480.2. With trichlorophosphate, Time= 3h, T= 90 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

O NH

Cl

HN N

N

O OH

HN

HN O N

Cl

N

N

OH

N


Conditions & References Example Name 80 Example 80 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-vinylbenzonitrile To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-vinylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.79 g, 1.86 mmol) in anhydrous THF (200 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (3 mmol base/g) (2.54 g, 5.59 mmol) followed by para-toluene sulfonyl chloride (p-TSCl) (355 mg, 1.86 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction, the residue then washed with acetone (300 mL) followed by methanol (300 mL) and then concentrated to furnish a yellow oil (0.92 g). Purification by flash column chromatography [EtOAc-hexanes (3:2) as eluent] afforded the title compound as a white crystalline solid (86 mg, 11percent). 1H NMR (400 MHz, d -acetone, δ in ppm) 8.20 (d, J=9 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 1H), 6.90 (d, J=9 6 Hz, 1H), 6.83 (dd, J=12 and 18 Hz), 6.22 (d, J=9 Hz, 1H), 5.94 (dd, J=2 and 12 Hz) 5.84 (dd, J=2 and 18 Hz), 5.19 (d, J=9 Hz, 1H), 4.68-4.60 (m, 1H) and 1.20 (d, J=7 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English


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View in Reaxys

O F NH

Cl

HN

N

O OH

HN

F

HN O N

Cl

N

OH

N



10%

Example Name 81 Example 81 2-chloro-4-((1R,2S)-1-(5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-fluorobenzohydrazide (1 g, 2.47 mmol) in anhydrous THF (15 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (3 mmol base/g) (3.37 g, 7.41 mmol) followed by para-toluene sulfonyl chloride (p-TSCl) (471 mg, 2.47 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction, the residue then washed with acetone (300 mL) followed by methanol (300 mL) and then concentrated to furnish a yellow oil (0.968 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (101 mg, 10percent). 1H NMR (400 MHz, δ in ppm) 7.86-7.83 (m, 1H), 7.75-7.71 (m, 1H), 7.67-7.61 (m, 2H), 7.49 (d, J=9 Hz, 1H), 7.43-7.37 (m, 1H), 6.87 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 5.13 (m, 1H), 4.82 (br s, 1H), 4.67-4.59 (m, 1H), 2.41 (s, 3H) and 1.41 (d, J=6.5 Hz). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O Cl NH

Cl

HN

N

Cl

O N

OH

HN

Cl

N

HN O N

Cl

Z

N

OH

N

O

N H

Cl

N



20 %, 33 % Example Name 21 Example 21; 2-chloro-4-((1R,2S)-1-(5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile; To a solution of 3-chloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (800 mg, 1.9 mmol) in anhydrous THF (20 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (2.59 g) followed by p-TSCl(435 mg, 2.28 mmol) and the mixture was stirred for 1 h. The mixture was filtered and the residue washed with acetone (800 mL) followed by Methanol (200 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (1:2)] to give two fractions. The first-eluted material was identified by 1H NMR spectroscopy as (Z)-2chloro-4-(1-(5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)-3-methylbenzonitrile (140 mg, 33percent) 1H NMR (500 MHz, CDCl3, δ in ppm) 8.03 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 7.03 (q, J=7 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 2.44 (s, 3H), 1.92 (d, J=6 Hz, 3H).The second-eluted material was the desired 2-chloro-4-((1R,2S)-1(5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (145 mg, 20percent). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.01 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.60-7.63 (m, 2H) 7.45 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 5.70 (d, J=9 Hz, 1H), 5.18 (m, 1H), 4.60-4.64 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6 Hz, 3H).


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With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

Cl

O

N

NH

Cl

HN

O

HN

N N

O

OH N H

N

N

N

OH



12 %

Example Name 50 Example 50 2-Chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)benzonitrile To a solution of N'-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (2 g, 5.03 mmol) in anhydrous THF (300 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (6.86 g) followed by p-TSCl (959 mg, 5.03 mmol) and the mixture was stirred for 1 h. The mixture was filtered and the residue washed with acetone (200 mL) followed by MeOH (200 mL). The filtrate was then concentrated and subjected to flash column chromatography [EtOAc-Hexanes (3:2)] to give two fractions. The second-eluted material was the desired 2-chloro-3-ethyl-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2yl)propylamino)benzonitrile (231 mg, 12percent). 1H NMR (500 MHz, CDCl , δ in ppm) 8.2 (d, J=8 Hz, 2H), 7.99 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 1H), 7.14 (s, 1H), 6.97 3 (d, J=8 Hz, 1H), 6.61 (d, J=8 Hz, 1H), 5.17-5.13 (m, 1H), 4.64-4.54 (m, 2H), 1.40 (d, J=6 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

O

H N Cl

N H

Cl O N N

O


Conditions & References Example Name 50.b Compound 3 (760mg, 3.35mmol) was suspended in POCl3 (6ml) and the reaction mixture was heated to 1 1O0C for 2.5 hours. The mixture was allowed to cool to ambient temperature and quenched by adding water, then it was extracted with EA and purified by chromatography eluting with (DCM: MeOH=20:l) to give Compound 4 as a white solid (415mg). Yield: 55percent. With trichlorophosphate, Time= 2.5h, T= 110 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys


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O O O O

N

H N N H

N

O

O

O

O O

O

O



93 %

Example Name 13 To 0.050 g (0.14 mmol) of hydrazide 25 was added 3 mL of POCl3. The mixture was refluxed 2 h, quenched with 50 g of ice, allowed to warm to 23 °C, and extracted twice with 25 mL of EtOAc . The organic layers were washed once with 25 mL water, twice with 25 mL of brine, dried with Na2S04, and concentrated to give 0.043 g (93percent yield) of 26 as a white solid. 1H NMR (200 MHz, CDC13) δ 7.72 (d, / = 8.0 Hz, 2H), 7.60 (d, J = 1.2 Hz, 1H), 7.07 (d, / = 8.4 Hz, 1H), 3.89 (s, 6H), 3.87 (s, 6H). With trichlorophosphate, Time= 2h, Reflux Patent; PROTEOTECH INC; ESPOSITO, Luke; YADON, Marisa, C.; CUMMINGS, Joel; HUDSON, F., Michael; LAKE, Thomas; HEFTI, Franz, F.; GOLDING, Geoffrey; CHOI, Seok-Rye; LI, Ximin; SNOW, Alan, D.; QUBAI, Hu; JUDY, Cam; WO2012/118935; (2012); (A1) English View in Reaxys

1.33 g

Stage 1: With triethylamine, p-toluenesulfonyl chloride in dichloromethane, T= 20 °C Stage 2: With water, triethylamine in methanol, Time= 24h, T= 20 °C Semenov, Victor V.; Titov, Ilia Y.; Sagamanova, Irina K.; Chernysheva, Natalia B.; Tsyganov, Dmitry V.; Konyushkin, Leonid D.; Firgang, Sergei I.; Semenov, Roman V.; Karmanova, Irina B.; Raihstat, Mikhail M.; Semenova, Marina N.; Kiselyov, Alex S.; Ikizalp, Natalie N.; Journal of Natural Products; vol. 73; nb. 11; (2010); p. 1796 - 1802 View in Reaxys

F F

H N

O

NH O

O O

O

NH 2

N N O

O NH 2


Conditions & References Example Name 1.8.31 To the hydrazide (500 mg, 1.056 mmol) in DCE (10 ml), Burgess reagent (629 mg, 2.64 mmol) was added and refluxed for 4h at which time reaction colour turned brown, then reaction mixture was cooled, diluted with DCM, washed with aq sodium bicarbonate solution, water brine and dried. Crude residue was column chromatographed. (50percentethyl acetae/hexane). Product is a yellow syrup and was obtained in 62percent yield. With Burgess Reagent in 1,2-dichloro-ethane, Time= 4h, Reflux Patent; COMENTIS, INC.; ASTELLAS PHARMA INC.; BILCER, Geoffrey, M.; DEVASAMUDRAM, Thippeswamy; LILLY, John, C.; ANKALA, Sudha, V.; MOSKALEV, Nikolai, V.; LIU, Chunfeng; INOUE, Makoto; KAWAKAMI, Shimpei; MUNAKATA, Ryosuke; HAMAJIMA, Toshihiro; WO2012/54510; (2012); (A1) English View in Reaxys


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O

O Cl

S

F

O

N N N

N

N H

F

Cl

S

O

F

O

N

H N

N

N N N

N O

N

F

N

O



13 %

Example Name 18.g 4-Cyano-benzoic acid N'- {3-[4-(2-chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H- [l,2,4]triazol-3-yl]-2,3-difluoroacryloyl} -hydrazide 11 was dissolved into dichloromethane (10 mL) and triphenylphosphine (0.27 g, 1.02 mmol), carbon tetrabromide (0.34 g, 1.02 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with methanol/ DCM 1/99-5/95) to give 4-(5-{2-[4-(2-chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2- yl)-4H-[l,2,4]triazol-3-yl]-l,2-difluoro-vinyl}-[l,3,4]oxadiazol-2-yl)-benzonitrile as a solid. Yield: 0.05 g, 13percent.1H-NMR (300 Hz, CDCI3) δ (ppm): 8.77 (s, 1 H), 8.61 (d, 1 H), 8.38 (d, 1 H), 8.10 (d, 2 H), 7.80 (d, 2 H), 7.58-7.51 (m, 3 H), 7.46-7.41 (m, 1 H), 3.10 (s, 3 H).MS: 566.2 (MH+).HPLC: 95percent With carbon tetrabromide, triethylamine, triphenylphosphine in dichloromethane, Time= 2h, T= 20 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Daniel; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; VORONKOV, Andrey Edward; GOLDING, Louise; WO2012/76898; (2012); (A1) English View in Reaxys

O S O

O

Cl N

N

O

E N

Cl

S

O

N

N

HN

NH

N

E

N

N

N

N

O

N

N

O



12.7 %

Example Name 13.h (E)-N'-(3-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H-l,2,4-triazol-3- yl)acryloyl)-4-cyanobenzohydrazide 10 was dissolved into dichloromethane (10 mL) and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) andtriethylamine (0.18 mL, 1.30 mmol) was added. The reaction was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1 :3) to give (E)-4-(5-(2-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridin-2-yl)-4H- l,2,4-triazol-3-yl)vinyl)-l,3,4-oxadiazol-2-yl)benzonitrile as a yellow solid. Yield: 0.035 g, 12.7percent.1H-NMR (300 Hz, CDCI3) δ ppm 8.74 (d, 1 H), 8.60 (d, 1 H), 8.32 (dd, 1 H), 8.17 (d, 2 H),7.82 (d, 2 H), 7.63 (d, 1 H), 7.62 (m, 2 H), 7.49 (td, 1 H), 7.41 (dd, 1 H), 7.13 (d, 1 H), 3.06 (s, 3 H). MS: 530.3 (M+H), 552.20 (M+Na).HPLC: 98percent With carbon tetrabromide, triethylamine, triphenylphosphine in dichloromethane, Time= 2h, T= 20 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Daniel; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; VORONKOV, Andrey Edward; GOLDING, Louise; WO2012/76898; (2012); (A1) English View in Reaxys

O S O

O

Cl N

N

O

E N

Cl

S

O

N

N

HN

NH

N

Cl

N

E

N

N

N

O Cl

O


Conditions & References Example Name 14.g


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4-chloro-N'-[(E)-3-[4-(2-chlorophenyl)-5-(5-methylsulfonyl-2-pyridyl)-l,2,4-triazol-3-yl]prop-2- enoyl]benzohydrazide 10 was dissolved into dichloromethane (10 mL) and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) was added. The reaction was kept at room temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1 :3) to give 2-(4(2- chlorophenyl)-5-((E)-2-(5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)vinyl)-4H-l,2,4-triazol-3-yl)-5- (methylsulfonyl)pyridine as a yellow solid. Yield: 0.03 g, 11percent.1 H-NMR (300 Hz, CDC13) δ (ppm): 8.74 (d, IH), 8.60 (d, IH), 8.32 (dd, IH), 8.17 (d, 2H),7.82 (d,2H), 7.63 (d,lH), 7.62 (m,2H), 7.49 (d, IH), 7.41 (dd, IH), 7.13 (d, IH), 3.06 (s, 3H).MS: 539.2 (MH+).HPLC: 98percent With carbon tetrabromide, triethylamine, triphenylphosphine in dichloromethane, Time= 2h, T= 20 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Daniel; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; VORONKOV, Andrey Edward; GOLDING, Louise; WO2012/76898; (2012); (A1) English View in Reaxys O N

O

O

O N

HN

NH

N

O

N O

O


Conditions & References With zirconium tetrachloride in dichloromethane, Time= 3h, T= 20 °C Sharma, G. V. M.; Begum, Asra; Rakesh; Krishna, Palakodety Radha; Synthetic Communications; vol. 34; nb. 13; (2004); p. 2387 - 2392 View in Reaxys

73 %

With pyridine, thionyl chloride, Time= 1h, Heating Blackhall, Alexander; Brydon, Donald L.; Saga, Anthony J. G.; Smith, David M.; Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999); (1980); p. 773 - 777 View in Reaxys With thionyl chloride, T= 100 °C , im Rohr Stolle; Leverkus; Chemische Berichte; vol. 46; (1913); p. 4076 View in Reaxys With trichlorophosphate Grekow et al.; Zhurnal Obshchei Khimii; vol. 29; (1959); p. 3054,3055; engl. Ausg. S. 3020, 3021 View in Reaxys With thionyl chloride Yasinskii,O.A. et al.; J. Gen. Chem. USSR (Engl. Transl.); vol. 47; (1977); p. 211 - 217,194 - 198 View in Reaxys With trichlorophosphate, Time= 0.5h, Heating Popova, N. A.; Yushko, E. G.; Krasovitskii, B. M.; Minkin, V. I.; Lyubarskaya, A. E.; Gol'dberg, M. L.; Chemistry of Heterocyclic Compounds (New York, NY, United States); (1983); p. 22 - 28; Khimiya Geterotsiklicheskikh Soedinenii; vol. 19; nb. 1; (1983); p. 26 - 32 View in Reaxys in N,N,N',N',N'',N''-hexamethylphosphoric triamide, Time= 0.0111111h, microwave irradiation Mashraqui, Sabir H.; Ghadigaonkar, Shailesh G.; Kenny, Rajesh S.; Synthetic Communications; vol. 33; nb. 14; (2003); p. 2541 - 2546 View in Reaxys With carbon tetrabromide, triphenylphosphine in dichloromethane, T= 0 °C


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Rajapakse, Hemaka A.; Zhu, Hong; Young, Mary Beth; Mott, Bryan T.; Tetrahedron Letters; vol. 47; nb. 28; (2006); p. 4827 - 4830 View in Reaxys With N-ethyl-N,N-diisopropylamine, p-toluenesulfonyl chloride in acetonitrile, T= 20 °C Stabile, Paolo; Lamonica, Alessandro; Ribecai, Arianna; Castoldi, Damiano; Guercio, Giuseppe; Curcuruto, Ornella; Tetrahedron Letters; vol. 51; nb. 37; (2010); p. 4801 - 4805 View in Reaxys With trichlorophosphate, T= 100 °C Brown, Matthew L.; Aaron, Wade; Austin, Richard J.; Chong, Angela; Huang, Tom; Jiang, Ben; Kaizerman, Jacob A.; Lee, Gary; Lucas, Brian S.; McMinn, Dustin L.; Orf, Jessica; Rong, Minqing; Toteva, Maria M.; Xu, Guifen; Ye, Qiuping; Zhong, Wendy; Degraffenreid, Michael R.; Wickramasinghe, Dineli; Powers, Jay P.; Hungate, Randall; Johnson, Michael G.; Bioorganic and Medicinal Chemistry Letters; vol. 21; nb. 18; (2011); p. 5206 5209 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys O N O

O

O

N

N HN

NH

N

O

O

Cl O

Cl


Conditions & References With zirconium tetrachloride in dichloromethane, Time= 2.75h, T= 20 °C Sharma, G. V. M.; Begum, Asra; Rakesh; Krishna, Palakodety Radha; Synthetic Communications; vol. 34; nb. 13; (2004); p. 2387 - 2392 View in Reaxys

83 %

With thionyl chloride, Time= 2h, Heating Zareef, Muhammad; Iqbal, Rashid; Al-Masoudi, Najim A.; Zaidi, Javid H.; Arfan, Muhammad; Shahzad, Sohail A.; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 182; nb. 2; (2007); p. 281 - 298 View in Reaxys With thionyl chloride Yasinskii,O.A. et al.; J. Gen. Chem. USSR (Engl. Transl.); vol. 47; (1977); p. 211 - 217,194 - 198 View in Reaxys With trichlorophosphate, Time= 10h, Reflux Gierczyk, Blazej; Zalas, MacIej; Kazmierczak, Marcin; Grajewski, Jakub; Pankiewicz, Radoslaw; Wyrzykiewicz, Bozena; Magnetic Resonance in Chemistry; vol. 49; nb. 10; (2011); p. 648 - 654 View in Reaxys


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O

N N

HN

O

NH Br O

Br


Conditions & References With 1-propanephosphonic acid cyclic anhydride, triethylamine in ethyl acetate, Time= 3h, Reflux Augustine, John Kallikat; Vairaperumal, Veeramani; Narasimhan, Sharmila; Alagarsamy, Padma; Radhakrishnan, Anbarasi; Tetrahedron; vol. 65; nb. 48; (2009); p. 9989 - 9996 View in Reaxys

79 %

With trichlorophosphate, Time= 2.5h, Heating Wang, Changsheng; Palsson, Lars-Olof; Batsanov, Andrei S.; Bryce, Martin R.; Journal of the American Chemical Society; vol. 128; nb. 11; (2006); p. 3789 - 3799 View in Reaxys

63.7 %

With trichlorophosphate, Time= 20h, T= 100 °C , Inert atmosphere Tsuchiya, Kousuke; Sakaguchi, Kota; Kasuga, Hidemasa; Ogino, Kenji; Kawakami, Akira; Taka, Hideo; Kita, Hiroshi; Polymer; vol. 51; nb. 3; (2010); p. 616 - 622 View in Reaxys

56 %

With trichlorophosphate, Time= 6h, Heating Hung, Ming-Chin; Liao, Jin-Long; Chen, Show-An; Chen, Su-Hua; Su, An-Chung; Journal of the American Chemical Society; vol. 127; nb. 42; (2005); p. 14576 - 14577 View in Reaxys With trichlorophosphate Xu, Qiu-Lei; Li, Hong-Yan; Wang, Cheng-Cheng; Zhang, Song; Li, Tian-Yi; Jing, Yi-Ming; Zheng, You-Xuan; Huang, Wei; Zuo, Jing-Lin; You, Xiao-Zeng; Inorganica Chimica Acta; vol. 391; (2012); p. 50 - 57 View in Reaxys

O

O O

Br O

O

O

O HN

NH

N

Br

O

N

O


Conditions & References Example Name 1 BK1_77 was refluxed in 125 ml POCl3 at 130 °C for 24 hours. The excess POCl3 (100 ml) was distilled off. The remaining solution was added to 600 ml of water and ice, upon which a white-brown oily solid forms. The solid was run through a column of silica using hexanes: ethyl acetate (10:1) as eluent to yield 2.08 g (45 percent) of white solid. 1H NMR (CDC13, 300 MHz) (at)8.065-8.038 (d, 2 H, J1 = 8.1 Hz), 7.491-7.463 (d, 2H, J= 8.4 Hz), 7.25 (s, 2H), 4.57 (s, 2H), 4.04-3.97 (m, 6H), 1.85-1.68 (m, 6H), 1.56-1.43 (m, 6H), 1.40-1.05 (m, 24 H), 0.86-0.82 (t, J= 6.6 Hz, 9H). 1 3C NMR (CDCl3,75 MHz) No. 164.71, 163.78, 153.49, 141.35, 140.84, 129.03, 127.09, 123.80, 118.26, 105.31, 77.42, 76.99, 76.57, 73.50, 69.26,45.28, 31.80, 31.73, 30.25,29.42, 29.27, 29.19, 25.99, 22.57, 13.99. With trichlorophosphate, Time= 24h, T= 130 °C , Heating / reflux


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Patent; GEORGIA TECH RESEARCH CORPORATION; WO2005/123737; (2005); (A2) English View in Reaxys

O

O O

O

N N

N H N N H

O

O

N

N

N

O

O

O


Conditions & References Example Name 4.2 Step 2: MethyB -(5-(4-(5-(4-tert-butylphenyl)-1.3.4-oxadiazol-2-yl)phenyl)-1.3.4- oxadiazol-2-yl)benzoate (YZ -1-253): Methyl 3 -(2-(4-(5-(4-tert-butylphenyl)-l,3,4-oxadiazol-2-yl)benzoyl)- hydrazinecarbonyl)benzoate (2.5 g, 5.01 mmol) was added in POCl 3 (25.0 ml). The reaction was heated to 90 0C and kept at this temperature for 2 hours. After cooling down to room temperature, the reaction mixture was slowly dropped into ice -water (300.0 ml). The yellow color solid that formed was collected by vacuum filtration. The crude material was purified by a silica gel column using dichloromethane/ethyl acetate, ratio of (9 : 1), as the eluent. After the removal of solvents, a pure product as a white solid was obtained in 1.22 g (50.6percent) yield by recrystallization from dichloromethane/ methanol. 1H NMR (400 MHz, CDCl 3) δ: 8.80 (t 1 H, J= 1.6 Hz), 8.39 (dt, 1 H, J1 = 8.0 Hz, J2 = 1.6 Hz), 8.34 (s, 2 H), 8.33 (s, 2 H), 8.25 (dt, I H, J1 = 8.0 Hz, J2 = 1.6 Hz), 8.09 (d, 2 H, J= 8.4 Hz), 7.67 (t, 1 H, J= 8.0 Hz), 7.58 ( d, 2 H, J= 8.4 Hz), 4.00 (s, 3 H, OCH3), 1.39 (s, 9 H, 3 x CH3) ppm. 13C NMR (100 MHz, CDCl 3) δ: 165.94, 165.16, 164.22, 164.02, 163.42, 155.73, 132.82, 131.29, 131.14, 129.44, 1 27.98, 127.58, 127.48, 126.88, 126.19, 126.13, 124.02, 120.70, 52.55, 35.12, 31.08 ppm. MS-FAB (m/z): [M]+ calcd for C28H24N4O4 480.2, found 480.8. With trichlorophosphate, Time= 2h, T= 90 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

O O HN

NH

O

O N

O

O

N


O O

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O O

O N N O O O N

N

O



50.2 %

Example Name 10.7 Step 7:4-(5 -(4 -(5 -(3 ,4,5 -Tris(dodecyloxy)phenyl) - 1 ,3 ,4 -oxadiazol -2-yl)phenyl) -1,3,4- oxadiazol-2-yl)phenyl acetate (YZ -1-219): 4-(2-(4-(5-(3,4,5- Tris(dodecyloxy)phenyl) - 1 ,3 ,4-oxadiazol-2-yl)benzoyl)hydrazinecarbonyl)phenyl acetate (2.5 g, 2.51 mmol) was added to POCl 3 (35.0 ml). The reaction was heated to 100 0C, and kept at this temperature for 5 h. After cooling, the reaction mixture was slowly added to ice water (400.0 ml). The cru de product was collected as yellow solid, and purified by silica gel column using dichloromethane/ethyl acetate (9 : 1) as eluent. Pure product was obtained in 1.23 g (50.2percent). 1H NMR (400 MHz, CDCl 3) δ: 8.32 (s, 4 H), 8.21 (d, 2 H, J= 8.8 Hz), 7.34 (s, 2 H), 7.32 (d, 2 H, J= 8.8 Hz), 4.11 - 4.04 (m, 6 H, 3 x CH2), 2.36 (s, 3 H, CH3), 1.90 - 1.75 (m, 6 H, 3 x CH 2), 1.504 (m, 6 H, 3 x CH2), 1.27 (m, 48 H, 24 x CH 2), 0.88 (m, 9 H, 3 x CH3), 0.68 (m) ppm. 13C NMR (100 MHz, CDCl 3) δ: 168.89, 165.22, 164.37, 163.77, 163.47, 153.63, 153.45, 141.57, 128.44, 127.48, 126.70, 126.36, 122.57, 121.17, 118.09, 105.46, 73.64, 69.38, 31.09, 30.32, 29.73, 29.69, 29.65, 29.63, 29.57, 29.40, 29.35, 29.30, 26.08, 22.68, 21.16, 14.11 ppm. MS-EI (m/z): [M]+ calcd for C60H88N4O7 976.7, found 976.5. With trichlorophosphate, Time= 5h, T= 100 °C Patent; Georgia Tech Research Corporation; SOLVAY (Societe Anonyme); WO2009/80797; (2009); (A1) English View in Reaxys

F

O

F

F F

NH

Cl

HN

N

O

F F

OH

HN

N

N

O

O F

Cl

N

HN

F F

N

N

Z

OH

N H

Cl

N



13 %, 35 % Example Name 68 Example 68; 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3methylbenzonitrile; To a solution of N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(trifluoromethyl)benzohydrazide (1.0 g, 2.20 mmol) in anhydrous THF (90 mL) at room temperature was added 2-tertbutylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (3.0 g, 6.60 mmol) followed by para-toluenesulfonyl chloride (419 mg, 2.20 mmol) and the mixture was stirred for one hour.


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The mixture was filtered under suction and the residue washed with acetone (2.x.100 mL) followed by Methanol (2.x. 150 mL). The filtrate was concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-40percent EtOAc in hexanes) to provided (Z)-2-chloro-3-methyl-4-(1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)prop-1-enylamino)benzonitrile, the less polar component as a colourless solid (122 mg, 13percent) and 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile, the more polar component as a yellow oil (336 mg, 35percent): Less polar compound; 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.27 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.13 (br s, 1H), 7.04 (q, J=7.2 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 2.47 (s, 3H), 1.91 (d, J=7.0 Hz, 3H): More polar compound; 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.22 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 5.70 (d, J=8.6 Hz, 1H), 5.16 (dd, J=3.5, 8.6 Hz, 1H), 4.86 (br d, J=4.3 Hz, 1H), 4.70-4.61 (m, 1H), 2.40 (s, 3H), 1.43 (d, J=6.4 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys

N O NH HN

O

HN N

OH

OH HN

O

N N

N

N


Conditions & References Example Name 51 Example 51 4-((1R,2R)-1-(5-(4-Cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-1-naphthonitrile To a solution of 4-cyano-N'-((2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (900 mg, 2.18 mmol) in anhydrous THF (90 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (2.97 g, 6.53 mmol) followed by p-TSCl (498 mg, 2.60 mmol) and the mixture was stirred for 75 minutes. The mixture was filtered and the residue washed with acetone (3*100 mL) followed by MeOH (3*150 mL). The filtrate was concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (30-50percent EtOAc in hexanes) to provided the title compound as a brown oil (25 mg, 3percent): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.19 (d, J=8.4 Hz, 2H), 8.18 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.2 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 5.69 (d, J=9.6 Hz, 1H), 5.47 (d, J=3.7 Hz, 1H), 4.71 (dqd, J=3.7, 6.5, 9.9 Hz, 1H), 1.65 (d, J=6.4 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1.25h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys


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N O NH HN

O

HN

OH

OH

HN

O

N N

N



0.3%

Example Name 52 Example 52 4-((1R,2R)-2-Hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-1-naphthonitrile To a solution of N'-((2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (846 mg, 2.18 mmol) in anhydrous THF (90 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol base/g) (2.97 g, 6.53 mmol) followed by p-TSCl (498 mg, 2.60 mmol) and the mixture was stirred for 75 min. The mixture was filtered under suction and the residue washed with acetone (3*100 mL) followed by MeOH (3*150 mL). The filtrate was concentrated under reduced pressure to provide a off white solid, which was purified by flash chromatography over silica gel (25-40percent EtOAc in hexanes) to provided the title compound as a yellow solid (2.1 mg, 0.3percent): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.19 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.84 (d, J=7.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.0 Hz, 1H), 7.63-7.53 (m, 2H), 7.49 (t, J=7.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 1H), 5.41 (d, J=9.4 Hz, 1H), 4.95 (d, J=2.9 Hz, 1H), 4.75-4.64 (m, 1H), 1.50 (d, J=6.4 Hz, 3H). With p-toluenesulfonyl chloride in tetrahydrofuran, Time= 1.25h, T= 20 °C Patent; Miller, Chris P.; US2009/253758; (2009); (A1) English View in Reaxys N

NH 2

H 2N

N

O N O

N O

NH N

N

N

HN

O

F O

N F


Conditions & References Example Name 2.A.IV.B.4 A suspension of 4-[5-amino-6-[[(3-fluorobenzoyl)amino]carbamoyl]pyrazin-2- yl]-Ν,Ν-dimethyl-benzamide (127 mg, 0.3007 mmol) in anhydrous acetonitrile (2.540 mL) cooled in an ice bath, was treated with DIPEA (1 16.6 mg, 157.1 μL, 0.9021 mmol) followed by dibromo(triphenyl)phosphorane (165.0 mg, 0.3909 mmol) portionwise. The reaction mixture was then placed under nitrogen and allowed to stir for 10 minutes. The resultant precipitate was isolated by filtration, washed with ether and dried to give the impure desired product. The material was purified further by reverse phase preparative HPLC [Waters Sunfire C 18, 1OmM, 100 A column, gradient 10percent - 95percent B (solvent A: 0.05percent TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (58.4mg, 48percent Yield). 1H NMR (400.0 MHz, DMSO) d 2.98 (6H, m), 7.55-7.61 (3H, m), 7.73-7.85 (3H, m), 7.96 (1H, m), 8.02 (1H, m), 8.19 (2H, m), 9.01 (1H, s) ppm; MS (ES+) 405.16 With N-ethyl-N,N-diisopropylamine, dibromotriphenyl-phosphorane in acetonitrile, Cooling with ice, Inert atmosphere Patent; VERTEX PHARMACEUTICALS INCORPORATED; CHARRIER, Jean-Damien; DURRANT, Steven; KAY, David; KNEGTEL, Ronald; MACCORMICK, Somhairle; MORTIMORE, Michael; O'DONNELL, Michael; PINDER, Joanne; RUTHERFORD, Alistair; VIRANI, Anisa, Nizarali; YOUNG, Stephen; REAPER, Philip, Michael; WO2010/71837; (2010); (A1) English View in Reaxys


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O

H N

Cl

O

N H

N N O Cl



45 %

Example Name 57.b Compound 4 (2.3g, 10.5mmol) was suspended in POCl3 (10 ml) and the. reaction mixture was heated to 1100C for 2.5 hours. The mixture was allowed to cool to ambient temperature and quenched by adding water, then it was extracted with EA and purified by chromatography eluting with (DCM:MeOH=20:l) to give Compound 5 as a white solid (Ig). Yield: 45percent. With trichlorophosphate, Time= 2.5h, T= 110 °C Patent; OSLO UNIVERSITY HOSPITAL HF; HOLSWORTH, Dan; WAALER, Jo; MACHON, Ondrej; KRAUSS, Stefan; GOLDING, Louise; WO2010/139966; (2010); (A1) English View in Reaxys

O

H N

O

O

N H O

O

O

N

O O

O

N

N N O

O



51 %

Example Name 293 Example 293:Methyl 4-(5-(4-nitrophenyl)-1 ,3,4-oxadiazol-2-yl)butanoateTo a solution of the compound of example 274 (6.2 g, 20.05 mmol) and phosphorus oxychloride (33.7 g, 220 mmol) in dry acetonitrile (150 mL) was heated at reflux temperature for 2-3 h. After completion of reaction, the solvent was removed and the material obtained was taken in ice water. The solution was made basic by addition of sodium bicarbonate and was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica gel, 30 percent ethyl acetate in petroleum ether). Yield: 51 percent; 1 H NMR (DMSO-d6, 300MHz): δ 8.41 (d, 2H), 8.26 (d, 2H), 3.71 (s, 3H), 3.10 (t, 2H), 2.69 (t, 2H), 2.29 (m, 2H); MS: m/z 292 (M+1 ). With trichlorophosphate in acetonitrile, Reflux Patent; PIRAMAL LIFE SCIENCES LIMITED; SHARMA, Rajiv; KADAM, Kishorkumar Shivajirao; JADHAV, Ravindra Dnyandev; KANDRE, Shivaji Sadashiv; GUPTE, Amol; WO2012/29032; (2012); (A2) English View in Reaxys

O

S

O

O

O

N

N

O

H N I

S

N H

N I

N O

O


Conditions & References Example Name 43 Preparation of compound 43b: 2-cyclopropyl-5-(3-iodo-l-tosyl-lH-indol-5-yl)-l,3,4- oxadiazoleIn a 50 mL RBF, N'-(cyclopropanecarbonyl)-3-iodo-l-tosyl-lH-indole-5- carbohydrazide (1.13 g, 2.159 mmol) was treated with POCl3 (5 mL, 53.6mmol), under argon. The flask was fitted with a reflux condenser. The reaction was stirred and heated at 1 10 °C for 1.25 h. The crude material was treatedwith water and extracted with EtOAc. The organic layer was washed withbrine, dried, filtered and concentrated to 20 mL of solvent. When about 20 mL of solvent remained, a brown solid precipitated


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and was collected by filtration.The mother liquor was purified with flash chromatography to give 2- cyclopropyl-5-(3iodo-l-tosyl-lH-indol-5-yl)-l,3,4-oxadiazole (570 mg, 1.128 mmol, 52.2 percent ). MS (ESI, pos. ion) m/z: 506.0 (M +l). .H NMR (400 MHz,DMSO-de) δ ppm 8.23 (s, 1 H), 8.15 (d, J=8.6 Hz, 1 H), 7.94 - 8.03 (m, 3 H),7.85 (s, 1 H), 7.43 (d, J=8.0 Hz, 2 H), 2.28 - 2.37 (m, 4 H), 1.09 - 1.21 (m, 4 H). With trichlorophosphate, Time= 1.25h, T= 110 °C , Inert atmosphere Patent; AMGEN INC.; WANG, Hui-Ling; CEE, Victor, C.; HERBERICH, Bradley, J.; JACKSON, Claire, L., M.; LANMAN, Brian, Alan; NIXEY, Thomas; PETTUS, Liping, H.; REED, Anthony, B.; WU, Bin; WURZ, Ryan; TASKER, Andrew; WO2012/129338; (2012); (A1) English View in Reaxys

F

F N

F

N O NH

NH O

HN

O

O

N

O

NH

N

O

O

H N

O

F N

N H

F

N

F

O


Conditions & References Example Name 86.A Part A: Preparation of 1-(3-((2-(tert butoxycarbonyl)aminopropanamido)methyl)phenyl)-N'-benzoyl-3-(trifluoromethyl)-1H-pyrazole-5-carbohydrazide PyBOP (86 mg, 0.16 mmol) was added to a solution of 1-(3-((2-(tert butoxycarbonyl)propanamido)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (50 mg, 0.11 mmol), benzoic hydrazide (23 mg, 0.16 mmol) and N,N-diisopropylethylamine (21.2 mg, 0.16 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane-water (10:2 Ml). The organic layer was washed with water, dried and concentrated to yield the intermediate which was carried as it to the next reaction. Diisopropylcarbodiimide (50 mg) was added to the solution of the intermediate (35 mg, 0.06 mmol) in DMF (0.1 Ml). The solution was heated at 100° C. for 18 hours. The solution was concentrated in vaccuo and the crude was purified using preparative HPLC using conditions below to yield 28.3 mg of tert-butyl 1-(3-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylamino)-1-oxopropan-2-ylcarbamate. Conditions: Column-YMC ODS (20.x.50 mm) Solvents-A-90percent water-10percent methanol-0.1percent TFA B-10percent water-90percent methanol-0.1percent TFA Gradient-20percent B to 100percent B in 12 min Retention time: 10.1 min MS (ESI) m/z 557.21 (M+H) NMR:8.12(m, 2H), 7.8(s, 1H), 7.6-7.5(m, 4H), 7.2-7.1 (m, 2H), 6.9(s, 1H), 4.5(dd, 2H), 4.2(, 1H), 1.46(s, 9H), 1.3(d, 3H) With diisopropyl-carbodiimide in N,N-dimethyl-formamide, Time= 18h, T= 100 °C Patent; Purandare, Ashok Vinayak; Chen, Zhong; US2007/60589; (2007); (A1) English View in Reaxys F

O

F N

HN

O

F

NH

O O

O O

O

N N

O

N

O

F F F


Conditions & References Example Name 1.6 To a solution of 2-oxo-2-[2-(4-{4-[2-(trifluoromethyl)phenoxy]piperidin-l- yl}benzoyl)hydrazino]ethyl acetate in tetrahydrofuran (0.12M) was added Burgess reagent (1.5 eq). The reaction was then stirred 30 min at 150 0C under microwave radiation. After cooling, the reaction mixture was concentrated and the crude residue was purified by column chromatography (acetone/CH2Cl2, 10:90 to 15:85) to afford the title compound. 1HNMR (400 MHz, acetone-^): d 7.90 (d, 2H), 7.67-7.57 (m, 2H), 7.36 (d, IH), 7.17 (d, 2H), 7.10 (t, IH), 5.38 (s, 2H), 5.0-4.90 (m, IH), 3.72- 3.62 (m, 2H), 3.56-3.46 (m, 2H), 2.22-2.12 (m, 5H), 2.0-1.90 (m, 2H). With Burgess Reagent in tetrahydrofuran, Time= 0.5h, T= 150 °C , Irradiation


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Patent; MERCK FROSST CANADA LTD.; WO2007/134457; (2007); (A1) English View in Reaxys

O

N

N

H N

O

N H

O N

O

O N


Conditions & References To a solution of isonicotinic acid 4 (150 mg, 0.744 mmol), 4-benzyloxy-3,5-dimethyl-benzoic acid hydrazide (200 mg, 0.740 mmol) and DIPEA (302 mg, 2.34 mmol) in DCM (15 ml.) PyBOP (420 mg, 0.807 mmol) is added portionwise at 00C. The mixture is stirred at 00C for 3 h before pyridine (295 mg, 3.73 mmol) followed by trifluoromethanosulfonic acid anhydride (214 mg, 1.17 mmol) is added. The mixtre is stirred at rt for 15 h before another portion of pyridine (295 mg, 3.73 mmol) and trifluoromethanosulfonic acid anhydride (214 mg, 1.17 mmol) is added. After stirring for 2 h yet another portion of pyridine (295 mg, 3.73 mmol) and trifluoromethanosulfonic acid anhydride (214 mg, 1.17 mmol) is added and stirring is continued for 2 h. Dimethylaminopropylamine (0.25 ml.) is added and the mixture is stirred for 30 min before it is diluted with ether (100 ml_), washed with 1 M aq. NaH2PO4 solution (2x30 ml.) and sat. aq. Na2COs solution. The washings are extracted back with EA (2x75 ml_). The combined org. extracts are dried over MgSO4, filtered and evaporated to give crude 4-[5-(4-benzyloxy-3,5-dimethyl-phenyl)-[1 ,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl- pyridine; LCMS: tR = 1.12 min; [M+1]+ = 400.22. To a solution of this material in formic acid (0.125 ml_), MeOH (5 ml.) and THF (10 ml_), Pd/C (50 mg, 10percent Pd) is added and the mixture is stirred at rt under 1 bar of H2 for 15 h. The catalyst is removed by filtration and the solvent of the filtrate is evaporated. The residue is dissolved in EA (100 ml_), washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with EA to give 4-[5-(2-ethyl-6-methyl-pyridin- 4-yl)-[1 ,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenol (209 mg) as a beige foam; LC-MS: tR = 0.74 min; [M+1]+ = 310.11. With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, Time= 19h, T= 20 °C Patent; ACTELION PHARMACEUTICALS LTD; WO2008/29371; (2008); (A1) English View in Reaxys

O

N

O H N N H

N O

O

O

O

O


Conditions & References Example Name 24.c c) A solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid N'-(4-isopropoxy-3- methyl-benzoyl)-hydrazide (1.57 g, 3.40 mmol) and Burgess reagent (1.06 g, 4.43 mmol) in THF (30 mL) is heated to 1100C under microwave irradiation for 3 min. The mixture is cooled, diluted with diethyl ether, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2-(4-benzyloxy-3-ethyl-5-methylphenyl)-5-(4- isopropoxy-3-methyl-phenyl)-[1 ,3,4]oxadiazole (1.25 g) as a colourless oil; LC-MS: tR = 1.24 min, [M +1]+ = 443.58. With Burgess Reagent in tetrahydrofuran, Time= 0.05h, T= 110 °C , Microwave irradiation Patent; ACTELION PHARMACEUTICALS LTD; WO2008/35239; (2008); (A1) English View in Reaxys


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O HN

NH O

O

O

O N

F F

N F

F

F F


Conditions & References Example Name 8.A Example Title Step A To a magnetically stirred solution of 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (8-A) (70 mg, 0.30 mmol) in methylene chloride (1 mL) at room temperature was added 2 M oxalyl chloride in methylene chloride (0.61 mL, 1.22 mmol). Two drops of catalytic DMF were added to catalyze the reaction. The reaction was stirred for 30 min and solvent and reagent removed in vacuo. Methylene chloride (1 mL) was added to the residue, followed by 4-(benzyloxy)-2-(trifluoromethyl)benzoic hydrazide (8-B) (141 mg, 0.46 mmol) and triethylamine (0.07 mL, 0.46 mmol). The reaction was stirred at room temperature overnight to afford intermediate 8-C, N'-[4-(benzyloxy)-2-(trifluoromethyl)benzoyl]-4-phenylbicyclo[2.2.2]octane-1-carbohydrazide, which was not isolated. To the crude product (8-C) were then added 2-chloro-1,3dimethylimidazolinium chloride (257 mg, 1.52 mmol), more triethylamine (0.42 mL, 3.04 mmol), and methylene chloride (2 mL). The reaction was stirred at room temperature for 4 h. The reaction mixture was then diluted with methylene chloride (30 mL) and washed with water (30 mL) two times and with brine (30 mL) once. The combined aqueous layers were extracted with methylene chloride (25 mL) once. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed on silica with 10percent ethyl acetate in hexanes as eluant to give 2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D). MS: m/z 505 (M+1). With DMEG, triethylamine in dichloromethane, Time= 4h, T= 20 °C Patent; Waddell, Sherman T.; Santorelli, Gina M.; Maletic, Milana M.; Leeman, Aaron H.; Gu, Xin; Graham, Donald W.; Balkovec, James M.; Aster, Susan D.; US2004/133011; (2004); (A1) English View in Reaxys

Br

Br Br O

N

NH HN

O

N O Br

O

O


Conditions & References Example Name 1.E Example Title Part E : Synthesis of 2-(2,5-Dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole A mixture of 2, 5-dibromo-N'- [4- (octyloxy) benzoyl] benzohydrazide (39.1 g, 0.0743 mol) and phosphorus oxychloride (203 mL) was refluxed for 8 hrs. Unreacted phosphorus oxychloride was distilled off and the residue poured onto crushed ice. The precipitated solid was collected by filtration and re-crystallized from EtOH/water to give 33.6 g (89 percent yield) 2- (2, 5-DIBROMOPHENYL)-5- [4- (OCTYLOXY) phenyl] 1, 3,4- oxadiazole. With trichlorophosphate, Time= 8h, Heating / reflux Patent; 3M INNOVATIVE PROPERTIES COMPANY; WO2004/96783; (2004); (A1) English View in Reaxys


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N

O O

H N

S

N H

N

O

O

O S

O

O N

N


Conditions & References Example Name 1 Example 1 Preparation of dimethyl- {6- [5- (2-phenoxy-ethylsulfanylmethyl)- [1,3, 4] oxadiazol-2-yl]- benzofuran-2-ylmethyl}-amine oxalate A THF solution of 2-dimethylaminomethyl-benzofuran-6-carboxylic acid N'- [2- (2-phenoxy-ethylsulfanyl) -acetyl] -hydrazide (2.2 g, 5.15 mmol, 1 eq. ) was treated with triethylamine (1.88 g, 18.54 mmol, 2.58 mL, 3.6 eq. ), triphenylphosphine (1.49 g, 5.67 mmol, 1.1 eq. ), and carbon tetrabromide (2.05 g, 6.18 mmol, 1.2 eq. ). The solution was allowed to stir at room temperature overnight. The solvent was removed from the suspension leaving a brown oil that was purified via normal phase chromatography leaving dimethyl- {6- [5- (2-phenoxy- ethylsulfanylmethyl)[1, 3,4] oxadiazol-2-yl]-benzofuran-2-ylmethyl}-amine as an orange oil contaminated with triphenylphosphine oxide. The oil was converted to the oxalate salt by adding an acetone solution of oxalic acid to an acetone solution of the amine. Obtained dimethyl- {6- [5-(2-phenoxy-ethylsulfanylmethyl)- [1, 3,4] oxadiazol-2-yl] - benzofuran-2-ylmethyl}amine oxalate (0.5244 g, 43percent yield) as an off-white solid by filtration. With carbon tetrabromide, triethylamine, triphenylphosphine in tetrahydrofuran, T= 20 °C Patent; ELI LILLY AND COMPANY; WO2005/40157; (2005); (A2) English View in Reaxys

O

N

O

H N

O

N

N H O

O

S

N

N

S

O

O


Conditions & References Example Name 2 Example 2 Preparation of dimethyl- {5- [5- (2-phenoxy-ethylsulfanylmethyl)- [1, 3,4] oxadiazol-2-yl] - benzofuran-2ylmethyl}-amine oxalate A THF solution of 2-dimethylaminomethyl-benzofuran-5-carboxylic acid N'- [2- (2-phenoxyethylsulfanyl) -acetyl] -hydrazide (4.0 g, 9.36 mmol, 1 eq. ) was treated with triethylamine (3.41 g, 33.7 mmol, 4.7 mL, 3. 6 eq. ), triphenylphosphine (2.70 g, 10.3 mmol, 1.1 eq. ), and carbon tetrabromide (3.72 g, 11.23 mmol, 1.2 eq. ). The solution was allowed to stir at room temperature overnight. The solvent was removed from the suspension leaving a brown oil that was purified via normal phase chromatography leaving dimethyl- {5- [5- (2-phenoxy- ethylsulfanylmethyl)- [1, 3,4] oxadiazol-2-yl]-benzofuran-2-ylmethyl}-amine as an orange oil contaminated with triphenylphosphine oxide. The oil was converted to the oxalate salt by adding an acetone solution of oxalic acid to an acetone solution of the amine. Obtained dimethyl- {5- [5- (2-phenoxy-ethylsulfanylmethyl)- [1, 3,4] oxadiazol-2-yl] - benzofuran-2-ylmethyl}amine oxalate (2.1557 g, 46percent yield) as an off-white solid by filtration. With carbon tetrabromide, triethylamine, triphenylphosphine in tetrahydrofuran, T= 20 °C Patent; ELI LILLY AND COMPANY; WO2005/40157; (2005); (A2) English View in Reaxys

O

N

H N N H

N O

O

S

S


Conditions & References Example Name 1.C


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Triethylamine (735 μL, 5.28 mmol) was added to a stirring solution of 2-(ethylthio)-N- (4-pentylbenzoyl) benzohydrazide (1-D) (326 mg, 0.88 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (448 mg, 2.64 mmol) in methylene chloride (10 mL). After stirring at room temperature for 18 h, the mixture was diluted with methylene chloride and washed with water, IN HCl, 10percent NaHC03, brine, dried (MgS04) and evaporated in vacuo. The oily residue was purified by preparative TLC (silica gel, hexane: ethyl acetate, 4:1) to provide 2-[2-(ethylthio)phenyl]-5-(4-pentylphenyl)-1,3,4-oxadiazole (1- E). Stage 1: With DMEG, triethylamine in dichloromethane, Time= 18h, T= 20 °C Stage 2: With hydrogenchloride in dichloromethane, water Stage 3: With sodium hydrogencarbonate in dichloromethane, water Patent; MERCK and CO., INC.; WO2005/97759; (2005); (A1) English View in Reaxys

N

O

N

O

O

HN

O

O H N

O

O

N H

O

O

HN

O O

N

N


Conditions & References Example Name A Intermediate XVIII: 5-(5- ( ( lR)- I -[(tert-butoxycarbonyl)amino] - I -methyl-2-phenylethyl ) - 1 ,3 ,4- oxadiazol-2-yl) -2'cyanobiphenyl-3-carboxylic acid; Step A: Coupling/Dehydration; To a stirring solution of 2'-cyano-5- (methoxycarbonyl)biphenyl-3-carboxylic (Intermediate XVII, 0.72 g, 2.56 mmol) and N-(tert-butoxycarbonyl)-a-methyl-D-phenylalanine hydrazide (Intermediate IT) (0.75, 2.56 mmol) in DMF (10 mL)was added BOP reagent (1.18 g, 2.68 mmol) and diisopropyl ethyl amine (1.32 mL, 7.67 mmol). The reaction was allowed to proceed for Ih, and then poured into water (200 mL). The aqueous was extracted with EtOAc (3x100 mL). The combined organics were washed with brine, dried over Na2S04, filtered and concentrated to obtain the crude bis amide which was used without further purification as an offwhite foam. The material thus obtained was dissolved in dichlorethane (10 mL) and was treated with methoxycarbonyl aminosulfamoyl triethylammonium hydroxide inner salt (Burgess reagent, 1.25g, 5.0 mmole) the resulting solution was then heated in a microwave reactor for 5 min at 120 °C. After cooling the product was purified directly by flash chromatography on silica gel eluting with 25percent to 75percent Ethyl acetate / hexane to give 780 mg of the product. 'H NMR (400 MHz, CDCL3) No. 8.71 (br s, 1H), 8.4 (m, 2H), 7.84 (d, J = 7.5 Hz, IH), 7.72 (t, J=7.5 Hz, 1H), 7.61-7.52(m, 2H), 7.32-7.24 (m, 3H), 7.10-7.04 (2H, m, ) 5.10 (br s, 1H), 4.0 (s, 3H), 3.60 (d, J = 13 Hz, IH), 3.47 (d, J = 13 Hz, 1H), 1.75 (s, 3H), 1.42 (s, 9H). LCMS [(M) +H]+ = 539. With Burgess Reagent in anhydrous dichloroethane, Time= 0.0833333h, T= 120 °C , Microwave Patent; MERCK and CO., INC.; WO2005/103020; (2005); (A1) English View in Reaxys

O S

O

O

N

N

O O

O

O O

O

O H N

S

HN N H

O

O

O O

N

HN

O

N


Conditions & References Intermediate V: 3-(5-( ( lR)-I-[(tert-butoxycarbonyl)amino]- I-methyl-2-phenylethyl ) -1 ,3,4-oxadiazol-2- yl)-5- [methyl(methylsulfonyl)amino]benzoic acid methyl ester; To a solution of Intermediate IV (0.520 g, 0.924 mmol) in 4 mL 1,2dichloroethane was added Burgess reagent (0.661 g, 2.77 mmol). The slurry was microwaved at 120 °C for 8 minutes.


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The reaction mixture was loaded directly onto a silica gel column equilibrated with 20percent EtOAc/hexanes, and purified using normal phase chromatography (20->70percent EtOAc/hexanes) to afford the desired oxadiazole as a white foam. 'H NMR (CDCI3, 400 MHz) No. 8.53 (app. t, J = 1.5 Hz, 1H), 8.24 (app. t, J = 0.6 Hz, 1H), 8.06 (m, 1H), 7.30-7.22 (m, 3H), 7.14-7.05 (m, 2H), 3.97 (s, 3H), 3.59 (d, J = 13.5 Hz, 1H), 3.42 (d, J = 13.5 Hz, 1H), 3.40 (s, 3H), 2.91 (s, 3H), 1.71 (s, 3H), 1.41 (s, 9H). LCMS [M+H]+ = 545. With Burgess Reagent in 1,2-dichloro-ethane, Time= 0.133333h, T= 120 °C , Microwave Patent; MERCK and CO., INC.; WO2005/103020; (2005); (A1) English View in Reaxys

O

O S

O

S

O

N

N O O

H N

HN

O O

O

N H

Z

O

HN

Z N trans trans transtrans

trans transO transtrans

N


Conditions & References Example Name 7.B Step B: Dehydrative cyclization; To a solution of adduct from Step A (0.082 g, 0.134 mmol) in 1.5 mL 1,2-dichloroethane was added Burgess reagent (0.128 g, 0.535 mmol). The slurry was microwaved at 120 °C for 10 min. The reaction mixture was loaded directly onto a silica gel column equilibrated with 10percent EtOAc/hexanes, and purified using normal phase chromatography (10->50percent EtOAc/hexanes) to afford the desired oxadiazole as a white foam. 'H NMR (CDC13) 8 7.97 (s, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 7.27-7.24 (m, 3H), 7.05-7.04 (m, 2H), 6.31 (d, J = 11.5 Hz, 1H), 5.22 (dd, J = 11.2, 10.3 Hz, 1H), 5.08 (br s, 1H), 3.68 (t, J = 7.5 Hz, 2H), 3.55 (d, J = 13.5 Hz, 1H), 3.41 (d, J = 13.5 Hz, 1H), 2.91 (s, 3H), 1.70 (s, 3H), 1.55-1.48 (m, 2H), 1.40 (s, 9H), 1.12 (d, J = 6.1 Hz, 3H), 0.96-0.89 (m, 5H), 0.71-0.62 (s, 2H), LCMS [M+H] + = 595. With Burgess Reagent in 1,2-dichloro-ethane, Time= 0.166667h, T= 120 °C , Microwave Patent; MERCK and CO., INC.; WO2005/103020; (2005); (A1) English View in Reaxys

O O N

S

N

O O H N

O

O

Si

O

Si

O O

N H O

S

O

O

O

N

N


Conditions & References Example Name 25.C Step C: Dehydration; To a solution of product from Step B (0.067 g, 0.116 mmol) in 1 mL 1,2-dichloroethane was added Burgess reagent (0.083 g, 0.348 mmol). The slurry was microwaved at 120° C for 8 min, and the reaction was loaded directly onto a silica gel column for purification (5->45percent EA/hex) to afford the desired product was a white foam. 1H NMR (CDCl3,400MHz) 8.51 (m, 1H), 8.20 (m, 1H), 8.16 (m, 1H), 7.24- 7.19 (m, 3H), 7.12-7.10 (m, 2H), 3.96 (s, 3H), 3.38 (s, 3H), 3.23 (d, J = 13.4 Hz, 1H), 3.15 (d, J = 13.4 Hz, 1H), 2.90 (s, 3H), 1.74 (s, 3H), 0.85 (t, J = 7.0 Hz, 9H), 0.55-0.43 (m, 6H) ; LCMS [M+H] += 560. With Burgess Reagent in 1,2-dichloro-ethane, Time= 0.133333h, T= 120 °C , Microwave Patent; MERCK and CO., INC.; WO2005/103020; (2005); (A1) English View in Reaxys


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N N

O O

O H N

O O

HN

O

O O

N H

O

O

O

N

NH

N


Conditions & References Example Name F Step F: Dehydrative cyclization A solution of ethyl 3-({2-[(R)-2-tert-butoxycarbonylamino-2-methyl-3- phenylpropanoyl]hydrazino}carbonyl)-5-(1-cyanocyclopentyl)benzoate (0.10 g, 0.18 mmol) and (methoxycarbonylsulfamoyl) triethylammonium hydroxide, inner salt (0.13 g, 0.54 mmol) in 1.5 mL dichloroethane was heated in the microwave at 120 °C for 8 min. Concentration and flash chromatography (silica gel, 0-45percent EtOAc/hexanes) gave ethyl 3-(5-((R)-2-tertbutoxycarbonylamino-1- phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-( 1-cyanocyclopentyl)benzoate. 'H NMR (400 MHz, CDCI3) No. 8.57 (app t, J = 1.5 Hz, 1H), 8.30 (d, J = 1.5 Hz, 2H), 7.29 (m, 3H), 7.08 (m, 2H), 5.11 (br s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.60 (d, J = 13.6 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 2.59 (m, 2H), 2.19-1.99 (m, 6H), 1.74 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H), 1.43 (s, 9H). With Burgess Reagent in anhydrous dichloroethane, Time= 0.133333h, T= 120 °C , Microwave Patent; MERCK and CO., INC.; WO2005/103020; (2005); (A1) English View in Reaxys O

OH

O

O H N

N

OH

N O

N H

HO

O

O


Conditions & References Example Name 1 Compound 2 was prepared as follows. A suspension of 30.34 g (0.108 mol) of N-(methyl suberoyl)-N'-salicyloylhydrazide and 138 mL of methylene chloride was cooled to 0°C in an ice bath and treated with 16.56 mL (12.0 g, 0.119 mol) of triethylamine, followed by 14.40 mL (12.3 g, 0.113 mol) of trimethylsilylchloride 15 minutes later. After warming to 25°C and stirring for 3 hours, the reaction mixture was concentrated in vacuo. The residue was taken up in 183 mL of acetonitrile and treated with 45.16 mL (32.8 g, 0.324 mol) of triethylamine, 50.4 mL (80.2 g, 0.522 mol) of carbon tetrachloride and 63.88 g (0.243 mol) of triphenylphosphine. The orange slurry was stirred for 18 hours. The solid was removed by filtration. The filtrate was diluted with 183 mL of ethyl acetate, washed with 2percent aqueous hydrochloric acid (2x100 mL) dried over sodium sulfate and concentrated in vacuo. The resulting solid was brought up in 60 mL of 2N aqueous sodium hydroxide and stirred at 65 °C for three hours. The undissolved solid was removed by filtration. The filtrate was acidified to pH 3 with 3percent aqueous hydrochloric acid. The resulting solid was isolated by filtration and recrystallized from ethanol/water. A total of 11.76 g, having a melting point of 109-112 °C, was collected. Compounds 1, 3-8, 10 and 12 were also prepared by this method with the appropriate starting materials. Compounds 9, 11 and 13 may also be prepared by this method using the appropriate starting materials. Stage 1: With chloro-trimethyl-silane, triethylamine in dichloromethane, Time= 3.25h, T= 0 - 25 °C Stage 2: With tetrachloromethane, triethylamine, triphenylphosphine in acetonitrile, Time= 18h Stage 3: With hydrogenchloride, sodium hydroxide, water, more than 3 stages Patent; Emisphere Technologies, Inc.; EP1156787; (2005); (B1) English View in Reaxys


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NH

N

O O HN

O

NH

O

N

N

N O

O


Conditions & References Example Name 1 ; In a 300 ml pear-shaped flask were placed 2.8 g of the intermediate, 150 ml of phosphoryl chloride, and 75 ml of 1,4-dioxane. The solution in the pear-shaped flask was heated to 115°C in a silicone oil bath, and allowed to react for 6 hours at around the temperature. After the termination of the reaction, the obtained was introduced into ice water. Precipitates were separated, and washed and neutralized with a 10percent aqueous solution of sodium hydroxide. Then, the neutralized precipitates were re-dissolved in benzene, and the resultant was filtered. The filtrate was concentrated and dried up. White crystals with a melting point of 310°C were obtained. An NMR spectrum chart and an IR spectrum chart of the obtained crystals are respectively shown in Figure 5 and Figure 6. These data confirmed that the crystals produced in this example were the blue light-emitting compound represented by formula (18). With trichlorophosphate in 1,4-dioxane, Time= 6h, T= 115 °C Patent; HIROSE ENGINEERING CO., LTD.; EP1607392; (2005); (A1) English View in Reaxys

HN

NH OO

HN

NH OO

N

N O

N

N O


Conditions & References Example Name 4 ; In a 300 ml pear-shaped flask were placed 3.8 g of the intermediate and 30 ml of phosphoryl chloride. The solution in the pear-shaped flask was heated to 110°C in a silicone oil bath, and allowed to react for 14.5 hours at around the temperature. After the termination of the reaction, precipitates that had been formed during the reaction were separated, and washed with chloroform. Then, the washed precipitates were redissolved in 300 ml of toluene, and the obtained was filtered. The filtrate was concentrated and dried up. 0.54 g of light yellow crystals with a melting point of 330°C was obtained. An NMR spectrum chart and an IR spectrum chart of the obtained crystals are respectively shown in Figure 14 and Figure 15. These data confirmed that the crystals produced in this example were the blue light-emitting compound represented by formula (25). With trichlorophosphate in 1,4-dioxane, Time= 14.5h, T= 110 °C Patent; HIROSE ENGINEERING CO., LTD.; EP1607392; (2005); (A1) English


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NH

HN

N

O

OO HN

N

NH

N

OO

N O


Conditions & References Example Name 5 ; In a 500 ml four-necked flask were placed 3.4 g of the intermediate, 65 ml of phosphoryl chloride, and 100 ml of dioxane. The solution in the four-necked flask was heated to 110°C in a silicone oil bath, and allowed to react for 9 hours at around the temperature. After the termination of the reaction, precipitates that had been formed during the reaction were separated, and re-dissolved in 40 ml of toluene. The obtained was filtered. The filtrate was concentrated and dried up. Light yellow crystals were obtained. An NMR spectrum chart and an IR spectrum chart of the obtained crystals are respectively shown in Figure 17 and Figure 18. These data confirmed that the crystals produced in this example were the blue light-emitting compound represented by formula (27). With trichlorophosphate in 1,4-dioxane, Time= 9h, T= 110 °C Patent; HIROSE ENGINEERING CO., LTD.; EP1607392; (2005); (A1) English View in Reaxys

HN

NH

N

N O

O O


Conditions & References Example Name 11 ; 5.0 g of the intermediate represented by formula (39), 120 ml of dioxane, and 150 ml of phosphorus oxychloride were placed in a pear-shaped flask. The mixture was refluxed for 10 hours at 115°C. Then, the reaction product was cooled and introduced into ice water. The resultant was extracted with chloroform, which was followed by drying the chloroform solution. The solvent was removed off the extract with an evaporator. Finally, the extract was vacuum dried. 4.6 g of the target compound represented by formula (35) above, the melting point of which ranged between 175°C and 181°C, was obtained. The identification of the target compound was made base on the NMR and IR spectrum charts of the target compound, which are respectively shown in Figure 29 and Figure 30. With trichlorophosphate in 1,4-dioxane, Time= 10h, T= 115 °C Patent; HIROSE ENGINEERING CO., LTD.; EP1607392; (2005); (A1) English View in Reaxys

N NH O

HN

I

O O N

N

N


Conditions & References Example Name 38


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Phosphorousoxychloride (2ml) was added to 1H-pyrrole-2-carboxylic acid, 1-methyl-2- (4-iodobenzoyl) hydrazide (Intermediate 39) (150mg) in acetonitrile (lml) and the reaction heated at 100°C for 18hours. The cooled reaction was poured onto ice/water (60ml) and extracted with ethyl acetate (3x40ml). The combined extracts were reduced to dryness under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, 2- (4-iodophenyl)- 5- (l-methyl-lH-pyrrol-2-yl)-1, 3,4-oxadiazole. LCMS: MH+ 352, retention time 3.7minutes. With trichlorophosphate in acetonitrile, Time= 18h, T= 100 °C Patent; SMITHKLINE BEECHAM CORPORATION; WO2003/93248; (2003); (A1) English View in Reaxys

O

O

O

O

O

O N HN O

O

O

N

NH

N N


Conditions & References Example Name 1 To a solution of the acridine (0.075 g, 0.17 mmol) in 1.5 mL of DMF was added the Burgess reagent (0.14 g, 0.6 mmol). The reaction was stirred at 150 °C for 4 h. Upon cooling, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was washed with brine and dried over MgSO4. The crude material was purified by silica chromatography (1-10percent MeOH/CH2C12) to afford the desired product. (Calc'd for C24H19N3O4: 413.4, [M+H]+ found: 414) With Burgess Reagent in N,N-dimethyl-formamide, Time= 4h, T= 150 °C Patent; SIRTRIS PHARMACEUTICALS, INC.; WO2006/94237; (2006); (A2) English View in Reaxys

O

O

O

O

Cl

O

NH

O

NH

N

Cl

N

O

Cl

Cl H N

O

O

HN

O O

O

N

HN

O

N H

N N

O O

N

O

O O

Cl O

O

O Cl


Conditions & References Example Name 17 Production of D-268C:; 6.6 g of D-268B and 6.4 g of triphenylphosphine were dissolved in 110 ml of methylene chloride, and 8.1 g of carbon tetrabromide and 6.7 ml of triethylamine were added to it and stirred at 40°C for 1 hour. The reaction solution was concentrated under reduced pressure, and purified through column chromatography to obtain 3.8 g of D-268C. With carbon tetrabromide, triethylamine, triphenylphosphine in dichloromethane, Time= 1h, T= 40 °C Patent; FUJI PHOTO FILM CO., LTD.; WO2006/98489; (2006); (A1) English


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O

O

O S

O

S

N

N

N

O

H N

O

N

H N

HN

O

O

O

O

N H O

N

N


Conditions & References Example Name 1.E CyclodehydrationTo a solution of tert-bxxtyl (lR)-l-benzyl-2-{2-[(7-ethyl-l-methyl-2,2-dioxido-3,4-dihydro-lH- [l,2,5]thiadiazepino[3,4,5-hi]indol-9-yl)carbonyl]hydrazino}-l-methyl-2-oxoethylcarbamate (719 mg, 1.23 mmol) in anhydrous. CH2Cl2 (20 mL) at 0°C under argon were added imidazole (210 mg, 3.08 mmol), triphenylphosphine (711 mg, 2.71 mmol), and carbon tetrabromide (899 mg, 2.71 mmol). After 5 min, the ice bath was removed, and the reaction was allowed to warm to rt. After 2 hr, it was concentrated in vacuo and purified by flash chromatography (silica, 10-65percent EtOAc/hexanes) to provide ^rt-butyl (lR)-l-[5-(7-ethyl-l-methyl-2,2-dioxido-3,4-dihydro-lH-[l,2,5]thiadiazepino[3,4,5hi]indol-9- yl)-l,3,4-oxadiazol-2-yl]-l-methyl-2-phenylethylcarbamate as an off-white solid. lH NMR (^-MeOH) δ 8.06 (s, IH), 7.68 (s, IH), 7.30-7.23 (m, 3H), 7.15 (s, IH), 7.12-7.09 (m, 2H), 4.59-4.55 (m, 2H), 3.98- 3.94 (m, 2H), 3.57-3.52 (m, 4H), 3.34 (d, B of AB, J^ = 13.4 Hz, IH), 2.79 (q, J = 7.5 Hz, 2H), 1.63 (s, 3H), 1.41 (br s, 9H), 1.34 (t, J = 7.5 Hz, 3H). With 1H-imidazole, carbon tetrabromide, triphenylphosphine in dichloromethane, Time= 2.08333h, T= 0 - 20 °C Patent; MERCK and CO., INC.; WO2007/19078; (2007); (A2) English View in Reaxys O

O N

O O

O

H N

N N H

O N N O


Conditions & References Example Name 84 280 mg of 3-Nitrobenzoic acid N'-acetyl-hydrazide and 616 mg of Burgess' reagent are heated in 6 ml of THF in a microwave for 5 minutes at 100°. The mixture obtained is concentrated.2-Methyl-5-(3-nitro-phenyl)-[1 ,3,4]oxadiazole is obtained. With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 100 °C Patent; NOVARTIS AG; NOVARTIS PHARMA GMBH; WO2007/48771; (2007); (A1) English View in Reaxys

O O

H N O

O

N O

N O

O O

N H

O


Conditions & References Example Name XVI.D A solution offers-butyl 4-{2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoate (O.lg, 0.26 mmol) in THF (2.5 mL) was treated with Burgess reagent (0.12g, 0.52 mmol), sealed and heated to 1000C for 10 minutes in the microwave.


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The reaction was evaporated in vacuo and purified by flash chromatography (0-2percent methanol/methylene chloride) to give the desired product as a white solid. ESIMS calcd 367.2 (M+ + H), found 367.1 (M+ + H). With Burgess reagent in trifluoroacetic acid, Time= 0.166667h, T= 100 °C , Microwave Patent; MERCK and CO., INC.; WO2007/55941; (2007); (A2) English View in Reaxys

S

N

O

O

N H

O

N

S

H N

O O


Conditions & References Example Name 28.c A solution of 4-allyloxy-3,5-dimethyl-benzoic acid N'-(4-isobutyl-3-methyl- thiophene-2-carbonyl)-hydrazide (160 mg, 0.4 mmol) and (methoxycarbonylsulfamoyl)thethylammonium hydroxide (350 mg, 1.27 mmol) in dry THF (5 ml_) is heated at 1100C in a microwave oven for 6 min. The mixture is poured into diethyl ether (10 ml_) and washed with 1 M aq. HCI (10 ml_). The aq. phase is re-extracted with ether (10 ml_). The combined organic extracts are dried (Na2SO4), filtered and evaporated to give 181 mg of crude 2-(4-allyloxy-3,5-dimethyl-phenyl)-5-(4-isobutyl- 3-methylthiophen-2-yl)-[1 ,3,4]oxadiazole; LC-MS: tR = 1.23 min, [M+1]+ = 383.35. With (methoxycarbonylsulfamoyl)-triethyl-ammonium hydroxide in tetrahydrofuran, Time= 0.1h, T= 110 °C , Microwave irradiation Patent; ACTELION PHARMACEUTICALS LTD; WO2007/80542; (2007); (A1) English View in Reaxys

N O O S

N H

N

S O

H N

O O


Conditions & References Example Name 59 To a solution of Intermediate A1 (291 mg, 1.47 mmol) in DCM (10 ml_), DIPEA (573 mg, 4.44 mmol) and TBTU (474 mg, 1.48 mmol) is added. The mixture is stirred for15 min before 4-benzyloxy-3,5-dimethyl-benzoic acid hydrazide (396 mg, 1.47 mmol) is added. Stirring is continued at rt for 16 h. The mixture is diluted with diethyl ether, washed twice with 1 N aq. NaOH solution, once with 1 N aq. HCI solution, dried over Na2SO4, and filtered. The solvent is evaporated to give 4- benzyloxy-3,5-dimethyl-benzoic acid N'-(4-isobutyl-5-methyl-thiophene-2-carbonyl)- hydrazide (371 mg) as a beige solid; LC-MS: tR = 1.07 min, [M+1] = 451.40. To a solution of this material in THF (5 mL), Burgess reagent (305 mg, 1.28 mmol) is added. The mixture is heated to 1100C for 5 min in a microwave oven. The mixture is cooled to rt, diluted with diethyl ether and washed with brine. The organic extract is dried over Na2SO4, filtered and concentrated to give 2-(4-benzyloxy-3,5-dimethyl- phenyl)-5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1 ,3,4]oxadiazole (348 mg) as an orange oil; LC-MS: tR = 1.26 min, [M+1] = 433.40. This material is dissolved in THF:ethanol 1 :1 (20 ml_) and treated with a suspension of Pd/C (100 mg, 10percent Pd) in ethanol. The mixture is stirred at rt for 3 h under 1 bar or H2. The catalyst is removed by filtration and the filtrate is evaporated to give 4-[5-(4-isobutyl-5-methylthiophen-2-yl)-[1 ,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenol (274 mg) as a grey solid, LC-MS: tR = 1.12 min, [M+1] = 343.25. With Burgess Reagent in tetrahydrofuran, Time= 0.0833333h, T= 110 °C , Microwave irradiation Patent; ACTELION PHARMACEUTICALS LTD; WO2007/80542; (2007); (A1) English View in Reaxys


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N

N

N

N O H N

E

O

O

O

E

F N H

F

N

O

N


Conditions & References Example Name 16.4 (4) Synthesis of 2-(3-fluorophenyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole A solution of 3-fluorobenzoic acid N'-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (86 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for one hour. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Methylene chloride and a 1 N sodium hydroxide solution were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier:Chromatorex.(TM). NH; elution solvent:heptane:ethyl acetate=1:1->ethyl acetate) to obtain 65 mg of the title compound. The property values of the compound are as follows. ESI-MS; m/z 377 [M++H]. 1H-NMR (CDCl ) δ (ppm): 2.31 (s, 3H), 3.94 (s, 3H), 6.96 (brs, 1H), 7.12 (d, J=16.4 Hz, 1H), 7.22-7.30 (m, 3H), 7.31 3 (d, J=8.4 Hz, 1H), 7.51 (td, J=8.0, 6.0 Hz, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.79-7.84 (m, 1H), 7.92-7.95 (m, 1H). Stage 1: With trichlorophosphate, Time= 1h, T= 120 °C Stage 2: With sodium hydroxide, water in dichloromethane, T= 20 °C Patent; Eisai RandD Management Co., Ltd.; US2007/219181; (2007); (A1) English View in Reaxys

F Cl

H N

F

HN

O

O E

N

O

O N

N Cl

N N

N

E

O


Conditions & References Example Name 20.4 (4) Synthesis of 2-{4-chloro-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorophenyl)-[1,3,4]oxadiazole A solution of 4-fluorobenzoic acid N'-{5-chloro-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}valeric acid}hydrazide (84 mg) in phosphorus oxychloride (2 mL) was stirred at 100° C. for 30 minutes. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Chloroform and a 1 N sodium hydroxide solution were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 85 mg of the title compound. The property values of the compound are as follows. ESI-MS; m/z 453 [M++H]. 1H-NMR (CDCl ) δ (ppm): 2.22-2.31 (m, 2H), 2.42 (s, 3H), 3.05-3.11 (m, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 7.03 3 (brs, 1H), 7.14 (d, J=1.6 Hz, 1H), 7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.23 (t, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 8.13 (dd, J=8.4, 4.8 Hz, 2H), 8.20 (brs, 1H). Stage 1: With trichlorophosphate, Time= 0.5h, T= 100 °C Stage 2: With sodium hydroxide, water in chloroform, T= 20 °C


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Patent; Eisai RandD Management Co., Ltd.; US2007/219181; (2007); (A1) English View in Reaxys

O

F

N H

F

H N

N

N

N

N

O

N

O

NH

N

S

O

F

O

F


Conditions & References Example Name 230 Phosphorus oxychloride (316 mg, 2.1 mmol) was added to a solution of intermediate 26 (125 mg, 0.26 mmol) in dry acetonitrile (1 mL) at rt. After stirring at 80°C for 2h, the volatiles were removed and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo to give a residue. The residue was treated with 2M hydrochloric acid and THF (1:1) at 8O0C for 1 h, then purified by reverse phase HPLC (KR100-5C18 100x21.2 mm column; 10- 100percentMeCN/H2O over 12 min) to afford the title compound. LC-MS: m/e 361 (M+H). With trichlorophosphate in acetonitrile, Time= 2h, T= 20 - 80 °C Patent; MERCK and CO., INC.; WO2008/51405; (2008); (A1) English View in Reaxys

O

O

O

H N

F

N

N H

O

N

F O

O

O

F

F


Conditions & References Example Name B To a solution of 4-[N'-(3,4-difluorobenzoyl)hydrazino]-4-oxo-butyric acid ethyl ester (590 mg, 1.96 mmol) and pyridine (474 μL, 5.88 mmol) in methylene chloride (25 mL) at - 78 °C was added dropwise trifiic anhydride (397 μL, 2.35 mmol) and the reaction was allowed to warm up to rt overnight. The reaction mixture was diluted with methylene chloride (100m L), washed with 0.1 M HCl and brine, dried over sodium sulfate and concentrated to provide 3-[5- (3,4-difluorophenyl)-[l,3,4]oxadiazol-2-yl]propionic acid ethyl ester. 1H νMR (300 MHz, CDCl3) δ 7.89-7.77 (m, 2H), 7.31 (m, IH), 4.19 (q, J = 7.1 Hz, 2H), 3.24 (t, J = 7.2 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). With pyridine, trifluoromethylsulfonic anhydride in dichloromethane, T= -78 °C Patent; MERCK and CO., INC.; WO2008/51405; (2008); (A1) English View in Reaxys

O

O

HN NH O

N

N


Conditions & References Example Name 7.3 Step 3 : 2-(3-Allyl-4-methyl-phenyl)-5-isobutyl-[l,3,4]oxadiazole; To a solution of 3-allyl-4-methyl-benzoic acid hydrazide (1.0 g, 5.26 mmol) and diisopropylethylamine (6.31 mL, 36.2 mmol) in acetonitrile (30 mL) was added isovaleric anhydride (1.31 mL, 6.58 mmol), and the mixture was allowed to stir for 18 hours at room temperature. To this mixture was added triphenylphosphine (5.66 g, 21.6 mmol), followed by hexachloro ethane (2.86 g, 12.11 mmol). The mixture was stirred for 5 hours at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography eluting with 0-30percent ethyl acetate in hexanes to give 2-(3-allyl-4-methylphenyl)-5-isobutyl-[l,3,4]oxadiazole (Yield: 1.32 g, 98percent).


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With 1,2,2-trichloro-1,1,2-trichloro-ethane, triphenylphosphine in acetonitrile, Time= 5h, T= 20 °C Patent; F. HOFFMANN-LA ROCHE AG; WO2008/55842; (2008); (A1) English View in Reaxys O

N

H N N H

N O

O N O

N

N

O

O

N O


Conditions & References Example Name A16.b b) Preparation of intermediate 44; A mixture of intermediate 43 (0.263 g; 0.6 mmol) and 10 ml of THF was stirred at room temperature. 7-Oxa-4-thia-3,5-diazaoctane-2,4-diaminium, 3,3-diethyl-6-oxo-, inner salt 4,4-dioxide (0.214 g; 0.9 mmol) (Burgess 'reagent) was added at once. The mixture was stirred at 6O0C for 3 hours. The solvent was evaporated. The residue was stirred in 2 ml of water and extracted with CH2Cl2. The mixture was dried over Isolute filter and the organic layer was evaporated. The residue was filtered over silicagel using a mixture of CH2Cl2 and CH3OH (96/4 by volume) as eluent. The pure fraction were collected and the solvent was evaporated. The residue was dried, yielding 0.214 g of intermediate 44. With Burgess Reagent in tetrahydrofuran, Time= 3h, T= 20 - 60 °C Patent; JANSSEN PHARMACEUTICA N.V.; WO2008/148840; (2008); (A1) English View in Reaxys

N

O H N N H

N O

O

N

N O

O

N

N O

O


Conditions & References Example Name A14.b b) Preparation of intermediate 39; A mixture of intermediate 38 (0.863 g; 1.9 mmol) and 15 ml of THF was stirred at room temperature. 7-Oxa-4-thia-3,5-diazaoctane-2,4-diaminium, 3,3-diethyl-6-oxo-, inner salt 4,4-dioxide (0.715 g; 3 mmol) (Burgess' reagent) was added. The mixture was stirred at 600C for 3 hours. The solvent was evaporated. The residue was stirred in 2 ml of water and extracted with CH2Cl2. The mixture was filtered over Isolute filter and the organic layer was evaporated. The residue was filtered over silicagel using a mixture Of CH2Cl2 and CH3OH (97/3 by volume) as eluent. The pure fraction were collected and the solvent was evaporated. The residue was dried, yielding 0.690 g of intermediate 39. With Burgess Reagent in tetrahydrofuran, Time= 3h, T= 20 - 60 °C Patent; JANSSEN PHARMACEUTICA N.V.; WO2008/148840; (2008); (A1) English View in Reaxys


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O

O

O

O

O O

NH NH

O O

NH

O

NH

N N


Conditions & References Example Name 136.3 A mixture of the hydrazide (K2), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine bound on polystyrene (2.3 mmol/g, 5 eq.) and TsCl (1.2 eq.) was suspended in anhydrous THF. The suspension was gently stirred and heated at 65° C. for 4 h. The mixture was filtered, and the resin was washed with THF. The combined filtrates were concentrated under reduced pressure and the crude product was used in the next step without purification. With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine bound on polystyrene, p-toluenesulfonyl chloride in tetrahydrofuran, Time= 4h, T= 65 °C Patent; Attenni, Barbara; Ferrigno, Federica; Jones, Philip; Ingenito, Raffaele; Kinzel, Olaf; Llauger Bufi, Laura; Ontoria, Jesus Maria; Pescatore, Giovanna; Rowley, Michael; Scarpelli, Rita; Schultz, Carsten; US2009/48228; (2009); (A1) English View in Reaxys

O O

O

H N

O

N

O

N

O N

O

N H O

N

O F

F

F

F

F

F


Conditions & References Example Name 11 A mixture of ethyl 3-(2-{[3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]carbonyl} hydrazino)-3-oxopropanoate (D10, 710 mg, 1.408 mmol) and Burgess reagent (587 mg, 2.464 mmol) in 1 ,2-dichloroethane (5 ml.) was heated in a microwave at 1200C for 10 minutes. The reaction mixture was concentrated and the residue purified by chromatography (Biotage SP4, gradient elution with 0percent to 50percent ethyl acetate in hexane, over 15 column volumes of solvent). The appropriate fractions were combined and concentrated to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 386 (C17H18F3N3O4 requires [M+H]+ at m/z 386). With Burgess Reagent in dichloromethane, Time= 0.166667h, T= 120 °C , Microwave irradition Patent; GLAXO GROUP LIMITED; WO2009/819; (2008); (A1) English View in Reaxys

O

Cl

O H N

O

Cl

N

O

N H O

N O

O

O

Cl

O

Cl


Conditions & References Example Name 14 A mixture of ethyl 3-{2-[(3,5-dichlorophenyl)carbonyl]hydrazino}-2-(methyloxy)-3- oxopropanoate (D13, 509 mg, 1.458 mmol), Burgess reagent (695 mg, 2.92 mmol) and 1 ,2-dichloroethane (3 ml.) was heated in the microwave at 1200C for 20 minutes.The mixture was transferred to a separating funnel and washed with water (x3), dried(magnesium sulfate), filtered and evaporated. The residue was purified by chromatography using a 25+M Biotage cartridge, eluting


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with gradient of 0-60percent ethyl acetate/hexane to give the title compound.LC/MS (ES+ve): [M+H]+ at m/z 331 , 333, 335 (Ci3H12CI2N2O4 requires [M+H]+ at m/z331 , 333, 335). With Burgess Reagent in 1,2-dichloro-ethane, Time= 0.333333h, T= 120 °C , Microwave irradition Patent; GLAXO GROUP LIMITED; WO2009/819; (2008); (A1) English View in Reaxys

Cl

Cl

O

N

O

HN

O

NH

O

N O

N

N

O O

N

N


Conditions & References Example Name 22 A suspension of ethyl 3-(2-{[3-chloro-5-(4-methyl-1- piperazinyl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (D21 , 0.58 g, 1.51 mmol) and Burgess reagent (0.67 g, 2.80 mmol) in dichloromethane (5 ml.) was heated at 100 0C in the microwave at high absorption for 10 minutes. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was then washed with dichloromethane and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a dark yellow oil.LC/MS (ES+ve): [M+H]+ at m/z 365, 367 (Ci7H2i CIN4O3 requires [M+H]+ at m/z 365, 367). With Burgess Reagent in dichloromethane, Time= 0.166667h, T= 100 °C , Microwave irradition Patent; GLAXO GROUP LIMITED; WO2009/819; (2008); (A1) English View in Reaxys Cl

Cl O

O HN O

NH N

N O

O

O

N

N

N

N

O


Conditions & References Example Name 41 A solution of ethyl 3-(2-{[3-chloro-5-(1 ,2-dimethyl-1 H-imidazol-4- yl)phenyl]carbonyl}hydrazino)-3-oxopropanoate (D40a, 480mg, 1.267 mmol) and Burgess reagent (604 mg, 2.53 mmol) in dichloromethane (5 ml.) was stirred for 20 minutes at 1000C in the microwave. To the reaction mixture was added furtherBurgess reagent (604 mg, 2.53 mmol) and the reaction stirred for a further 20 minutes at 100 0C in the microwave.The reaction mixture was transferred directly to a silica column and purified by column chromatography, eluting with 0-20percent 2N ammonia in methanol in dichloromethane to give the title compound.LC/MS (ES+ve): [M+H]+ 361 , 363 (Ci7H17CIN4O3 requires [M+H]+ 361 , 363). With Burgess Reagent in dichloromethane, Time= 0.666667h, T= 100 °C , Microwave irradition Patent; GLAXO GROUP LIMITED; WO2009/819; (2008); (A1) English View in Reaxys O

O NH

O

O

N N

HN O

H 2N

N

N

O

O

O

O

NH 2


Conditions & References Example Name 1-58.B


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B. 4-[5-(4-Methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-2-nitrophenylamine; A solution of 4-methoxybenzoic acid N'-(4-amino-3-nitrobenzoyl)-hydrazide (750 mg, 2.27 mmol) and Burgess reagent (1.62 g, 6.81 mmol) in THF (15 ml_) was microwaved at 150 0C for 20 min. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (heptane/EtOAc = 1 :3) to give the title compound as a yellow solid. MS: m/z 313 (M+1). With Burgess Reagent in tetrahydrofuran, Time= 0.333333h, T= 150 °C , Microwave irradiation Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys

O

O O

O

O NH

O

O

H N

HN

N H

O

N

N

O


Conditions & References Example Name 1-66.F F. Methyl 3-(4-{6-[5-(4-methoxypheny I)-[1 ,3,4]oxadiazol-2-yl]-1 H-indol-2-yl}-3,5- dimethylphenyl)-propionate; A mixture of methyl 3-(4-{6-[N'-(4-methoxybenzoyl)-hydrazinocarbonyl]-1 H-indol- 2-yl}-3,5-dimethy.-phenyl)-propionate (220 mg, 440 μmol) and Burgess reagent (210 mg, 880 μmol) in THF (10 mL) was heated in a microwave apparatus at 150 0C for 30 min. The solvent was removed under reduced pressure, and the residue chromatographed using a 30-70percent gradient of heptane/ethyl acetate to afford the title compound. With Burgess Reagent in tetrahydrofuran, Time= 0.5h, T= 150 °C , Microwave irradiation Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys

O O

H N

N NH

N H

O

O

O

N

N

NH N


Conditions & References Example Name 1-16 Example 1-16; 2-(2,6-Dimethyl-phenyl)-6-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H- benzoimidazole.; To a 5 mL microwave vial was added .2225 g (.537 mmol) of 4-Methoxy-benzoic acid N'-[2-(2,6-dimethyl-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide, 4 mL of THF, and .2558 g (1.07 mmol) of burgess reagent. The suspension was placed in the microwave at 150 °C for 15 min. The crude solution was concentrated and the residue was purified by silica gel column chromatography (EtOAc/DCM, 1:9 to 6:4) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 6 H) 4.02 (s, 3 H) 7.35 (dd, J=15.73, 8.27 Hz, 4 H) 7.50 (t, J=7.64 Hz, 1 H) 7.87 (d, J=8.34 Hz, 0.5 H) 8.04 (d, J=8.46 Hz, 0.5 H) 8.15 (dd, J=12.19, 8.65 Hz, 1 H) 8.24 - 8.29 (m, 2 H) 8.38 (s, 0.4 H) 8.60 (s, 0.5 H) 13.15 (d, J=14.27 Hz, 1 H). MS (m/z) 397.2 M (+1), tR = 1.48, Meth 10 With Burgess Reagent in tetrahydrofuran, Time= 0.25h, T= 150 °C Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys

O

H N

O

N H

Cl NH

Cl N

N

F

Cl

N

N

F F

F

O N

NH N

Cl

F F



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Yield

Conditions & References Example Name 1-19 Example 1-19; 2-(2,6-Dichloro-phenyl)-6-[5-{6-trifluoromethyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]- 1 H-benzoimidazoIe.; 6-Trifluoromethyl-nicotinoyl chloride (119 uL, 0.817 mmol) was added to a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol) in THF (10 mL) and EDIPA (149 uL, 0.856 mmol). The reaction was stirred for 17 hr. The reaction was diluted with EtOAc (75 mL) and extracted with water (20 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was taken up in DMF (3 mL) and transferred to a microwave vial charged with Burgess reagent (555 mg, 2.33 mmol). The reaction was heated to 150° C for 15 min by microwave irradiation. The reaction was diluted with EtOAc (75 mL) and extracted with water (15 mL). The organic phase was dried over Na2SO4 and concentrated. The concentrate was purified by silica gel column chromatography (15-40 percent ACN / DCM) and the resulting colorless film triturated with MeOH / DCM to afford the title compound (214 mg): 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.64 - 7.68 (m, 1 H) 7.71 (s, 1 H) 7.73 (d, J=2.02 Hz, 1 H) 7.83 (tautomer, d, J=8.46 Hz, 1 H) 7.97 (tautomer, d, J=8.59 Hz, 1 H) 8.12 (dd, J=14.15, 8.72 Hz, 1 H) 8.21 (d, J=8.34 Hz, 1 H) 8.41 (tautomer, s, 1 H) 8.60 (tautomer, s, 1 H) 8.85 (d, J=8.34 Hz, 1 H) 9.54 (s, 1 H) 13.41 (d, J=14.15 Hz, 1 H); LCMS tR= 1.53 min, MS (m/z) 476.7. With Burgess Reagent in N,N-dimethyl-formamide, Time= 0.25h, T= 150 °C , Microwave irradiation Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys O

Cl

H N

O

NH

N H

Cl N

N Cl

O

HN Cl

N

N

N

N


Conditions & References Example Name 1-20 Example 1-20; 4-{5-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazol-2-yl}- benzonitrile.; Combine 4cyano-benzoic acid (120 mg, 0.817 mmol), 2-(2,6-dichloro-phenyl)- 3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol), HATU (445 mg, 1.17 mmol), EDIPA (204 uL, 1.17 mmol), and DMF (5 mL) and stir for 25 hr. Dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Take the concentrate up in DMF (3 mL) and add Burgess reagent (555 mg, 2.33 mmol). Heat the reaction to 150° C for 20 min by microwave irradiation. Dilute the reaction with EtOAc (75 mL) and extract with water (20 mL). Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the concentrate by silica gel chromatography (10-40 percent ACN / DCM) to afford a white solid. Suspend the solid in water and stir for 6 hr. Collect the solid by filtration and wash with Et2O. Dry the solid under vacuum at 4O0C for 2 days to afford the title compound (138 mg) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.63 - 7.68 (m, 1 H) 7.70 7.74 (m, 2 H) 7.79 - 7.85 (tautomer, m, 1 H) 7.96 (tautomer, d, J=8.59 Hz, 1 H) 8.06 - 8.15 (m, 3 H) 8.35 - 8.40 (m + tautomer, 2 H) 8.52 - 8.60 (m, 1 H) 13.39 (d, J=12.76 Hz, 1 H); LCMS tR = 1.35 min, MS (m/z) 432.0. With Burgess Reagent in N,N-dimethyl-formamide, Time= 0.333333h, T= 150 °C , Microwave irradiation Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys

N O O

N

O H N

HN

N H

O

HN O

N O

N

O


Conditions & References Example Name 1-68.B B. 3-{3,5-Dimethyl-4-[6-(5-o-tolyl-[1 ,3,4]oxadiazol-2-yl)-1 H-benzoimidazol-2-yl]- phenyl}-2,2-dimethyl-propionic acid methyl ester.; Add EDC (380 mg, 1.98 mmol) and HOBt (268 mg, 1.98 mmol) to a stirring solution of 2-[4-(2-methox-


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ycarbonyl-2- methyl-propyO-σ.ψ-dimethyl-phenylj-SH-benzoimidazole-S-carboxylic acid (626 mg, 1.65 mmol) and 2methyl-benzoic acid hydrazide (248 mg, 1.65 mmol) in DMF (6 mL) under N2. Upon disappearance of the carboxylic acid by LC/MS, dilute the reaction with EtOAc (60 mL) and extract with water (20 mL) followed by brine (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Dissolve the residue in DMF (6 mL) and add Burgess reagent (1.18 g, 4.95 mmol). Heat the mixture my microwave irradiation to 150° C for 15 min. Dilute the reaction with EtOAc (100 mL) and extract with water (25 mL). Extract the organic phase with saturated NaHCO3 (2 x 25 mL) followed by brine (20 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by silica gel chromatography (10-45percent ACN / DCM) to afford the title compound as a yellow oil: (M+H)+ 495.3. With Burgess Reagent in N,N-dimethyl-formamide, Time= 0.25h, T= 150 °C , Microwave irradiation Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys

O

Cl O

N O Br

O Cl

N

H N

O

O

N H O

N

Br N


Conditions & References Example Name 1-69.A To a 500 mL round-bottom flask was added 4.95 g (12.0 mmol) of 3- nitro-4-bromomethyl-benzoic acid N'-(4-chlorobenzoyl)-hydrazide, 6.09 g (36.0 mmol) DMC, and 100 mL of DCE . To this pale yellow solution was added 6.70 mL (48.0 mmol) of Et3N, slowly over 5 min. The dark green solution was allowed to stir at 40 °C for 30 min. then cooled to room temperature stirred for 18 h. Removed solvent and purified over a silica plug 10-30percent EtOAc/Hep to give the title compound as yellow solid. MS (m/z) 350.0 M (+1), retention time = 1.51 , Method 10. With (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid, triethylamine in DCE, Time= 18.5h, T= 20 - 40 °C Patent; NOVARTIS AG; WO2009/40410; (2009); (A1) English View in Reaxys


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Product, Substructure

Product, Substructure

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