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Letters in Organic Chemistry, 2009, 6, 8-10
An Efficient Synthesis of Raloxifene in Ionic Liquid: A Green Approach Pravin S. Shinde, Sandip S. Shinde, Atul S. Renge, Gajanan H. Patil, Ambadas B. Rode and Rajendra R. Pawar* Organic Chemistry Synthesis Laboratory, Dynopasak College, Parbhani-431 401, India Received June 14, 2008: Revised October 02, 2008: Accepted October 08, 2008
Abstract: An efficient and green procedure for the synthesis of raloxifene has been developed by using Suzuki couplings, Friedel-Crafts acylation, and copper catalyzed coupling reactions in an ionic liquid.
Keywords: Raloxifene, ionic liquids, Suzuki coupling, Friedel-Crafts acylation. INTRODUCTION During the past two decades, room temperature ionic liquids (ILs, Fig. 1) have attracted much attention in organic synthesis. ILs were used to enhance reaction rates and avoid the process of expensive catalysts recovery via multilayer extraction systems [1]. Due to unique physicochemical properties of ILs they were used as reaction media in various organic methodologies including Friedel-Crafts acylation [2], Suzuki [3], Sonogashira [4], Heck [5] and couplings reactions. Nowadays, ILs were considered as eco-friendly reaction media for the total synthesis of biologically active molecules such as pravadoline [6], haloperidol [7] and fenpropimorph [8]. A significant reduction of by-products and improved yield of target products was achieved in ILs solvents. After reaction workup, ILs were recycled and reused for several times. N
N X
[bmim][X] (X = BF4, PF6)
Fig. (1). Room temperature ionic liquids.
Biologically active raloxifene (1, Fig. 2) is a selective estrogen receptor modulators (SERMs), used for the treatment and prevention of postmenopausal disorder in woman [9]. Various synthetic pathways for the synthesis of raloxifene have been reported using hazardous chemicals and large amount of flammable, volatile and toxic organic solvents [10]. From economical point of view, the growing green chemistry concept prompted to study and explore the possibility of replacing volatile organic solvents with alternative non-toxic, non-flammable and non-volatile solvents. We recently reported various organic methodologies by using ILs as a media [11]. Herein, we describe the total synthesis of raloxifene in ILs media via Suzuki coupling, FriedelCrafts acylation and copper catalyzed coupling as key steps.
*Address correspondence to this author at the Organic Chemistry Synthesis Laboratory, Dynopasak College, Parbhani-431 401, India; Tel: (+91-2452240365); E-mail:
[email protected],
[email protected]
1570-1786/09 $55.00+.00
O
O
N
OH HO
S 1
Fig. (2). Raloxifene (1).
RESULTS AND DISCUSSION The complete synthesis of raloxifene in various ionic liquid solvents has been discussed as shown in Scheme 1. Raloxifene is prepared from the commercially available 6methoxybenzothiophene-2-boronic acid (2). First two steps of this synthesis are carbon-carbon bond-forming reactions, which were carried out by Suzuki coupling and FriedelCrafts acylation reactons respectively. Suzuki coupling reactions have been studied extensively in ionic liquids using various halo and other substituted aromatic boronic acids as an starting. Thus, 6-methoxybenzothiophene-2-boronic acid (2) was treated with 4-iodoanisole in presence of 2 M aqueous Na2CO3 solution in [bmim][BF4] (butylmethylimidazolium tetrafluoroborate), at 110 °C to gave 6-methoxy-2-(4methoxyphenyl)benzo[b]thiophene (3) in 81% yield. The product was extracted with solvent toluene (25mL X 3). The toluene was removed from the product by distillation under reduced pressure. The ionic liquid was recovered by washing it with water to remove Na2 CO3. After successful Suzuki coupling, second step was performed by using Friedel-Crafts acylation reaction with 4-bromobenzoylchloride in the IL [bmim][BF4] and catalytic amount of Cu(OTf)2 to furnish 4. The product was extracted with toluene and the IL was recovered after successive washing with water. The next step was the introduction of 2-hydroxyethyl piperidine side chain on substrate 4. Conventionally, this reaction has been carried out in a dipolar aprotic solvent such as DMF or DMSO using strong bases such as NaH, or alkoxide. Both these conditions suffer from the disadvantage that the removal of solvent is difficult to separate the product. In addition, NaH and alkoxide bases are highly hygroscopic and can not be used with imidazolium-based IL because of the acidic proton-2 [12].
© 2009 Bentham Science Publishers Ltd.
An Efficient Synthesis of Raloxifene in Ionic Liquid
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
a
B(OH)2 S
MeO
O
MeO
S
S
MeO
Br
OMe
b
OMe
81%
79%
O
O
c OMe 70%
MeO
9
S
N d 1 61%
Scheme 1. Reagents and conditions: (a) Pd(PPh3)4, 4-iodoanisole, aq. Na2CO3(2 M), [bmim][BF4], 110 °C; (b) Cu(OTf)2, 4bromobenzoylchloride, [bmim][BF4], 100 °C; (c) 2-hydroxyethylpiperidine, CuI, Cs2CO3, 3,4,7,8-tetramethyl-1,10-phenanthroline [bmim][PF6], 150 °C; (d) [TMAH][Al2Cl7].
Therefore, 5 was synthesised by modifying the procedure reported by using copper catalyzed coupling condition [13]. Substrate 4 was treated with 2-hydroxyethyl piperidine in presence of copper(I) iodide, 3,4,7,8-tetramethyl-1,10phenanthroline, and Cs2 CO3 in [bmim][PF6] at 150 ºC to yield 70 % of 5. Copper and Cs2 CO3 free ionic liquid [bmim][PF6] was recovered after product isolation using toluene. The final step to achieve the target was carried out in presence of Lewis acidic ionic liquid [TMAH][Al2 Cl7 ] (trimethylammonium aluminium chloride) [14] with cosolvent methylene chloride to yield raloxifene (1) in 61% yield. All products are known compounds and exhibited satisfactory 1H and 13C NMR as reported in the literature. In conclusion, we have successfully achieved a synthesis of raloxifene via Suzuki coupling, Friedel-Crafts acylation and copper catalyzed coupling in ionic liquid media. The use of an easily recoverable and recyclable expensive ionic liquid makes this synthetic procedure convenient, economic and eco friendly. EXPERIMENTAL All chemicals were obtained from commercial suppliers and were used without further purification unless otherwise stated. Flash chromatography was carried out using Merck silica gel 60 (230-400 mesh). Analytical thin layer chromatography (TLC) was performed with Merck Silica gel F-254 glass-backed plates. Visualization on TLC was monitored by UV light or phosphomolybdic acid indicator. 1 H and 13C NMR spectra were recorded using Varian Gemini-2000 (200 MHz). 6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (3) 4-Iodoanisole (2 g, 8.54 mmol) was added to a suspension of Pd (PPh3)4 (197 mg, 0.1 mmol) in [bmim][BF4] (20 mL) at room temperature under nitrogen atmosphere. The mixture was slowly heated to 110 °C with vigorous stirring affording a yellow-orange solution. The solution was cooled at room temperature and boronic acid 2 (2 g, 9.3 mmol) and a solution of Na2CO3 (2 mL, 2 M aqueous solution) was added. The mixture was further heated at 110 °C with vigorous stirring for 12 h. After completion of the reaction, as
indicated by TLC, the reaction mixture was cooled and extracted with toluene (15 mL 3). The combined organic extracts were washed with brine, water and dried over Na2SO4. Solvent toluene was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography to yield 3 (2.1 g, 81 %). mp 193-195 °C (Lit.[9d] mp 193-194 °C); 1H NMR (200 MHz, CDCl3) 3.80 (s, 3H), 3.85 (s, 3H), 6.89 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7. 54 (d, J = 2 Hz, 2H), 7.63 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3) 55.4 (OCH3), 55.8 (OCH3), 104.9 (benzthio, CH), 112.0 (arom. 2, CH), 114.1 (benzthio. CH), 116.2 (benzthio, CH), 123.4 (benzthio, CH), 126.0 (C), 135.0 (2, arom. CH), 136.2 (C), 139.5 (C), 144.8 (C), 155.2 (C), 156.7 (C); Analysis: Calcd for C16H14O2S: C, 71.08; H, 5.22; S, 11.86. Found: C, 70.94; H, 5.18; S, 11.57. Known compound [9d]. Procedure to recover ionic liquid: The separated ionic liquid layer was successively washed with water (15 mL 4) and kept under vacuum for 24 h. 6-Methoxy-3-(4-bromobenzoyl)-2(4-methoxyphenyl) benzo[b]thiophene (4) A mixture of 3 (2.1 g, 7.7 mmol), 4-bromobenzoyl chloride (5.2 g, 11.5 mmol) and Cu(OTf)2 (279 mg, 0.7 mmol) in [bmim][BF4] (20 mL,) was stirred at 100 °C under nitrogen atmosphere. After 2 h the reaction mixture was poured over ice water and extracted with toluene (20 mL 3). The combined organic extracts were washed with brine, water and dried over Na2SO4. Solvent toluene was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography to yield 4 (2.78 g, 79%). mp 126-128 °C (lit. [15] mp 127-129 °C ); 1H NMR (200 MHz, CDCl3) 3.72 (s, 3H), 3.89 (s, 3H), 6.73 (d, J = 8 Hz, 2H), 6.92 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.21 (d, J = 8 Hz, 2H), 7.36 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 7.42-7.61 (m, 3H); 13C NMR (50 MHz, CDCl3) 55. 6 (OCH3), 55.8 (OCH3), 104.1 (benzothio, CH), 110.2 (C) 114.5 (arom, 2, CH), 120.8 (arom, 2, CH), 125.0 (benzothio, CH), 126.2 (C), 127.8 (arom, 2, CH), 131.2 (arom, 2, CH), 134.2 (arom, 2, CH), 135.6 (arom, 2, CH), 137.6 (C), 143.3 (C), 159.1 (C), 160.4 (C), 162.2 (C), 192.8 (C=O); Analysis: Calcd for
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Letters in Organic Chemistry, 2009, Vol. 6, No. 1
C23H17BrO3S: C, 60.93; H, 3.78; S, 7.07. Found: C, 61.22; H, 3.98; S, 6.85. Known compound [15]. [6-methoxy-2-(4-methoxyphenyl)benzo[b]thophene][4-(2(piperidin-1-yl)ethoxy)phenyl] methanone (5) To a solution of 4 (2.78 g, 6.1 mmol), 2-hydroxyethyl piperidine (2.3 g, 18 mmol), Cs2 CO3 (6.0 g, 18 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (10 mmol%) in [bmim][PF6] (20 mL), CuI (10mmol %) was added and the reaction mixture stirred at 150 °C. After 12 h the reaction mixture was extracted with toluene (20 mL 3). The combined toluene extracts were washed with brine, water, and dried over Na2SO4. Solvent toluene was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography to yield 5 (1.86 g, 70 %). mp 212-213 °C; 1H NMR (200 MHz, CDCl3) 1.64-1.90 (m, 2H), 2.28-2.85 (m, 4H), 2.89-3.13 (m, 4H), 3.25-3.32 (m, 2H), 3.69 (s, 3H), 3.81 (s, 3H), 4.52 (t, J = 2.8 Hz, 2H), 6.71 (d, J = 8 Hz, 2H), 7.11(d, J = 8.8 Hz, 2H), 7. 33 (s, 1H), 7.41-7. 82 (m, 6H); 13C NMR (50 MHz, CDCl3) 24.6 (piperidine, CH2), 24.8 (piperidine, 2, CH2), 54.0 (piperidine, 2, N-CH2), 54.6 (N-CH2), 55.2 (OCH3), 55.8 (OCH3), 66.2 (O-CH2), 107.6 (benzothio, CH), 113.0 (C), 114.9 (arom, 2, CH), 116.2 (arom, 2, CH), 124.3 (benzothio, CH), 124.9 (benzothio, CH), 126.3 (C ), 129.0 (C ), 131.2 (arom, 2, CH), 132.8 (arom, 2, CH), 135.0 (C), 143.6 (C), 152.2 (C), 156.2 (C), 159.8 (C), 162.4 (C), 193.6 (C=O); Analysis: Calcd for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found: C, 72.12; H, 6.23; N, 2. 82, S, 6.66. Known compound [9d].
Shinde et al.
ACKNOWLEDGEMENTS Authors are thankful to Dr. W. N. Jadhav, Head, Department of Chemistry, Dnyanopasak College, Parbhani, India for his valuable cooperation to carry out this work. REFERENCES [1]
[2] [3] [4] [5] [6] [7] [8] [9]
Raloxifene (1) The stirred solution of substrate 5 (2.0 g, 3.9 mmol) in dichoromethane (30 mL), ionic liquid (3.0 equiv, [TMAH][Al2Cl7]) [16] was added gradually. The reaction mixture was refluxed for 6 h and poured onto dilute hydrochloric acid (1 M). The aqueous layer was washed with saturated NaHCO3, brine and extracted with dichloromethane. The separated organic layer was dried over Na2SO4, filtered and evaporated to yield 1 (1.15 g 61 %). mp 145-147 °C (Lit [9d] mp, 143-47 °C) ; 1H NMR (200 MHz, CDCl3) 1.201.65 (m, 6H) 2.30-2.45 (m, 4H ), 2.60 (t, J = 6 Hz, 2H), 4.06 (t, J = 6 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.85 (q, J = 8.6 Hz, 2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H) 9.72 (br, 2H); 13C NMR (50 MHz, CDCl3) 24.9 (piperidine, CH2), 25.4 (piperidine, 2, CH2), 54.6 (piperidine, 2, N-CH2), 54.9 (N-CH2), 66.5 (O-CH2), 107.8 (benzothio, CH), 113.8 (C), 115.1 (arom, 2, CH), 116.4 (arom, 2, CH), 124.5 (benzothio, CH), 125.1 (benzothio, CH), 126.9 (C), 129.2 (C), 131.6 (arom, 2, CH), 133.2 (arom, 2, CH), 136.0 (C), 143.8 (C), 154.1 (C), 158.8 (C), 160.0 (C), 163.8 (C), 194.2 (C); Analysis: Calcd for C28H27NO4S: C, 71.01; H, 5.75; N, 2.96; S, 6.77. Found: C, 70.78; H, 5.61; N, 2. 90; S, 7.02. Known compound [9d].
[10] [11]
[12] [13] [14] [15]
For recent reviews on ionic liquids, see (a) Dupont, J.; Suarez, P.A.Z. Phys. Chem. Chem. Phys., 2006, 8, 2442; (b) Dupont, J.; de Souza, R.F.; Suarez, P.A.Z. Chem. Rev., 2002, 102, 3667; (c) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A Chem., 2002, 182, 419; (d) Sheldon, R. Chem. Commun., 2001, 23, 2399; (e) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. Engl., 2000, 39, 3772; (f) Welton, T. Chem. Rev., 1999, 99, 2071; (g) Ranke, J.; Stolte, S.; Stormann, R.; Arning, J.; Jastorff, B. Chem. Rev., 2007, 107, 21832206; (h) Parvulescu, V.I.; Hardacre, C. Chem. Rev., 2007, 107, 2615-2665; (i) Greaves, T.L.; Durmmond, C.J. Chem. Rev., 2008, 108, 206-237; (j) Martins, M.A.P.; Frizzo, C.P.; Moreira, D.N.; Zanatta, N.; Bonacorso, H.G. Chem. Rev., 2008, 108, 2015-2050. Boon, J.A.; Levisky, J.A.; Pflug, L.; Wilkes, J.S. J. Org. Chem., 1986, 51, 480. (a) Mathews, C.J.; Smith, P.J.; Welton, T. Chem. Commun., 2000, 14, 1249; (b) Wang, R.; Twamley, B.; Shreeve, J.M. J. Org. Chem., 2006, 71, 426. Corma, A.; Garcia, H.; Leyva, A. Tetrahedron Lett., 2005, 61, 9848; Kaufmann, D.E.; Nouroozian, M.; Henze, H. Synlett, 1996, 11, 1091. Earle, M.J.; McCormac, P.B.; Seddon, K.R. Green Chem., 2000, 2, 261. Anjajah, S.; Chandrasekhar, S.; Gree, R. Adv. Synth. Catal., 2004, 346, 1329. Forsyth, S.A.; Nimalgunarate, H.Q.; Hardacre, G.; Mckeown, A.; Rooney, D.W.; Org. Proc. Res. Dev., 2006, 10, 94. (a) Grese, T.A.; Dodge, J.A. Curr. Pharm. Des., 1998, 4, 71; (b) Bryant, H.U.; Dere, W.H. Proc. Soc. Exp. Biol. Med., 1998 217, 45; (b) Grese, T.A.; Cho, S.; Finley, D.R.; Godfrey, A.G.; Jones, C.D.; Lugar III, C.W.; Martin, M.J.; Matsumoto, K.; Pennington, L.D.; Winter, M.A.; Adrian, M.D.; Cole, H.W.; Magee, D.E.; Phillips, D.L.; Rowley, E.R.; Short, L.L.; Glasebrook, A.L;. Bryant, H.U. J. Med. Chem., 1997, 40, 146; (c) Grese, T.A.; Pennington, L.D.; Sluka, J.P.; Adrian, M.D.; Cole, H.W.; Fuson, T.R.; Magee, D.E.; Phillips, D.L.; Rowley, E.R.; Shetler, P.K.; Short, L.L.; Venugopalan, M.; Yang, N.N.; Sato, M.; Glasebrook, A.L.; Bryant, H.U. J. Med. Chem., 1998, 41, 1272; (d) Jones, C.D.; Jevnikar, M.G.; Pike, A.J.; Peters, M.K.; Black, L.J.; Thompson, A.R.; Falcone, J.F.; Clemens, J.A. J. Med. Chem., 1984, 27, 1057. Bradley, D.A; Godfrey, A.G.; Schmid, C.R. Tetrahedron Lett., 1999, 40, 5155; (b) Schmid, C.R.; Sluka, J.P.; Duke, K.M. Tetrahedron Lett., 1999, 40, 675. Bhosale, R.S.; Suryawanshi, P.A.; Ingle, S.A.; Lokhande, M.N.; More, S.P.; Mane, S.B.; Bhosale, S.V.; Pawar, R.P. Synlett., 2006, 6, 933; (b) Sarda, S.R.; Pathan, M.Y.; Paike, V.V.; Pachmase, P.R. Jadhav, W.N.; Pawar, R.P. Arkivoc, 2006, 16, 43; (c) More, S.V.; Ardhapure, S.S.; Naik, N.H.; Bhusare, S.R.; Jadhav, W.N.; Pawar, R.P. Synth. Commun., 2005, 35, 3113. Arnold, P.L.; Rodden, M.; Davis, K.M.; Scarisbrick, A.C.; Blake, A.J.; Wilson, C. Chem. Commun., 2004, 14, 1612. Altman, R.A.; Shafir, A.; Choi, A.; Lichtor, P.A.; Buchwald, S.L. J. Org. Chem. 2008, 73, 284-286 Kemperman, G.J.; Roeters, T.A.; Hilberink, P.W. Eur. J. Org. Chem., 2003, 9, 1681. Peter, J. U.S. Patent, 5827876A, 1998.
