Design and Synthesis of Some Carbamazepine

Send Orders for Reprints to [email protected] Letters in Organic Chemistry, 2015, 12, ???-???

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Design and Synthesis of Some Carbamazepine Derivatives Using Several Strategies Figueroa-Valverde Lauro*,1, Díaz-Cedillo Francisco2, Rosas-Nexticapa Marcela3, MaldonadoVelázquez Guadalupe1, García-Cervera Elodia1, Pool-Gómez Eduardo1, Jarquín-Barberena Horacio4, López-Ramos María1, Rodríguez-Hurtado Fernanda1 and Chan-Salvador Marissa1 1

Laboratory of Pharmaco-Chemistry at the Faculty of Chemical Biological Sciences from the University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista C.P.24039 Campeche Cam., México; 2Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala s/n Col. Santo Tomas, México, D.F. C.P. 11340; 3Facultad de Nutrición, Universidad Veracruzana. Médicos y Odontólogos s/n, 91010, Xalapa Veracruz, México; 4Universidad Juárez Autónoma de Tabasco, División Académica de Ciencias de la Salud. Av. Gregorio Méndez 2838-A Col. Tamulté. CP. 86100. Villahermosa, Tabasco, México.

F.-V. Lauro

Received February 06, 2015: Revised March 17, 2015: Accepted March 30, 2015

Abstract: In this study, is reported a straightforward route is reported for the synthesis of a series of carbamazepine derivatives using some strategies. The first stage was achieved by the reaction of carbamazepine with thiourea in the presence of pyridine to form the compound 3-(5H-dibenzo[b,f]azepin-5-yl)-2,5-dihydro-1,2,4-thiadiazol-5-amine (3). After 3 was made reacting with chloroacetyl chloride using triethylamine as catalyst to synthesis of a propanamide derivative (4). The following stage a carboxamide derivative (5) was synthesized by the reaction of 4 with benzaldehyde in basic medium. The fourth stage was achieved by the reaction of carbamazepine with ethylenediamine in presence of formaldehyde to form a new carboxamide derivative (7). Then, the compound 7 was made reacting with 2-hydroxy-1-naphthaldehyde using boric acid as catalyst to synthesis of a carbamazepine derivative (8). Finally, 8 was made reacting with 3,5dintrobenzoic acid in the presence of dimetyhyl sulfoxide at mild conditions to form a new carbamazepine derivative 9. The structure of the compounds obtained was confirmed by elemental analysis, spectroscopy and spectrometry data. The proposed method offers some advantages such as simple procedure, low cost, and ease of workup.

Keywords: Carbamazepine, synthesis, thiourea, boric acid. 1. INTRODUCTION Since several years ago, a series of heterocyclic derivatives have been synthesized using protocols different; for example, a series of 3-oxobutyramide derivatives by the reaction of the appropriate benzofuroxane with chloroform [1]. Other data indicate the synthesis of N-[5-(2-furanyl)-2methyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl]-carboxamide by the reaction of 3-amino-5-(2-furanyl)-2-methyl-3Hthieno [2,3-d]pyrimidin-4-one with triethylamine in presence of acid chloride [2]. Other study reported the reaction of 3Amino-2-oxazolidinone with N-ethyl-N-(3-dimethylaminopropyl)carbodiimide and 4-(dimethylamino)-pyridine to form N-(2-Oxazolidinone-3-yl)-3-(phenylsulfonyl)-5-chloro1H-indole-2-carboxamide [3]. Other data showed the synthesis of N-[(2-Dimethylamino)ethyl]-1-[2-((dimethylamino)ethyl)amino]-6-methylbenzo[b][1,6]naph- thyridine4-carboxamide by the reaction of 6-Methyl-1-oxo-1,2dihydrobenzo[b][1,6] naphthyridine-4-carboxylic Acid with phosphoryl chloride [4]. In addition, other study indicate the

*Address correspondence to this author at the Department of Pharmacochemistry, Faculty of Biological-Chemical Sciences, University Autonomous of Campeche, Mexico; Tel/Fax: 9818119800; E-mail: [email protected]

1570-1786/15 $58.00+.00

preparation of N-(3-(dimethylamino)propyl)-2-methyl-4trifluoromethyl-thiazo le-5-carboxamide by the reaction of 3(dimethyl-aniino)propylamine with 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride in the presence of trimethylamine [5]. Other report [6] showed the synthesis of 1H-1,2,3-Triazole-4-carboxamide derivative by the reaction of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid and aryl poperazine using carbodiimide hydrochloride as catalyst. Other data indicate the synthesis of N-{(substituted)1,3benzothiazol-2-yl}-1,1í-biphenyl-4-carboxamide derivatives by the reaction of aminobenzothiazole with biphenyl acid chloride in basic medium [7]. On the other hand, other types of heterocyclic compounds (carbamazepine derivatives) have been prepared; for example, the synthesis of oxcarbazepine via remote metalation of protected N-o-tolyl-anthranilamide derivatives [8]. Other data indicate the synthesis of 10-(E-Hydroxyimino)10,11-dihydro-dibenz[b,f]azepine-5-carboxamide by the reaction of oxcarbazepine with hydroxylamine hydrochloride in the presence of pyridine [9]. In addition, other carbamazepine derivative (N-hex-1-ynyl-N-phenyl-5H-dibenzo[b,f]azepine-5-carboxamide) was prepared using the three component system (carbamazepine, 1-hexyne and benzaldehyde) [10]. All these experimental results show several

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Letters in Organic Chemistry, 2015, Vol. 12, No. 6

Lauro et al.

S i

H2N

+ N

N

NH2

3 2

NH2

O

NH

N

S

1 H2N

ii

N

N

iii

5 O

4

NH

N

N O

S

NH S

NH

NH Cl

O

Fig. (1). Synthesis of (2R,3S)-N-(3-(5-H-dibenzo[b,f]azepin-5-yl)-2,5-dihydro-1,2,4-thiadiazol-5-yl)-3-phenyloxirane-2-carboxamide (5). i = pyridine/rt; ii = trimethylamine/rt; iii = NaOH/rt. A H2O

N O B

N NH2

N

S H2N

NH2

N

S

NH3

C

N

N

N

S

N

N N S

N

N N

N

N

S

S NH3

N

NH3

NH2 3

Fig. (2). Mechanism of reaction involved in the synthesis of compound 3.

procedures which are available for the synthesis of several heterocyclic derivatives; nevertheless, expensive reagents and special conditions are required. Therefore, in this study, some carbamazepine derivatives were synthesized using several strategies. 2. RESULTS AND DISCUSSION In this study, several straightforward routes are reported for the synthesis of new carbamazepine derivatives using strategies different; the first stage (Figs. 1 and 2) was achieved by the synthesis of 3-(5H-dibenzo[b,f]azepin-5-yl)-

2,5-dihydro-1,2,4-thiadiazol-5-amine (3). Many procedures for preparation of several carbamazepine derivatives; in addition, some procedures have been used for the introduction of functional groups on carbamazepine structure. However, despite its wide scope, there are some drawbacks; for example, several agents used, have limited stability and their preparation requires special conditions [8, 10-12]. Therefore the carbamazepine derivative (3) was synthesized by the reaction of the compound 1 with thiourea in the presence of pyridine (Fig. 1). The 1H NMR spectrum of 3 shows signals at 4.80 ppm for both amino groups; at 6.68 ppm for thiadiazole ring; at 6.80 ppm for azepine ring; at 7.00-7.15 ppm for

Design and Synthesis of Some Carbamazepine Derivatives


3

H

H

H

H 13

11

14

20

12

H 10

H

15

7

19

16 6

9

18

8

17

H

H H

H 3 4

5

N

H

S 1

21

H

2

N

N H

Fig. (3). 1H-1H COSY spectrum of compound 3.

phenyl groups. The 13C NMR spectra display chemical shifts at 93.46 and 161.10 ppm for thiadiazole ring; at 115.60133.00 and 140.36 ppm for phenyl groups; at 138.38 ppm for azepine ring. In order to confirm the chemical structure of 3, the H-H COSY spectra (Fig. 3) were carried out. The results reveal interaction and coupling effects between the adjacent protons NH2 (21) and NH (2) (3J) with H (5) to 4.80 ppm. In addition, other confirmatory long range correlations are shown in the Figure 3. Finally, the presence of 3 was further confirmed from mass spectrum which showed a molecular ion at m/z 294.08. The second stage (Figs. 1 and 3) was achieved by the synthesis of a chloroamide derivative (4); it is important to

mention that there are many procedures for the formation of chloroamides which are known in the literature, for example the reaction of amine with trichloroisocyanuric Acid [13] or amide secondary with N-chlorobenzotriazole to form a chloroamide derivative [14]; in addition, some chloroamide groups have been prepared using chloroacetyl chloride [15]. In this study, the compound 4 was synthesized by the reaction of 3 with chloroacetyl chloride using triethylamine as a catalyst. The results of 1H NMR spectrum of 4 show signals at 3.90 ppm for methylene involved in the chloroacetamide group; at 6.70 ppm for azepine ring; at 7.28 ppm for thiadiazole ring; at 7.56-7.64 and 8.26 ppm for phenyl groups; at 7.98 ppm for amino groups. The 13C NMR spectra display

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Lauro et al.

N

D

N NH

N

N

S H

N

O

S

Cl

HN

H O

Cl

Cl N

E HN

O

N N

HN

S

H

+

N

S NH

NH

O H

NaOH

Na

O

Cl

Cl

O

O Na

O

O

Na H Cl

R

H

H O

Cl

R

O

R 5

R=

N HN

N

S NH

Fig. (4). Reaction mechanism involved in the synthesis of compound 5.

chemical shifts at 42.30 ppm for methylene involved in the chloroacetamide group; at 92.78 and 159.89 ppm for thiadiazole ring; at 115.56-132.80 and 140.88 ppm for phenyl groups; at 138.45 ppm for azepine ring; at 165.76 ppm for amide group. Finally, the presence of 4 was further confirmed from mass spectrum which showed a molecular ion at m/z 370.06. The third stage was achieved by the synthesis of an oxirane derivative (5); it is important to mention that there are many procedures and catalyst different for the formation of oxirane derivatives such as Sulfur hylides [16], Indium (III) chloride [17], methyllithium [18] and haloamide [19] between others. However, some of these reagents require special conditions and are very costs. Therefore, in this study, the compound 5 was prepared by the reaction of 4 with benzaldehyde in basic conditions. The 1H NMR spectrum of 5 shows signals at 3.70-3.80 ppm for oxirane ring; at 6.80 ppm for azepine ring, at 6.88 and 7.24-7.28 ppm for phenyl group bound to oxirane ring; at 7.18 ppm for thiadiazole ring; at 7.56-7.64 and 8.28 ppm for phenyl groups bound to azepine ring; at 7.84 ppm for amino groups. The 13C NMR spectra

display chemical shifts at 51.30-59.66 ppm for oxirane ring; 94.50 and 159.86 ppm for thiadiazole ring; at 115.60-122.54, 126.90-127.43, 132.88 and 140.87 ppm for phenyl groups bound to azepine ring; at 126.20, 128.16-128.52 and 136.00 ppm for phenyl groups bound to oxirane ring; at 138.40 ppm for azepine ring; at 173.40 ppm for amide group. Finally, the presence of 5 was further confirmed from mass spectrum which showed a molecular ion at m/z 440.13. The four stage (Figs. 4 and 5) was achieved by the synthesis of the compound 7 using the Mannich reaction. The Mannich reaction involves the reaction of several compounds (ketone, aldehydes or nitroalkene groups) [20-22] with formaldehyde and a compound containing an activate hydrogen; for example ammonia, a primary or secondary amine. In this study, the compound 7 was prepared by the reaction of carbamazepine and ethylenediamine and the presence of formaldehyde in the basic medium. The 1 H NMR spectrum of 5 shows signals at 2.64-2.70 ppm for methylene groups involved in the arm bound to azepine ring; at 3.68 ppm for methylene group bound to both amino group and azepine ring; at 3.64 ppm for amino group; at 7.06 ppm



5

NH H2N

N

NH2

N

6

NH2

O

iv

H2N

+

O

1

NH2 7

HO v N

O N

HN

N+ NO

v

8

N

HN

N O

N

NH2

9

O NH2

Fig. (5). Synthesis of (E)-4-((1-(((2-(((5-carbomoyl-5H-dibenzo[b,f]azepin-10-yl)methyl)amino) yl)oxy)benzoyl azide (9). iv = formaldehyde/rt; v = boric acid/rt; vi = K2CO3/DMSO/rt.

for proton involved in the azepine ring; at 7.10-8.16 ppm for phenyl groups. The 13C NMR spectra display chemical shifts at 41.10 and 52.22 ppm for methylene groups bound to azepine ring; at 55.94 for methylene group bound to both amino group and azepine ring; at 115.60 and 142.77 ppm for carbons involved in the azepine ring; at 119.21-142.60 for phenyl groups; at 159.86 ppm for amide group. Finally, the presence of 7 was further confirmed from mass spectrum which showed a molecular ion at m/z 308.16. The following stage (Fig. 4) was achieved by the reaction of the compound 7 with 2-hydroxy-1-naphthaldehyde (Fig. 1) resulting an imino bond formation involved in the compound 8. Many procedures for the synthesis of imino groups are described in the literature [23-24]; nevertheless, in this study, boric acid was used as a catalyst, because it is not an expensive reagent and no special conditions for its use are required [25]. The results of 1H NMR spectrum of 7 show signals at 2.84 and 3.80 ppm for methylene groups involved in the arm bound to imino and amino groups; at 3.68 ppm for methylene group bound to both amino and phenyl groups; at 6.78, 7.56-7.64, 7.76-8.16 and 8.40 ppm for phenyl groups bound to imino group; at 7.06 ppm for both hydroxyl and amino groups; at 7.07 ppm for azepine ring; at 7.10-7.40, 7.69 and 8.20 ppm for phenyl groups bound to azepine ring; at 8.50 ppm for methylene of imino group. The 13C NMR spectra display chemical shifts at 50.30 and 58.79 ppm for methylene groups bound to both amino groups; at 55.88 for carbon bound to both phenyl and amino groups; at 105.66, 121.10, 122.70, 123.70, 126.20-127.28, 129.06, 133.92, 136.50 and 159.78 ppm for phenyl groups bound to azepine ring; at 15.64 and 142.80 ppm for carbons of azepine ring; at 119.30, 122.00-122.50, 123.28, 125.50-125.76, 127.70127.90, 132.68, 136.28 and 137.32-142.58 ppm for phenyl

ethyl)imino)methyl)naphtalen-2-

groups bound to azepine ring; at 159.88 amide group; at 160.00 ppm for imino group. In addition, the presence of 8 was further confirmed from mass spectrum which showed a molecular ion at m/z 462.20. Finally, the last stage (Fig. 4) was achieved by the synthesis of the compound 9 via displacement of nitro group from 3,5-dinitrobenzoic acid. It is important to mention that there are several methods for the displacement of nitro groups using dipolar aprotic solvent [26-27]; in general, dipolar solvents are used to attain high yield of ether groups. Therefore, in this study, the compound 9 was synthetized by the reaction of 3,5-dinitro benzoic acid with the compound 8 in the presence of dimetyhyl sulfoxide at mild conditions. The1H NMR spectrum of 9 shows signals at 2.80 and 3.80 ppm for methylene groups bound to both amino and imino groups; at 3.68 ppm for methylene group bound to both amino and phenyl groups; at 4.50 ppm for both amino groups; at 7.08 ppm for azepine ring; at 7.09 and 7.88 for phenyl group bound to both ether and formyl azide groups; at 7.11-7.17, 7.26-7.40, 7.74 and 8.20 ppm for phenyl groups bound to azepine ring; at 7.20, 7.64, 7.82-7.86 and 8.74 ppm for phenyl groups bound to both ether and imino groups; at 8.66 ppm for imino group. The 13C NMR spectra display chemical shifts at 50.30 and 58.87 ppm for methylene groups bound to both amino and imino groups; at 55.88 ppm for methylene group bound to both amino and phenyl groups; at 113.20, 118.44, 122.98, 124.08-12.86, 125.94, 129.13, 133.64 and 152.30 ppm for phenyl groups bound to both ether and imino groups; at 115.65 ppm for azepine ring; at 116.69-116.78, 123.34-123.70, 134.70-134.77 and 164.80 ppm for phenyl group bound to both ether and formyl azide

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Lauro et al.

O + H

HCl

O

Cl

H

H

O H2N

NH2

H

N

H

H H

H2N

H

N

OH

H

H

- H2O H2N

H

N

H

H

H H2N

H

H2N

H N H

H

H N O

N NH2

O

NH2

H2N N H

7

N O

NH2

Fig. (6). Reaction mechanism involved in the synthesis of the compound 7.

groups; at 119.31-122.50, 125.50-125.76, 127.75-127.90, 132.72 and 136.33-142.81 ppm for phenyl groups bound to azepine ring; at 159.90 ppm for amide group; at 160.48 for imino group; at171.56 formyl azide group. Finally, the presence of 9 was further confirmed from mass spectrum which showed a molecular ion at m/z 607.23. 3. MATERIALS AND METHOD General Methods The compounds evaluated in this study were purchased from Sigma-Aldrich Co. Ltd. The melting points for the different compounds were determined on an Electrothermal (900 model). Infrared spectra (IR) were recorded using KBr pellets on a Perkin Elmer Lambda 40 spectrometer. 1H and 13 C NMR and 2D-COSY spectra were recorded on a Varian VXR-300/5 FT NMR spectrometer at 300 and 75.4 MHz in CDCl3 using TMS as an internal standard. EIMS spectra were obtained with a Finnigan Trace GCPolaris Q. spectrometer. Elementary analysis data were acquired from a Perkin Elmer Ser. II CHNS/0 2400 elemental analyzer. Synthesis of 3-(5H-dibenzo[b,f]azepin-5-yl)-2,5-dihydro1,2,4-thiadiazol-5-amine (3) A solution of carbamazepine (100 mg, 0.42 mmol), thiourea (60 mg, 0.78 mmol) and pyridine (5 ml) was left on stirring for 48 h at reflux. The reaction mixture was evaporated to dryness under reduced pressure. After, the residue

was purified by crystallization from methanol:water (3:1) yielding 80 % of product, m.p. 168-170 oC; IR (Vmax, cm-1): 3380, 3310, 1198 and 690; 1H NMR (300 MHz, CDCl3) H: 4.80 (broad, 3H), 6.68 (m, 1H), 6.80 (m, 2H), 7.00-7.15 (m, 8H) ppm. 13C NMR (75.4 Hz, CDCl3) C: 93.46 (C-5), 115.60 (C-8, C-17), 122.50 (C-10, C-19), 126.88 (C-9, C18), 127.40 (C-11, C-20), 133.00 (C-12, C-15), 138.38 (C13, C-14), 140.63 (C-7, C-16), 161.10 (C-2) ppm. EI-MS m/z: 294.08 (M+ 11). Anal. Calcd. for C16H14N4S: C, 65.28; H, 4.79; N, 19.03; S, 10.89. Found: C, 65.20; H, 4.72. Sinthesis of N-[3-(5H-dibenzo[b,f]azepin-5-yl)-2,5dihydro-1,2,4-thiadiazol-5-yl] propanamide (4) A solution of 3 (200 mg, 0.68 mmol), triethylamine (100 μl, 1.50 mmol) and chloroacetyl chloride (128 μl, 1.60 mmol) in 10 mL of methanol was kept on stirring for 72 h at room temperature. The reaction mixture was evaporated to a smaller volume. After the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 46 % of product, m.p. 154-156 oC; IR (Vmax, cm1 ):1680, 3312 and 692; 1H NMR (300 MHz, CDCl3) H: 3.90 (m, 2H), 6.70 (m, 2H), 7.28 (m, 1H), 7.56-7.64 (m, 6H), 7.98 (broad, 2H), 8.26 (m, 2H) ppm. 13C NMR (75.4 Hz, CDCl3 ) C: 42.30 (C-24), 92.78 (C-5), 115.56 (C-8, C-17), 122.54 (C-10, C-19), 126.94 (C-9, C-18), 127.49 (C-11, C-20), 132.80 (C-12, C-15), 138.45 (C-13, C-14), 140.88 (C-7, C-


16), 159.89 (C-3), 165.76 (C-22) ppm. EI-MS m/z: 370.06 (M+ 12). Anal. Calcd. for C18H15Cl N4OS: C, 58.30; H, 4.08; Cl, 9.56, N, 15.11; O, 4.31; S, 8.65. Found: C, 58.26; H, 4.00. Sinthesis of (2R,3S)-N-(3-(5-H-dibenzo[b,f]azepin-5-yl)2,5-dihydro-1,2,4-thiadiazol-5-yl)-3-phenyloxirane-2carboxamide (5) A solution of 4 (200 mg, 0.54 mmol), benzaldehyde (100 l, 0.98 mmol) and sodium hydroxide (20 mg, 0.50 mmol) in 10 ml of ethanol was kept on stirring for 72 h at room temperature. The reaction mixture was evaporated to a smaller volume. After the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 45 % of product, m.p. 98-100 oC; IR (Vmax, cm-1): 3310, 1682 and 690; 1H NMR (300 MHz, CDCl3) H: 3.70 (m, 1H), 3.80 (m, 1H), 6.68 (m, 2H), 6.88 (m, 2H), 7.18 (m, 1H), 7.24-7.28 (m, 3H), 7.56-7.64 (m, 6H), 7.84 (broad, 2H), 8.28 (m, 2H) ppm. 13 C NMR (75.4 Hz, CDCl3) C: 51.30 (C-24), 59.66 (C-26), 94.50 (C-5), 115.60 (C-8, C-17), 122.54 (C-10, C-19), 126.20 (C-28, C-32), 126.90 (C-9, C-18), 127.43 (C-11, C20), 128.16 (C-30), 128.52 (C-29, C-31), 132.88 (C-12, C15), 136.00 (C-27), 138.40 (C-13, C-14), 140.87 (C-7, C16), 159.86 (C-3), 173.40 (C-22) ppm. EI-MS m/z: 440.13 (M+10). Anal. Calcd. for C25H20N4O2S: C, 68.16; H, 4.58; N, 12.72; O, 7.26; S, 7.28. Found: C, 68.10; H, 4.52. Synthesis of 10-{[(2-aminoethyl)amino]methyl}-5Hdibenzo[b,f]azepine-5-carboxa-mide (7) A solution of carbamazepine (200 mg, 0.85 mmol), ethylenediamine (70 l, 1.04 mmol) formaldehyde (1 ml) and sodium hydroxide (20 mg, 0.50 mmol) in 10 ml of ethanol was stirring for 72 h at room temperature. The reaction mixture was evaporated to a smaller volume. After the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 80 % of product, m.p. 96-98 oC; IR (Vmax, cm-1): 3378, 3312 and 1670; 1H NMR (300 MHz, CDCl3) H: 2.64 (t, 2H, J = 5.97 Hz), 2.70 (t, 2H, J = 5.97 Hz), 3.64 (broad, 5H), 3.68 (m, 2H), 7.06 (m, 1H), 7.10-8.16 (m, 8H) ppm. 13C NMR (75.4 Hz, CDCl3) C: 41.10 (C-21), 52.22 (C-20), 55.94 (C-18), 115.60 (C-9), 119.31 (C-6), 122.00 (C-12), 122.5 (C-5), 123.34 (C-3), 125.53 (C-14), 125.70 (C-15), 127.88 (C-4, C-13), 132.72 (C-7), 136.33 (C-10), 137.32 (C-11), 142.60 (C-2), 142.77 (C-8), 159.86 (C-16) ppm. EI-MS m/z: 308.16 (M+ 10). Anal. Calcd. for C18H20N4O: C, 70.11; H, 6.54; N, 18.17; O, 5.19. Found: C, 70.06; H, 6.50. Synthesis of 10-({2[2-hydroxy-naphtalen-1-ylmethylene)amino]-ethylamino}methyl)-dibenzo[b,f]azepine-5-carbo xamide (8) A solution of 7 (100 mg, 0.69 mmol), 2-hydroxy-1naphthaldehyde (120 mg, 0.70 mmol), boric acid (40 mg,


7

0.65 mmol) in 10 ml of methanol was kept on stirring for 72 h to room temperature. The reaction mixture was evaporated to a smaller volume. After the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 80 % of product, m.p. 106-108 oC; IR (Vmax, cm-1): 3418, 3320, 3314 and 1672; 1H NMR (300 MHz, CDCl3) H: 2.84 (m, 2H), 3.84 (t, 2H, J = 15.80), 3.80 (m, 2H), 6.78 (m, 1H), 7.06 (broad, 4H), 7.07 (m, 1), 7.10-7.40 (m, 6H), 7.567.64 (m, 2H), 7.69 (m, 1H), 7.76-8.16 (m, 2H), 8.20 (m, 1H), 8.40 (m, 1H), 8.50 (d, 1H, J = 1.20). 13C NMR (75.4 Hz, CDCl3) C: 50.30 (C-20), 55.88 (C-18), 58.79 (C-21), 105.66 (C-24), 115.64 (C-9), 119.30 (C-6), 121.10 (C-30), 12.00 (C-12), 122.50 (C-5), 122.70 (C-32), 123.28 (C-3), 123.70 (C-26), 125.50 (C-14), 125.76 (C-15), 126.20 (C28), 127.28 (C-31), 127.70 (C-4), 127.90 (C-13), 129.06 (C33), 132.68 (C-7), 133.92 (C-29), 136.28 (C-10), 136.50 (C27), 137.32 (C-11), 142.58 (C-2), 142.80 (C-8), 159.78 (25), 159.88 (C-16), 160.00 (C-23) ppm. EI-MS m/z: 462.20 (M+ 8). Anal. Calcd. for C29H26N4O2: C, 75.30; H, 5.67; N, 12.11; O, 6.92. Found: C, 75.24; H, 5.63. Synthesis of (E)-4-((1-(((2-(((5-carbomoyl-5H-dibenzo [b,f]azepin-10-yl)methyl)amino)ethyl)imino)methyl)naph talen-2-yl)oxy)benzoyl azide (9) A solution of 8 (100 mg, 0.69 mmol), 3,5-dintrobenzoic acid (120 mg, 0.70 mmol), potassium carbonate anhydride (25 mg, 0.18 mmol) in 10 ml of DMSO was kept on stirring for 72 h to room temperature. The reaction mixture was evaporated to a smaller volume. After the mixture was diluted with water and extracted with chloroform. The organic phase was evaporated to dryness under reduced pressure, the residue was purified by crystallization from methanol:water (3:1) yielding 80 % of product, m.p. 88-90 oC; IR (Vmax, cm1 ): 3318, 1676 and 1142; 1H NMR (300 MHz, CDCl3) H: 2.80 (t, 2H), 368 (m, 2H), 3.80 (t, 2H), 450 (broad, 3H), 7.08 (m, 1H), 7.09 (m, 2H), 7.11-7.17 (m, 2H), 7.20 (m, 1H), 7.26-7.40 (m, 4H), 7.64 (m, 2H), 7.74 (m, 1H), 7.82 7.86 (m, 2H), 7.88 (m, 2H), 8.20 (m, 1H), 8.66 (m, 1H), 8.74 (m, 1H) ppm. 13C NMR (75.4 Hz, CDCl3) C: 50.30 (C-20, 55.88 (C18), 58.87 (C-21), 113.20 (C-24), 115.65 (C-9), 116.89 (C37), 116.78 (C-41), 118.44 (C-32), 119.31 (C-6), 122.04 (C12), 122.5 (C-5), 122.98 (C-26), 123.34 (C-3), 123.70 (C39), 124.08 (C-30), 124.10 (C-31), 124.86 (C-28), 125.50 (C-14), 125.76 (C-15), 125.94 (C-33), 127.75 (C-4), 127.90 (C-13), 129.13 (C-29), 132.72 (C-7), 133.64 (C-27), 134.70 (C-38), 134.77 (C-40), 136.33 (C-10), 137.39 (C-11), 142.66 (C-2), 142.81 (C-8), 152.30 (C-25), 159.90 (C-16), 160.48 (C-23), 164.80 (C-36), 171.56 (C-42) ppm. EI-MS m/z: 607.23 (M+ 11). Anal. Calcd. for C36H29N7O3: C, 71.16; H, 4.81; N, 16.14; O, 7.90. Found: C, 71.10; H, 4.78. CONCLUSION In this study, a straightforward route is reported for the synthesis of a series of carbamazepine derivatives using some strategies. The proposed methods offer some advantages such as simple procedure and ease of workup.

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Lauro et al.

CONFLICT OF INTEREST We declare that this manuscript does not have any conflict of financial interests (political, personal, religious, ideological, academic, intellectual, commercial or otherwise) for its publication.

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ACKNOWLEDGEMENTS Declared none.

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