101

CHAPTER - 4

SYNTHESIS OF SUBSTITUTED CARBAZOLE AND

PYRAZOLES

This chapter is divided into two sections namely Section-A and

Section-B. Section-A deals with the synthesis of substituted carbazole

and pyrazoles. Section-B describes an alternate synthesis of

naratriptan drug using a new intermediate, N-benzyl-N-

methylethanesulfonamide.

SECTION-A

4A.1 INTRODUCTION:

Carbazole derivatives are well known for their pharmacological

activities [130]. These compounds have been reported to possess

diverse biological activity like antibacterial [131], antifungal [132],

anticancer and anti-HIV activities [133-134]. Pyrazole derivatives also

well established in the literature as important biologically active

heterocyclic compounds [135]. These compounds exhibit anti-

inflammatory [136], antipyretic [137], antimicrobial [138], antiviral

[139] antitumour [140] and antidepressant [141] etc. In this chapter

we synthesized and characterized some new sulfonamide carbazole

and pyrazole derivatives.

4A.2 LITERATURE SURVEY

Several synthetic methods have been reported in the literature

for carbazole and pyrazoles. Some of the synthetic methods are

discussed below.

102

4A.2.1 CARBAZOLE

Deoxygenation of o-nitrobiphenyl (113) to carbazole (114)

(Scheme- 4A.1) was first reported by Waterman and Viviens [142] by

using iron oxalate at 200 ºC. The widely accepted mechanism involves

exhaustive deoxygenation to singlet nitrene that undergoes a down

stream C-H insertion.

….. Scheme - 4A.1

Cadogan et. al. [143] reported a similar deoxygenative

cyclization of o-nitrobiphenyl (113) to carbazole (114) (Scheme-4A.2)

under reflux using triethylphosphite as solvent.

….. Scheme 4A.2

Smith and brown [144] reported the synthesis of carbazole (116)

(Scheme-4A.3) by thermal decomposition of o-azidobiphenyl (115) in

kerosene at 180 ºC. The reaction is believed to proceed via loss of

nitrogen gas forming nitrene, followed by cyclization to 9a-hydro-9H-

carbazole.

103

….. Scheme - 4A.3

In 1982, Tauber et. al. [145] reported the synthesis of carbazole

(114) (Scheme-4A.4) by the cyclization of 2,2-diaminobiphenyl (117).

This reaction relies on high temperature and acidic conditions

involving cyclization with the elimination of ammonia.

….. Scheme - 4A.4

The Fischer method [146] of indole synthesis by the indolization

of an arylhydrazone by treatment with an acid catalyst was applied to

the synthesis of tetrahydrocarbazole by Borsche [147]. The

cyclohexanone phenylhydrazone (120) obtained by reacting

cyclohexanone (118) with substituted phenylhydrazine (119), on

indolization, furnished tetra hydrocarbazole (121) which on

dehydrogenation, afforded carbazole (122) (Scheme-4A.5). The

mechanism for the formation of tetrahydrocarbazole involves a

tautomeric equilibrium and formation of new C-C bond via [3,3]-

sigmatropic rearrangement followed by elimination of ammonia.

104

….. Scheme - 4A.5

Graebe et. al. [148] reported the conversion of 1-

arylbenzotriazole (124) to carbazole (114) (Scheme-4A.6) under

thermal conditions. The required starting material 124 was prepared

by the diazotization of N-(2-aminophenyl) aniline (123). The reaction

mechanism, presumably, has a diradical intermediate involved in the

thermolysis of the triazole.

….. Scheme - 4A.6

Bucherer et. al. [149] reported that treatment of 2-naphthol or

2-naphthylamine (125) with phenyl hydrazine (126) in the presence of

105

aq. NaHSO3 afforded benzocarbazole (127) (Scheme-4A.7).

Mechanistically, this reaction resembles the Fiscβher indole synthesis

and is based on the condensation of the 2-naphthol or 2-

naphthylamine in its oxo form with phenyl hydrazine and subsequent

rearrangement.

….. Scheme - 4A.7

Oikawa et. al. [150] reported a general method for the synthesis of 2-

hydroxycarbazoles (129) (Scheme-4A.8) by the cyclization of the β-

ketosulfoxides (128) in acidic medium. The required β-ketosulfoxides

was derived from nucleophilic attack of dimethyl sulfoxide on methyl

3-indolepropionate.

….. Scheme - 4A.8

Takano et. al. [151] reported an efficient synthesis of the

carbazole using the annulation of 2, 3-disubstituted indole. This

method involves the condensation of 2-benzyltryptamine (130) with

ethoxymethyleneaceto actate (131) to give the enamine (132), which

106

on treatment with acetic anhydride/acetic acid (3:2) cyclizes the

carbazole (133) (Scheme-4A.9). This one pot transformation is

believed to proceed via a Fisher-base-type intermediate which

promotes the crucial cyclization and the removal of the ethylamine

side chain.

….. Scheme - 4A.9

Ivachtchenko et. al. [152] reported that by reacting N-

methylpiperidone (134) with 4-hydrazinobenzenesulfonicacid (135) in

a mixture of Con.H2SO4 and acetic acid at 80-90 ºC, a novel carbazole

derivative 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole-8-

sulfonicacid was obtained (136) (Scheme-4A.10).

….. Scheme - 4A.10

107

Various carbazoles (138) were synthesized from substituted

biaryl azides (137) at 60°C using Rh2(OCOC3F7)4 or Rh2(OCOC7H15)4

as catalysts was reported by Stokes et. al. [153] (Scheme-4A.11).

….. Scheme - 4A.11

4A.2.2 PYRAZOLES

Knorr et. al. [154] reported the synthesis of two isomers of

pyrazoles i.e. 1,5-isomer (140) and 1,3-isomer (141) (Scheme-4A.12)

by condensing substituted-1,3-dicarbonyl compounds (139) with aryl

hydrazines.

….. Scheme - 4A.12

Gewald et. al. [155] reported one of the classical approaches for

the synthesis of substituted pyrazoles (144) (Scheme-4A.13) by the

condensation of substituted phenylhydrazones (142) with -

haloketones (143).

108

….. Scheme - 4A.13

In another synthesis, the preparation of N-arylpyrazoles (147)

was reported by Joshi et. al. [156] by the cyclocondensation of

phenylhydrazines (146) with substituted-, β-dihaloketones (145)

(Scheme - 4A.14).

….. Scheme - 4A.14

Penning et. al. [157] reported a new method for the preparation

of pyrazoles which are effective as COX-2 inhibitors. In this method,

1,5-diarylpyrazoles (152) (Scheme-4A.15) were synthesized by

Claisen condensation of substituted acetophenone (148) with ethyl

trifluoroacetate (149) to yield a 1,3-dicarbonyl product (150). This was

further reacted with substituted phenylhydrazines (151) in ethanol at

reflux temperature to obtain 152 in good yield.

109

….. Scheme - 4A.15

Pechmann et. al. [158] reported another classical approach for

the synthesis of substituted pyrazoles (155) (Scheme-4A.16) by the

condensation of acetylene (153) with diazomethane (154).

….. Scheme - 4A.16

4-Substituted-1H-pyrazole-5-carboxylate (158) was prepared by

the cyclocondensation of unsymmetrical enaminodiketone (156) with

substituted hydrazine hydrochloride (157) as reported by Rosa et. al.

[159] (Scheme-4A.17). The compounds were obtained regiospecifically

and in very good yields.

….. Scheme - 4A.17

110

Heller et. al. [160] synthesized 1,3-Diketones, in situ from

substituted ketones (159) and substituted acidchlorides, which were

converted into pyrazoles (160) (Scheme-4A.18) by the addition of

hydrazine hydrate. This method allows a fast and general synthesis of

previously inaccessible pyrazoles and synthetically demanding

pyrazole-containing fused rings.

….. Scheme - 4A.18

Dinoiu et. al. [161] reported that 3,5-dialkyl-4-

hydroxybenzylhydrazine (161) reacted with 1,1,1-trifluoropentane-2,4-

dione (149) to afford the corresponding pyrazole 161 (Scheme-

4A.19).

….. Scheme - 4A.19

111

4A.3 PRESENT WORK

It is obvious from the references cited above number of

researchers have synthesized carbazole and pyrazole analogues which

are biologically active molecules. Hence, in this chapter the synthesis

of new pyrazole and carbazole derivatives are reported by combining

these ring compounds with methanesulfonamide functionality as

potentially biologically active compounds.

4A.4 RESULTS AND DISCUSSIONS

4A.4.1 CARBAZOLES

The required starting materials substituted hydrazines 163(a-c)

were prepared by using reported procedure [95] as depicted in

scheme- 4A.20. Thus, diazotization of 26a, 26d, and 26e resulting

the corresponding diazonium salts, which on reduction with stannous

chloride gave 163(a-c).

….. Scheme - 4A.20

2-(4-Hydrazinylphenyl)-N-methylethanesulfonamide hydrochloride

163c (i.e. 163, R=-NHCH3 n=2) was reacted with cyclohexanone (118)

(Scheme-4A.21) to give a new compound whose structure was

established by its spectral data as N-methyl-2-(2,3,4,9-tetrahydro-1H-

carbazol-6-yl)ethanesulfonamide 164c (i.e. 164, R=-NHCH3, n=2).

112

Thus, its IR spectrum in KBr (Fig.4A.1) showed a characteristic peak

at 3386 cm-1 which can be attributed to -NH group. The peaks at 1310

cm-1 and 1148 cm-1 indicate the presence of -SO2 group. Its 1H NMR

spectrum (CDCl3/TMS) (Fig.4A.2) showed multiplets at 1.92-2.75

with eight proton integration can be assigned to eight aliphatic

protons. The signals at 2.7 and 6.9 confirm the presence of –

NHCH3. Two triplets at 3.2 and 3.4 corresponding to the (-Ar-CH2-

CH2-SO2-). The peaks between 7.0-7.4 confirm the three aromatic

protons. Broard singlet at 7.8 can be assigned to –NH of carbazole

ring. The mass spectrum of 164c showed the molecular ion at m/z

293 (M++1) ion peak corresponding to a molecular mass of 292 which

further supports the assigned structure (Fig.4A.3). Its 13C NMR

(Fig.4A.4) showed the peaks at δ 21.03, 23.18, 23.25, 23.40, 29.02,

29.89, 52.01, 108.26, 110.90, 116.99, 121.01, 127.95, 128.16,

134.89 and 135.23.

….. Scheme - 4A.21

The above reaction of 163c with cyclohexanone has been found

to be a general one and has been extended to substituted hydrazines

113

(163a-b). The products 165a-b, obtained was assigned structures on

the basis of their spectral and analytical data.

Similarly, condensation of 163c (i.e. 163, R=-NHCH3 n=2) with N-

methyl-4-piperidone (134), followed by cyclisation in Con.HCl gave the

corresponding N-methyl-2-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido

[4,3-b]indol-8-yl)ethanesulfonamide (165c) (i.e. 165, R=-NHCH3 n=2)

(Scheme-4A.22). Its IR spectrum in KBr (Fig.4A.5) showed

characteristic peak at 3436 cm-1, which can be attributed to -NH

group. Peaks at 1319 cm-1 and 1125 cm-1 indicates the presence of -

SO2 group. Its 1H NMR spectrum (DMSO-d6/TMS) (Fig.4A.6) showed

signal at 2.4 (3H) and 2.6 (3H) which can be attributed to methyl

protons of –NHCH3 and –NCH3 respectively. Two multiplets between

2.70-2.78 can be assigned to –CH2-CH2NCH3. Two triplets at 2.9-3.2

(4H) can be assigned to -Ar-CH2-CH2-SO2. The singlet at 3.4 (2H)

can be assigned to –CH2NCH3. The three aromatic protons and –

NHCH3 proton appeared between 6.8-7.1 as a multiplet. A singlet at

10.6 can be attributed to –NH proton of carbazole. The mass

spectrum (Fig.4A.7) of 165c showed a molecular ion at m/z 307. Its

13C NMR (Fig.4A.8) showed the peaks at δ 23.7, 29.0, 29.8, 45.8,

51.8, 52.4, 107.1, 111.1, 116.8, 121.2, 126.0, 128.4, 133.2 and

135.1.

114

….. Scheme - 4A.22

The above reaction of 163c with N-methylpiperidone has been

found to be a general one and has been extended to other substituted

hydrazines 163a and 163c. The products 165a-b, obtained was

assigned structures on the basis of their spectral and analytical data.

4A.4.2 PYRAZOLES

2-(4-Hydrazinophenyl)-N-methylethanesulfonamide

hydrochloride (163c) (i.e. 163, R= NHCH3, n=2) was reacted with

substituted-1,3-diketone 166(a-c) (Scheme-4A.23) to give a new

compound whose structure was established by its spectral data as N-

methyl-2-(4-(3-methyl-5-(thiophen-2-yl)-1H-pyrazol-1-yl)phenyl)ethane

sulfonamide (167g) (i.e. 167, R=NHCH3, n=2, R1 = Thiophene, R2 =

CH3) as the major product regioselectively, which was purified by

recrystalization from methanol to obtain the pure compound. Its IR

spectrum in KBr (Fig.4A.9) showed characteristic peak at 3435 cm-1

due to -NH and absorption peaks at 1315 cm-1 and 1124 cm-1 can be

assigned to -SO2 group. Its 1H NMR spectrum (CDCl3/TMS)

115

(Fig.4A.10) showed three proton singlets at 2.35 due to the methyl

group of pyrazole and doublet at 2.75 is due to –NHCH3. Two

triplets at 3.25-3.45 can be assigned to (–Ph-CH2-CH2-SO2-). A

multpilet appeared at 4.0 is due to -NHCH3. A singlet at 6.35 can

be assigned to pyrazole-CH. The multiplet between 6.9-7.3 with

seven protons integration can be assigned to the four aryl protons and

three thiazole protons. The mass spectrum (Fig.4A.11) of 167g

showed the molecular ion at m/z 361. Its 13C NMR (DMSO-d6)

spectrum (Fig. 3.22) showed peaks at 13.16, 28.53, 28.73, 50.12,

107.29, 126.00, 127.24, 127.36, 127.55, 129.08, 130.74, 136.92,

137.91, 138.78 and 148.30.

….. Scheme - 4A.23

116

The above reaction of 163a has been found to be a general one

and has been extended to other substituted diketones. The products

167a-i, obtained has been assigned on the basis of their spectral and

analytical data.

All the above sequences of reactions are summarised in

Schemes 4A.24 respectively.

….. Scheme - 4A.24

117

4A.5. EXPERIMENTAL SECTION:

PREPARATION OF 164:

4A.5.1. GENERAL PROCEDURE FOR THE SYNTHESIS OF 164(a-c):

A mixture of 163(a-c) (0.011 mol), cyclohexanone (118) (0.011 mol),

sodium acetate (0.015 mol) and acetic acid (25 mL) was refluxed with

stirring for 5 hours. The solvent was distilled off under reduced

pressure. The residue was partitioned between water and ethyl

acetate. The organic layer was dried, concentrated and crystallized

from methanol (10 mL). The crude compound was re-crystallized from

a suitable solvent to obtain pure 164(a-c).

164a: R = pyrrolidine, n=1, Yield: 2.23 gm (64 %), M.R: ~250 ºC; IR

(KBr, cm-1) 3372 (-NH), 1300, 1144 (-SO2); 1H NMR (DMSO-d6/TMS) δ

1.80-1.90 (m, 8H, 2 x -CH2 pyrrolidine and 2 x -CH2 carbazole), 2.70

(m, 2H, -CH2 carbazole), 2.75 (m, 2H, -CH2 carbazole), 3.2 (m, 4H,

pyrrolidine), 4.3 (s, 2H, -SO2CH2), 7.0-7.4 (m, 3H, Ar-H), 7.8 (bs, 1H,

-NH indole, D2O exchangable), M++1: 318; Anal.Calcd for

(C17H22N2O2S) requires: C, 64.12; H, 6.96; N, 8.80. Found: C, 64.02;

H, 6.91; N, 8.80.

164b: R = -NHCH3, n=1, Yield: 1.8 gm (59 %), M.R: 213-215 ºC; IR

(KBr, cm-1) 3362 (-NH), 1139, 1120 (-SO2); 1H NMR (CDCl3/TMS) δ 1.9

(m, 4H, 2 x CH2 carbazole), 2.6 (d, 3H, -NHCH3), 2.70 (m, 2H, -CH2

carbazole), 2.75 (m, 2H, -CH2 carbazole) 3.8 (m, 1H, -NHCH3, D2O

exchangable), 4.3 (s, 2H, -SO2CH2), 7.0-7.4 (m, 3H, Ar-H), 7.8 (bs, 1H,

-NH indole, D20 exchangable), M++1: 278. Anal.Calcd for

118

(C14H18N2O2S) requires: C, 60.41; H, 6.52; N, 10.06. Found: C, 60.45;

H, 6.50; N, 10.16.

164c: R = -NHCH3, n=2, Yield: 2.0 gm (65 %), M.R: 154-157 °C; IR

(KBr, cm-1) 3386 (-NH),1310, 1144 (-SO2); 1H NMR (CDCl3/TMS): δ

1.92 (m, 4H, 2 x -CH2 carbazole), 2.6 (d, 3H, -NHCH3), 2.70 (m, 2H, -

CH2 carbazole), 2.75 (m, 2H, -CH2 carbazole) 3.2 (m, 2H,- SO2CH2),

3.4 (m, 2H, -Ar-CH2), 3.8 (m, 1H, -NHCH3, D2O exchangable), 7.0-7.4

(m, 3H, Ar-H), 7.8 (bs, 1H, -NH indole, D20 exchangable), M++1: 293.

Anal.Calcd for (C15H20N2O2S) requires: C, 61.62; H, 6.89; N, 9.58.

Found: C, 61.52; H, 6.81; N, 9.53.

4A.5.2. GENERAL PROCEDURE FOR THE SYNTHESIS OF 165(a-c):

163(a-c) (0.011 mol), was dissolved in water (47.4 mL) and N-

Methyl-4-piperidone (134) (0.011 mol) was added over a period of five

minutes. After the addition, the mixture was slowly heated to 50-55 ºC

and Con.HCl (7 mL) was added over period of 30 minutes. The

reaction mass was stirred overnight at 50-55 ºC, then cooled to 25-30

ºC and the pH adjusted to 12.0 with sodium hydroxide solution. The

slurry was allowed to stirr for 30 minutes and then cooled to 10-15 ºC,

filtered and washed with water. The crude compound was

recrystallized from a suitable solvent to get pure compound 165(a-c).

165a: R = pyrrolidine, n=1, Yield: 1.97 gm (54 %), M.R: 170-172 ºC; IR

(KBr, cm-1) 1330, 1120 (-SO2); 1H NMR (DMSO-d6/TMS) δ 1.8-1.9 (m,

4H, pyrrolidine), 2.4 (s, 3H, -NCH3), 2.6-2.9 (m, 4H, 2 x -CH2

carbazole) 3.2 (m, 4H, pyrrolidine) 3.40 (s, 2H, -CH2 carbazole), 4.3

119

(s, 2H, -SO2 CH2), 6.8-7.3 (m, 3H, Ar-H), 10.6 (br, s, -NH, D2O

exchangable); M++1: 334.43. Anal.Calcd for (C17H23N3O2S) requires: C,

61.23; H, 6.95; N, 12.60. Found: C, 61.13; H, 6.90; N, 12.58.

165b: R = -NHCH3, n=1, Yield: 1.57 gm (49 %), M.R: 142-145 ºC; IR

(KBr, cm-1) 3372 (-NH), 1275, 1118 (-SO2); 1H NMR (DMSO-d6/TMS): δ

2.4 (s, 3H, -NCH3), 2.6 (d, 3H, -NHCH3), 2.6-2.9 (m, 4H, 2 x -CH2

carbazole) 3.40 (s, 2H, -CH2 carbazole), 4.3 (s, 2H, -SO2CH2), 6.8-7.3

(m, 4H, Ar-H and –NHCH3), 10.6 (br, s, -NH, D2O exchangable); M++1:

318.43; Anal.Calcd for (C17H22N2O2S) requires: C, 64.12; H, 6.96; N,

8.80. Found: C, 64.02; H, 6.91; N, 8.80.

165c: R = -NHCH3, n=2, Yield: 2.45 gm (73 %), M.R: 158-160 °C; IR

(KBr, cm-1) 3436 (-NH), 1319, 1125 (-SO2); 1H NMR (DMSO-d6/TMS): δ

2.4 (s, 3H, -NCH3), 2.6 (d, 3H, -NHCH3), 2.6-2.9 (m, 4H, 2 x -CH2

carbazole) 3.0 (t, 2H, -Ar-CH2), 3.2 (t, 2H, -SO2CH2), 3.40 (s, 2H, -CH2

carbazole), 6.8-7.3 (m, 4H, Ar-H and –NHCH3), 10.6 (bs, -NH, D2O

exchangable); M++1: 318.43. Anal.Calcd for (C17H22N2O2S) requires: C,

64.12; H, 6.96; N, 8.80. Found: C, 64.02; H, 6.91; N, 8.80.

4A.5.3. GENERAL PROCEDURE FOR THE SYNTHESIS OF 167(a-c):

163(a-c) (0.01 mol) was added to a stirred solution of the 1-

(thiophen-2-yl) butane-1,3-dione 166(a-c) (0.01 mol) in N,N-

dimethylformamide (20 mL). The mixture was heated to 80-85 ºC and

stirred for 3 hours. After cooling to room temperature, the reaction

mixture was quenched into water (50 mL) and extracted into ethyl

acetate. The organic layer was washed with water and dried over anh.

MgSO4. The organic layer was filtered and concentrated under

120

reduced pressure to give a light brown solid. The crude product was

recrystallized from methanol to give pure 167(a-i).

167a: R = pyrrolidine, n=1, R1 = Thiophene, R2 = CH3, Yield: 2.48 gm

(64 %), M.R: 122-125 ºC; IR (KBr, cm-1) 1320, 1125 (-SO2); 1H NMR

(CDCl3): δ 1.70-1.90 (m, 4H, pyrrolidine), 2.30 (s, 3H, -CH3 pyrazole),

3.0-3.2 (m, 4H, pyrrolidine), 4.50 (s, 2H, -SO2CH2), 6.50 (s, 1H, CH

pyrazole), 6.90 (m, 1H, CH thiazole), 6.95 (m, 1H, CH thiazole), 7.30

(d, 4H, Ar-H J= 8.4), 7.40 (d, 4H, Ar-H J= 8.4), 7.50 (m, 1H, CH

thiazole); M++1: 386. Anal.Calcd for (C20H22N2O2S2) requires: C, 62.15;

H, 5.74; N, 7.25. Found: C, 62.10; H, 5.64; N, 7.20.

167b: R = pyrrolidine, n=1, R1 = Phenyl, R2 = CF3, Yield: 3.14 gm (73

%), M.R: 162-165 ºC; IR (KBr, cm-1) 1320, 1120 (-SO2); 1H NMR

(CDCl3): δ 1.70-1.90 (m, 4H, pyrrolidine), 3.0-3.2 (m, 4H,

pyrrolidine), 4.50 (s, 2H, -SO2CH2), 6.70 (s, 1H, CH pyrazole), 7.0 (m,

1H, -NHCH3), 7.20-7.60 (m, 9H, Ar-H); M++1: 435; Anal.Calcd for

(C22H21F3N2O2S) requires: C, 60.82; H, 4.87; N, 6.45. Found: C, 60.72;

H, 4.85; N, 6.35.

167c: R = pyrrolidine, n=1, R1 = 4-Methylphenyl, R2 = CF3, Yield: 4.20

gm (94 %), M.R: 147-149 ºC; IR (KBr, cm-1) 1317, 1124 (-SO2); 1H

NMR (DMSO-d6/TMS): δ 1.70-1.90 (m, 4H, pyrrolidine), 2.30 (s, 3H, -

CH3), 3.00-3.20 (m, 4H, pyrrolidine), 4.50 (s, 2H, -SO2CH2), 6.70 (s,

1H, CH pyrazole), 7.20-7.60 (m, 8H, Ar-H); M++1: 449; Anal.Calcd for

(C23H23F3N2O2S) requires: C, 61.59; H, 5.17; N, 6.25. Found: C, 61.49;

H, 5.10; N, 6.20.

121

167d: R = -NHCH3, n=1, R1 = Thiophene, R2 = CH3, Yield: 2.70 gm

(79 %), M.R: 150-152 ºC; IR (KBr, cm-1) 3345 (-NH), 1322, 1124 (-

SO2); 1H NMR (CDCl3/TMS) δ 2.30 (s, 3H, -CH3 pyrazole), 2.75 (d, 3H,

-NHCH3), 4.00 (m, 1H, -NHCH3, D2O exchangable), 4.40 (s, 2H, -

SO2CH2), 6.35 (s, 1H, CH pyrazole), 6.90 (m, 1H, CH thiazole), 6.95

(m, 1H, CH thiazole), 7.25-7.4 (m, 4H, Ar-H), 7.35 (s, 1H, CH thiazole);

M++1: 348; Anal.Calcd for (C16H17N3O2S2) requires: C, 55.31; H, 4.93;

N, 12.09. Found: C, 55.21; H, 4.96; N, 12.00.

167e: R = -NHCH3, n=1, R1 = Phenyl, R2 = CF3, Yield: 2.50 gm (64 %),

M.R: 181-183 ºC; IR (KBr, cm-1) 3347 (-NH), 1309, 1135 (-SO2); 1H

NMR (CDCl3/TMS): δ 2.75 (d, 3H, -NHCH3), 4.00 (m, 1H, -NHCH3, D2O

exchangable), 4.40 (s, 2H, -SO2CH2), 6.70 (s, 1H, CH pyrazole), 7.20-

7.60 (m, 9H, Ar-H); M++1: 396. Anal.Calcd for (C18H16F3N3O2S)

requires: C, 54.68; H, 4.08; 10.63. Found: C, 54.63; H, 4.04; 10.73.

167f: R = -NHCH3, n=1, R1 = 4-Methylphenyl, R2 = CF3, Yield: 3.19 gm

(79 %), M.R: 139-141 ºC; IR (KBr, cm-1) 3347 (-NH), 1332, 1126 (-

SO2); 1H NMR (CDCl3/TMS): δ 2.30 (s, 3H, -CH3), 2.75 (d, 3H, -

NHCH3), 4.40 (s, 2H, -Ar-CH2), 6.70 (s, 1H, CH pyrazole), 4.00 (q, 1H,

-NHCH3, D2O exchangable), 7.20-7.60 (m, 8H, Ar-H); M++1: 410.

Anal.Calcd for (C19H18F3N3O2S) requires: C, 55.74; H, 4.43; N, 10.26.

Found: C, 55.64; H, 4.33; N, 10.29.

167g: R = -NHCH3 n=2, R1 = Thiophene, R2 = CH3, Yield: 2.70 gm (75

%), M.R: 191-194 °C; IR (KBr, cm-1) 3347, 1280, 1120 ; 1H NMR

(CDCl3): 2.35 (s, 3H, -CH3 pyrazole), 2.75 (d, 3H, -NHCH3), 3.25 (t,

2H, -Ar- CH2), 3.45 (t, 2H, -SO2CH2), 4.00 (q, 1H, -NHCH3, D20

122

exchangable), 6.35 (s, 1H, CH pyrazole), 6.90 (dd, 1H, thiazole), 6.95

(dd, 1H, thiazole), 7.25-7.4 (m, 4H, Ar-H), 7.35 (s, 1H, thiazole); M++1:

362. Anal.Calcd for (C17H19N3O2S2) requires: C, 56.48; H, 5.30; N,

11.62. Found: C, 56.40; H, 5.20; N, 11.52.

167h: R = -NHCH3, n=2, R1 = Phenyl, R2 = CF3, Yield: 2.82 gm (70 %),

M.R: 174-176 °C; IR (KBr, cm-1) 3343, 1265, 1130; 1H NMR (CDCl3): δ

2.80 (d, 3H, -NHCH3), 3.20 (t, 2H, - Ar-CH2), 3.45 (t, 2H, -SO2CH2),

4.10 (q, 1H, -NHCH3, D2O exchangable), 6.70 (s, 1H, CH pyrazole),

7.20-7.60 (m, 9H, Ar-H); M++1: 410. Anal.Calcd for (C19H18F3N3O2S)

requires: C, 55.74; H, 4.43; N, 10.26. Found: C, 55.64; H, 4.40; N,

10.16.

167i: R = -NHCH3 n=2, R1 = 4-Methylphenyl, R2 = CF3, Yield: 3.77 gm

(90 %), M.R: 160-165 °C; IR (KBr, cm-1) 3337, 1270, 1117; 1H NMR

(DMSO-d6/TMS): δ 2.30 (s, 3H, -CH3), 2.60 (d, 3H, -NHCH3), 3.00 (t,

2H, -Ar- CH2), 3.30 (m, 2H, -SO2CH2), 6.90 (s, 1H, CH pyrazole), 7.00

(q, 1H, -NHCH3, D2O exchangable), 7.00 7.20-7.60 (m, 8H, Ar-H);

M++1: 424. Anal.Calcd for (C20H20F3N3O2S) requires: C, 56.73; H, 4.76;

N, 9.92. Found: C, 56.63; H, 4.72; N, 9.82.

123

CHAPTER-4

SYNTHESIS OF NARATRIPTAN USING N-BENZYL-N-

METHYL ETHENESULFONAMIDE

SECTION-B

4B.1 INTRODUCTION:

Triptans are a new class of compounds developed for the

treatment of migraine attacks [13]. The first one of this class,

sumatriptan [162] and the newer triptans are zolmitriptan [163],

naratriptan [164], rizatriptan [165], eletriptan [166], almotriptan [167]

and frovatriptan [168] display high antagonist activity mainly at the

serotonin 5-HT1B and 5-HT1D receptor subtypes. Among these

triptans, naratriptan is one of the important drugs for the treatment of

acute attacks of migraine exhibiting high affinity for 5-HT1D

receptors, a serotonin (5-hydroxytryotamine, 5-HT) receptor. This

chapter describes synthesis of naratriptan using new intermediate N-

benzyl-N-methylethenesulfonamide.

4B.2 LITERATURE SURVEY

Several methods for the synthesis of naratriptan have been

reported in the literature and few of them are discussed below.

Oxford et. al. [169] reported that 5-bromoindole (168), when

subjected to Heck coupling with N-methylethenesulfonamide (169)

gave 2-(1H-Indol-5-yl)-N-methylethenesulfonamide (170), which on

124

condensation with 1-methyl-4-piperidone, followed by hydrogenation

afforded naratriptan (172) (Scheme–4B.1).

….. Scheme - 4B.1

Oxford et. al. [169] also reported another slightly modified

method. The indole derivative 170 was hydrogenated to give 2-(1H-

indol-5-yl)-N-methylethanesulfonamide (173), which was condensed

with 1-methyl-4-piperidone (134) to give the N-methyl-2-(3-(1-methyl-

1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl)ethanesulfonamide

(174). This product was then hydrogenated to give the naratriptan

(172) (Scheme–4B.2).

125

….. Scheme - 4B.2

The third method described by Oxford et. al. [169] in

GB2208646 is given in Scheme-4B.3. Condensation of 5-bromo

indole (168) and 1-methyl-4-piperidone (134) gave the 5-bromo-3-(1-

methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (175), which was

hydrogenation, followed by Heck coupling, gave N-methyl-2-(3-(1-

methylpiperidin-4-yl)-1H-indol-5-yl)ethenesulfonamide (177). This

was hydrogenated to give the naratriptan (172) (Scheme–4B.3).

126

….. Scheme - 4B.3

Another method also described by Oxford et. al. [169] in the

same patent by adopting a traditional Fischer indole methodology as

depicted in Scheme-4B.4. In this method, the 2-(4-aminophenyl)-N-

methylethane sulfonamide (26e) was diazotized and reduced to give

the phenyl hydrazine (163). This was converted into the hydrazone

(179) by reaction with 2-(N-methyl piperidin-4-yl) acetaldehyde (178).

Fisher indole cyclization of the hydrazone (179) using ethyl

polyphosphate yielded naratriptan (172).

127

….. Scheme - 4B.4

Bela et. al. [170] reported a new method, wherein the aniline

derivative 180 was reacted with 2, 2-dimethoxyacetaldehyde to give

the product 181, which on reaction with trifluoroacetic acid and

triethylamine, afforded compound 182. Cyclization of 182 with TiCl4

gave the indole derivative 183, which on hydrolysis, followed by

condensation with 1-methyl-4-piperidone, gave the indole derivative

184. This was hydrogenated and debenzylated to give naratriptan

(172) (Scheme – 4B.5).

128

….. Scheme - 4B.5

Poszavacz et. al. [171] reported a new synthetic method, which

starts with dehydrogenation of 1-benzylindoline-5-carbaldehyde (187)

to give 1-benzyl-1H-indole-5-carbaldehyde (188). The compound 188

on condensation with (N-t-butoxy carbonyl-N-methyl) methane

sulfonamide, gave 2-(1-benzyl-1H-indol-5-yl)-N-methylethenesulfon

129

amide (189). Catalytic hydrogenation of 189 gave 2-(1-benzyl-1H-

indol-5-yl)-N-methyl ethane sulfonamide (190). The indole derivative

190 on condensation with 1-methyl-4-piperidone, gave 2-(1-benzyl-3-

(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indol-5-yl)-N-methyl

ethanesulfonamide (191). Hydrogenation of 191 gave 2-(1-benzyl-3-(1-

methylpiperidin-4-yl)-1H-indol-5-yl)-N-methylethanesulfonamide

(192), which was debenzylated to yield naratriptan (172). (Scheme –

4B.6).

….. Scheme - 4B.6

Islam et. al. [172] reported a method based on Japp-Klingemann

reaction as key step in building the indole moiety. Accordingly aniline

derivative 26e was diazotized and reacted with pyridyl/piperdinyl

acetoacetate derivative to get the corresponding hydrazone derivative

130

(193), which on cyclization gave the indole-2-carboxylate (194).

Hydrolysis of 194, followed by decarboxylation afforded naratriptan

172. Similarly cylisation of 196 gave the corresponding indole

carboxylate 197. The intermediate 197 was converted into naratriptan

172 by methylation followed by reduction and decarboxylation. All the

above sequence of reactions is depcicted in (Scheme–4B.7).

….. Scheme - 4B.7

131

4B.3 PRESENT WORK

Synthesis of a novel intermediate N-benzyl-N-methylethene

sulfonamide was achieved. 5-Bromo-3-(1-methyl-1,2,3,6-tetrahydro-

pyridin-4-yl)-1H-indole was reacted with N-methyl-N-benzyl

ethenesulfonamide using Heck coupling method. The resulting

intermediate was subjected to hydrogenation followed by

debenzylation to afford naratriptan in high purity. These results are

described below.

4B.4 RESULTS AND DISCUSSIONS

A new compound N-benzyl-N-methylethenesulfonamide (202)

was prepared by reaction of 2-chloroethanesulfonyl chloride (200)

with N-methylbenzylamine (201) in the presence of triethylamine at

-20 to -10 ºC (Scheme-4B.8). The progress of this reaction was

studied in various solvents such as dimethylformamide, diethylether,

diisopropylether, tetrahydrofuran, dichloromethane, ethylene

dichloride and chloroform using triethylamine as a base. Among all

the solvents, dichloromethane was found to be the best solvent to get

good yield. The product was characterized by its spectral data. Thus,

its IR spectrum (neat) (Fig.4B.1) showed peak at 1606 cm-1 due to

C=C and presence of the peaks at 1338 cm-1 and 1151 cm-1

conforming the -SO2 group. Its 1H NMR (CDCl3/TMS) (Fig.4B.2)

showed singlet at 2.6 due to the methyl group and 4.2 is due to –

CH2-Ph. A three proton multiplet at 6.0-6.5 can be assigned to (–

CH2=CH-SO2-) and multpilet at 7.3-7.6 due to five Ar-H. Its APCI

132

mass spectrum (Fig. 3.3) showed M++1 ion peak at 212 corresponding

to a molecular mass of 211 further confirms the structur 202.

….. Scheme - 4B.8

The compound 202 was reacted with 5-bromo-3-(1-methyl-

1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (175) in the presence of

palladium acetate and tri-o-tolylphosphine using triethylamine as a

base at 100-110 ºC in dimethylformamide and obtained 2-(3-(1,2,3,6-

tetrahydro-1-methylpyridin-4-yl)-1H-indol-5-yl)vinylsulfonyl)-N-methyl

(phenyl)methan amine (203) (Scheme–4B.9). The product was

characterized by spectral methods. Thus, its IR spectrum (Fig. 4B.4)

in KBr showed a peak at 1607 cm-1 indicates the presence of C=C.

Peaks at 1331 cm-1 and 1142 cm-1 absorptions assignable to

asymmetric and symmetric stretching of –SO2 group. Its 1H-NMR

spectrum (DMSO-d6/TMS) (Fig.4B.5) showed signals at δ 2.25 (s, 3H,

-NCH3), 2.4-2.5 (m, 4H, Piperidine), 2.6 (s, 3H, -NCH3), 3.3 (m, 2H,

Piperdine), 4.2 (s, 2H, -NCH2Ar), 6.2 (s, 1H, Piperdine), 6.50 (d, 1H

J=15.2 Hz, -SO2CH=CH), 7.2-7.4 (m, 8H, Ar-H), 7.5 (d, 1H J=15.2 Hz,

CH=CH-Ar), 7.8 (s, 1H, CH indole), 11.0 (br, s, 1H, -NH indole D2O

exchangable). Its mass spectrum (Fig. 4B.6) showed its molecular ion

peak at m/z 422 corresponding to molecular mass of 421 when

recorded in the Q+1 mode.

133

….. Scheme - 4B.9

The product 203 was hydrogenated in methanol using 10%

Pd/C to give the known coompound N-benzyl-N-methyl-2-[3-(-

methylpiperidine-4-yl)-1H-indole-5-yl] ethane sulfonamide (186)

(Scheme–4B.10).

….. Scheme - 4B.10

Debenzylation of N-benzyl-N-methyl-2-[3-(-methyl piperidine-4-

yl)-1H-indole-5-yl] ethane sulfonamide (186) was tried catalytically,

but the reaction did not proceed. The reaction was finally successful

by employing the Birch reduction conditions. The reaction was

conducted in liquid ammonia containing tetrahydrofuran and sodium

metal at temperature –80 to -85 ºC to give naratriptan with 92% purity

by HPLC (Scheme–4B.11).

134

….. Scheme - 4B.11

In order to get pure compound the crude product is to be

purified. Crystallisation in different solvents did not help. Hence other

methods of purification like salt formation were tried. Of the several

salts viz., hydrochloride, sulphate, succinate, maleate and oxalate ete.,

Among these oxalate salt was most favourable. Naratriptan oxalate

salt on basification yielded naratriptan base of 99.8% HPLC purity.

The product was characterised by its analytical and spectral data, IR

(Fig.4B.7), 1H NMR (Fig.4B.8), Mass (Fig.4B.9) and 13C NMR

(Fig.4B.10) and the product was identical, in all the respects when

compared with reference standard of naratriptan.

All the above sequences of reactions were summarized in

Schemes- 4B.12.

135

….. Scheme - 4B.12

4B.5. EXPERIMENTAL SECTION:

4B.5.1 PREPARATION OF 202:

Chloroethanesulfonyl chloride 200 (50.0 gm) was dissolved in

dichloromethane (500 mL) in a RB flask and cooled to -20 to -15 ºC.

To the cooled solution under stirring, triethylamine (31.2 gm) was

added maintaining the temperature at -20 to -15 ºC. The reaction

mixture was stirred at -10 ºC for 30 minutes. Then a mixture of 201

(33.0 gm) and triethylamine (31.2 gm) was added to the reaction

136

mixture at -10 ºC. After completion of the addition, the temperature of

the reaction was raised to 0 ºC and water (100 mL) was added. The

reaction mixture was stirred for 10 to 20 minutes and the organic

layer was separated, dried over anh.Na2SO4 and the solvent was

evaporated. The residue obtained was repeatedly triturated with

diethylether. The ether extract, on concentration, gave oil product (42

gm, 70%) of N-benzyl-N-methylethenesulfonamide (202) with 95%

purity (by GC). This was used as such in subsequent reactions.

IR (neat): 3030, 3059, 1606, 1338, 1152, 978, 779; 1H NMR:

(CDCl3/TMS) 2.69 (s, 3H, -NCH3), 4.25 (s, 2H, -CH2Ph), 6.02 (m, 1H,

CH2), 6.27 (m, 1H, CH2), 6.45 (m, 1H, CH), 7.31 (m, 5H, Ar-H); M+1:

212; Anal. Calcd. for (C10H13NO2S) requires: C, 56.85; H, 6.20; N,

6.63 Found: C, 56.79; H, 6.27; N, 6.60.

4B.5.2. PREPARATION OF 203:

In a round bottom flask fitted with a mechanical stirrer and

condenser, were charged N,N- dimethylformamide (100 mL) and 175

(25 gm), 202 (30 gm), triethylamine (32.1 gm), triorthotolylphosphine

(7.75 gm) and palladium acetate (0.42 gm). The reaction mixture was

gradually heated to 100-110 ºC under stirring and maintained for 8

hours. The reaction mass was cooled to 60 ºC and then filtered. The

filterate was diluted with water (300 mL) and extracted with ethyl

acetate (3x100 mL). The ethyl acetate layer was washed with water (75

mL) and dried over anh.Na2SO4, filtered and then concentrated. The

residue was stirred with methanol (100 mL), cooled to 0-5 ºC and solid

137

formed was filtered and dried to give 27.0 gm (75%) of the product. An

analytical sample was obtained after recrystalization from methanol

M.R: 205-210 ºC; IR (KBr): 3416, 3027, 2847, 2890, 1647,1607, 1494,

1445, 1337, 1148, 1073, 938, 846; 1H NMR: (DMSO-d6/TMS) δ 2.25

(s, 3H, -NCH3), 2.4-2.5 (m, 4H, Piperdine), 2.6 (s, 3H, -NCH3), 3.3 (m,

2H, Piperdine), 4.2 (s, 2H, -NCH2Ar), 6.2 (s, 1H, Piperdine), 6.50 (d,

1H J=15.2 Hz, -SO2CH=CH), 7.2-7.4 (m, 8H, Ar-H), 7.5 (d, 1H J=15.2

Hz, CH=CH-Ar), 7.8 (s, 1H, indole), 11.0 (br, s, 1H, -NH indole D2O

exchangable). M+1: 422. Anal. Calcd. for (C24H27N3O2S) requires: C,

68.38; H, 6.46; N, 9.97; Found: C, 68.30; H, 6.51; N, 9.92.

4B.5.3. PREPARATION OF 186:

A hydrogenation kettle was charged methanol (500 mL), 10%

Pd/C (20 gm) slurrey and 203 (30 gm) at room tempreature.

Hydrogenation was carried out at 6kg/cm2 pressure and continued for

20-24 hours till hydrogen gas absorption ceased. The reaction mass

was filtered to remove the catalyst and filterate was concentrated

under reduced pressure. The resulting residue was dissolved in

methanol (100 mL), cooled to 20-25 ºC and solid formed was filtered

and dried to give (14 gm, 47%) of product with m.p: 155-160 ºC. IR

(KBr): 3441, 3127, 2913, 1448, 1323, 1144, 987. 1H NMR: (DMSO-

d6/TMS) 2.0-2.1 (m, 4H, piperdine), 2.6 (s, 2H, -NCH3), 2.7 (s, 3H,-

NCH3), 3.02 (m, 3H, piperidine), 3.20 (m, 2H, -SO2CH2), 3.40 (m, 2H,

piperdine), 3.5 (m, 2H, -CH2-Ar), 4.1 (s, 2H, -CH2-Ar), 7.2-7.5 (m, 8H

Ar-H), 7.8 (s, 1H, CH indole), 10.90 (s, 1H, NH indole, D2O

138

exchangable). M+1: 425. Anal. Calcd. for (C24H31N3O2S) requires: C,

67.73; H, 7.34; N, 9.87; Found: C, 67.30; H, 7.51; N, 9.89.

4B.5.4. PREPARATION OF 172:

To a stirred solution of 186 (25 gm) in liquid ammonia (250 mL) and

THF (100 mL), was added sodium metal (18 gm) at -80 ºC over a

period of 30 min. The reaction mixture was stirred for another one

hour at -80 ºC. The reaction mass was treated with aqueous

ammonium chloride solution (25 gm in 75 mL water) at -80 ºC and

then allowed to warm to room temperature and extracted with

dichloromethane (3x150 mL). The organic layer was washed with

water (75 mL), dried over anh.Na2SO4, filtered and then concentrated.

The residue was stirred with methanol (100 mL), cooled to 0-5 ºC and

the solid was filtered and dried to give 17 gm (80%) of the crude

naratriptan base, M.R: 170-172 ºC.

Purification: In to a round bottomed flask fitted with a mechanical

stirrer and condenser was charged methanol (100 mL) and crude

naratriptan (25 gm). The reaction mixture was gradually heated to

about 45- 50 ºC under stirring and maintained for 30 min. Oxalic acid

(17 gm) was added at 40-45 ºC and stirred for another 30min. The

reaction mixture was then slowly cooled to 10-15 ºC and filtered to

give naratriptan oxalate with a purity of 99.5% (HPLC). The wet cake

of naratriptan oxalate was taken in to water (200 mL) and basified

with potassium carbonate to pH 9.5-10.0 and stirred for 20 minutes.

The solid was filtered, washed with water and dried to give 20 gm of

naratriptan with HPLC purity 99.8%. IR (KBr): 3441, 3127, 2913,

139

1448, 1323, 1144, 987. 1H NMR: (DMSO-d6/TMS) 2.09 (m, 4H,

piperidine), 2.62 (d, 3H, -NHCH3), 2.76 (s, 3H, -NCH3), 3.02 (m, 3H,

piperdine), 3.1 (m, 2H, -SO2CH2), 3.3 (m, 2H, piperidine), 3.4 (m, 2H,-

CH2-Ar), 7.0 (m, 2H, Ar-H) ), 7.1 (m, 1H, -NHCH3), 7.3 (d, 1H, Ar-H),

7.6 (s, 1H, CH indole), 10.70 (br, s, 1H, -NH indole D2O exchangable);

M+1: 336. Anal. Calcd. for (C17H25N3O2S) requires: C, 60.87; H, 7.51;

N, 12.53; Found: C, 60.85; H, 7.51; N, 12.50.