WO2004020401A1

WO2004020401A1 - Synthesis of sulfonamide derivatives

Info

Publication number: WO2004020401A1
Application number: PCT/IN2002/000179
Authority: WO
Inventors: John Kallikat; Ashis Baran Mandal; Sambasivam Ganesh
Original assignee: Syngene International Private Limited
Priority date: 2002-09-02
Filing date: 2002-09-02
Publication date: 2004-03-11
Also published as: AU2002330734A1

Abstract

The novel method of synthesis of sulphonamide derivatives (I), comprising reaction of alkyl-4-halophenylsulfonate with an amine. Formula (I) wherein X is halogen and R1 and R2 are independently selected from group comprising (i) C1 to C15 alkyl, straight or branched, (ii) C3 to C15 cycloalkyl, substituted or unsubstituted, (iii) C2 to C15 alkenyl, straight or branched, (iv) C2 to C15 alkynyl, straight or branched, (v) phenyl or benzyl, substituted or unsubstituted, (vi) heterocycloalkyl, substituted or unsubstituted, (vii) hydrogen, (viii) form with the nitrogen to which they are attached a 3-7 membered heterocyclic moiety such as pyrolidine, piperidine, piperazine, imidazole, pyrazole, (ix) the alkyl in i) may be attached to a moiety selected from cycloalkyl or heterocycloalkyl, substituted or unsubstituted

Description

TITLE OF INVENTION

SYNTHESIS OF SULFONAMIDE DERIVATIVES FIELD OF THE INVENTION

The present invention relates to a novel method for the synthesis of 4-halo-benzenesulfonamide derivatives. BACKGROUND OF THE INVENTION

The present invention is related to a method for synthesis of 4-halo- benzenesulfonamide derivatives.

The importance of sub-unit sulfonamide stems from their role in biological activity of the molecule and could have potential application as an herbicides and/or plant growth regulant, endothelin antagonists, HIV protease inhibitors, catalytic antibodies, etc.

US 4,632,693 discloses synthesis, formulations and herbicidal properties of 4-methoxy-2-[[(4-methoxy-6-methyl-l ,3,5-triazin-2- yl)aminocarbonyl] aminosulfonyl]benzoate used as plant growth regulant. This sulfonamide derivative was prepared by the reaction of 4-methoxy-6- methyl-1 ,3,5-triazin-2-amine and methyl-2-(isocyanatosulfonyl)-4- methoxybenzoate in dichloromethane under reflux conditions for 4h.

Mayer et.al. (J. Med. Chem. 2000, 43, 3653-3664) have synthesized and studied the biological activity of several α₂-adrenoceptor antagonists used for neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. These antagonists are sulfonamide derivatives and in general, prepared by the reaction of arylsulfonyl chloride with an amine. For example, N-{2-[l -(2,3-dihydrobenzo[l,4]dioxin-2-ylmethyl)piperidin- 4yl]ethyl}toluene-4-sιιlfonamide has been synthesized by the reaction of 2- [l-(2,3-dihydrobenzo[l,4]dioxin-2-ylmethyl)piperidin-4yl]-2-ethylamine (lequi) with -toluenesulfonyl chloride (lequi) in presence of Et₃N (2.5equi) in CH₂C1₂ at 0°C-RT for lh.

A new class of proline sulfonamide derivatives was used by Natchus and co-workers [J. Med. Chem. 2000, 43, 4948-4963] as matrix metalloproteinases (MMPs) inhibitors. The proline sulfonamide derivatives were synthesized by the reaction of free amine derived from l-N-tert- butoxycarbonyl-2-carbomethoxy-4(S)-(pyrrolidin-l -/V-yl)pyrrolidine or 1 - N-tert-butoxycarbonyl-2-carbomethoxy-4(S)-(γ-sultam-l-N-yl)-pyrrolidine by TV-tet -butoxycaronyl group cleavage followed by coupling with 4- phenoxybenzenesulfonylchloride or 4-n-propoxybenzenesulfonyl chloride respectively in presence of dioxane:water:Et₃N (3 : 1 :2) to give the corresponding l-N-(4-phenyloxybenzenesulfonyl)-2-carbomethoxy-4(S)- (pyrrolidin-l-N-yl)pyrrolidine or l-N-(4-r?-propoxybenzenesulfonyl)-2- carbomethoxy-4(S)-(γ-sultam- 1 -/V-yl)pyrrolidine.

A recent review on the synthesis of biphenyl isoxazole sulfonamides from workers at Bristol-Meyers Squibb Company belongs to endothelin antagonists, provide valuable information about the wide application of 'sulfonamide' derivatives (WO 00/56685). Typically, in this process the biphenyl sulfonamide was synthesized by reaction of unsubstituted or substituted 4'-(2-oxazolyl)[l,ι ' -biphenyl] -2-sulfonyl chloride (lmol) with 5-amino-3,4-dimethylisoxazole (lmol) in THF in presence of sodium-/- butoxide (2.2mol) at -15°C. Wherein, the unsubstituted or substituted biphenyl sulfonyl chlorides were prepared by the reaction of corresponding 2-sulfonic acid, sodium salt with ' Vilsmeier' chlorinating reagent such as thionylchloride, oxalylchloride or phosphorous oxychloπde in toluene at

RT for 3h.

The above observations reveal that the sulfonamide derivatives are commonly synthesized by the reaction of aryl/alkyl-sulfonylchloride with aryl/alkyl-amine in suitable solvent such as dichloromethane or chloroform in presence of base such as triethylamine, pyridine etc. Other method involves in-situ preparation of sulfonylchloride by the reaction of sulfonic acid or sulfonic acid salt and chlorinating reagent such as oxalylchloride or thionylchloride and subsequent reaction with amine to give corresponding

'sulfonamide' derivatives. There is demand for a search of suitable intermediate for the synthesis of sulfonamides, as the most commonly used aryl/alkyl- sulfonylchlorides are shown to be i) unstable, ii) moisture sensitive, iii) slowly degrade to sulfonic acid.

SUMMARY OF THE INVENTION In the present is invention the sulphonamide derivatives are synthesized from alkyl-4-halophenylsulfonate.

The present invention related to a novel process of synthesis of sulphonamide derivatives of formula I from alkyl -4-halo-benzenesulfonate.

FORMULA I

Wherein X is halogen and

Ri and R₂ are independently selected from group comprising (i) C| to C₁₅ alkyl, straight or branched,

(ii) C₃ to C₁₅ cycloalkyl, substituted or unsubstituted,

(iii) C₂ to C|₅ alkenyl, straight or branched,

(iv) C₂ to C₁₅ alkynyl, straight or branched,

(v) phenyl or benzyl, substituted or unsubstituted, (vi) heterocycloalkyl, substituted or unsubstituted,

(vii) hydrogen, (viii) form with the nitrogen to which they are attached a

3-7 membered heterocyclic moiety such as pyrolidine, piperidine, piperazine, imidazole, pyrazole, (ix) the alkyl in (i) may be attached to a moiety selected from cycloalkyl or heterocycloalkyl, substituted or unsubstituted

DETAILED DESCRIPTION OF THE INVENTION

In this process, sulfonamides are prepared by the reaction of etliylsulfonate and primary or secondary amines in hydrocarbon solvent at about 60-140°C under nitrogen atmosphere. The hydrocarbon solvent used may be dry benzene or toluene.

The reaction is carried out at high temperature, preferably at about 80-100°C. The reaction can be carried out for a time range of about 1 to 24 hour, preferably 6hr to lOhr.

The process for preparing sulfonamide derivatives of formula I comprises the steps of treating a compound of formula II

FORMULA II wherein X is halogen and R is selected from group comprising (i) Ci to Cio alkyl, straight or branched, (ii) C to C₇ cycloalkyl, substituted or unsubstituted,

(iii) C₃ to C₇ heterocyclycloalkyl, substituted or unsubstituted, with an amine of formula III,

R1

/

NH

\ FORMULA III ^rø wherein,

(ii) C₃ to C₁₅ cycloalkyl, substituted or unsubstituted, (iii) C₂ to C ₁₅ alkenyl, straight or branched,

(iv) C₂ to C₁₅ alkynyl, straight or branched,

(v) phenyl or benzyl, substituted or unsubstitute ,

(vi) heterocycloalkyl, substituted or unsubstituted,

(vii) hydrogen, (viii) form with the nitrogen to which they are attached a 3-7 membered heterocyclic moiety such as pyrolidine, piperidine, piperazine, imidazole, pyrazole, (ix) the alkyl in (i) may be attached to a moiety seleced from cycloalkyl or heterocycloalkyl, substituted or unsubstituted. The amines used for the present invention may be selected from but not limiting to i) benzylamine, ii) 2-pyridin-2yl ethylamine, iii) piperidine,

> iv) morpholine, v) pyrrolidine, vi) pyrrolidin-2-carboxylic acid and vii) N-

(2-methoxyphenyl)urea.

The present method for the preparation of sulfonamides has the following characteristics i) The reaction is carried out under neutral conditions by mixing the etliylsulfonate and amine in benzene or toluene. ii) This reaction involves removal of ethanol to give the corresponding sulfonamide. iii) This method could be suitable for compounds containing acid sensitive group. iv) Use of ethyl-4-bromophenylsulfonate for the preparation of sulfonamides in the present invention could find the following application for metal mediated reactions such as: a) Suzuki coupling, b) Stille coupling, c) Heck coupling etc.

The instant invention has the following advantages over other methods in prior art

1. The sulfonylester is stable.

2. The sulfonylester is less moisture sensitive. 3. The sulfonylester employed does not degrade and could be stored at RT for longer period. 4. The process employed is economic and industrially applicable. EXAMPLES The present invention will next be described in more detail by way of examples, which should not be construed as limiting the invention thereto.

REFERENCE EXAMPLE

SYNTHESIS OF ETHYL-4-BROMOBENZENESULFONATE

To a solution of 4-bromobenzenesιιlfonylchloride (lequi.) in dry dichloromethane at 0°C, was added pyridine (1.2equi.) followed by ethanol

(1.5equi.) drop-wise with stirring and allowed to stir at RT for 12h. The reaction mixture was acidified with 1.5N HC1 to pH=5-6 and separated the organic layer. The organic layer was washed with brine, dried over Na₂S0₄ and concentrated. The crude was purified by column chromatography over silica gel to give ethyl-4-bromobenzenesulfonate in 86% yield. The title compound exhibits the following NMR pattern.

[¹H NMR (300 MHz, CD₃OD): δ 1.22-1.25(3H, m), 4.1 1-4.16(2H, m),

7.8(4H, s).]

EXAMPLE I SYNTHESIS OF N-BENZYL-4-BROMOBENZENESULFONAMIDE

(Formula la)

A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and benzylamine (lequi.) in toluene (15vol.) was heated to I 00°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The solid was washed with toluene and dried under vacuum to give N-benzyl-4-bromobenzenesulfonamide in 90% yield. The title compound exhibits the following NMR pattern.

[Η NMR (300 MHz, DMSO-d₆): δ 3.91 (2H, s), 7.44-7.60(9H, m), 8.22(1 H, br. s).] EXAMPLE II

SYNTHESIS OF 4-BROMO-N-(2-PYRIDIN-2-YL-ETHYL) BENZENE

SULFONAMIDE

(Formula lb)

A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and 2-pyridin- 2yl ethylamine (lequi.) in toluene (15vol.) was heated to 100°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The precipitate was washed with toluene and dried under vacuum to give crude product. The crude was purified by column cliromatography over silica gel (chloroform) to give 4-bromo-Λ/-(2-pyridin- 2yl ethyl)benzenesulfonamide in 87% yield. The title compound exhibits the following NMR pattern.

[^!H NMR (300 MHz, CDC1₃): δ 2.91-2.95(2H, m), 3.32-3.37(2H,m), 6.46(1H, br. s), 7.05-7.15(2H, m), 7.56-7.71(5H, m) and 8.44(1H, br. d); ^, C NMR (75 MHz, CDCl₃): δ 35.9, 42.2, 121.7, 123.4, 127.2, 128.5, 132.2, 136.7, 139.2, 148.9 and 158.6.] EXAMPLE III

SYNTHESIS OF 1 -[(4-BROMOPHENYL) SULFONYL] PIPERIDINE (Formula Ic)

A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and piperidine (lequi.) in toluene (15vol.) was heated to 100°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The solid was washed with toluene and dried under vacuum to give 1 -[(4-bromophenyl) sulfonyl] piperidine in 86% yield. The title compound exhibits the following NMR pattern. [Η NMR (300 MHz, CDC1 ): δ 1.61-2.1 1(6H, m), 2.49-2.58(2H, m), 2.98- 3.13(2H, m), 7.48 (2H, d, .7=8.2 Hz), 7.71(2H, d, J=8.2 Hz).] EXAMPLE IV

SYNTHESIS OF 4-[(4-BROMOPHENYL) SULFONYL] MORPHOLINE (Formula Id) A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and morpholine (lequi.) in toluene (15vol.) was heated to 100°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The solid was washed with toluene and dried under vacuum to give 4-[(4-bromophenyl) sulfonyl] morpholine in 88% yield. The title compound exhibits the following NMR pattern.

[Η NMR (300 MHz, CD₃OD): δ 3.21-3.28(4H, m), 3.8-3.87(4H, m),

7.61(2H, d), 7.77(2H, d).]

EXAMPLE V

SYNTHESIS OF l-[(4-BROMOPHENYL) SULFONYL] PYRROLIDINE (Formula Ie)

A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and pyrrolidine (lequi.) in toluene (15vol.) was heated to 100°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The precipitate was washed with toluene and dried under vacuum to give l-[(4-bromophenyl) sulfonyl] pyrrolidine in 74% yield. The title compound exhibits the following NMR pattern. [Η NMR (300 MHz, CD₃OD): δ 1.94-2.15(4H, m), 3.02-3.28(4H,m), 7.64(2H, d, J=8.4 Hz) and 7.76(2H, d, J=8.4 Hz), ^l C NMR (75 MHz, CD₃OD): δ 23.8, 24.9, 46.5, 51.1 , 125.3, 128.8, 132.5 and 145.5] EXAMPLE VI

SYNTHESIS OF l -[(4-BROMOPHENYL) SULFONYL] PYRROLIDIN- 2-CARBOXYLIC ACID (Formula If)

A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and pyrrolidin- 2-carboxylic acid (l equi.) in toluene (15vol.) was heated to 100°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The solid was washed with toluene and dried under vacuum to give crude product. The crude material was purified by column cliromatography over silica gel (chloroform/methanol, 9: 1 ) to give l-[(4- bromopheϊiyl) sulfonyl] pyrrolidin-2-carboxylic acid in 47% yield. The title compound exhibits the following NMR pattern.

[Η NMR (300 MHz, CDCI₃): δ 1.80-1.86(1 H, m), 1.95-2. 15(3H, m) 3.25- 3.33(1H, m), 3.46-3.51(1H, m), 4.33(1H, t, J= 6.0 Hz), 7.67(2H, d, J-8.6 Hz) and 7.75(2H, d, J=8.6 Hz) and 9.3 (1H, br. s); ¹ C NMR (75 MHz, CDCI₃): δ 24.5, 30.8, 48.4, 60.2, 128.0, 128.9, 132.3, 136.8 and 177.1] EXAMPLE VII

4-BROMO-7V-{[(2-METHOXYPHENYL)AMINO]CARBONYLj BENZENE SULFONAMIDE (Formula Ig) A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and N-(2- methoxyphenyl) urea(l equi.) in toluene (1 5vol.) was heated to 100°C for 8h. The reaction mixture was cooled to room temperature and filtered off the solid precipitate. The solid was washed with toluene and dried under vacuum to 4-bromo-N-{[(2-methoxyphenyl) aιnino]carbonyl }benzene sulfonamide in 67% yield. The title compound exhibits the following NMR pattern.

[Η NMR (300 MHz, DMSO-d₆): δ 3.8(3H, s), 6.85(1H, br. s), 6.88-

7.13(6H, m), 8.12 (2H, d), 9.7(1H, br. s).]

FORMULA I

FORMULA II

R1

NH

\

R2

FORMULA III

FORMULA la

FORMULA Tb

FORMULA Ic

FORMULA Id

FORMULA le

COOH

FORMULA If

FORMULA Ig

Claims

WE CLAIM:

1 . A method for the preparation of compound of formula

FORMULA I wherein X is halogen and

Rl and R2 are independently selected from group comprising

(i) Ci to C₁₅ alkyl, straight or branched, (ii) C₃ to Cis cycloalkyl, substituted or unsubstituted,

(iii) C₂ to C₁₅ alkenyl, straight or branched, (iv) C₂ to Cis alkynyl, straight or branched,

(v) phenyl or benzyl, substituted or unsubstituted, (vi) heterocycloalkyl, substituted or unsubstituted, (vii) hydrogen, (viii) form with the nitrogen to which they are attached a 3-7 membered heterocyclic moiety such as py olidine, piperidine, piperazine, imidazole, pyrazole,

(ix) the alkyl in (i) may be attached to a moiety seleced from cycloalkyl or heterocycloalkyl, substituted or unsubstituted by treating the compound of formula II

FORMULA II wherein X is halogen and R is selected from group comprising (i) Cι to Cio alkyl, straight or branched,

(ii) C₃ to C₇ cycloalkyl, substituted or unsubstituted, (iii) C₃ to C7 heterocyclycloalkyl, substituted or unsubstituted, with an amine of the compound of formula III,

R1

/

NH

FORMULA III ^X _m wherein,

Ri and R₂ are independently selected from group comprising

(i) Ci to C1₅ alkyl, straight or branched,

(ii) C₃ to C₁₅ cycloalkyl, substituted or unsubstituted,

(iii) C₂ to C1₅ alkenyl, straight or branched, (iv) C₂ to C₁₅ alkynyl, straight or branched,

(v) phenyl or benzyl, substituted or unsubstituted,

(vi) heterocycloalkyl, substituted or unsubstituted,

(vii) hydrogen,

(viii) form with the nitrogen to which they are attached a 3-7 membered heterocyclic moiety such as pyrolidine, piperidine, piperazine, imidazole, pyrazole,

(ix) the alkyl in (i) may be attached to a moiety seleced from cycloalkyl or heterocycloalkyl, substituted or unsubstituted.

2. A method according to claim 1 wherein, the reaction is performed in an organic solvent.

3. A method according to claim 2 wherein, the organic solvent used is hydrocarbon.

4. A method according to claim 3 wherein, the organic solvent is benzene or toluene.

5. A method according to claim 1 wherein, the amine is selected from benzylamine, 2-pyridin-2-yl-ethylamine, piperidine, morpholine, pyrrolidine, pyrrolidine-2-carboxylic acid and N-(2- meth oxypheny 1 )urea.

6. A method according to claim 1 wherein, the reaction mixture is heated at a temperature ranging from about 60°C to about 140°C.

7. A method according to claim 1 wherein, the reaction is carried out for a time ranging from about 60 min to about 24 hr.

8. A method according to claim 1 wherein, the product is purified using cliromatography.

9. A method according to claim 8 wherein, the chromatography used is silica based.

10. A method according to claim 1 wherein, the solid product is afforded after cooling.

11. A method according to claim 10 wherein, the solid product is afforded by drying, optionally under vacuum.

12. A novel compound of formula lb is 4-biOino-t?-(2-pyridin-2-yl- ethyl) benzene sulfonamide.

13. A novel compound of formula le is l -[(4-bromophenyl) sulfonyl] pyrrolidine.

14. A novel compound of formula If is l -[(4-bromophenyl) sulfonyl] pyπolidin-2-carboxylic acid