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-1, 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. Cllem. 2000,43, 3653-3664) have synthesized and studied the biological activity of several a2-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- [1- (2, 3-dillydrobenzo [1, 4] dioxin-2-ylmethyl) piperidin- 4yl] ethyl} toluene-4-sulfonamide has been synthesized by the reaction of 2- [1-(2, 3-dihydrobenzo [1, 4] dioxin-2-ylmethyl) piperidin-4yl]-2-ethylamine

(1equi) with p-toluenesulfonyl chloride (1equi) in presence of Et3N (2. 5equi) in CH2CI2 at 0°C-RT for I h.

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 1-N-tert- butoxycarbonyl-2-carbometlioxy-4 (S)- (pyrrolidin-l-N-yl) pyrrolidine or 1- <BR> <BR> <BR> <BR> N-tert-butoxycarbonyl-2-carbomethoxy-4 (S)-(γ-sultam-1-N-yl)-pyrrolidine by N-tert-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 1-N-(4-phenyloxybenzenesulfonyl)-2-carbomethoxy-4 (S) - (pyrrolidin-1-N-yl) pyrrolidine or 1-N- (4-n-propoxybenzenesulfonyl)-2- carbomethoxy-4 (S)- (y-sultam-1-N-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) [1, 1'-biphenyl]-2-sulfonyl chloride (lmol) with 5-amino-3, 4-dimethylisoxazole (lmol) in THF in presence of sodium-l- butoxid (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 oxychlonde 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 R, and R2 are independently selected from group comprising

(i) Cl to C15 alkyl, straight or branched, (ii) C3 to C, ; cycloalkyl, substituted or unsubstituted, (iii) C2 to Cl5 alkenyl, straight or branched, (iv) C2 to C 15 atkynyt, 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, pyrazol, (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 ethylsulfonate 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 10hr.

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) Cl to C10 alkyl, straight or branched, (ii) C3 to C7 cycloalkyl, substituted or unsubstituted, (iii) C3 to C7 heterocyclycloalkyl, substituted or unsubstituted, with an amine of formula III, FORMULA III wherein, R, and R2 are independently selected from group comprising (i) to 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 C 15 alkynyl, straight or branched, (v) phenyl or benzyl, substituted or unsubstitutect, (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, (is) 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 ethylsulfonate 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-bromopl1enylsulfonate 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 lias 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-bromobenzenesulfollylollloride (lequi.) in dry dichloromethane at 0°C, was added pyridine (1. 2equi.) followed by ethanol (l. 5equi.) drop-wise with stirring and allowed to stir at RT for 12h. The reaction mixture was acidified with 1. 5N HCl 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.

['H NMR (300 MHz, CD30D) : # 1.22-1. 25 (3H, m), 4.11-4. 16 (2H, m), 7.8 (4H, s).] EXAMPLE I SYNTHESIS OF N-BENZYL-4-BROMOBENZENESULFONAMIDE (Formula la) A mixture of etllyl-4-bromobenzenesulfonate (lequi.) and benzylamine (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 N-benzyl-4-bromobenzenesulfonamide in 90% yield. The title compound exhibits the following NMR pattern.

['H NMR (300 MHz, DMSO-d6) : 6 3. 91 (2H, s), 7.44-7. 60 (9H, m), 8.22 (l. H, br. s).]

EXAMPLE II SYNTHESIS OF 4-BROMO-N- (2-PYRIDIN-2-YL-ETHYL) BENZENE SULFONAMIDE (Formula Ib) A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and 2-pyridin- 2yl ethylamine (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 precipitate was washed with toluene and dried under vacuum to give crude product. The crude was purified by column chromatography over silica gel (chloroform) to give 4-bromo-N-(2-pyridin- 2yl ethyl) benzenesulfonamide in 87% yield. The title compound exhibits the following NMR pattern.

[1H NMR (300 MHz, CDCl3) : 8 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) ; ßC NMR (75 MHz, CDCl3) : 8 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 (1equi). and piperidine (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 1- [ (4-bromoplienyl) sulfonyl] piperidine in 86% yield. The title compound exhibits the following NMR pattern.

['H NMR (300 MHz, CDCI 1.61-2. 11 (6H, m), 2.49-2. 58 (2H, m), 2. 98- 3.13 (2H, m), 7.48 (2H, d, J=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 (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 4- [ (4-bromophenyl) sulfonyl] morpholine in 88% yield. The title compound exhibits the following NMR pattern.

['H NMR (300 MHz, CDsOD) : 8 3.21-3. 28 (4H, m), 3.8-3. 87 (4H, m), 7.61 (2H, d), 7.77 (2H, d).] EXAMPLE V SYNTHESIS OF 1- [ (4-BROMOPHENYL) SULFONYL] PYRROLIDINE (Formula Ie) A mixture of ethyl-4-bromobenzenesulfollate (1equi) and pyrrolidine (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 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.

['H NMR (300 MHz, CD3OD) : # 1. 94-2. 15 (4H, m), 3. 02-3.28 (4H, m), 7.64 (2H, d, S=8. 4 Hz) and 7.76 (2H, d, J=8. 4 Hz),"C NMR (75 MHz, CDsOD) : 6 23. 8,24. 9, 46. 5, 51. 1, 125.3, 128.8, 132.5 and 145. 5]

EXAMPLE VI SYNTHESIS OF 1- [ (4-BROMOPHENYL) SULFONYL] PYRROLIDIN- 2-CARBOXYLIC ACID (Formula If) A mixture of ethyl-4-bromobenzenesulfonate (lequi.) and pyrrolidin- 2-carboxylic acid (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 chromatography over silica gel (chloroform/methanol, 9: 1) to give 1- [ (4- bromophenyl) sulfonyl] pyrrolidin-2-carboxylic acid in 47% yield. The title compound exhibits the following NMR pattern.

['H NMR (300 MHz, CDC13) : 8 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) ; 13C NMR (75 MHz, CDC13) : 6 24.5, 30.8, 48.4, 60.2, 128.0, 128.9, 132.3, 136.8 and 177. 1] EXAMPLE VII 4-BROMO-N-{[(2-METHOXYPHENYL)AMINO]CARBONYL} BENZENE SULFONAMIDE (Formula Ig) A mixture of ethyl-4-bromobenzenesulfonate (1equi.) and N-(2- methoxyphenyl) urea (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 4-bromo-N-{[(2-methoxyphenyl)amino]carbonyl} benzene

sulfonamide in 67% yield. The title compound exhibits the following NMR pattern.

['H NMR (300 MHz, DMSO-d6) : # 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 FORMULA III

FORMULA la FORMULA lb FORMULA Ic FORMULA Id

FORMULA le FORMULA If FORMULA Ig