Title of Invention

A PROCESS FOR PREPARING 2-[(2,6-DICHLOROPHENYL) AMINO] BENZENEACETIC ACID CARBOXYMETHYL ESTER

Abstract

The present invention provides a process for preparing aceclofenac of formula IV which comprises reacting a compound of formula I with a-haloacetic acid ester of formula II to obtain a compound of formula III which is reacted with a deprotecting agent to obtain a compound of formula IV, wherein said reaction is carried out without isolation of compound of formula III. The step of reacting a compound of formula I with a compound of formula II is carried out in a solvent and a phase transfer catalyst. Formula I wherein M represents alkali metal atom; X is a halogen atom, R is alkyl or phenyl substituent.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See section 10, Rule 13] A PROCESS FOR PREPARING 2-[(2,6-DICHLOROPHENYL) AMINO] BENZENE-ACETIC ACID CARBOXYMETHYL ESTER; AMOLI ORGANICS PVT. LTD., A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 407, DALAMAL HOUSE, J. BAJAJ ROAD, NARIMAN POINT, MUMBAI-400 021, MAHARASHTRA, INDIA. THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. FIELD OF THE INVENTION The present invention relates to a process for preparing non-steroidal anti¬inflammatory drug and its intermediate. BACKGROUND OF THE INVENTION Formula IV Compound of formula IV can be prepared by an intermediate of formula III. Formula III Aceclofenac is a non-steroidal anti-inflammatory drug, which acts specifically on inflammatory sites and thereby decreases the inflammation. It is highly effective as an anti-inflammatory drug for various inflammatory conditions. The chemical name of aceclofenac is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid carboxymethyl ester and is represented by formula IV in the present invention. US 4,548,952 discloses a process for preparing aceclofenac. It is synthesized by reacting 2-[(2,6-dichlorophenyl) amino] phenylacetic acid salt with benzyl haloacetate in an anhydrous organic liquid medium of polar and aprotic character like dimethylformamide, acetonitrils, dimethylsulphoxide, and the like to form a benzyl ester. The benzyl ester is isolated and then hydrogenated in the presence of palladium absorbed on carbon to give aceclofenac. Thisprocess uses an expensive catalyst. The reaction time is also lengthy. KR 200001448 discloses a method for preparing aceclofenac. Sodium 2-[(2,6-dichlorophenyl) amino] phenylacetate and alkyl haloacetate are reacted in lower aliphatic alcohol derivatives or its ester in the presence of alkali metal carbonate and phase transfer catalyst to give 2-[2-(2,6-dichlorophenyl) amino] phenyl] acetoxy] acetate. This product is hydrolyzed in the presence of a solvent and a catalyst to give aceclofenac. The above reaction being a solid-liquid reaction is difficult for commercial production. SUMMARY OF THE INVENTION An object of the present invention is to provide a simple process for the preparation of Aceclofenac. Another object of the present invention is to reduce the number of steps in the manufacturing process. The first aspect oftiie present invention provides a process for the preparation of 2-[(2,6-dichlorophenyl) amino] b^nzeneacetic acid carboxymethyl ester (aceclofenac) offormula IV which comprises reacting a compound of formula I with a-haloacetic acid ester of formula II to obtain a compound of formula III which is reacted with a deprotecting agent to obtain a compound of formula IV, wherein said reaction is carried out without isolation of compound of formula III. The step of reacting a compound of formula I with a compound of formula II is carried out in a solvent and a phase transfer catalyst. O^ „0^ ^COOR wherein M represents alkali metal atom; X is a halogen atom, R is alkyl or phenyl substituent. The second aspect of the present invention provides a process for the preparation of compound of formula III which comprises reacting a compound of formula I with a compound of formula II to obtain a compound of formula III, the above step is carriec out in a solvent and a phase transfer catalyst. wherein M represents alkali metal atom; X is a halogen atom and R is an alkyl or phenyl substituent. M in formula I depicts sodium or potassium; X is CI or Br, preferably CI and R is preferably t-butyl. The solvent is selected from the group comprising of hexane, cyclohexane, aliphatic, aromatic solvents, preferably toluene. The phase transfer catalyst is selected from the group comprising of ammonium and phosphonium salts, preferably triethyl benzyl ammonium bromide. The deprotecting agent is formic acid or trifluoroacetic acid. The reaction sequence is carried out without isolation of compound of formula III, which makes it economical. However, the steps can be carried out by separating compound of formula III in the first aspect of the invention. DESCRIPTION OF THE INVENTION The present invention encompasses a process for preparing compound of formula IV i.e. 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid carboxymethyl ester (aceclofenac). The reaction is represented by the following scheme: In the above scheme, M represents sodium or potassium; X is Br or CI, preferably CI; R is alkyl or phenyl substituent, preferably t-butyl. According to the present invention, 2-[(2,6-dichlorophenyl) amino] phenylacetic acid salt of formula I is reacted with a-haloacetic acid ester of formula II in the presence of a solvent and a phase transfer catalyst to form a compound of formula III. The a-haloacetic acid ester is preferably t-butyl-chloroacetate. the solvent is selected from the group comprising of hexane, cyclohexane, aliphatic, aromatic solvents. The preferable solvent is toluene. The phase transfer catalyst is selected from the group comprising of ammonium and phosphonium salts. The preferable phase transfer catalyst is triethyl benzyl ammonium bromide. The ratio of solvent to phase transfer catalyst is 1:0.0025 to 1:0.1. The reaction is carried out at a temperature from 35-120 deg C, preferably 60-80 deg C. The reaction mass is heated for about 8 hours to form a compound of formula III. Toluene is distilled out from the reaction mixture. The reaction mass is cooled to 45- 50 deg C. In the same reaction vessel, without the isolation of compound of formula III and phase transfer catalyst, a deprotecting agent is added. The deprotecting agent is formic acid or trifluoroacetic acid. The temperature of the reaction mixture is maintained between 45-50 deg C, for about 8 hours to form compound of formula IV i.e. 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid carboxymethyl ester (aceclofenac). The following examples illustrate the invention, but are not limiting thereof. EXAMPLE-1 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 100 gm (0.314 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 150 ml toluene at room temperature. 60 gm (0.398 mol) of tert-Butyl-chloroacetate were added. 1 gm tetra Butyl ammonium bromide was added. The mixture was heated to 70-75°C for 3-4 hr. After completion the reaction 75% organic solvent was removed and 187.5 gms of formic acid was affcled. The mixture was stirred at 45-50X for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 98 gms (88 %) EXAMPLE-2 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml toluene at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm tetra Butyl ammonium bromide was added. The mixture was heated to 50-60°C for 15-20 hr. After completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 37 gms (66 %) EXAMPLE-3 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml Dichloroethane at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm tetra Butyl ammonium bromide was added. The mixture was heated to 702750C_3-4 hours. After completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 47 gms (84 %) EXAMPLE-4 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml Cyclohexane at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm tetra Butyl ammonium bromide was added. The mixture was heated to 70-75°C for 3-4 hr. After completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 50 gms (90 %) EXAMPLE-5 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml o-xylene at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm tetra Butyl ammonium bromide was added. The mixture was heated to 70-75°C for 3-4 hours. After completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 45.5 gms (82 %) EXAMPLE-6 Preparation of 2-[(2,6-dichlorophenyl)amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml Benzene at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm tetra Butyl ammonium bromide was added. The mixture was heated to 70-75X for 3-4 hours after completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 47 gms (84 %) EXAMPLE-7 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml toluene at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm Benzyl triethyl ammonium chloride were added. The mixture was heated to 70-75°C for 3-4 hours. After completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After oiynpletion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 48 gms (86 %) EXAMPLE-8 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 50 gm (0.157 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 75 ml toluene at room temperature. 30 gm (0.199 mol) of tert-Butyl-chloroacetate were added. 0.5 gm tetra Butyl ammonium bromide was added. The mixture was heated to 108-112°C for 1-2 hours. After completion the reaction 75% organic solvent was removed and 93.75 gms of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 min and diluted with water. The product was filtered off and purified with toluene. Overall yield 47 gms (84 %). EXAMPLE-9 Preparation of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid in a one pot process. 400 kgs (1.25 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetic acid sodium salt (Diclofenac sodium) were suspended in 600 lit toluene at room temperature. 240 kgs (1.59 mol) of tert-Butyl-chloroacetate were added. 4 kgs tetra Butyl ammonium bromide were added. The mixture was heated to 65-75°C for 8 hours. After completion the reaction 75% organic solvent was removed and 750 kgs of formic acid were added. The mixture was stirred at 45-50°C for 8 hrs. After completion of reaction, cooled to room temperature after approximately 30 mm and diluted wnn water. The product was filtered off and purified with toluene. Overall yield 784 gms (88 %). EXAMPLE-10- (Prior art process) A. Preparation of 2-[(2,6-dichlorophenyl) amine]phenyl acetoxyacetacetic ester. 100 gm (0.314 mol) of 2-[(2,6-dichlorophenyl) amine] phenylacetacetic acid sodium salt (Diclofenac sodium) were suspended in 150 ml toluene at room temperature. 60 gm (0.398 mol) of tert.-Butyl-chloroacetate were added. 1 gm tetra Butyl ammonium bromide were added. The mixture was heated to 70-75°C for 3-4 hr. After completion the reaction organic solvent was removed and 500 ml water were added. The mixture was stirred at 45-50°C for 1 hrs, cooled to room temperature after approximately 30 min and stirred for 1 hr. The product was filtered off and purified with hexane. Overall yield 125 gms (96 %) Melting Point: 78-80°C. B. Hydrolysis Preparation of 2-[(2,6-dichlorophenyl) amine]phenylacetoxyacetic acid 118 gm (0.288 mol) of 2-[(2,6-dichlorophenyl) amine] phenyl acetoxyacetacetic ester (Aceclofenac t-butyl ester) were suspended in 187 kgs of formic acid. The mixture was stirred at 45-50 deg C for 8 hrs. After completion of the reaction, the mixture was cooled to room temperature after approximately 30 min and diluted with water. Yield: 88.5 gms (87 %). Melting Point: 150-154 deg C. Overall yield 0.885 gms (79%) of 2-[(2,6-dichlorophenyl) amine] phenylacetoxyacetic acid from Diclofenac sodium. We Claim: 1. A process for preparing aceclofenac of formula IV which comprises reacting a compound of formula I with a-haloacetic acid ester of formula II to obtain a compound of formula III which is reacted with a deprotecting agent to obtain a compound of formula IV, wherein said reaction is carried out without isolation of compound of formula III. Formula I wherein M represents alkali metal atom; X is a halogen atom, R is alkyl or phenyl substituent. 2. The process as claimed in any one of claim 1, wherein the step of reacting a compound of formula I with a compound of formula II is carried out in a solvent and a phase transfer catalyst. 3. The process as claimed in any one of claim 1, wherein M is sodium or potassium. 4. The process as claimed in any one of claim 1, wherein X is CI or Br, preferably CI. 5. The process as claimed in any one of claim 1, wherein R is preferably t-butyl. 6. The process as claimed in any one of claim 1, wherein the deprotecting agent is formic acid or trifluoroacetic acid. 7. The process as claimed in claim 2, wherein the solvent is selected from the group comprising of hexane, cyclohexane, aliphatic, aromatic solvents. 8. The process as claimed in claim 7, wherein the solvent is preferably toluene. 9. The process as claimed in claim 2, wherein the phase transfer catalyst is selected from the group comprising of ammonium and phosphonium salts. 10.The process as claimed in claim 9, wherein the phase transfer catalyst is preferably triethyl benzyl ammonium bromide. 11. The process as claimed in any one of claim 1, wherein the step of reacting a compound of formula I with a-haloacetic acid ester of formula II is carried out at a temperature range from 35-120° C, preferably 60-80 ° C. 12.The process as claimed in claim 2, wherein the ratio of solvent to phase transfer catalyst is 1:0.0025 to 1:0.1. Dated this 21st day of December 2006 FOR AMOLI ORGANICS PVT LTD By their Agent GIRISH VIJAYANAND SHETH KRISHNA & SAURASTRI

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