FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTIONA PROCESS FOR THE PREPARATION AND PURIFICATION OF REPAGLINIDE
2. APPLICANT (S)(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(C) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTIONThe present invention provides a process for the preparation and purification of repaglinide
The folowing specification particularly describes the invention and the manner in which it is to be performed
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4. DESCRIPTION
The present invention provides a process for the preparation and purification of repaglinide.
Chemically, repaglinide is (S) (+)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-rnethyl-1-butyl} aminocarbonylmethyl] benzoic acid having the Formula I. It offers significantly better biological profile as compared to sulphonylurea class of compounds for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

U.S. Patent No. 5,312,924 provides the process for preparation of S-enantiomer of repaglinide via resolution of racemic 3-methyl-1-(2-piperidinophenyl)-1-butyl amine with N-acetyl-L-glutamic acid to afford the (S)-enantiomer of corresponding amine. The resultant amine was then reacted with 3-ethoxy-4-ethoxy carbonylphenyl acetic acid to give ethyl ester of repaglinide. The ethyl ester of repaglinide on saponification gave repaglinide.
U.S. Patent No. 6,686,497 and U.S. Patent No. 6,818,786 provide the process for the preparation of 3-ethoxy-4-ethoxy-carbonyl-phenyl acetic acid, which is a key intermediate for the synthesis of repaglinide.
U.S. Application 2004-0192921 provides the process for the preparation of (RS) 3-methy1-(2-piperidinyl phenyl) butyl amine an intermediate for the synthesis of repaglinide
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U.S. Application 2005-107614 provides another process of preparation of repaglinide via reaction of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine with protected carboxylic acid.
PCT patent application WO 2004-101540 provides the process for the preparation of repaglinide, which involves reacting corresponding amine with 2-alkoxy -4-carboxymethyl benzoic acid derivatives.
U.S. Application 2004-0102477 and PCT patent application WO 2005-021524 provides the different crystalline and amorphous forms of repaglinide and the processes for preparation thereof.
The present inventors have developed an easy single step process for the preparation of repaglinide. This involves the reaction of 4-(carboxymethyl)-2-alkoxybenzoic acid instead of ester with an (S)-3-methyl-1-(2-piperidino-phenyl)-1-butyiamine. The process of present invention can be carried out with or without base.
In one of the aspect of the present invention there is provided a process for preparation of repaglinide wherein the said process includes steps of,
a) reacting 4-(carboxymethyl)-2-alkoxybenzoic acid with (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine in organic solvent, optionally in presence of base,
b) isolating repaglinide from reaction mass thereof.
In yet another aspect of the present invention there is provided a process for purification of repaglinide by column chromatography.
The process of present invention is related to process of preparation of repaglinide. The 4-(carboxymethyl)-2-ethoxybenzoic acid in organic solvent was reacted with (S)-3-methyl-1-(2-piperidino-pnenyl)-1-butylamirte after addition of either triphenylphosphine or dicyclohexylcarbodiimide at temperature below 60
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°C. The reaction was carried out with or without base. The reaction mixture was then concentrated and repaglinide was isolated from the reaction mass thereof. The repaglinide obtained thereof was then purified by chromatography such as column chromatography, which includes flash chromatography or preparative high performance liquid chromatography. The repaglinide prepared by this invention was characterized by 1H NMR (400 MHz, CDCI3): 6 0.90 (3H,d), 0.92 (3H,d), 1.38-1.78(12H,m), 2.56-2.66(2H, m), 2.84-2.96(2H, m), 3.53 (2H, dd), 4.19 (2H, m), 5.28 (1H, m), 6.94-7.10 (4H, m), 7.18-7.24 (3H, m), 8.08 (1H,d), 10.89 (1H, bs) and mass m/e: 453 (M+1).
The organic solvent includes class II solvents such as toluene, xylene, dichloromethane, chloroform, acetonitrile and the like.
The non-limiting examples of base include organic and inorganic bases such as alkyl or aryl amines like methyl amine, dimethyl amine, triethyl amine, pyridine, N,N-dimethylaniline, 2,6-dimethylpyridine, 4-methylpyridine, 4-dimethylamino pyridine, diclyclohexyl amine, alkalimetal earth carbonates, bicarbonates or hydroxides.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example-1 Preparation and purification of repaglinide
4-(carboxymethyl)-2-ethoxybenzoic acid (1.0 gm), (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (1.1 gm), triphenylphosphine (1.75 gm), triethylamine ( 1.0 gm) in a mixture of acetonitrile (20 ml) and carbon tetrachloride (10 ml) was stirred at 25°C for 24 hours. The reaction mixture was concentrated and purified
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by silica column chromatography. The eluting solvent was ethyl acetate - hexane mixture in 1:2 ratio.
HPLC purity: 97.7%
Example-2 Preparation and purification of repaglinide
4-(carboxymethyl)-2-ethoxybenzoic acid (0.5 gm), (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (1.1 gm), dicyclohexyl carbodiimide (0.45 gm) in toluene (10 ml) was stirred at 25°C for 22 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (20 ml) and washed with water. The organic layer was separated and concentrated. The product was isolated by the method as mentioned in Example-1. HPLC purity: 97.5%
Example-3
Preparation and purification of repaglinide
4-(carboxymethyl)-2-ethoxybenzoic acid (1.0 gm), (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (1.1 gm), dicyclohexyl carbodiimide (0.90 gm), dimethylaminopyridine ( 0.045 gm) in a dichloromethane (10 ml) was stirred at 25°C for 5 hours. The reaction mixture was concentrated and the product was isolated by the method as mentioned in Example-1. HPLC purity: 97.9%.
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WE CLAIM:
1. A process for preparation of repaglinide wherein the said process comprising,
a) reacting 4-(carboxymethyl)-2-alkoxybenzoic acid with (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine in organic solvent, optionally in presence of base,
b) isolating repaglinide from reaction mass thereof.

2. A process of claim 1 wherein the organic solvent includes class II solvents or mixture thereof.
3. A process of claim 2 wherein the organic solvent is toluene, acetonitrile, dichloromethane, chloroform and the like.
4. A process of claim 1 wherein the reaction is carried out in presence of dicydohexylcarbodiimide or triphenylphosphine.
5. A process of claim 1 wherein base is selected from the group of alkyl or aryl amine or alkalimetal carbonates bicarbonate or hydroxide.
6. A process of claim 1 wherein the 4-(carboxymethyl)-2-alkoxybenzoic acid is 4-(carboxymethyl)-2-ethoxybenzoic acid.

7. A process wherein the purification of repaglinide is performed by using chromatography technique.
8. A process of claim 7 wherein silica gel column chromatography technique is used.
9. A process of claim 8 wherein the eluting solvent is mixture of ethyl acetate in hexane.
10. A process of claim 9 wherein the ethyl acetate and hexane ratio is 1:2.
Dated this19th day of Jan, 2007 For Wockhardt Limited
(Mandar Kddgule) Authorized Signatory
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