FORM 2THE PATENT ACT 1970(39 Of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule 13)
1. TITLE OF THE INVENTIONA PROCESS FOR THE PREPARATION OF 4-(CARBOXYMETHYL)-2-ETHOXYBENZOIC ACID INTERMEDIATE USEFUL IN THE PREPARATION 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 of 4-(carboxy methyl)-2-ethoxybenzoic acid intermediate useful in the preparation of repaglinide
The following specification particularly describes the invention and the mannerin which it is to be performed
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4. DESCRIPTION
The present invention provides a process for the preparation of 4-(carboxy methyl)-2-ethoxybenzoic acid intermediate useful in the preparation of repaglinide.
Chemically, repaglinide is (S)(+)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoic acid having the Formula I. It belongs to a new class of hypoglycemic benzoic acid derivatives. 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.
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U.S. Application 2004-0192921 provides the process for the preparation of (RS) 3-methyl-1-(2-piperidinyl phenyl) butyl amine an intermediate for the synthesis of repaglinide
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.
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The present inventors have developed an easy process of preparation of 4-(carboxymethyl)-2-ethoxybenzoic acid (Formula-ll), an intermediate useful in the preparation of repaglinide. This involves the reaction of monoester intermediate or diester intermediate or mixed diester intermediate (formula-Ill) with base.


Wherein R1 is selected from group consisting of independently hydrogen, methyl, ethyl, propyl or butyl. R2 is selected from group consisting of independently hydrogen, methyl, ethyl, propyl, butyl or benzyl.
In one of the aspect of the present invention there is provided a process for preparation 4-(carboxymethyl)-2-ethoxybenzoic acid (Formula-ll), an
intermediate useful in the preparation of repaglinide wherein the said process includes the steps of,
a) reacting the compound of formula-Ill with base in solvent,
b) isolating 4-(carboxymethyl)-2-ethoxybenzoic acid (formula-ll) from reaction mass thereof.

The process of present invention is related to a process for preparation 4-(carboxymethyl)-2-ethoxybenzoic acid (Formula-ll), an intermediate useful in the preparation of repaglinide. This involves the reaction of monoester intermediate or diester intermediate or mixed diester of formula-Ill with base such as sodium hydroxide, potassium hydroxide and the like dissolved in water. The reaction is carried out using solvent such as water, tetrahydrofuran, acetonitrile, diethyl ether and the like or the mixture thereof. After completion of reaction, the product 4-(carboxymethyl)-2-ethoxybenzoic acid was isolated from the reaction mixture thereof. The intermediate was characterized by 1H NMR (400 MHz, DMSO): δ 1.30 (3H,t), 3.6 (2H,s), 4.04 (2H, q), 6.84 (1H, d, J=8 Hz), 6.99(1 H, s), 7.53 (1H, d, J=8Hz), 12.41(2H,s), and Mass: (m/e): 225 (M+1).
The 4-(carboxymethyl)-2-ethoxybenzoic acid is then converted to repaglinide by reacting with an (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine. The repaglinide prepared by using this intermediate was also characterised by 1H NMR of (400 MHz, CDCl3): δ 0.90 (3H,d), 0.92 (3H,d), 1.38-1.78(12H,m), 2.56-
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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).
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 of 4-(carboxymethyl)-2-ethoxybenzoic acid (Formula-ll)
A solution of sodium hydroxide (12 gm) in water (20 ml) was prepared. The 3-ethoxy-4-(ethoxy carbonyl)phenyl] acetic acid (25 gm) was added in portions at room temperature. The reaction mixture was stirred for 4 hours. After the completion of reaction, the reaction mixture was acidified (pH =1) and the solid separated was filtered and dried.
Yield: 20 gm
Example-2
Preparation of 4-(carboxymethyl)-2-ethoxybenzoic acid (Formula-ll)
The ethyl 4-[(ethoxy carbonyl) methyl] -2-ethoxybenzoate (3.1 gm) was dissolved in tetrahydrofuran (10 ml). To this solution of sodium hydroxide (2.3 gm) in water (20 ml) was added at 0°C - 5°C. The reaction mixture was stirred for 4 hours. After the completion of reaction, the reaction mixture was acidified (pH =1) and the solid separated was filtered and dried.
Yield: 1.9 gm
Example-3
Preparation of 4-{carboxymethyl)-2-ethoxybenzoic acid (Formula-ll)
The ethyl 4-[(methoxy carbonyl) methyl] -2-ethoxybenzoate (2.0 gm) was dissolved in tetrahydrofuran (10 ml). To this solution of sodium hydroxide (0.6 gm) in water (20 ml) was added at 0°C - 5°C. The reaction mixture was stirred for
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4 hours. After the completion of reaction, the reaction mixture was acidified (pH =1) and the solid separated was filtered and dried.
Yield: 1.3 gm
Example-4 Preparation of repaglinide
A mixture of 4-(carboxymethyl)-2-ethoxybenzoic acid (1.0 gm), (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (1 gm), triphenylphosphine (1.75 gm), triethyl amine( 1 gm) in a mixture of acetonitrile (20 ml) and carbon tetrachloride (10 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by column chromatography using silica gel. The repaglinide was obtained by eluting the column with 30% ethyl acetate in hexane.
HPLC purity: 97.7%
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WE CLAIM:
1. A process for preparation of 4-(carboxymethyl)-2-ethoxybenzoic acid of formula-ll, an intermediate useful in the preparation of repaglinide wherein the said process comprising,
a) reacting the compound of formula-Ill with base in solvent,
b) isolating 4-(carboxymethyl)-2-ethoxybenzoic acid from reaction mass thereof.

2. A process of claim 1 wherein the R1 and R2 is independently methyl, ethyl, propyl or butyl.
3. A process of claim 1, wherein the R1 and R2 are methyl, ethyl, propyl or butyl.
4. A process of claim 1, wherein the R1 is methyl, ethyl, propyl or butyl and R2 is hydrogen.
5. A process of claim 1 wherein the solvent is water, tetrahydrofuran, acetonitrile, diethyl ether and the like or mixture thereof.
6. A process of claim 1 wherein the base used is solution of base in water.
7. A process of claim 6, wherein the base used is sodium hydroxide, potassium hydroxide and the like.

Dated this 19TH day of Jan, 2007

For Wockhardt Limited


(Mandar Kodgule) Authorized Signatory

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