FORM 2THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION(See section 10 and rule 13)
1. TITLE OF THE INVENTIONA DIAMIDE IMPURITY OF REPAGLINIDE AND PROCESS FOR THE PREPARATION THEREOF
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 diamide impurity of repaglinide and process for the preparation thereof
The following 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 diamide impurity of repaglinide and process for the preparation thereof.
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 is reacted with [3-ethoxy-4-(ethoxy carbonyl)phenyl] 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-methyl-(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-piperidino-phenyl)-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 provide different crystalline and amorphous forms of repaglinide and the processes for preparation thereof.
The present inventors while developing a process for the preparation of repaglinide have surprisingly found that 4-(((S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butylcarbamoyl)methyl)-2-ethoxy-N-((S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)benzamide (hereafter referred as diamide impurity of repaglinide) (formula-ll) is formed during the reaction. Further the present inventors developed a process for preparation of diamide impurity of repaglinide of formula-ll which involves the reaction of 4-(carboxymethyl)-2-alkoxy benzoic acid (Formula-Ill) with (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (Formula-IV).

In one of the aspect of the present invention there is provided a diamide impurity of repaglinide of formula -II.
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In second aspect of the present invention there is provided a process for the preparation of diamide impurity of repaglinide of formula-ll wherein the said process includes steps of,
a) reacting 4-(carboxymethyl)-2-ethoxybenzoic acid (Formula-Ill) with (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (Formula-IV) in organic solvent.
b) isolating diamide impurity of repaglinide of formula-ll from reaction mass thereof.

The process of present invention is related to preparation of diamide impurity of repaglinide of formula -II. The 4-(carboxymethyl)-2-ethoxybenzoic acid in organic solvent was reacted with (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine by stirring after addition of either triphenylphosphine or dicyclohexyl carbodiimide at room temperature. The reaction was carried out in presence or absence of base. The reaction mixture was then concentrated and diamide impurity of repaglinide of formula-ll was isolated from the reaction mass thereof and purified.
The organic solvent include aromatic hydrocarbons, halogenated solvents, nitrile solvent or the mixture thereof. The non-limiting examples of aromatic hydrocarbon include benzene, toluene, xylene and the like. The non-limiting examples of halogenated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like. The non-limiting examples of nitrile solvent include acetonitrile and the like.
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The non-limiting examples of bases includes N,N-dimethylaniline, 2,6-dimethyl pyridine, pyridine, 4-methylpyridine, 4-dimethylaminopyridine (DMAP), monoalkyl amine such as methyl amine, dialkyl amine such as dimethyl amine, trialkyl amines such as triethyl amine and the like.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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
Preparation and purification of 4-(((S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butylcarbamoyl)methyl)-2-ethoxy-N-((S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)benzamide of formula-ll
A mixture of 4-(carboxymethyl)-2-ethoxybenzoic acid (0.227 gm), (S)-3-methyl-1-
(2-piperidino-phenyl)-1-butylamine (0.5 gm), N,N'-dicyclohexyl carbodiimide
(0.412 gm), dimethylaminopyridine (0.012 gm) in a dichloromethane (10 ml) was
stirred at room temperature for 4 hours. The reaction mixture was concentrated
and the residue was purified by column chromatography using silica gel. The
diamide impurity of repaglinide of formula-ll was obtained by eluting the column
with 30% ethyl acetate in hexane.
Yield: 80 %
HPLC purity: 98.48%
Mass: 681 (M+1).
1H NMR : (400 MHz, CDCI3): δ 0.90 (6H,d), 0.98 (3H,d), 0.99 (3H,d), 1.15-1.78
(21H, m), 2.60-2.69 (4H,m), 2.92(2H, bs), 3.16(21-1, bs), 3.53 (2H, s), 4.04-4.11
(2H, m), 5.30(1 H, q), 5.66(1 H, q), 6.66-6.74 (1H, d), 6.86-7.27 (10H, m), 8.09
(1H,d),8.34(1H,d).
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WE CLAIM:
1. The 4-(((S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butylcarbamoyl)methyl)-2-ethoxy-N-((S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)benzamide of formula-ll

2. A process for preparation of diamide impurity of repaglinide of Formula-ll
wherein the said process comprises of,
a) reacting 4-(carboxymethyl)-2-ethoxybenzoic acid with (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine in organic solvent.
b) isolating diamide impurity of repaglinide of formula-ll from reaction mass thereof.
3. A process of claim 2 wherein the organic solvent is halogenated solvents such
as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like
or nitrile solvent such as acetonitrile and the like or the mixture thereof.
4. A process of claim 2 wherein the reaction is carried out in presence or absence of base.
5. A process of claim 2 wherein the reaction is carried out in presence of dicyclohexylcarbodiimide or triphenylphosphine.

Dated this 19TH day of JAN, 2007

For Wockhardt Limited

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