FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION (S)-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 DESCRIPTION
The present invention provides a process for the preparation of (S)-
repaglinide.
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 process for the preparation of (S)-repaglinide. Chemically, repaglinide is S (+)-2-ethoxy-4-[N-{1-(2-piperidinophenyl)-3-methyl-1-butyl} aminocarbonylmethyl] benzoic acid of Formula I.

Formula I
US Patent RE 37,035 and U.S. Pat. No. 5,312,924 described 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 in presence of triphenyl phosphine to give ethyl ester of (S)-repaglinide. The ethyl ester of (S)-repaglinide on saponification gave (S)-repaglinide.
The present inventors have found an industrially advantageous process for the preparation of (S)-repaglinide. 3-ethoxy-4-ethoxy carbonyl phenyl acetic acid of formula II via acid halide intermediate of formula III was reacted with (S)-3-methyl-1-[2-(1-piperidinyl)phenyl] butyl amine of formula IV to give ethyl ester of (S)-repaglinide of formula V which on saponification yielded (S)-repaglinide of formula I. The process of present invention is easily scalable at commercial scale.
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Scheme

HO

Formula II

^OC2H5
OC2H5

X= Halogen Formula III

OC2H5 "OC2H5

Formula IV

Formula V
In the aspect of the present invention there is provided a process for preparation of (S)-repaglinide wherein the said process comprises of,
a) reacting compound of formula II with halogenating agent in a solvent comprising of halogenated hydrocarbon to get corresponding acid halide of formula III,
b) reacting the compound of formula III with compound of formula IV in presence of base to give compound of formula V,
c) isolating (S)-repaglinide of formula I from reaction mass thereof after saponification.
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The process of present invention involves the acid halide conversion of compound of formula II with halogenating agent in halogenated organic solvents optionally in presence of dimethyl acetamide to get corresponding acid halide at temperature below 5°C. After completion of reaction the reaction mixture was washed with chilled water to remove excessive acidity. The organic layer containing acid halide was reacted with solution of compound of formula III in halogenated solvent in presence of alkylamine base. The reaction mixture was stirred at below 10°C till completion of reaction and concentrated under vacuum. The concentrated mass washed with aqueous alkali solution to get semisolid mass of formula IV. The compound of formula IV is then hydrolyzed in presence of base. After completion of reaction the pH of reaction mixture was adjusted to less than 5 and the (S)-repaglinide of formula I was isolated.
The non-limiting examples halogenated solvents such as dichloromethane, dichloroethane, chloroform, and the like. Alkyl amine base includes monoalkyl amine, dialkyl amine and trialkyl amines such as methylamine, dimethyl amine, triethyl amine and the like.
The non-limiting examples of halogenating agent includes from the group of thiophosphoryl chloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorous oxychloride and the like.
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
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Example Preparation of Compound of Formula V
The 3-ethoxy-4-ethoxycarbonylphenyl acetic acid (5 g) was added in solution of dichloromethane (75 ml), dimethyl acetamide (5ml) and phosphorous pentachloride (8.3 gm) at 0°C. The reaction mixture was further cooled to -5°C after completion of reaction; mixture was washed with chilled water (100 ml). The separated organic layer was added into a mixture (S)-3-methyl-1-[2-(1-piperidinyl) phenyl] butyl amine (4.9 g) and triethylamine (4 g) the reaction mixture was stirred at -10 °C for 2 hrs. It was then washed with saturated solution of sodium bicarbonate and evaporated under vacuum to get title compound as semi solid material.
Yield: 10.0 g.
Preparation of (S)-repaglinide
Compound of above example (10 g) was charged in mixture of sodium hydroxide (1N, 20 ml) and ethyl alcohol (100 ml) heat at 60°C for 3 hours. The pH of resultant mixture was adjusted 4.0 to 4.5 by using hydrochloric acid (1N) and ethyl alcohol was removed under reduced pressure. The concentrated mass was heated at 65°C to 70°C in mixture of ethyl alcohol and water (100 ml, 2:1) for 1.0 hour and cooled to 0 °C to 5 °C and stirred for 3 hours the titled compound was filtered and dried.
Yield: 4.0 g,
Purity: 99.9 % (by HPLC).
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WE CLAIM:
1. A process for preparation of (S)-repaglinide wherein the said process
comprises of,
a) reacting 3-ethoxy-4-ethoxy carbonyl phenyl acetic acid with halogenating agent in a solvent comprising of halogenated hydrocarbon to get corresponding acid halide of formula III,
b) reacting the compound of formula III with (S)-3-methyl-1-[2-(1-piperidinyl)phenyl] butyl amine in presence of base to give ethyl ester of (S)-repaglinide,
c) isolating (S)-repaglinide of formula I from reaction mass thereof after saponification.

2. A process of claim 1 wherein the halogenating agents are phosphorus trichloride, phosphorus pentachloride and phosphorous oxychloride.
3. A process of claim 1 wherein the base comprises of C1 to C4 monoalkyl, dialkyl or trialkyl amine.
4. A process of claim 1 wherein the saponification is carried out in presence of sodium hydroxide, potassium hydroxide etc.
5. A process of claim 1 wherein the (S)-repaglinide is having the purity of 99.9 %.
Dated this 23 th day of September, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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