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:
AN IMPROVED PROCESS FOR THE PREPARATION OF IMINE
INTERMEDIATE USEFUL IN PREPARATION OF PIOGLITAZONE OR
SALT 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 DESCRIPTION
The present invention provides an improved process for the preparation of imine intermediate useful in preparation of pioglitazone or salt 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 an improved process for the preparation of imine intermediate useful in preparation of pioglitazone or salt thereof.
Pioglitazone hydrochloride of formula I is chemically known as [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride. It is an active antidiabetic agent.
US patent No. 4,687,777 describes the process of preparation of pioglitazone involving reaction of ethyl substituted pyridyl ethanol with 4-fluoronitrobenzene in presence of sodium hydride in dimethyl formamide and tetrahydrofuran to form 4-nitrophenol ether compound. This 4-nitrophenol ether compound was reduced to amino ether derivative by palladium on carbon with hydrogen gas at high pressure. The ether derivative in turn then converted to pioglitazone via a-Bromoester intermediate. The pioglitazone free base upon treatment with hydrochloric acid formed the pioglitazone hydrochloride of formula I.

Formula I
US patent 6,100,403 described the process of preparation of pioglitazone via condensing 4-[2-(5-ethyl-2-pyridyl) ethoxy] benzaldehyde with 2,4-thiazolidinone using piperidine acetate to get 5-[4-2(-ethyl-2-pyridyl) ethoxy] benzilidene-2, 4-thiazolidinone that after hydrogenation of double bond afforded Pioglitazone.
The processes of preparation of 2, 4 thiazolidinediones are also disclosed in US patents 4,812,570; US 4,895,947; US 5,554,758; US 5,952,509 and EP 0257781 patents. The polymorphism of Pioglitazone hydrochloride is discussed in PCT application WO 2003/026586.
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The present inventors have surprisingly found that using ketone solvent instead of alcoholic solvent, results in easy isolation of imine compound (Formula-Ill). Also use of ketone solvent results in high purity imine compound, which can be directly used for formation of pioglitazone or salt thereof.
In the aspect of present invention there is provided a process for the preparation of imine intermediate useful in preparation of pioglitazone or salt thereof, wherein the said process comprises of
a) reacting compound of Formula II (bromoester) with thiourea in presence of
ketone solvent and sodium acetate

Formula II
b) isolating the imine compound of formula III at pH 7-9 from reaction mass
and thereof

Formula III
c) converting compound of formula III to pioglitazone or salt thereof.
The process involves reacting bromoester compound, obtained by the method known in the prior art, with thiourea in presence of ketone solvent (such as acetone, butanone and the like) and sodium acetate. After completion of reaction, water was added and imine compound is isolated from the reaction mixture thereof by using base like sodium or potassium hydroxide, carbonates bicarbonates.
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The imine compound of formula III was then converted to pioglitazone hydrochloride by the method known in the prior art.
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 Preparation of the compound of Formula-Ill
A mixture of 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}propionate methyl ester (1700 g), thiourea (330 g), sodium acetate (356 g) and acetone (17 Litre) were refluxed on water bath for 4 to 6 hours. After completion of reaction, water (35 Litre) was added and pH of reaction mixture was adjusted to 8.0 using a saturated solution of sodium bicarbonate (6.0 Litre). Solid obtained was filtered washed with water and finally with acetone. Wet cake is dried in oven at 80°C for 2 hours to get off white titled compound. Yield = 691 g, Purity by HPLC = 96%.
Preparation of Pioglitazone Hydrochloride
A solution of 5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4-thiazolidinone (Formula III) (690 g) in 2 N hydrochloric acid (5.80 Litre) was refluxed for 6 hours. Charcoal (35 g) was added and refluxing was continued for half an hour. Reaction mixture was filtered and filtrate was cooled to 0 to 5°C, stirred for 2 hours. Crystallized solid was filtered and dried in oven to get Pioglitazone hydrochloride. Yield = 600 g.
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WE CLAIM
1. A process for the preparation of imine intermediate useful in preparation of pioglitazone or salt thereof, wherein the said process comprises of
a) reacting compound of Formula II (bromoester) with thiourea in presence of
ketone solvent and sodium acetate

Formula II
b) isolating the imine compound of formula III at pH 7-9 from reaction mass thereof.

Formula III
c) converting compound of formula III to pioglitazone or salt thereof.
2. A process of claim 1 wherein the ketone solvent is such as acetone, butanone and the like.
3. A process of claim 1 wherein the base is sodium or potassium hydroxide, carbonate or bicarbonate.
4. A process of claim 1 wherein the purity of imine compound is 96% and above.
Dated this 30th day of October, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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