FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTION:AN IMPROVED PROCESS FOR THE 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 DESCRIPTIONThe present invention provides an improved process for the preparation of pioglitazone or salt thereof
The following specification particularly describes the invention and the manner in which it is to be performed.
1

4. DESCRIPTION
The present invention provides an improved process for the preparation of pioglitazone or salt thereof.
Pioglitazone hydrochloride of formula I is chemically [(±)-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. The pioglitazone free base upon treatment with hydrochloric acid formed the pioglitazone hydrochloride of 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.
2

The processes of preparation of 2, 4 thiazolidinediones are also disclosed in US 4,812,570; US 4,895,947; US 5, 554,758; US 5,952,509 and EP 0257781 patents.
The inventors have found that coupling of 5-ethyl-2-pyridyl ethanol (HEEP) with 4-fluoronitrobenzene by using sodium hydroxide instead of sodium hydride affords safe and non-hazardous process. It was also noted that when reaction was carried out in dimethyl sulphoxide and toluene solvent mixture instead of dimethyl formamide and tetrahydrofuran mixture, then the formation of impurity was reduced which occurs due to side reaction of starting material with dimethyl formamide. The present process provides nitroether intermediate as a solid filterable material.
The present invention successfully replaces costly palladium on carbon by cheaper raney nickel catalyst.
The present inventors have also surprisingly found that by changing the mode of reactant addition i.e by adding reaction mixture to methyl acrylate exothermicity of the reaction can be controlled.
In one of the aspect of the present invention there is provided a process for the preparation of nitroether intermediate of formula II useful in preparation of pioglitazone or salt thereof, wherein the said process comprises of

b) isolating the nitroether compound of formula II from reaction mass thereof.
3
a) reacting 5-ethyl-2-pyridyl ethanol (HEEP) with 4-fluoronitrobenzene (4-FNB) using organic solvent mixture in presence of alkali metal hydroxide

In another aspect of the present invention there is provided a process for the preparation of aminoether intermediate of formula III useful in preparation of pioglitazone or salt thereof, wherein the said process comprises of
a) adding the nitro ether compound of formula II in alcohol solvent
b) exposing the resultant reaction mixture in presence of raney nickel catalyst to hydrogen gas.

c) isolating the aminoether compound of Formula III from reaction mass thereof.
In yet another aspect of present invention, there is provided a process for the preparation of pioglitazone hydrochloride, wherein the said process comprises of,
a) reacting compound of formula III in organic solvent with sodium nitrite and hydrobromic acid at low temperature
b) adding resultant mixture to solution of methyl acrylate and cuprous oxide in organic solvent to obtain bromoester compound of formula IV.

c) isolating the bromoester compound of formula IV from reaction mass thereof.
d) converting compound of formula IV to pioglitazone hydrochloride.
4

The process involves reacting 5-ethyl-2-pyridylethanol (HEEP) with 4-fluoronitrobenzene using organic solvent mixture such as dimethyl sulphoxide and toluene in presence of alkali metal hydroxide at temperature 10°C or less to obtain compound of formula II. The isolated compound of Formula II in alcohol solvent was treated with raney nickel catalyst and stirred in presence of hydrogen gas till completion of reaction. The catalyst was filtered and filtrate was concentrated under reduced pressure to get oily aminoether compound of formula III. The isolated compound of formula III was dissolved in a mixture of organic solvent such as acetone and alcohol. This reaction mixture was added hydrobromic acid solution followed by an addition of a solution of sodium nitrite in water at temperature 5°C or less. The resultant reaction mixture was then added to methyl acrylate and cuprous oxide solution at temperature 40°C or less. After completion of reaction, reaction mixture was distilled under reduced pressure. The pH of concentrated reaction mixture was adjusted to 7 to 9 with ammonia solution and extracted with ether repeatedly. The combined extract was concentrated under reduced pressure to get oily bromoester compound of formula IV.
A bromoester compound was then converted to pioglitazone hydrochloride by the method known in the prior art.
Alkali metal hydroxides include but not limited to lithium hydroxide, sodium hydroxide and potassium hydroxide.
The non-limiting examples of alcohol include straight chain and branched chain C1-C6 alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, n-pentanol 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
5

skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE I Stage-I: Preparation of compound of formula II
To the solution of HEEP (2-(5-Ethyl-2-pyridyl)-ethanol) (1.060 Kg) and 4-FNB (4-fluoronitrobenzene) (1.10 Kg) in a mixture of dimethylsulfoxide (1.0 Ltr) and toluene (5.0 Ltr) was added powdered sodium hydroxide (1.20 Kg) at -5 to -10°C. It was then stirred at 0 to 5°C for 2 hours and at 25 to 30°C for 1 hour. After aqueous work-up it was filtered on Buchner funnel under industrial vacuum to get yellowish off white titled compound. Yield = 1.40 Kg, Purity by HPLC = 99%.
EXAMPLE II
Stage-ll: Preparation of compound of formula III
To the solution of 4-[2-(5-ethyl-2-pyridyl) ethoxy] nitrobenzene (1.40 Kg) in methanol (14 Ltr) was added wet methanol washed raney nickel catalyst (0.14 Kg). It was then vigorously stirred and a slow stream of hydrogen gas was bubbled for 6 to 8 hours. After complete disappearance of starting nitro compound as monitored by TLC, filtered to recover Raney nickel, washed with fresh methanol (0.50 Ltr) and the combined methanolic solution was concentrated under reduced pressure to get a brownish thick oily titled compound. Yield = 1.20 Kg, Purity by HPLC = 99%.
6

EXAMPLE III
Stage-Ill: Preparation of compound of formula IV
4-[2-(5-Ethyl-2-pyridyl) ethoxy] aminobenzene (1.20 Kg) was dissolved in a mixture of acetone (2.70 Ltr) and methanol (1.10 Ltr) and was cooled to 0 to 2°c. To it was added 47% hydrobromic acid solution (3.40 Kg) at 0 to 2°C. This was followed by an addition of a solution of sodium nitrite (0.504 Kg) in water (1.0 Ltr) over a period of half an hour. This diazonium solution was then added to methyl acrylate (2.53 Kg) and warmed to 38 to 40°C. Cuprous oxide (0.045 Kg) was added in portions under vigorous stirring. This initiated evolution of nitrogen and reaction temperature increased to 50 to 55°C. After ceasing of nitrogen evolution, reaction mixture was distilled under vacuum below 40°C to recover excess methyl acrylate, acetone and methanol. The pH of concentrated reaction mixture was adjusted to 8.0 using ammonia solution (4.10 Ltr) and extracted three times with ether (4.0 Ltr for each extraction). Combined extract was washed with water (5.0 Ltr), dried over sodium sulfate and concentrated under reduced pressure to get brown coloured thick oily titled compound. Yield = 1.70 Kg, Purity by HPLC = 55%.
7

WE CLAIM:
1. A process for the preparation of nitroether intermediate of formula II useful in preparation of pioglitazone or salt thereof, wherein the said process comprises of a) reacting 5-ethyl-2-pyridyl ethanol (HEEP) with 4-fluoronitrobenzene (4-FNB) using organic solvent mixture in presence of alkali metal hydroxide

b) isolating the nitroether compound of formula II from reaction mass thereof.
2. A process of claim 1 wherein the alkali metal hydroxide is from the group of lithium hydroxide, sodium hydroxide, potassium hydroxide.
3. A process of claim 1 wherein the organic solvent mixture is dimethylsulphoxide and toluene.
4. A process for the preparation of aminoether intermediate of formula III useful in preparation of pioglitazone or salt thereof, wherein the said process comprises of
5. A process of claim 4 wherein the alcohol solvent is methanol
8
a) adding the nitro ether compound of formula II in alcohol solvent
b) exposing the resultant reaction mixture in presence of raney nickel catalyst to hydrogen gas.
c) isolating the aminoether compound of Formula III from reaction mass thereof.


6. A process for the preparation of pioglitazone hydrochloride, wherein the said process comprises of,
a) reacting compound of formula III in organic solvent with sodium nitrite and hydrobromic acid at low temperature
b) adding resultant mixture to solution of methyl acrylate and cuprous oxide in organic solvent to obtain bromoester compound of formula IV.

c) isolating the bromoester compound of formula IV from reaction mass thereof.
d) converting compound of formula IV to pioglitazone hydrochloride.
7. A process of claim 6 wherein the organic solvent is mixture of acetone and methanol

Dated this 29TH day of September, 2006

For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory

9