This application claims priority to Indian patent application 2387/CHE/2010 filed on Aug 19.

FIELD OF THE INVENTION:

The present invention relates an improved process for the preparation of intermediates of 2-arylthiazole derivatives and further conversion to 2-arylthiazole derivatives or their pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:

2-arylthiazole derivatives are used as xanthine oxidase inhibitors for use in the treatment of hyperuricemia and gout.

Febuxostat, 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I is an example of 2-arylthiazole derivatives used as xanthine oxidase inhibitors for use in the treatment of hyperuricemia and gout.

Formula-I

Febuxostat of Formula-I is approved by USFDA for the treatment of hyperuricemia in patients with gout under the brand name of ULORIC. ULORIC is recommended at 40 mg or 80 mg once daily.

Febuxostat and its pharmaceutically acceptable salts were first disclosed in United States patent publication US 5,614,520. This patent also discloses process for the preparation of Febuxostat through the intermediate of compound of Formula-II.

wherein Ri and R2, independently of each other, represent a hydrogen or halogen atom, or a nitro, cyano, formyl, Q.4 alkyl or C 1.4 halo alkyl group or a group of-OR (wherein R is a hydrogen atom, or an unsubstituted or substituted CMO alkyl, aryl, arylalkyl, alkylcarbonyl group); R3 represents a Ci-6 alkoxy group or aryloxy group or C1.6 alkylamino; R4 represents a hydrogen atom, or a CM alkyl, hydroxyl or CM alkoxy group.

Japan patent publication JP 2706037 also discloses process for the preparation of compound of Formula-II and further conversion to Febuxostat. JP 2706037 discloses process for the preparation of compound of Formula-II by the reaction of compound of Formula-Ill with compound of Formula-IV.

Formula-Ill

Formula-IV

wherein R1, R2, R3 and R4 are defined above in connection with the formula-II, Y represents a halogen atom or a leaving group.

Heterocycles; vol. 47 (2); 1998 also discloses similar process for the preparation of compound of Formula-II by the reaction of compound of Formula-Ill and compound of Formula-IV.

Yield obtained by the above mentioned processes in the preparation of compound of Formula-II is very less.

There is a continuing need in the art to provide a process for the preparation of compound of Formula-II in high yields.

Thus the present invention provides process for the preparation of compound of Formula-II with high yield and it is further converted into Febuxostat and its pharmaceutically acceptable salts.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide an improved process for the preparation of compound of Formula-II by the reaction of compound of Formula-Ill with compound of Formula-IV in a suitable solvent in presence of a base.

Another object of the present invention is to provide further conversion of compound of Formula-II into Febuxostat and its pharmaceutically acceptable salts by the conventional methods.

One aspect of the present invention provides process for the preparation of arylthiazole compound of Formula-II

Formula-II wherein R\ and R2, independently of each other, represent a hydrogen or halogen atom, or a nitro, cyano, formyl, CM alkyl or C1-4 halo alkyl group or a group of-OR (wherein R is a hydrogen atom, or an unsubstituted or substituted CMO alkyl, aryl, arylalkyl, alkylcarbonyl group); R3 represents a C1-6 alkoxy group or aryloxy group or C1.6 lino; R4 represents a hydrogen atom, or a CM alkyl, hydroxyl or CM alkoxy group, by reacting substituted thiobenzamide compound of Formula-Ill with P-ketoesters of compound of Formula-IV in a suitable solvent in presence of a base.

Formula-Ill Formula-IV

wherein R1, R2, R3 and R4 are defined above and Y is a halogen atom or a leaving group.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of arylthiazole compound of Formula-II by reacting substituted thiobenzamide compound of Formula-Ill with P-ketoesters of compound of Formula-IV in a suitable solvent in presence of a base. The present invention further relates to the conversion of compound of Formula-II to Febuxostat.

Accordingly the present invention provides a process for the preparation of compound of Formula-II as summarized in scheme-I

SCHEME-1

wherein R1 and R2, independently of each other, represent a hydrogen or halogen atom, or a nitro, cyano, formyl, CM alkyl or C 1.4 halo alkyl group or a group of-OR (wherein R is a hydrogen atom, or an unsubstituted or substituted CMo alkyl, aryl, arylalkyl, alkylcarbonyl group); R3 represents a Q.6 alkoxy group or aryloxy group; R4 represents a hydrogen atom, or a CM alkyl, hydroxyl or CM alkoxy group and Y represents a halogen atom or a leaving group.

In one embodiment of the present invention, base used for the preparation of compound of Formula-II is selected from an organic base like alkalimetal alkoxide. Alkalimetal alkoxide used in this reaction is selected from Sodium alkoxide, Potassium alkoxide, preferably Sodium methoxide.

In another embodiment of the present invention, the suitable solvent is selected from alcohols such as ethanol, methanol and isopropanol, preferably isopropanol.

In one more embodiment of the present invention, the compound of Formula-II is Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate.

In one more embodiment of the present invention, the compound of Formula-II is further hydrolyzed to get Febuxostat by the conventional methods described in US 5614520, JP 2706037 and JP 3202607.

As per the present invention, 3-cyano isobutoxy benzothioamide (Formula-Ill) and Ethyl-2-chloro-3-oxo butanoate (Formula-IV) are reacted in presence of base such as alkalimetal alkoxide preferably sodium methoxide at reflux temperature in an alcoholic solvent, preferably isopropanol for 3-5 hours to get arylthiazole compound Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxyltae (Formula-II).

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way

Experimental procedure:

Example - 1: Preparation of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate

A mixture of 10.0g of 3-cyano isobutoxy benzothioamide, 9.13g of Ethyl-2-chloro-3-oxo butanoate and 346 mg of sodium methoxide was heated under reflux in 70 ml of isopropanol for 5 hours. After the reaction mass was cooled to ambient temperature and precipitated crystal was collected by filtration to give 13.7g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate (yield 93.0%)

Example - 2: Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid

A mixture of l0.0g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate, 2.0g of sodium hydroxide was heated at 55-60°C in 75 ml of Aqueous methanol for 1 hour. After the reaction mass was cooled to ambient temperature and adjusted pH to 2.0 to 2.5 with dilute hydrochloric acid and precipitated crystal was collected by filtration to give 8.8g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 95.8%).

Example - 3: Preparation of pure 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid

10.0 g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid was dissolved in 100 ml of ethanol at reflux temperature. After dissolution reaction mass was cooled and precipitated crystal was collected by filtration to give 9.6 g of pure 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 96%).

We claim:

1. A process for preparing arylthiazole compound of Formula-II

Formula-II wherein R1 and R2, independently of each other, represent a hydrogen or halogen atom, or a nitro, cyano, formyl, CM alkyl or CM halo alkyl group or a group of-OR (wherein R is a hydrogen atom, or an unsubstituted or substituted C1-10 alkyl, aryl, arylalkyl, alkylcarbonyl group); R3 represents a C1-6 alkoxy group or aryloxy group or C1-6 alkylamino; R4 represents a hydrogen atom, or a CM alkyl, hydroxyl or CM alkoxy group, by reacting substituted thiobenzamide compound of Formula-Ill and P-ketoesters of compound of Formula-IV in a suitable solvent in presence of abase.

Formula-Ill Formula-IV

wherein R1, R2, R3 and R4 are defined above and Y is a halogen atom or a leaving group.

2. The process according to claim 1, wherein the base is alkalimetal alkoxide.

3. The process according to claim 2, wherein the alkalimetal alkoxide is selected from Sodium alkoxide, Potassium alkoxide.

4. The process according to claim 2, wherein the alkalimetal alkoxide is Sodium methoxide.

5. The process according to claim 1, wherein the solvent used in the reaction is an alcoholic solvent.

6. The process according to claim 5, wherein the solvent is selected from ethanol, methanol and isopropanol.

7. The process according to claim 1, wherein compound of formula II is Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylate.

8. The process according to claim 7, wherein compound of formula II is further converted to Febuxostat.