FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
PROVISIONAL TO COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - A novel process for preparation of Febuxostat crystal G
2. Applicant(s)
(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention :


Field of the Invention
The present invention relates to a novel process for preparation of crystal G of Febuxostat.
Background of the Invention
Febuxostat, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-l, 3-thiazole-5-carboxylic acid, has the following structure, Formula (I)

As described in international publication WO92/09279, it is known that Febuxostat has an activity for inhibiting xanthine oxidase inhibitor indicated for the chronic management of hyperuricemia in patients with gout. Febuxostat is not recommended for the treatment of asymptomatic hyperuricemia. Febuxostat is administrated in the form of tablets that are marketed in the USA and the EU under the name ULORIC(R).
However, the above mentioned publication does not describe polymorphism. US patent no. US6225474B1 discloses crystalline form of Febuxostat and process for preparation thereof.
US patent no. US6225474B1 discloses the presence of five crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, crystals A, B, C, D, and G and an amorphous form and a method for producing them. The method for producing crystal polymorphs described here involves the production of each crystal polymorph by adding a predetermined mixed solvent of methanol and water to 2-(3-cyano-4-isobutyl oxyphenyl)-4-methyl-5-thiazolecarboxylic acid, dissolving the resultant mixture by heating with stirring,

cooling the mixture by the addition of water to obtain the predetermined methanol and water composition and temperature, then collecting crystals by filtration, and drying the crystals.
Accordingly in case where a plurality of polymorphs is present it is important to develop a technique of preferentially producing each polymorph. Particularly in case where a pharmaceutical composition comprising a useful compound as a drug is produced, it is suitable to control polymorphism so as to formulate a pharmaceutical composition containing only a superior specific polymorph.
Summary of the invention:
It is a general aspect of the present invention to provide a novel process for the preparation of crystal G of Febuxostat.
Accordingly it is an aspect of the invention is to provide a process for the preparation of crystal G of Febuxostat, comprising:
a. dissolving crude Febuxostat in the ketone at reflux temperature;
b. Optionally, subjecting the solution to carbon treatment;
c. filtering hot through hyflo bed;
d. adding this solution in to the water;
e. stirring the reaction mixture;
f. filtering the precipitated solid;
g. Drying at 30-35°C without vacuum.
Accordingly it is another aspect of the invention is to provide a process for the preparation of crystal G of Febuxostat, comprising:
a. Providing a solution of crude Febuxostat in a mixture of ketone and water;
b. Heating it till get clear solution;
c. Optionally, subjecting the solution to carbon treatment;
d. Precipitating Febuxostat crystal G from the solution on cooling.
e. filtering the precipitated solid;
f. Drying at 30-35°C without vacuum.

In one aspect the ketone used in step (a) is acetone, methyl ethyl ketone or methyl isobutyl ketone, more preferably, acetone.
Accordingly it is an aspect of the invention is to provide a process for preparation of Febuxostat comprising, conversion of ethyl 2-[3-formyl-4-hydroxyphenyl]-4-methylthiazole-5-carboxylate to ethyl 2-[3-formyl-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylate using tetra butyl ammonium bromide.
Accordingly it is another aspect of the invention is to provide a process for preparation of Febuxostat comprising, a process for preparation of Febuxostat comprising, recrystallising ethyl 2-[3-formyI-4-isobutoxyphenyI]-4-methyIthiazoIe-5-carboxyIate in isopropyl alcohol.
Brief Description of the Drawing
Figure 1 shows an X-ray diffraction pattern of the crystal G of Febuxostat prepared by inventors.
Detailed Description of the Invention:
The present invention provides a novel process to prepare crystal G of Febuxostat.
The crystal G is a hydrate and is obtained by crystallizing a sodium salt of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid from an acid, or drying a wet product, which has been obtained by recrystallisation from a mixed solvent of ketone and water, at low temperature under a reduced pressure or air-drying the wet product under a normal pressure.
Present invention gives a novel process for the preparation of crystal G of Febuxostat, comprising:
a. dissolving crude Febuxostat in the ketone at reflux temperature;
b. Optionally, subjecting the solution to carbon treatment;
c. filtering hot through hyflo bed;
d. adding this solution in to the water;

e. stirring the reaction mixture;
f. filtering the precipitated solid;
g. Drying at 30-35°C without vacuum.
Present invention gives a novel process for the preparation of crystal G of Febuxostat, comprising,
g. Providing a solution of crude Febuxostat in a mixture of ketone and water;
h. Heating it till get clear solution;
i. Optionally, subjecting the solution to carbon treatment;
j. Precipitating Febuxostat crystal G from the solution on cooling.
k. filtering the precipitated solid;
1. Drying at 30-35°C without vacuum.
Where, the ketone used in step (a) is selected from acetone, methyl ethyl ketone or methyl isobutyl ketone. More preferably acetone is used.
The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention.
Examplel: Preparation of ethyl 2-[4-hydroxyphenyl]-4-methyIthiazole-5-carboxyIate
4-hydroxy benzonitrile (lOO.Og), thioacetamide (75.7g) and ethyl acetate.HCl (800ml) were charged in the reactor and heated at 42-47°C. The reaction mixture was maintained at this temperature till completion of the reaction. The ethyl acetate was removed and water (1000ml) was charged. Stirred it for 3 hrs and then filtered the solid. The wet cake was stirred with IPA (360ml) and ethyl 2-chloroacetoacetate (141.8g). The reaction mixture was stirred at 60-65 °C for 3 hrs. After completion of the reaction charged water (700ml) and stirred at ambient temperature for 2-3 hrs. Filtered the solid and washed with water. Dried it.

Example 2: Preparation of ethyl 2-[3-formyI-4-hydroxyphenyl]-4-methylrhiazole-5-carboxylate
Charged ethyl 2-[4-hydroxyphenyl]-4-methylthiazole-5-carboxylate (200.0gm), PPA (250gm) and methyl sulphonic acid (200gm) in a reactor and stirred for 10 minutes. Slowly HMTA (53.2gm) was charged in the reaction mixture at room temperature. The reaction mixture was stirred at 90°C for 14 hrs or till completion of the reaction. Slowly charged water (2000ml) in the reaction mixture and stirred at room temperature for 2 hrs. Filtered the solid and washed with water. The wet solid was stirred with water and adjusted pH 8.0 using ammonia solution. Stirred it for 3 hrs and then filtered and dried it.
Example 3: Preparation of ethyl 2-[3-formyl-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylate
Charged DMF (300ml), K2C03 powder (118.5g), TBAB (5.0g), ethyl 2-[3-formyI-4-hydroxyphenyl]-4-methylthiazole-5-carboxylate (100gm) and isobutyl bromide (75.2gm) in the reactor and heated at 100°C for 8 hrs. After completion of the reaction added water (1000ml) and stirred for 1 hour. Filtered the solid and washed with water and then dried it. Finally it was recrystallized in IPA.
Example 4; Preparation of ethyl 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylate
Formic acid (350ml) was charged in the reactor and then portion wisely charged sodium carbonate (21.4g) in to it under nitrogen atmosphere. Ethyl 2-[3-formyl-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylate and hydroxyl amine hydrochloride (22.0gm) was charged under nitrogen. The reaction mixture was heated at 100°C for 5 hrs. After completion of the reaction IPA-water (300-200ml) was charged and stirred at 80°C for 15 minutes. Stirred the reaction mixture at room temperature for 2 hrs and then filtered and dried it.
Example 5: Preparation of Febuxostat
Ethanol (750ml), sodium hydroxide (15.1gm) and ethyl 2-[3-cyano~4-isobutoxyphenyl]-4-methylthiazole-5-carboxylate (lOO.Ogm) were Charged in the reactor and then heated at 50°C for 8 hrs. After completion of the reaction water (400ml) was charged and the pH was

adjusted at 1.0-2.0 using Conc. HC1 (~40.0ml). Stirred for 4 hrs and then filtered it. The solid was washed with ethanol-water (1:1) (100*3ml) and then dried the solid at 30-35°C for 8 hrs without vacuum.
Example 6: Purification of Febuxostat
Crude Febuxostat (100gms) was charged in a mixture of acetone (1330ml) and water (570ml) at 25-30°C. Heat the reaction mixture to 55-60°C and stir till get clear solution. Charge activated carbon and stir at 55-60°C for half an hour. Filtered the solution through hyflo and wash the bed with mixture of acetone and water (100ml, 2:1). Cool the reaction mixture at 0-5°C and maintain for two hours. Filtered the solid and washed with mixture of acetone and water (50ml*2, 2:l).Dry the material at 25-30°C under vaccum. (Yield 75-90%)
Example 7: Purification of Febuxostat
Charged crude Febuxostat (1 OO.Ogm) and acetone (1090ml) in the reactor and heated it at 55-60°C to get clear solution. Charged activated carbon (2.0g) and refluxed it for 30 minutes. Filtered the solution hot and then washed the bed with hot acetone (100ml). The filtrate was charged in the reactor containing water (510ml). The reaction mixture was stirred at room temperature for two hours followed by 0°C for two hrs. Filtered the solid and washed with acetone -water (2:1) mixture.

Claims
1. A process for preparation of crystal form G of Febuxostat comprising:
a. dissolving crude Febuxostat in the ketone at reflux temperature;
b. Optionally, subjecting the solution to carbon treatment;
c. filtering hot through hyflo bed;
d. adding this solution in to the water;
e. stirring the reaction mixture;
f. filtering the precipitated solid;
g. Drying at 30-35°C without vacuum.
2. A process for the preparation of crystal G of Febuxostat, comprising,
a. Providing a solution of crude Febuxostat in a mixture of ketone and water;
b. Heating it till get clear solution;
c. Optionally, subjecting the solution to carbon treatment;
d. Precipitating Febuxostat crystal G from the solution on cooling;
e. filtering the precipitated solid;
f. Drying at 30-35°C without vacuum.
3. A process claimed in claim 1 and 2, wherein ketone is selected from the group of acetone, 2-butanone and methyl isobutyl ketone more preferably, acetone.
4. A process fro preparation of Febuxostat comprising, conversion of ethyl 2-[3-formyl-4-hydroxyphenyl]-4-methylthiazole-5-carboxylate to ethyl 2-[3-formyl-4-isobutoxyphenyl]-4-methylthiazoIe-5-carboxylate using tetra butyl ammonium bromide.
5. A process fro preparation of Febuxostat comprising, recrystallising ethyl 2-[3-formyl-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylate in isopropyl alcohol.