FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF FEBUXOSTAT"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17lhFloor, Kesar Solitaire, PlotNo.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF FEBUXOSTAT
FIELD OF THE INVENTION:
The present invention relates to a process for preparing Febuxostat comprising reacting an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid with lithium hydroxide in an organic solvent.
BACKGROUND OF THE INVENTION:
Chemically Febuxostat is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-l, 3-thiazole-5-carboxylic acid. Febuxostat is known from U.S. Patent No. 5,614,520 and is represented by compound of general formula I.

Formula I
Febuxostat is marketed in USA under proprietary name "ULORIC" and is indicated for the chronic management of hyperuricemia in patients with gout.
U.S. Patent No. 5,614,520 does not describe specific process for the preparation of febuxostat. Instead analog compounds are being prepared by the hydrolysis of their corresponding ester compounds with IN sodium hydroxide in the mixture of ethanol and tetrahydrofuran at 60°C for 1 hour. When the process described for analog compounds is being repeated on ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate for preparing febuxostat, then "Febuxostat Diacid" impurity, which is represented by a compound of formula II, is being produced due to the hydrolysis of cyano group of Febuxostat by sodium hydroxide.


Accordingly there is a need in the art to develop an improved process for the preparation of Febuxostat, which obviates the prior-art problems.
SUMMARY OF THE INVENTION:
The first aspect of the present invention is to provide an improved process for preparing substantially pure febuxostat compound of structural formula I comprising reacting an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III with lithium hydroxide in an organic solvent.

Wherein R represents a CrC8 substituted and unsubstitued alkyl group
The another aspect of the present invention is to provide a compound of structural formula IV, which is being used for the preparation of febuxostat compound of structural formula I.


The another aspect of the present invention is to provide substantially pure febuxostat compound of structural formula I, which is substantially free from "Febuxostat Diacid" compound of structural formula II.

The another aspect of the present invention is to provide a pharmaceutical composition comprising substantially pure febuxostat compound of structural formula I substantially free from "Febuxostat Diacid" compound of structural formula II.


DETAIL DESCRIPTION OF THE INVENTION:
The alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III may be prepared by methods described in US Patent No.5,614,520; Chinese Patent Application No.101497589 and Japanese Patent Application No. JP06293746, which are incorporated herein by reference only.
The alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III may be ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate or methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazote-5-carboxylate.
The reaction of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III with lithium hydroxide may be carried out in an organic solvent.
Examples of organic solvent may include alcoholic and ether solvents.
The alcoholic solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof.
The ether solvents may be selected from the group comprising of tetrahydrofuran, dioxane, diethyl ether, methyl tertiary butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl ethyl ether, methyl isopropyl ether, methyl propyl ether or mixture(s) thereof.
The alcoholic solvents may be used in the range of a 4 volumes/weight to 12 volumes/weight of alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.
The ether solvents may be used in the range of a 2 volumes/weight to 8 volumes/weight of alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.

The lithium hydroxide as such or the solution of Lithium hydroxide in water may be used for the hydrolysis of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.
The lithium hydroxide used for the reaction may be in the form of hydrates.
The lithium hydroxide may be used in the molar ratio of 0.75 moles to 5 moles per mole of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.
The reaction of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III with lithium hydroxide may be carried out at a temperature in the range of 20°C to 35°C for 4 hours to 14 hours.
The substantially pure febuxostat compound of structural formula I may be isolated from the reaction mixture by filtering reaction mixture on hyflow bed and then adjusting pH up to 1.5 by aqueous solution of hydrochloric acid followed by the agitation of resulting solution at a temperature in the range of 0°C to 5°C for 2 hours to 5 hours; filtration and drying.
The substantially pure febuxostat compound of structural formula I obtained by following the present invention may be dried at a temperature in the range of 45-70°C for 5 hours to 24 hours.
The substantially pure febuxostat compound of structural formula I obtained by following the present invention may be further dried by slurring in alcoholic solvents at a temperature in the range of 25°C to 30°C.
The substantially pure febuxostat compound of structural formula I obtained by following the present invention may contain less than 0.1% weight/weight of "Febuxostat Diacid" compound of structural formula II.

The present inventions are further illustrated by the following examples which are provided merely to be exemplary of the inventions and are not intended to limit the scope of the invention.
Example 1. Preparation of substantially pure febuxostat
The solution of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (25 gm) in
tetrahydrofuran (125 ml) and methanol (207 ml) was added lithium hydroxide (5.23 gm) and
resulting reaction mixture was agitated for 8 hours at 25°C.The reaction mixture was filtered on
hyflow bed and the pH up to 1.5 of reaction mixture was adjusted by aqueous solution of
hydrochloric acid and resulting solution was agitated for 2 hours at 0°C to 5°C. The resulting
solids were filtered, washed with water (2x50 ml) and dried at 55-65°C under reduced pressure
for 6 hours.
Yield: 21.4 gm
Purity: 99.91% (By HPLC)
Febuxostat Diacid: 0.04% wt/wt
Example 2. Preparation of substantially pure febuxostat
The solution of methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (25 gm)
in tetrahydrofuran (100 ml) and ethanol (200 ml) was added lithium hydroxide (5.0 gm) and
resulting reaction mixture was agitated for 4 hours at 25°C.The reaction mixture was filtered on
hyflow bed and the pH up to 1.5 of reaction mixture was adjusted by aqueous solution of
hydrochloric acid and resulting solution was agitated for 3 hours at 0°C to 5°C. The resulting
solids were filtered, washed with water (2x50 ml) and dried at 55-65°C under reduced pressure
for 8 hours.
Yield: 22 gm
Purity: 99.96 % (By HPLC)
Febuxostat Diacid: 0.01% wt/wt
Water Content: 1% wt/wt (By KF method)
Example 3. Preparation of substantially pure febuxostat
The solution of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (25 gm) in
tetrahydrofuran (125 ml) and methanol (207 ml) was added lithium hydroxide (5.23 gm) and

resulting reaction mixture was agitated for 7 hours at 25°C.The reaction mixture was filtered on
hyflow bed and the pH up to 1.5 of reaction mixture was adjusted by aqueous solution of
hydrochloric acid and resulting solution was agitated for 2 hours at 0°C to 5°C. The resulting
solids were filtered and dried at 55-65°C under reduced pressure for 9 hours
Yield: 19gm
Purity: 99.94 % (By HPLC)
Febuxostat Diacid: 0.02% wt/wt
Example 4. Preparation of substantially pure febuxostat
The solution of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (25 gm) in
tetrahydrofuran (125 ml) and methanol (207 ml) was added lithium hydroxide (5.23 gm) and
resulting reaction mixture was agitated for 8 hours at 25°C.The reaction mixture was filtered on
hyflow bed and the pH up to 1.5 of reaction mixture was adjusted by aqueous solution of
hydrochloric acid and resulting solution was agitated for 2 hours at 0°C to 5°C. The resulting
solids were filtered, washed with water (2x50 ml) and then dried at 55-65°C under reduced
pressure for 6 hours.
Yield: 21.4 gm
Purity: 99.98 % (By HPLC)
Febuxostat Diacid: 0.01% wt/wt
Water Content: 1% wt/wt (By KF method)

WE CLAIM:
1. An improved process for preparing substantially pure febuxostat compound of structural formula I comprising reacting an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III with lithium hydroxide in an organic solvent.

Wherein R represents a C1C8 substituted and unsubstitued alkyl group
2. A compound of structural formula IV, which is being used for the preparation of febuxostat compound of structural formula I.

3. Substantially pure febuxostat compound of structural formula I, which is substantially free from "Febuxostat Diacid" compound of structural formula II.


4. The process according to claim no. 1 wherein reaction of aikyi ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III with lithium hydroxide is carried out at a temperature in the range of 20°C to 35°C for 4 hours to 14 hours.
5. The process according to claim no. 1 wherein organic solvent is selected from the group comprising of an alcoholic solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof and an ether solvents such as tetrahydrofuran, dioxane, diethyl ether, methyl tertiary butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl ethyl ether, methyl isopropyl ether, methyl propyl ether or mixture(s) thereof.
6. The process according to claim 5, wherein an alcoholic solvents is used in the range of a 4 volumes/weight to 12 volumes/weight of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III and an ether solvents is used in the range of a 2 volumes/weight to 8 volumes/weight of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.
7. The process according to claim no. 1 or 4, wherein lithium hydroxide is being used as such or the solution of lithium hydroxide in water is being used for the hydrolysis of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.

8. The process according to claim nos. 1, 4 or 7, wherein lithium hydroxide is used in the molar ratio of 0.75 moles to 5 moles per mole of an alkyl ester of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid compound of structural formula III.
9. The process according to claim 1, wherein substantially pure febuxostat compound of structural formula I is isolated from the reaction mixture by filtering reaction mixture on hyflow bed and then adjusting pH up to 1.5 by aqueous solution of hydrochloric acid followed by the agitation of resulting solution at a temperature in the range of 0°C to 5°C for 2 hours to 5 hours; filtration and drying at a temperature in the range of 45-70°C for 5 hours to 24 hours.
10. The process according to claim no. 1 wherein substantially pure febuxostat compound of
structural formula I contain less than 0.1% weight/weight of "Febuxostat Diacid" compound of
structural formula II.