Field of the Invention:

The present invention provides an improved and novel processes for the preparation of anti-hyperuricemia drug 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1 and its pharmaceutically acceptable salts.

Formula-1

2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid is commonly known as Febuxostat. It is an inhibitor of xanthine oxidase that is indicated for use in the treatment of hyperuricemia and gout.

Febuxostat was approved by the European Medicines and the U.S. Food and Drug Administration. Febuxostat is marketed by Takeda Pharmaceuticals with the brand names Adenuric (EU) and Uloric (US).

Background of the Invention:

2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid was first disclosed in US 5614520 patent. The disclosed synthetic process comprises of reacting the ethyl 2-(4-hydroxy)-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate with l-bromo-2-methylpropane in presence of potassium carbonate in dimethyl formamide provides 2-(3-nitro-2-methylpropoxy)-4-methyl-5-thiazolecarboxylate which is reduced with Pd/C and the obtained compound is treated with sodium nitrite in water and followed by a mixture of cuprous cyanide and potassium cyanide provides ethyl 2-(2-methylpropoxy-3-cyanophenyl)-4-methyl-5-thiazolecarboxylate. The obtained ethyl 2-(2-methylpropoxy-3-cyanophenyl)-4-methyl-5-thiazolecarboxylate was hydrolyzed by treating with aqueous sodium hydroxide in a mixture of ethanol and tetrahydrofuran solvent provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid having melting range of 238 - 239°C.

Heterocycles, Vol. 47, No. 2, 1998 discloses a process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which comprises of reacting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile in presence of hydrochloric acid with thioacetamide in dimethyl formamide provides 4-(2-methylpropoxy)-3-cyanobenzthioamide. It was reacted with 2-chloroacetoacetate in ethanol provides ethyl 2-(2-methylpropoxy-3 -cyanophenyl)-4-methy 1-5 -thiazolecarboxylate, which on further hydrolysis with aqueous sodium hydroxide solution in a mixture of tetrahydrofuran and ethanol provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which on further recrystallization from acetone provides a colourless crystals having the melting range of 201 -202°C.

JP10-045733 discloses a process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid which comprises of reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with hydroxyl amine in presence of formic acid and sodium formate provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. The obtained compound was reacted with l-bromo-2-methylpropane in presence of potassium carbonate providing ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate, which on further hydrolysis with aq sodium hydroxide provides 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid.

2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid produced by above processes contains 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid as an impurity. So the purification is required to get the pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid.

Hence there is a necessity for the novel and improved processes which overcome the formation of above said impurity and to produce the pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid.

The present invention provides a novel and also improved processes for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid with high yield and purity.

Brief Description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) Hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate compound of formula-8 with a suitable base in a suitable solvent in anhydrous condition to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of novel 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl)-4-methylthiazole -5-carboxylic acid compound of formula-6, an intermediate used in the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1, which comprises the following steps

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-2 with l-bromo-2-methylpropane compound of formula-3, in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate compound of formula-4,

b) treating compound of formula-4 with hydroxylamine hydrochloride in a suitable solvent to provide ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylate, compound of formula-5,

c) hydrolyzing the compound of formula-5 with a suitable base in a suitable solvent to provide 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6.

The third aspect of the present invention is to provide a novel process for the
preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) Reacting the 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methyl
thiazole-5-carboxylic acid, compound of formula-6 with formic acid and sodium formate, to provide 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1, b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

The fourth aspect of the present invention is to provide a novel intermediate 2- [3 -formyl-4-(2-methylpropoxy)phenyl] -4-methylthiazole-5 -carboxylic acid, compound of formula-7, an intermediate useful in the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-2 with l-bromo-2-methylpropane compound of formula-3, in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-4,

b) hydrolyzing the compound of formula-4, with a suitable base in a suitable solvent to provide 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-7.

The fifth aspect of the present invention is to provide a novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) treating 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-7 with hydroxylamine hydrochloride in a suitable solvent, followed by reaction with formic acid and sodium formate to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

The sixth aspect of the present invention is to provide a novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-rnethylthiazole-5-carboxylic acid, compound of formula-1, which comprises of the following steps,

a) Reacting the ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-10 with a suitable halogenating agent to provide ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula-11,

b) reacting the ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula-11 with a suitable cyanide source in a suitable solvent to provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-12,

c) reacting the ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-12 with l-bromo-2-methylpropane compound of formula-3 in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate compound of formula-8,

d) hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate compound of formula-8 with a suitable base in a suitable solvent under anhydrous conditions to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-rnethylthiazole-5-carboxylic acid, compound of formula-1.

e) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

Detailed Description of the Invention:

The present invention provides an improved and novel processes for the preparation of anti-hyperuricemia drug 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1 and its pharmaceutically acceptable salts.

Formula-1

The suitable solvents, wherever necessary, used in the present invention are selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropnol, n-butanol and isobutanol; "chloro solvents" like dichloromethane, chloroform and ethylene dichloride; polar solvents like water; and also mixtures thereof.

The suitable bases wherever used in the present invention are selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine and pyridine.

The first aspect of the present invention is to provide an improved process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) Hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8,

Formula-8 with a suitable base in a suitable solvent under anhydrous conditions to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

In step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ether solvents, acetone solvents, chloro solvents, polar aprotic solvents; preferably tetrahydrofuran.

In step b) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents and alcoholic solvents, chloro solvents and their mixtures thereof.

The process for the preparation of febuxostat disclosed in US 5614520 and Heterocycles, Vol. 47, No. 2, 1998 involves the usage of aqueous sodium hydroxide for the hydrolysis of ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate in a mixture of ethanol and tetrahydrofuran to get febuxostat. When we carryout the experiment in our laboratory to prepare the febuxostat as per the said process we have observed the formation of 2-[3-carbamoyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid as an impurity at higher levels of from 1 to 4%. The said impurity herein designated as "amide impurity" which is represented by the following structure.

Formula-9

When we are trying to ruled out the formation of the said amide impurity by varying the process parameters in laboratory we surprisingly found that the hydrolysis of ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate with base under anhydrous conditions provides the desirable results i.e., reduces the formation of amide impurity to less than 0.1%. Carrying out hydrolysis at aqueous conditions as per the prior art leads to the formation of amide impurity and wherein the present invention the formation of said impurity reduced by the carrying hydrolysis under anhydrous conditions. Hence the process is advantages over the prior art process.

Wherein in present invention "anhydrous conditions" refers to that the reaction takes place under the absence of water.

Finally the compound was extracted with ethyl acetate, and isolated from acetone 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 obtained as a crystalline solid having melting range 201-202°C.

The second aspect of the present invention is to provide a process for the preparation of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5-carboxylic acid compound of formula-6, a novel intermediate useful in the preparation of febuxostat, which comprises of the following steps

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
compound of formula-2,

Formula-2 with l-bromo-2-methylpropane compound of formula-3,

Formula-3 in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-4,

Formula-4

b) treating compound of formula-4 with hydroxylamine hydrochloride in a suitable
solvent to provide ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-
methylthiazole-5-carboxylate, compound of formula-5,

Formula-5 c) hydrolyzing the compound of formula-5 with a suitable base in a suitable solvent to provide 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-6.

Formula-6

wherein, in step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step b) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step c) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

The third aspect of the present invention provides a novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) Reacting the 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-6,

Formula-6 with formic acid and sodium formate, in presence or absence of a suitable solvent to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

wherein, in step b) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

The fourth aspect of the present invention is to provide 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, compound of formula-7 a novel intermediate, useful in the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-2,

Formula-2

with l-bromo-2-methylpropane compound of formula-3,

Formula-3 in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-4,

Formula-4 b) hydrolyzing the compound of formula-4, with a suitable base in a suitable solvent to provide 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-7.

Formula-7

In step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

In step b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

The fifth aspect of aspect of the present invention is to provide a novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1. The process comprises of the following steps,

a) treating the 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-7,

Formula-7 with hydroxylamine hydrochloride in the presence or absence of a solvent, followed by formic acid and sodium formate to provide compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

In step b) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

The sixth aspect of the present invention is to provide a novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1, which comprises of the following steps, a) Reacting the ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-10,

Formula-10 with a suitable halogenating agent in a suitable solvent to provide ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula-11,

Formula-11

b) reacting the ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
compound of general formula-11 with a suitable cyanide source in a suitable solvent
to provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
compound of formula-12,

Formula-12

c) reacting the ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
compound of formula-12 with l-bromo-2-methylpropane compound of formula-3,

Formula-3 in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8,

Formula-8

d) hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8 with a suitable base in a suitable solvent in anhydrous condition to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1,

e) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

In step a) the halogenation reaction can be carried out in presence/absence of Lewis acid and the suitable halogenating agent is selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, n-chloro succinamide, Phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in presence or absence of triphenyl phosphene; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, polar aprotic solvents or mixtures thereof preferably Methylene chloride.
In step b) the suitable cyanide source is selected from sodium cyanide, potassium cyanide and cuprous cyanide etc, the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

In step c) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

In step d) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, chloro solvents and also mixtures thereof.

In step e) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

The process disclosed in Heterocycles, Vol. 47, No. 2, 1998 was repeated in the laboratory and subjected the obtained febuxostat for PXRD in two stages i.e., first is at the wet material obtained by the filtration after neutralization with aqueous hydrochloric acid (crude compound) and another one is after recerystallisation of the wet compound in acetone.

The wet material was dried under arial condition and analyzed by PXRD and found that its matches with the crystalline form-G and having the water content of 2.5-2.7%. The PXRD of febuxostat obtained after recrystallisation of wet material from acetone followed by drying under arial condition also having the similar to the crystalline form-G with the water content of 2.5%. When both the above were dried at higher temperature leads to the crystalline form-B which is has a water content upto 0.5% i.e, anhydrous form. One who skilled in the art known the drying techniques to reduce the water content and arial drying to remove water partially.

We have also analyzed the DSC of febuxostat at stages as mentioned above and found that crystalline febuxostat having melting point of 201-202°C, which is similar to the melting point disclosed in Heterocycles, Vol. 47, No. 2,1998.

Hence both the crystalline form G and B are prior art forms disclosed in Heterocycles, Vol. 47, No. 2, 1998.

The following are the potential impurities observed during the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

1) ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-
carboxylate(Ethyl ester impurity):

2) methyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazo!e-5-carboxylate
(Methyl ester impurity)

3) 2-[3-carboxy-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid (di acid impurity)

The present invention is schematically represented as follows.

Scheme-I:

Scheme-II:

Scheme-Ill:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:

Example 1: Preparation of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-4.

To a stirred solution of ethyl 2-[3-formyl-4-hydroxyphenyl]-4-methylthiazole-5-carboxylate (10 gms) in dimethylformamide (40 ml) added potassium carbonate (9.78 gms) and potassium iodide (2.35 gms). Heated the reaction mixture to 70 - 75°C and stirred for 30 minutes. To the above reaction added a solution of l-bromo-2-methylpropane (9.72 gms) in dimethyl formamide (10 ml) and stirred for 5 hours. Cooled the reaction mixture to 25°C, quenched with water and stirred for one hour. Filtered the precipitated solid and dried the material to get the title compound. Yield: 9 gms.

Example 2: Preparation of ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5 -carboxylate compound of formula-4 (10 gms) in formic acid (40 ml) added hydroxylamine hydrochloride (2.38 gms) and sodium formate (2.35 gms). Stirred the reaction mixture for 10 minutes. Heated the reaction mixture to 100°C and stirred for four hours at same temperature. Cooled the reaction mixture to 25°C and quenched with water. Stirred the reaction mixture for 10 hours, filtered the precipitated solid and washed with water. Dried the material to get the title compound. Yield: 10 gms

Take the dry material, added 30 ml of ethyl acetate and heated to reflux temperature. Stirred the reaction mixture for 30 minutes at reflux temperature. Cooled the reaction mixture to 25°C and filtered the precipitated solid. Dry the material to get the title compound as a pure material. Yield: 8.5 gms.

Example 3: Preparation of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formuIa-7.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate (100 gms) in methanol (500 ml) added pre cooled sodium hydroxide solution (23.25 gms in 500 ml of water). Heated the reaction mixture to 75°C and stirred for 30 minutes at same temperature. Added hydrose (5 gms) to the reaction mixture and cooled the reaction mixture to 25°C. Added methanol (100 ml) and water (100 ml) to the reaction mixture. Adjusted the PH to 2.0 - 3.0 using aqueous hydrochloric acid. Stirred the reaction mixture for 5 hours. Filtered the precipitated solid and washed with methanol and water. Dry the obtained material. To the obtained dry material added tetrahydrofuran (270 ml) and carbon (2.25 gms). Stirred the reaction mixture for 30 minutes and filtered through hyflow. Distilled off the solvent completely from filtrate. Added methanol (450 ml) to the obtained compound and stirred for 30 minutes at 60°C. Cooled the reaction mixture to 25°C and stirred for 2 hours. Filtered the precipitated solid and dried the material to get the pure title compound. Yield: 70 gms.

Example 4: Preparation of ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate, compound of formula-5.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate (10 gms) in methanol (50 ml) added hydroxylamine hydrochloride (2.38 gms) and stirred for 10 minutes. Heated the reaction mixture to 65°C and stirred for 7 hours at same temperature. Cooled the reaction mixture to 25°C and quenched with water. Stirred the reaction mixture for 1 hour and filtered the precipitated solid. Dried the obtained compound to get the title compound. Yield: 8.5 gms.

Example 5: Preparation of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxylie acid, compound of formula -6.

To the solution of ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate (100 gms) in methanol (500 ml) added pre cooled sodium hydroxide solution (22.10 gms in 500 ml of water). Heated the reaction mixture to 75°C and stirred for 30 minutes at same temperature. Added hydrose (5 gms) to the reaction
mixture and cooled the reaction mixture to 25°C. Added methanol (100 ml) and water
(100 ml) to the reaction mixture. Adjusted the PHto 2.0 - 3.0 using aqueous hydrochloric
acid. Stirred the reaction mixture for 5 hours. Filtered the precipitated solid and washed
with methanol and water. Dried the obtained material. To the obtained material added
tetrahydrofuran (270 ml) and carbon (2.25 gms). Stirred the reaction mixture for 30
minutes and filtered through hyflow. Distilled off the solvent completely from filtrate.
Added methanol (450 ml) to the obtained compound and stirred for 30 minutes at 60°C.
Cooled the reaction mixture to 25°C and stirred for 2 hours. Filtered the precipitated solid
and dried the material to get the pure title compound.

Yield: 70 gms.

Example 6: Preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-
methylthiazole-5-carboxylic acid, compound of formula-1.

To the solution of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-
methylthiazole-5-carboxylic acid, compound of formula -6 (10 gms) in formic acid (40
ml) added sodium formate (2.36 gms). Stirred the reaction mixture for 10 minutes.

Heated the reaction mixture to 100°C and stirred for 4 hours at same temperature. Cooled
the reaction mixture to 25 °C and quenched with water. Stirred the reaction mixture for
hours, filtered the precipitated solid and washed with water. Dried the material to get the
title compound. Yield: 10 gms

Take the dry material, added 30 ml of ethyl acetate and heated to reflux temperature.
Stirred the reaction mixture for 30 minutes at reflux temperature. Cooled the reaction
mixture to 25 °C and filtered the precipitated solid. Dry the material to get the pure title
compound. Yield: 8.5 gms.

Example 7: Preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-
methylthiazole-5-carboxylic acid, compound of formula-1.

To the solution of ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-
carboxylate compound of formula-8 (100 gms) in tetrahydrofuran (500 ml) added sodium
hydroxide (25.25 gms) and heated the reaction mixture to 60 - 65°C. Stirred the reaction
mixture for 10 hours at same temperature. Cooled the reaction mixture to 0-5 °C and
added water(500 ml). Acidifying the reaction mixture using aqueous hydrochloric acid.

Raised the temperature to 25-30°C. Extracted the reaction mixture with ethyl acetate and
washed with water. Distilled off the solvent completely under reduced pressure. Added
acetone (100 ml) to the obtained compound and distilled off completely under reduced
pressure. To the obtained compound added acetone (500 ml) and water (500 ml). Heated
the reaction mixture to 50-60°C and stirred for one hour at same temperature. Cooled the
reaction mixture to 0-5 °C and stirred for one hour. Filtered the precipitated solid and
washed with 1: 1 water, acetone mixture. Dried the material to get the title compound.
Yield: 88 gms. MR: 201 - 202°C.

Example 8: Preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-
methylthiazole-5-carboxylic acid, compound of formula-1.

A solution of 4-(2-methylpropoxy)-3-cyanobenzthioamide (400 mg, 1.65 mmol)and ethyl
2-chloroacetoacetate(340 mg, 1.65 mmol)in ethanol(4 ml) was heated at 100°C with
stirring for 2 h. After cooling, the mixture was washed with brine, and the products were
extracted with two portions of AcOEt. The combined organic layers was dried over
Na2S04, and evaporated. Purification by column chromatography (hexane/AcOEt; 3:1) on silica gel afforded ethyl 4-methyl-2-(4-(2-methylpropyloxy)-3-cyanophenyl)-5-thiazolecarboxylate (306 mg). It was hydrolyzed with lN-NaOH solution (1.2 ml) in the
mixture of THF(3 ml) and EtOH (3 ml)for 1 h. at 60°C. The mixture was neutralized with
1N-HC1 solution, and the formed crystal was collected by filtration.

The PXRD of the obtained material similar to the crystalline form-G of febuxostat.
The wet material was further recrystallized from acetone to give 2-[3-cyano-4-(2-
methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid. The PXRD of the obtained
compound was similar to the crystalline form-G of febuxostat.
Yield: 183 mg, MR: 201-202°C.

We Claim:

1. An improved process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1, comprises of:

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-2, with l-bromo-2-methylpropane compound of formula-3, in presence of a suitable base in a suitable solvent to provide ethyl 2- [3 -formyl-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5 -carboxylate compound of formula-4,

b) treating compound of formula-4 with hydroxylamine hydrochloride in a suitable solvent to provide ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5-carboxylate, compound of formula-5,

c) hydrolyzing the compound of formula-5 with a suitable base in a suitable solvent to provide 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methyl thiazole-5-carboxylic acid compound of formula-6,

d) reacting the obtained compound of formula-6, with formic acid and sodium formate, in presence or absence of a suitable solvent to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1,

e) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

2. A process according to claim 1, wherein,

in step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step b) & e) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step c) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

3. The compound according to the process of claim 1, contains less than 0.2 %, preferably 0.15 %, more preferably 0.1 % of amide impurity.

4. A process for the preparation of 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, comprises of,

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate
compound of formula-2, with l-bromo-2-methylpropane compound of formula-3,
in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-4,

b) hydrolyzing the compound of formula-4, with a suitable base in a suitable solvent
to provide 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-
carboxylic acid, compound of formula-7.

5. A process according to claim 4, wherein,

in step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step b) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

6. A novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1, comprises of,

a) Reacting the 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-7, with hydroxylamine hydrochloride in the presence or absence of a solvent, followed by treating with formic acid and sodium formate to provide compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof to provide pure compound of formula-1.

7. An improved process for the preparation of 2-[3-cyano-4-(2-methylpropoxy)
phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1, comprises of

a) Hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8,

Formula-8

with a suitable base in a suitable solvent under anhydrous conditions to provide 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid, compound of formula-1,

b) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

8. A process according to claim 7, wherein,

in step a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases, preferably alkali metal hydroxides such as sodium hydroxide; and the suitable solvent is selected from ether solvents, acetone solvents, chloro solvents, polar aprotic solvents; preferably ether solvents such as tetrahydrofuran, in step b) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents and alcoholic solvents, chloro solvents and their mixtures thereof.

9. A novel process for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1, comprises of

a) Reacting the ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-10, with a suitable halogenating agent in a suitable solvent to provide ethyl 2-(3- halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula-11,

b) reacting the ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula-11 with a suitable cyanide source in a suitable solvent to provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-12,

c) reacting the ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-12 with l-bromo-2-methylpropane compound of formula-3, in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8,

d) hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-8 with a suitable base in a suitable solvent in anhydrous condition to provide 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, compound of formula-1,

e) optionally purifying the compound of formula-1 in a suitable solvent to provide pure compound of formula-1.

10. A process according to claim 9, wherein,

in step a) the halogenation reaction can be carried out in presence/absence of Lewis acid and the suitable halogenating agent is selected from carbon terra chloride, oxalyl chloride, thionyl chloride, phosphorous pentachloride, n-chloro succinamide, phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in presence or absence of triphenyl phosphene; the suitable solvent is selected from hydrocarbon solvents, chloro solvents, polar aprotic solvents or mixtures thereof; preferably chloro solvents such as methylene chloride.

in step b) the suitable cyanide source is selected from sodium cyanide, potassium cyanide and cuprous cyanide; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step c) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably potassium carbonate and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.

in step d) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; preferably sodium hydroxide and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, chloro solvents and also mixtures thereof.

in step e) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents like water and also mixtures thereof.