Field of Invention:

The present invention relates to an improved process for the preparation of anti- hyperuricemia drug 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylic acid (commonly known as Febuxostat), represented by following structural formula-1.

Formula I

The present invention also provides a novel process for the preparation of crystalline forms A, B and G of Febuxostat. Febuxostat 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).

Back Ground of Invention:

2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid was first disclosed in US 5614520. The disclosed process comprises of reacting the ethyl 2-[4- hydroxy-3-nitrophenyl]-4-methyl-5-thiazolecarboxylate with 1 -bromo-2-methylpropane in the presence of potassium carbonate in dimethyl formamide provides ethyl 2-[4-(2- methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazole carboxylate which is reduced with Pd/C and the obtained compound treated with sodium nitrite in water and followed by a mixture of cuprous cyanide and potassium cyanide provides ethyl 2-[4-(2- methylpropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylate. The obtained ethyl 2- [3-cyano-4-(2-methylpropoxy)phenyl)-4-methyl-5-thiazolecarboxylate was hydrolyzed by treating with aqueous sodium hydroxide in a mixture of ethanol and tetrahydrofliran provides 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid having melting range of 238 - 239°C with the yield of 33%. The above process utilizes Pd/C, which is difficult to handle in the laboratory, hence it is not recommended on large scale. However, the yield and purity were also not satisfactory. The said process involves more number of steps, hence there is a need to produce the process for the preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid with less number of steps.

Heterocycles, 1998, Vol. 47, No. 2, 857-864 disclosed 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 the presence of hydrochloric acid with thioacetamide in dimethyl formamide provides 4-(2- methylpropoxy)-3-cyanobenzthioamide. It was reacted with ethyl 2-chloroacetoacetate in ethanol provides ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5- thiazolecarboxylate which is further hydrolyzed 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 with the yield of 35% which on further recrystallized from acetone provides a colorless crystals having the melting range of 201 - 202°C. However the yield and purity were not satisfactory.

In the aforementioned processes using aqueous sodium hydroxide for hydrolyzation of ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5- thiazolecarboxylate, which lead to the formation of impurities such as ethyl ester impurity, methyl ester impurity, amide impurity and high polar impurities. Hence there is a need to develop a process for the preparation of highly pure febuxostat with high yield.

The crystalline forms A, B, C, D and G of febuxostat and their preparations were first disclosed in US 6225474. However as on date, there is no alternative processes were reported in the prior art for preparing the said polymorphs. Henceforth, there is a need to develop a novel process for the preparation of said crystalline polymorphs.

In view of the forgoing, there is a necessity for the improved process which overcome the problems of prior art and to produce the highly pure 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid with high yield.

Advantages of Present Invention:

• Avoids the usage of Pd/C.
• Provides the highly pure 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-
thiazole carboxylic acid with high yield.
• Controls the impurities (such as methyl impurity, ethyl impurity, amide impurity and high polar impurities) levels to meet the ICH guidelines.
• Provides a novel process for the preparation of crystalline forms A, B and G of 2-[3- cyano-4-(2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid.
• Provides a novel processes for the preparation of 4-(2-methylpropoxy)-1,3-benzene dicarbonitrile and also provides a simplest process for the purification of 2-[3-cyano- 4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid.
• Eco-friendly process.
• Uses simple, milder reagents which are easier to handle and use in large scale.

Brief Description of Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form of febuxostat obtained as per the reference example-1.

Brief description of Invention:

The first aspect of the present invention is to provide an improved process for the preparation of ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylate compound of formula-5, which comprises of condensing the 3-cyano-4-(2- methylpropoxy)benzothiamide compound of formula-3 with ethyl 2-chloroacetoacetate compound of formula-4 in a suitable solvent.

The second aspect of the present invention is to provide a process for the purification of febuxostat compound of formula-1, which comprises of following steps;

a) Dissolving the febuxostat in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get highly pure febuxostat compound of formula-1.

The third aspect of the present invention is to provide a novel process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of following steps of:

a) Reacting the 2,4-dibromo phenol compound of formula-6 with a suitable cyano source in the presence of a suitable catalyst and optionally in the presence of a suitable base in a suitable solvent to provide 4-hydroxy-1,3-benzene dicarbonitrile compound of formula-7,

b) reacting the compound of formula-7 with l-bromo-2-methylpropane in the presence of a suitable base and suitable catalyst in a suitable solvent provides the compound of formula-2.

The fourth aspect of the present invention is to provide a process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of following steps:

a) Brominating the 4-cyano phenol compound of formula-8 with a suitable brominating agent in the presence of a catalyst in a suitable solvent to provide 3-bromo-4- hydroxybenzonitrile compound of formula-9,

b) reacting the compound of fonnula-9 with l-bromo-2-methylpropane in the presence of a suitable base and suitable catalyst in a suitable solvent provides 3-bromo-4-(2- methylpropoxy)benzonitrile compound of formula-10,

c) reacting the compound of formula-10 with a suitable cyano source in the presence of a suitable catalyst and optionally in the presence of a suitable base in a suitable solvent provides the compound of formula-2.

The fifth aspect of the present invention is to provide an improved process for the preparation of febuxostat compound of formula-1, which comprises of following steps;

a) Converting the 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2 into 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 by reacting it with thioacetamide in the presence of a suitable acid in a suitable solvent,

b) condensing the compound of formula-3 with ethyl 2-chloroacetoacetate compound of formula-4 in a suitable solvent provides ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-5,

c) hydrolyzing the compound of formula-5 in the presence of a suitable base in a suitable solvent to get the febuxostat compound of formula-1,

d) slurring the solid obtained in step-c in a suitable solvent to provide febuxostat compound of formula-1,

e) dissolving the obtained compound of formula-1 in step-d in a suitable solvent and precipitating it by adding a suitable antisolvent to provide highly pure compound of formula-1,

The sixth aspect of the present invention is to provide a process for the preparation of crystalline form-B of febuxostat compound of formula-1, which comprises of following steps;

a) Dissolving the febuxostat in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get crystalline form-B of febuxostat compound of formula-1.

The seventh aspect of the present invention is to provide a process for the preparation of crystalline form-G of febuxostat compound of formula-1, which comprises of following steps;

a) Dissolving the febuxostat in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get crystalline form-G of febuxostat compound of formula-1.

The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-A, which comprises of following steps;

a) Dissolving the febuxostat compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) cooling the obtained filtrate,
e) filtering the precipitated solid and washing with a suitable solvent,
f) drying the solid to get crystalline form-A of febuxostat compound of formula-1.

Detailed description of Invention:

As used herein the present invention, the term "suitable solvent" refers to the solvent selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like; "chloro solvents" such as dichloro methane, dichloro ethane, carbon tetra chloride, and the like; "ketone solvents" such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, methyl tert-butyl ketone, methyl isopropyl ketone, diisopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; "polar aprotic solvents" such as dimethylsulfoxide, dimethyl acetamide, N- methyl pyrrolidinone, dimethyl formamide, propylene carbonate and the like; "ether solvents" such as tetrahydrofuran, dioxane and the like; "nitrile solvents" such as acetonitrile and the like.

As used herein the present invention, the term "antisolvent" refers to the solvent which is used to precipitate the solid from a solution and the suitable antisolvent used herein the present invention is water.

As used herein the present invention, the suitable base is an inorganic base selected from hydroxides, carbonates, bicarbonates and alkoxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonates, calcium carbonate, potassiums carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide and the like; or an organic base selected from tertiary amines such as triethyl amine, diisopropyl ethyl amine, tetramethyl ethylenediamine, tribuyl amine, N-methyl morpholine, tetramethyl urea, N-methyl pyrrolidinone, pyridine, 4-dimethylamino pyridine, dimethyl aniline and the like.

As used herein the present invention, the suitable brominating agent include, but are not limited to, bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N- bromo succinamide, carbon tetrabromide, phosphorous tribromide.

As used herein the present invention, the suitable cyano source include, but are not limited to, cuprous cyanide, potassium ferro cyanide, potassium cyanide, sodium cyanide, trimethylsilyl cyanide.

As used herein the present invention, metal is selected from the transition metals, such as palladium and copper.

The first aspect of the present invention is to provide an improved process for the preparation of ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylate compound of formula-5,

Formula-5

which comprises of condensing 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3

Formula-3

with ethyl 2-chloroacetoacetae compound of formula-4 in a suitable solvent.

Formula-4

Wherein, the suitable solvent is selected from ketone solvents, ester solvents and polar aprotic solvents or mixture thereof. The said reaction can be carried out optionally in the presence of a base.

In a preferred embodiment, an improved process for the preparation of ethyl 2- [3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate compound of formula-5, comprises of condensing 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 with ethyl 2-chloro acetoacetate in dimethylformamide and ethylacetate at 80-85°C.

In the present invention, it has found that the usage of a mixture of solvents for above said condensation enhances the rate of the reaction and also improves the quality of the obtained product. Whereas, the prior art processes leading to the product with more impurities. Hence the present invention is more advantageous over the prior art.

The second aspect of the present invention is to provide a process for the purification of febuxostat compound of formula-1, which comprises of following steps;

a) Dissolving the febuxostat in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get highly pure febuxostat compound of formula-1.

Wherein, the suitable solvent is ketone solvents and the suitable antisolvent is water.

The process for the preparation of febuxostat is disclosed in US 5614520 and Heterocycles, Vol. 47, No. 2, 1998, which 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 2-[3- cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid.

When we carryout the experiment in our laboratory to prepare the febuxostat as per the said process we have observed the formation of impurities like 2-[3-carbamoyl- 4-(2-methylpropoxy)phenyl]-4-methylthiazole carboxylic acid (herein designated as amide impurity), ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole carboxylate (herein designated as ethyl ester impurity), methyl 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole carboxylate (herein designated as methyl ester impurity) and 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methylthiazole carboxylic acid (herein designated as di acid impurity).

In the present invention, we surprisingly found that the said impurities are controlled to the levels to meet the ICH guidelines by dissolving the febuxostat in acetone and precipitating the solid by adding water to it.

The third aspect of the present invention is to provide a process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2,

Formula-2

which comprises of following steps;

a) Reacting the 2,4-dibromo phenol compound of formula-6

formula-6

with a suitable cyano source in the presence of a suitable catalyst and optionally in the presence of a suitable base in a suitable solvent provides 4-hydroxy-l,3- benzendicarbonitrile compound of formula-7,

formula-7

b) reacting the compound of formula-7 in-situ with l-bromo-2-methylpropane in the presence of a suitable base and a suitable catalyst in a suitable solvent provides the compound of formula-2.

c) Wherein in step a) the suitable solvent is polar aprotic solvent; the suitable catalyst used is selected from palladium acetate, palladium chloride, tris(dibenzylidene acetone) dipalladium(O), tetrakis(triphenyl phosphine)palladium (0) or from a catalytic system comprising a metal and optionally an organic ligand. The organic ligand if used, may be selected from phosphine such as triarylphosphine, trialkyl phoshine; a bidentate diphosphine ligand (xantphos ligands) such as xantphos, t-butyl xantphos; Nixantphos ligands such as 4,6-bis(diphenyl phosphino)phenoxazine; (oxydi-2,l-phenylene) bis(diphenyl phosphine); 1,1'- bis(diphenyl phosphino) ferrocene; or a bidentate amine ligand such as ethylene diamine, o-phenylene diamine, tetramethyl ethylenediamine, propane-1,3-diamine.

In step b) the suitable solvent is polar aprotic solvent; the suitable base is selected from alkali metal hydroxides, carbonates, bicarbonates and alkoxides; the suitable catalyst is potassiums iodide.

In the present invention, optionally the compound of formula-7 is isolated and further reacts with l-bromo-2-methylpropane to provide compound of formula-2.

In an another embodiment of the present invention, a process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of following steps;

a) Reacting the 2,4-dibromo phenol compound of formula-6 with copper cyanide in the presence of palladium acetate in dimethylsulfoxide provides 4-hydroxy-1,3- benzendicarbonitrile compound of formula-7,

b) reacting the compound of formula-7 in-situ with l-bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethylsulfoxide provides the compound of formula-2.

In an another embodiment of the present invention, a process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of following steps;

a) Reacting the 2,4-dibromo phenol compound of formula-6 with potassium ferro cyanide in the presence of palladium acetate and sodium carbonate in dimethyl formamide provides 4-hydroxy-l,3-benzenedicarbonitrile compound of formula-7, b) reacting the compound of formula-7 in-situ with l-bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethyl formamide provides the compound of formula-2.

The fourth aspect of the present invention is to provide a novel process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of following steps;

a) Brominating the 4-cyano phenol compound of formula-8

b) with a suitable brominating agent in the presence of a suitable catalyst in a suitable solvent to provide 3-bromo-4-hydroxybenzonitrile compound of formula-9,

c) reacting the compound of formula-9 with l-bromo-2-methylpropane in the presence of a suitable base and suitable catalyst in a suitable solvent provides 3-bromo-4-(2- methylpropoxy)benzonitrile compound of formula-10,

d) reacting the compound of formula-10 with a suitable cyano source in the presence of a suitable catalyst and optionally in the presence of a suitable base in a suitable solvent provides compound of formula-2.

Wherein in step a) the suitable solvent is selected from polar aprotic solvents, nitrile solvents, chloro solvents; the suitable catalyst is selected from dilute sulfuric acid, paratoluenesulfonic acid, fluoro sulfuric acid, fluoro boric acid etherate, trifluoro methane sulfonic acid,

in step b) the suitable solvent is polar solvents; the suitable base is selected from alkali metal hydroxides, carbonates, bicarbonates, alkoxides; the suitable catalyst is potassium iodide,

in step c) the suitable solvent is polar aprotic solvent; the suitable catalyst used is selected from palladiumacetate, palladiumchloride, tris(dibenzylideneacetone) dipalladium(O), tetrakis(triphenyl phosphine)palladium (0) or from a catalytic system comprising a metal and optionally an organic ligand. The organic ligand may be selected from phosphine such as triarylphosphine, trialkyl phoshine; a bidentate diphosphine ligand (xantphos ligands) such as xantphos, t-butyl xantphos; Nixantphos ligands such as 4,6-bis(diphenyl phosphino)phenoxazine; (oxydi-2,l-phenylene)bis(diphenyl phosphine); 1,1'- bis(diphenyl phosphino)ferrocene; or a bidentate amine ligand such as ethylene diamine, o-phenylene diamine, tetramethyl ethylenediamine, propane-1,3-diamine.

In a preferred embodiment, a process for the preparation of 4-(2-methylpropoxy)- 1, 3-benzenedicarbonitrile compound of formula-2, comprises of following steps;

a) Brominating the 4-cyanophenol compound of formula's with N-bromosuccinamide in the presence of trifluoromethane sulfonic acid in acetonitrile to provide 3-bromo-4- hydroxy benzonitrile compound of formula-9,

b) reacting the compound of formula-9 with l-bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethylformamide provides 3- bromo-4-(2-methylpropoxy)benzonitrile compound of formula-10,

c) reacting the compound of formula-10 with potassium ferro cyanide in the presence of palladium acetate and sodium carbonate in dimethyl formamide provides compound of formula-2.

The fifth aspect of the present invention is to provide an improved process for the preparation of febuxostat compound of formula-1, which comprises of following steps; a) Converting the 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2 to 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3

Formula-3

by reacting it with thioacetamide in the presence of a suitable acid in a suitable solvent,

b) condensing the compound of formula-3 with ethyl 2-chloroacetoacetae compound of formula-4

formula-4

in a suitable solvent to provide ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methyl thiazole-5-carboxylate compound of formula-5,

formula-5

c) hydrolyzing the compound of formula-5 in the presence of a suitable base in a suitable solvent provides the febuxostat compound of formula-1,

d) slurring the solid obtained in step-c in a suitable solvent to provide febuxostat compound of formula-1,

e) dissolving the obtained solid in step-d in a suitable solvent and precipitating the solid by adding a suitable anti solvent to provide highly pure compound of formula-1.

Wherein in step a) the suitable solvent is selected from polar aprotic solvents, alcohol solvents; the suitable acid is selected from an inorganic acid such as dilute hydrochloric acid, dilute sulfuric acid and dilute nitric acid,

in step b) the suitable solvent is selected from ketone solvents, ester solvents, polar aprotic solvents; the said reaction can be carried out in the presence of a suitable base selected from alkali metal hydroxide, carbonates, bicarbonates and alkoxides,

in step c) the suitable solvent is selected from ether solvents, alcohlic solvents or mixture there of; the suitable base is selected from alkali metal hydroxides, carbonates, bicarbonates and alkoxides,

in step d) the suitable solvent is ester solvents,

in step e) the suitable solvent is ketone solvent and the suitable antisolvent is water.

However, the ester hydrolysis of compound of formula-5 may takes place in the presence of a suitable acid in a suitable solvent.

Wherein the suitable acid is selected from inorganic acids such as dilute hydrochloric acid, dilute sulfuric acid, dilute nitric acid or organic acid such as trifluoroacetic acid and the suitable solvent is selected from chlorosolvents or ether solvents.

Purification of febuxostat from ethyl acetate as discussed above eliminates the less polar impurities and the purification from acetone-water as discussed above eliminates the high polar impurities.

In a preferred embodiment, an improved process for the preparation of febuxostat compound of formula-1, comprises of the following steps;

a) Converting 4-(2-methylpropoxy)-l,3-benzendicarbonitrile compound of formula-2 to 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 by reacting it with thioacetamide in the presence of dilute hydrochloric acid in isopropyl alcohol,

b) condensing the compound of formula-3 with ethyl 2- chloroacetoacetate compound of formula-4 in a mixture of ethylacetate and dimethylformamide to provide ethyl 2-[3- cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate compound of formula-5,

c) hydrolyzing the compound of formula-5 in the presence of an aqueous sodium hydroxide in tetrahydrofuran to provide the febuxostat compound of formula-1,

d) slurring the solid obtained in step-c in ethyl acetate to provide febuxostat,

e) dissolving the obtained solid in step-d in acetone and precipitating the solid by adding water to provide pure compound of formula-1,

Febuxostat obtained from the prior art process, for example US 5614520 and heterocycles, 1998, Vol. 47, No. 2, 857-864 with the yield of-35%. Whereas, the present invention provides with high yield of 85%. Hence the present invention is more advantages over the prior art.

The sixth aspect of the present invention is to provide a novel process for the preparation of crytsalline form-B of febuxostat compound of formula-1, which comprises of following steps;

a) Dissolving the febuxostat compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get crystalline form-B of febuxostat compound of formula-1.

Wherein, the suitable solvent is selected from ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, methyl tert-butyl ketone, methyl isopropyl ketone, diisopropyl ketone, preferably acetone; the suitable antisolvent is water and the drying process is carried out at a temperature range of 60-70°C.

The seventh aspect of the present invention is to provide a process for the preparation of crystalline form-G of febuxostat, which comprises of following steps;

a) Dissolving the febuxostat compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get the crystalline form-G of febuxostat compound of formula-1.

Wherein the suitable solvent is selected from ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, methyl tert-butyl ketone, methyl isopropyl ketone, diisopropyl ketone, preferably acetone; the suitable antisolvent is water and the drying process is carried out at a temperature range of 40-45°C.

The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-A of febuxostat, which comprises of following steps;

a) Dissolving the febuxostat compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) cooling the obtained filtrate,
e) filtering the precipitated solid and washing with a suitable solvent,
f) drying the solid to get crystalline form-A of febuxostat compound of formula-1.

Wherein, the suitable solvent is selected from ketone solvent, polar solvents such as water or mixture thereof.

In preferred embodiment, a process for the preparation of crystalline form-A of febuxostat compound of formula-1 which comprises of following steps;

a) Dissolving the febuxostat compound of formula-1 in aqueous acetone,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with aqueous acetone,
d) cooling the obtained filtrate,
e) filtering the precipitated solid and washing with aqueous acetone,
f) drying the solid to get crystalline form-A of febuxostat compound of formula-1.

The present invention is represented schematically as follows:

Scheme-I:

Scheme-II

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

Reference example 1: Preparation of Febuxostat (Repeatation of part of example-76 of US 5614520)

IN sodium hydroxide (2 ml) was added to a solution of ethyl 2-[3-cyano-4-(2-methyl propoxy)phenyl]-4-methylthiazole-5-carboxylate (400 mg) in ethanol (3 ml) and tetrahydrofuran (4 ml) and heated to 60°C for about 1 hour. After completion of the reaction, distilled off the solvent completely and the residue obtained was neutralized with IN hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated to get the crystalline febuxostat. Yield: 121 mg Example 1: Preparation of 3-cyano-4-(2-metliylpropoxy)benzothiamide (Formula-3) A mixture of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2 (25 g) and thioacetamide (23.43 g) in isopropylalcohol-hydrochloride (75 ml) was heated to 40-45°C and stirred for 14 hours at 40-45°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and the reaction mixture was quenched with water. P" of the reaction mixture was adjusted to 6.3 with sodium hydroxide. The reaction mixture was extracted thrice with ethylacetate. Combined the organic layers, washed with water and distilled off the solvent completely under reduced pressure. Cyclohexane (3125 ml) was added to the obtained residue, heated to 50-55°C and then stirred for 30 minutes at 50-55°C. The reaction mixture was cooled to 25-30°C. Filtered the obtained solid, washed with cyclohexane and then dried to get title compound, field: 20 grams

Example 2: Preparation of ethyl 2-[3-cyano-4-(2-metliylpropoxy)phenyl]-4- methylthiazole-5-carboxylate (Formula-5)

A mixture of 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3
(25 g), ethyl 2-chloroacetoactate compound of formula-4 (17.5 g), ethylacetate (75 ml)
and dimethylformamide (13 ml) was heated to 80-85°C and stirred for 22 hours. After
completion of the reaction, the reaction mixture was cooled to 25-30°C and stirred for 3
hours. The obtained residue was filtered and washed with ethylacetate. Ethylacetate (75
-19- ml) was added to the obtained wet residue, heated to 70-75°C and stirred for 45 minutes. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes. Filtered the obtained solid, washed with ethylacetate and dried to get title compound. Yield: 20
grams

Example 3: Preparation of Febuxostat (Formula-1)

A mixture of compound of formula-5 (50 g), sodium hydroxide (23.25 g), tetrahydrofuran (250 ml) and water (13 ml) was heated to 60-65°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched it with water. The reaction mixture was stirred for 1 hour at 25-30°C. A solution of hydrose (2.5 g) in water (25 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes. P" of the reaction mixture was adjusted to 1.3 with hydrochloric acid. The reaction mixture was extracted thrice with ethylacetate, washed with water and the organic layer was dried with sodium sulfate. Carbon (2.5 g) was added to the organic layer and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and washed with ethylacetate. Distilled off the solvent completely from the obtained filtrate to get the solid. Ethyl acetate (200 ml) was added to the obtained solid and heated to reflux temperature and stirred for 30 minutes. The reaction mixture was cooled to 25-30°C, filtered the solid obtained and washed with ethyl acetate. Acetone (250 ml) was added to the wet solid obtained, heated to 55-60°C and stirred for 15 minutes. Water (250 ml) was added to the reaction mixture and stirred for 2 hours. The obtained solid was filtered, washed with aqueous acetone and then dried to get the title compound. Yield: 38 grams

Example 4: Preparation of Febuxostat (Formula-1)

A mixture of compound of formula-5 (50 g), sodium hydroxide (23.25 g), tetrahydrofuran (250 ml) and water (13 ml) was heated to 60-65°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched it with water. The reaction mixture was stirred for 1 hour at 25-30°C. A solution of hydrose (2.5 g) in water (25 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes. P" of the reaction mixture was adjusted to 1.3 with hydrochloric acid. The compound was extracted thrice with ethyl acetate, washed with water and the organic layer was dried with sodium sulfate. Carbon (2.5 g) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and washed with ethylacetate. Distilled off the solvent completely from the obtained filtrate to get the solid. Acetone (250 ml) was added to the solid obtained, heated to 55-60°C and stirred for 15 minutes. Water (250 ml) was added to the reaction mixture and stirred for 45 minutes . Cooled the reaction mixture to 25-30°C and stirred for 30 minutes, further to 0-5°C and stirred for 2 hours. The obtained solid was filtered, washed with aqueous acetone and then dried. Ethylacetate (200 ml) was added to the obtained solid and heated to reflux temperature and stirred for 30 minutes. The reaction mixture was cooled to 25-30°C. Filtered the solid, washed with ethyl acetate and then dried to get the pure title compound. Yield: 39 grams

Example 5: Purification of Febuxostat (Formula-1)

Acetone (350 ml) was added to febuxostat (25 g) and heated to 50-55°C. Carbon (1.25 g) was added to the reaction mixture and stirred for 40 minutes at 50-55°C. Filtered the reaction mixture through hyflow bed, washed with acetone and the filtrate was heated to 50-55°C. Water (375 ml) was added to the reaction mixture and stirred for 45 minutes at 50-55°C. Cooled the reaction mixture to 25-30°C, further to 0-5°C and stirred for 2 hours. Filtered the obtained solid, washed with water and then dried to get highly pure Febuxostat. HPLC purity: 99.95%, Yield: 21 grams

Example 6: Preparation of crystalline form-G of Febuxostat

Acetone (350 ml) was added to febuxostat (25 g) and heated to 50-55°C. Carbon (1.25 g) was added to the reaction mixture and stirred for 40 minutes at 50-55°C. Filtered the reaction mixture through hyflow bed, washed with acetone and the filtrate was heated to 50-55°C. Water (375 ml) was added to the reaction mixture and stirred for 45 minutes at 50-55°C. Cooled the reaction mixture to 25-30°C, further to 0-5°C and stirred for 2 hours. Filtered the obtained solid, washed with water and then dried at 40-45°C to get crystalline form-G of Febuxostat, Yield: 20 grams

Example 7: Preparation of crystalline form-B of Febuxostat

Acetone (350 ml) was added to febuxostat (25 g) and heated to 50-55°C. Carbon
-21- (1.25 g) was added to the reaction mixture and stirred for 40 minutes at 50-55°C. Filtered the reaction mixture through hyflow bed, washed with acetone and heated the filtrate to 50-55°C. Water (375 ml) was added to the reaction mixture and stirred for 45 minutes at 50-55°C. Cooled the reaction mixture to 25-30°C, further to 0-5°C and stirred for 2 hours. Filtered the obtained solid, washed with water and then dried at 60-70°C to get the crystalline form-B of Febuxostat. Yield: 20 grams

Example 8: Preparation of crystalline form-A of Febuxostat

A mixture of Acetone (350 ml) and water (350 ml) was added to the febuxostat (25 g) and heated to 50-55°C. Carbon (1.25 g) was added to the reaction mixture at 50- 55°C and stirred for 40 minutes. Filtered the reaction mixture and washed with aqueous acetone. The obtained filtrate was cooled to 25-30°C and stirred for 1 hour. Filtered the obtained solid, washed with aqueous acetone and then dried to get the crystalline form-A of Febuxostat. Yield: 20 grams

Example 9: Preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile (Formula-2)

A mixture of 2,4-dibromo phenol (25 g), dimethylsulfoxide (125 ml), cuprous cyanide (26.6 g) and palladium acetate (1.25 g) was heated to 40-45°C and then stirred for 4 hours. After completion of the reaction, potassium carbonate (30.11 g) followed by potassium iodide (6.58 g) were added to the reaction mixture and then heated to 70-75°C. A solution of l-bromo-2-methylpropane (29.9 g) in dimethylsulfoxide (25 ml) was added to the reaction mixture and then stirred for 16 hours at 70-75°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched it with water. The reaction mixture was extracted with ethylacetate, washed with water and distilled off the solvent completely under reduced pressure. Isopropyl alcohol was added to the obtained residue and distilled off the solvent at a temperature of below 60°C. Isopropyl alcohol (50 ml) was added to the obtained residue and stirred for 30 minutes at 50-55°C. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at 0-5°C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 20 grams

Example 10: Preparation of 4-(2-methylpropoxy)-13-benzenedicarbonitrile (Formula-2)

A mixture of 2,4-dibromophenol (25 g), potassium ferrocyanide (8.3 g), sodium carbonate (10.5 g), palladium acetate (0.2 g) in dimethyl formamide (125 ml) was heated to 140-145°C and then stirred for 18 hours. After completion of the reaction, potassium carbonate (30.11 g) followed by potassiums iodide (6.58 g) were added to the reaction mixture and then heated to 70-75°C. A solution of l-bromo-2-methylpropane (29.9 g) in dimethyl formamide (25 ml) was added to the reaction mixture and then stirred for 16 hours at 70-75°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and quenched it with water. The reaction mixture was extracted with ethylacetate, washed with water and distilled off the solvent completely under reduced pressure. Isopropyl alcohol was added to the obtained residue and distilled off the solvent at a temperature of below 60°C. Isopropyl alcohol (50 ml) was added to the obtained residue and stirred for 30 minutes at 50-55°C. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at 0-5 °C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 21 grams

Example 11: Preparation of 3-bromo-4-hydroxybenzonitrile (Formula-9)

Trifluoromethane sulfonic acid (12.6 g) was added to a solution of 4-cyano phenol compound of formula-8 (10 g) in acetonitrile (40 ml) at -15 to -20°C and the temperature of reaction mixture was raised to 10°C. N-bromo succinamide (16.4 g) was added to the reaction mixture by lot wise. The temperature of the reaction mixture was raised to 25- 30°C and then stirred for 4 hours. After completion of the reaction, sodium carbonate solution (50 ml) was added to the reaction mixture. The reaction mixture was extracted with dichloromethane, dried with sodium sulfate and distilled off the solvent under reduced pressure. Cyclohexane was added (50 ml) to the obtained residue and then cooled to 25-30°C. Filtered the obtained solid, washed with cyclohexane and dried to get the title compound. Yield: 14.5 grams

Example 12: Preparation of 3-bromo-4-(2-methylpropoxy)benzonitrile (Formula-10)

A mixture of 3-bromo-4-hydroxybenzonitrile compound of formula-9 obtained in example-10 (18 g), potassium carbonate (25 g), potassium iodide (6.1 g) and dimethylformamide (72 ml) was heated to 70-75°C. A solution of l-bromo-2- methylpropane (25.96 g) in dimethylformamide (18 ml) was added to the reaction mixture at 70-75°C for about 2 hours and then stirred for 10 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and water was added to it. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water and then dried with sodiimi sulfate & distilled off the solvent to get the title compound. Yield: 25 grams

Example 13: Preparation of 4-(2-methylpropoxy)-13-benzenedicarbonitrile (Formula-2)

A mixture of 3-bromo-4-(2-methylpropoxy)benzonitrile compound of formula-10 obtained in example-11 (10 g), potassium ferro cyanide (3.3 g), sodium carbonate (4.16 g), palladium acetate (0.1 g) in dimethylformamide (50 ml) was heated to 140-145°G and then stirred for 18 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and extracted with dichloromethane. Distilled off the solvent completely under reduced pressure and cyclohexane was added to it. The reaction mixture was cooled to 25-30°C. Filtered the solid, washed with cyclohexane and then dried to get the title compound. Yield: 5 grams; MR: 128-132°C

We Claim:

1. An improved process for the preparation of ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula-5, which comprises of condensing 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 with ethyl 2-chloroacetoacetate compound of formula-4, characterized in that the said reaction was carried out in a mixture of solvents selected from ketone solvents, ester solvents and polar aprotic solvents.

2. A process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of

a) Reacting the 2,4-dibromo phenol compound of formula-6 with a suitable cyano source in the presence of a suitable catalyst, optionally in the presence of a suitable base in suitable solvent provides 4-hydroxy-1,3-benzendicarbonitrile compound of formula-7,

b) reacting the compound of formula-7 in-situ with l-bromo-2-methylpropane in the presence of a suitable base and a suitable catalyst such as potassium iodide in a suitable solvent to provide compound of formula-2.

3. A process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, which comprises of

a) Brominating the 4-cyano phenol compound of formula-8 with a suitable brominating agent in the presence of a suitable catalyst in a suitable solvent to provide 3-bromo-4-hydroxybenzonitrile compound of formula-9,

b) reacting the compound of formula-9 with l-bromo-2-methylpropane in the presence of a suitable base in a suitable catalyst such as potassium iodide in a suitable solvent provides 3-bromo-4-(2-methylpropoxy)benzonitrile compound of formula- 10,

c) reacting the compound of formula-10 with a suitable cyano source in the presence of a suitable catalyst, optionally in the presence of a suitable base in a suitable solvent provides compound of formula-2.

4. According to claims 2 & 3, a process for the preparation of 4-(2-methylpropoxy)-l,3- benzenedicarbonitrile compound of formula-2, wherein the suitable cyano source is selected from cuprous cyanide, potassium ferro cyanide, potassium cyanide, trimethyl-25- silyl cyanide; the suitable base is selected from alkali metal hydroxides, carbonates, bicarbonates, alkoxides; the suitable brominating agent is selected from bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromo succinamide, phosphorous tribromide; the suitable catalyst used for cyanation is selected from palladium acetate, palladium chloride, tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenyl phosphine)palladium (0) or a catalytic system comprising a metal and optionally an organic ligand; the suitable catalyst used for bromination is selected from dilute sulfuric acid, paratoluene sulfonic acid, fluoro sulfuric acid, fluoro boric acid etherate, trifluoro methane sulfonic acid.

5. According to claim 2, a process for the preparation of 4-(2-methylpropoxy)-l,3- benzene dicarbonitrile compound of formula-2, which comprises of

a) Reacting the 2,4-dibromo phenol compound of formula-6 with potassium ferro cyanide in the presence of palladium acetate and sodium carbonate in dimethylformamide provides 4-hydroxy-1,3-benzene dicarbonitrile compound of formula-7,

b) reacting the compound of formula-7 in-situ with l-bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethylformamide to provide compound of formula-2.

6. According to claim 3, A process for the preparation of 4-(2-methylpropoxy)-l,3- benzenedicarbonitrile compound of formula-2

a) Brominating the 4-cyano phenol compound of formula-8 with N-bromo succinamide in the presence of trifluoro sulfonic acid in acetonitrile to provide 3- bromo-4-hydroxybenzonitrile compound of formula-9,

b) reacting the compound of formula-9 with l-bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethylformamide provides 3-bromo-4-(2-methylpropoxy)benzonitrile compound of formula-10,

c) reacting the compound of formula-10 with potassium ferro cyanide in the presence of palladium acetate and sodium carbonate in dimethylformamide provides compound of formula-2.

7. An improved process for the preparation of febuxostat compound of formula-1, which comprises of

a) Converting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula- 2 to 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 by reacting with thioacetamide in the presence of a suitable acid selected from dilute hydrochloric acid, dilute sulfuric acid, dilute nitric acid in a suitable solvent,

b) condensing the 3-cyano-4-(2-methyl propoxy)benzothiamide compound of formula-3 with ethyl 2-chloroacetoacetate compound of formula-4 in a suitable solvent to provide ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylate compound of formula-5,

c) hydrolyzing the compound of formula-5 in presence of a suitable base selected from alkali metal hydroxides, carbonates, bicarbonates, alkoxides in a suitable solvent provides the febuxostat compound of formula-1,

d) slurring the solid obtained in step-c in a suitable solvent such as ester solvent to get febuxostat compound of formula-1,

e) dissolving the obtained solid in step-d in a suitable solvent such as ketone solvent and precipitating the solid by adding a suitable antisolvent such as water to provide pure compound of formula-1.

8. According to claim 7, an improved process for the preparation of febuxostat compound
of formula-1, which comprises of

a) Converting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2 to 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 by reacting with thioacetamide in the presence of dilute hydrochloric acid in isopropanol,

b) condensing the 3-cyano-4-(2-methyl propoxy)benzothiamide compound of formula- 3 with ethyl 2-chloroacetoacetate compound of formula-4 in dimethyl formamide and ethyl acetate to provide ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylate compound of formula-5,

c) hydrolyzing the compound of formula-5 in the presence of aqueous sodium hydroxide in tefrahydrofuran to provides the febuxostat compound of formula-1,

d) slurring the solid obtained in step-c in ethyl acetate to get febuxostat compound of formula-1,

e) dissolving the obtained solid in step-d in acetone and precipitating the solid by
adding water to provide pure compound of formula-1.

9. A process for the purification of febuxostat compound of formula-1 which comprises of following steps

a) Dissolving the febuxostat compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) heating the obtained filtrate,
e) adding a suitable antisolvent to it,
f) cooling the reaction mixture,
g) filtering the precipitated solid and washing with a suitable solvent,
h) drying the solid to get highly pure febuxostat compound of formula-1, characterized in that the suitable solvent is selected from ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, methyl tert- butyl ketone, methyl isopropyl ketone, diisopropyl ketone; the suitable antisolvent is water; the said drying process is carried out at 60-70°C to get the crystalline form-B and drying at 40-45°C to get the crystalline form-G of febuxostat.

10. A process for the preparation of crystalline form-A of febuxostat, which comprises of

a) Dissolving the febuxostat compound of formula-1 in a suitable solvent,

b) treating with charcoal,

c) filtering the reaction mixture and washing with a suitable solvent,

d) cooling the obtained filtrate,

e) filtering the precipitated solid and washing with a suitable solvent,

f) drying the solid to get crystalline form-A of febuxostat compound of formula-1, characterized in that the suitable solvent selected from ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, methyl tert- butyl ketone, methyl isopropyl ketone, diisopropyl ketone and polar protic solvent like water or mixture thereof.