WO2011141933A2

WO2011141933A2 - Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts

Info

Publication number: WO2011141933A2
Application number: PCT/IN2011/000328
Authority: WO
Inventors: Manne Satyanarayana Reddy; Gogulapati Venkata Panakala Rao; Gadamsetty Prasad
Original assignee: Msn Laboratories Limited
Priority date: 2010-05-12
Filing date: 2011-05-11
Publication date: 2011-11-17
Also published as: WO2011141933A3

Abstract

Disclosed are novel and improved processes for the preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]^l-methyl thiazole-5-carboxylic acid compound of Formula- 1 and pharmaceutically acceptable salts thereof. Novel processes for the preparation of crystalline forms of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of Formula-1 and its intermediates are also provided. (I)

Description

Process for the preparation of 2-[3-cvano-4-(2-methylpropoxy)phenyl]- 4-methyIthiazole-5-carboxylic acid and its pharmaceutically acceptable salts Related Application:

This application claims the benefit of priority of our Indian patent application numbers 1325/CHE/2010 filed on 12^th May 2010, 1400/CHE/2010 filed on 19^th May 2010 and 351 /CHE/2011 filed on 7^th Feb 2011 which is incorporated herein by reference. 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) and its pharmaceutically acceptable salts, represented by the following structural formula- 1.

Formula- 1

Further, the present invention provides novel amine salts of compound of formula- 1 and its process for the preparation.

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).

Background 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 is 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 tetrahydrofuran 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-cyanobenzthioarnide. It was reacted with ethyl 2-chloroacetoacetate in ethanol provides ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazole carboxylate 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. JP10-045733 disclosed 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 2011/000328 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 provides 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 the above processes contains 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid as an impurity. So there is a need for the purification to get the highly pure 2-[3-cyano-4-(2-methylpropoxy) phenyI]-4-methylthiazole-5-carboxylic acid.

In general, febuxostat prepared by the reported processes contain impurities like amide impurity, ethyl ester impurity and methyl ester impurity etc. It is important that any pharmaceutical compound or intermediate should free of impurities or if present they must be limited to the maximum level set by ICH guidelines. The purification technique of by recrystallisation of the compound from a suitable solvent such as the recrystallisation of febuxostat as disclosed in Heterocycles, Vol. 47, No. 2, 1998 does not yields the desired purity. Hence it is necessary to have an alternate purification technique for the preparation of highly pure febuxostat.

In the aforementioned processes using aqueous sodium hydroxide for hydrolyzation of ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazole carboxylate, 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 preparation 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 foregoing, 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 and improved 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-M of methyl amine salt of 2- [3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 19a.

Figure 2: Illustrates the IR spectrum of crystalline form-M of methyl amine salt of 2- [3- cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 19a.

Figure 3: Illustrates the PXRD pattern of crystalline form-S of tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid of compound of formula- 19b.

Figure 4: Illustrates the IR spectrum of crystalline form-S of tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid of compound of formula- 19b.

Figure 5: Illustrates the PXRD pattern of crystalline form-M of methyl amine salt of 2- [3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20a.

Figure 6: Illustrates the IR spectrum of crystalline form-M of methyl amine salt of 2-[3- formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20a.

Figure 7: Illustrates the PXRD pattern of crystalline form-N of n-butyl amine salt of 2- [3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20b.

Figure 8: Illustrates the IR spectrum of crystalline form-N of n-butyl amine salt of 2-[3- formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20b.

Figure 9: Illustrates the PXRD pattern of crystalline form-M of methyl amine salt of 2- [3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-21 a.

Figure 10: Illustrates the IR spectrum of crystalline form-M of methyl amine salt of 2-[3- ((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-21 a.

Figure 11: Illustrates the PXRD pattern of crystalline form-N of n-butyl amine salt of 2- [3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-2 lb.

Figure 12: Illustrates the IR spectrum of crystalline form-N of n-butyl amine salt of 2-[3- ((hydroxyimino)methyl)-4-(2-methy Ipropoxy) pheny l]-4-methylthiazole-5 -carboxylic acid compound of formula-2 lb.

Figure 13: 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 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 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 a suitable base in a suitable solvent to get the febuxostat compound of formula- 1,

d) suspending 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 second 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 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:

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 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 in-situ with l-bromo-2-methylpropane in the presence of a suitable base and suitable catalyst in a suitable solvent to provide 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 presence of a 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 and suitable catalyst in a suitable solvent to provide 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 to provide the compound of formula-2.

The fifth 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-5 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 sixth 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- 14, 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 of the following steps:

a) Reacting the ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5 -carboxylate compound of formula- 11 with 1 -bromo-2-methylpropane, 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-12,

b) reacting the compound of formula-12 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- 13, c) hydrolyzing the compound of formula- 13 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- 14. The seventh 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- 14 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 eighth 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-15, 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-methylthiazoIe-5-carboxylate compound of formula- 11 with l-bromo-2-methylpropane, 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- 12,

b) hydrolyzing the compound of formula- 12, with a suitable base in a suitable solvent to provide 2-[3-formyl-4-(2-methylpropoxy) phenyI]-4-methylthiazole-5-carboxylic acid, compound of formula-15.

The ninth 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-15 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 ,

The tenth 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, comprises of the following steps:

a) Reacting the ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula- 16 with a suitable halogenating agent to provide ethyl 2-(3-halo-4- hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula-17, b) reacting the ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula- 17 with a suitable cyanide source in a suitable solvent to provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-18,

c) reacting the ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula- 18 with l-bromo-2-methylpropane 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-5,

d) hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylate compound of formula-5 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.

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

The eleventh aspect of the present invention is to provide novel amine salts of 2- [3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula- 19. The salts of compound of general formula- 19 are useful in the preparation of highly pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula- 1.

The twelfth aspect of the present invention is to provide a process for the preparation of novel salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of general formula- 19.

The thirteenth aspect of the present invention is to provide novel amine salts of 2- [3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-20. The salts of compound of general formula-20 are useful in the preparation of highly pure 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula- 15 as well as 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

The fourteenth aspect of the present invention is to provide a process for the preparation of novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5 -carboxylic acid compound of general formula-20.

The fifteenth aspect of the present invention is to provide novel amine salts of 2- [3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-21. The salts of compound of general formula-21 are useful in the preparation of highly pure 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-14 as well as 2-[3-cyano-4-(2-methyl propoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1.

The sixteenth aspect of the present invention provides a process for the preparation of novel amine salts of 2- [3 -((hydroxyimino)methyl)-4-(2 -methylpropoxy) phenyl]-4-methyl thiazole-5-carboxylicacid compound of general formula-21. The seventeenth aspect of the present invention is to provide a process for the purification of febuxostat compound of formula-1, comprises of the 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 eighteenth aspect of the present invention is to provide a process for the preparation of crystalline form-B of febuxostat compound of formula- 1, comprises of the 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 nineteenth aspect of the present invention is to provide a process for the preparation of crystalline form-G of febuxostat compound of formula- 1, comprises of the 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 twentieth aspect of the present invention is to provide a process for the preparation of crystalline form- A of febuxostat compound of formula- 1, comprises of the 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; "ester 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; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; polar solvents like water; "nitrile solvents" such as acetonitrile and the like.

As used herein the present invention, the term "antisolvent" refers to a 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, potassium 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 term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "Ci-i2 alkyl" refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-l-yl, pent- 2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth- 1-yl, n-hexyl and the like; and the term "aryl" refers to C₆-C₁₂ aromatic group include phenyl, tolyl, xylyl, biphenyl, naphthyl and the like. The aryl may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxyl; and the term "aralkyl" refers to Ci-C₆ lower alkyl substituted C₆-C₁₂ aromatic aryl group defined above. For example are benzyl, phenylethyl, phenylpropyl and the like each of which may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxy 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 febuxostat compound of formula- 1, comprises of the 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- c) hydrolyzing the compound of formula-5 in the presence of a suitable base in a suitable solvent to provide the febuxostat compound of formula- 1,

d) suspending 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 selected from ester solvents,

in step e) the suitable solvent is selected from 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 chloro solvents 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) suspending 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 second 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 3-cyano-4-(2- methylpropoxy)benzothiamide compound of formula-3 with ethyl 2-chloroacetoacetae compound of formula-4 in a suitable solvent.

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 ethyl acetate 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 third aspect of the present invention is to provide a process for the preparation of 4-(2-methylpropox -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 to provide 4-hydroxy-l,3- benzendicarbonitrile compound of formula-7,

Formula-7

b) reacting the compound of formula-7 in-situ with 1 -bromo-2-methylpropane in the presence of a suitable base and a suitable catalyst in a suitable solvent to provide the compound of formula-2.

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); Ι ,Γ- 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 potassium 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 0328 of 4-(2-n ethylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, comprises of the following steps:

a) Reacting the 2,4-dibromo phenol compound of formula-6 with copper cyanide in the presence of palladium acetate in dimethylsulfoxide to provide 4-hydroxy-l,3- benzenedicarbonitrile compound of formula-7,

b) reacting the compound of formula-7 in-situ with 1 -bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethylsulfoxide to provide the compound of formula-2. In an another embodiment of the present invention, a process for the preparation of 4-(2-methylpropoxy)- 1,3 -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 to provide 4-hydroxy- 1 ,3 -benzenedicarbonitrile compound of formula-7, b) reacting the compound of formula-7 in-situ with 1 -bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethyl formamide to provide 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, comprises of the following steps:

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

Formula-8

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

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 to provide 3-bromo-4-(2- methylpropoxy)benzonitrile compound of formula- 10,

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 to provide 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 selected from 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); Ι,Γ- bis(diphenyl phosphino)ferrocene; or a bidentate amine ligand such as ethylene diamine, o-phenylene diamine, tetramethyl ethylenediamine, propane-l,3-diamine.

In a preferred embodiment, a process for the preparation of 4-(2-methylpropoxy)- 1, 3-benzenedicarbonitrile compound of formula-2, comprises of the following steps: a) Brominating the 4-cyanophenol compound of formula-8 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 1 -bromo-2-methylpropane in the presence of potassium carbonate and potassium iodide in dimethylformamide to provide 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 to provide compound of formula-2.

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

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 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 was 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 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.

Amide Impurity

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, whereas in the present invention the formation of said impurity reduced by carrying out the hydrolysis under anhydrous conditions. Hence the present process is advantageous over the prior art process.

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

Finally the compound was extracted with ethyl acetate, and isolated from acetone to get 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 sixth 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- 14, a novel intermediate useful in the preparation of febuxostat, comprises of the following steps:

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-11 ,

Formula- 11 with 1 -bromo-2-methylpropane, 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- 12,

Formula- 12

b) reacting the compound of formula- 12 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-13,

Formula-13

c) hydrolyzing the compound of formula-13 with a suitable base in a suitable solvent to provide 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole- 5-carbox lic acid compound of formula- 14.

Formula- 14

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. 0328 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 seventh 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-methyl thiazole-5-carboxylic acid compound of formula- 14, 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-carboxyIic 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 eighth aspect of the present invention is to provide 2-(3-formyl-4-(2- methyIpropoxy)-4-methylthiazole-5-carboxylic acid compound of formula- 15 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-11, with 1 -bromo-2-methylpropane 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- 12, b) hydrolyzing the compound of formula- 12, 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-15.

Formula-15

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 ninth 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-15, with hydroxylamine hydrochloride in the presence or absence of a solvent, followed by formic acid and sodium formate to provide the 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 tenth 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- 16,

Formula- 16

with a suitable halogenating agent in a suitable solvent to provide ethyl 2-(3-halo-4- hydroxyphenyl)-4-methylthiazole-5-carbox late compound of general formula- 17,

Formula- 17

b) reacting the ethyl 2-(3-halo-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of general formula- 17 with a suitable cyanide source in a suitable solvent to provide ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula- 18,

Formula- 18

c) reacting the ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula- 18 with 1 -bromo-2-methylpropane, 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-5,

d) hydrolyzing the ethyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methyIthiazole-5- carboxylate compound of formula-5 with a suitable base in a suitable solvent in anhydrous conditions 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 (or) absence of Lewis acid and the suitable halogenating agent is selected from carbon tetra chloride, oxalyl chloride, thionyl chloride, phosphorous penta chloride, n-chloro succinamide, Phosphorus tribromide, carbon tetrabromide, N-bromo succinamide in presence or absence of triphenylphosphene; 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 eleventh aspect of the present invention provides novel amine salts of 2-[3- cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound represented by the following eneral formula- 19.

Formula- 19

wherein, R and R¹ are the same or different; selected from hydrogen or alkyl or aryl or aralkyl or substituted aryl;

The suitable organic amine (RNHR¹) is selected from ammonia, methyl amine, ethyl amine, di methyl amine, tri methyl amine, diethyl amine, tri ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, Ν,Ν-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzy! amine, cyclopentylamine, cyclohexyl - amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, Ν,Ν-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like.

The twelfth aspect of the present invention provides a process for the preparation of novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazoie-5- carboxylic acid compound of general formula- 19, which comprises of reacting the 2-[3- cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1, with a suitable organic amine (as defined above) in a suitable solvent selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof, to provide corresponding amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenylj-4- methylthiazole-5-carboxylic acid compound of general formula- 19.

The other embodiment of the present invention provides a crystalline form-M of methyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula-19a.

H₃NH₂

Formula- 19a

The crystalline form-M of compound of formula- 19a of the present invention is characterized by it's powder x-ray diffractogram having the peaks at 8.89, 13.18, 14.33, 17.84, 18.92, 21.37, 21.76, 23.42, 24.76, 26.53, 26.93, 27.64, 28.95, 29.38, 31.67, 32.83 and 45.41 ± 0.2 degrees of 2Θ and substantially as shown in figure- 1 ; its IR spectrum having peaks at about 1270, 2234 and 3402 cm^"1 and substantially as shown in figure-2; The crystalline form-M of compound of formula- 19a is useful in the preparation of highly pure febuxostat compound of formula- 1.

A process for the preparation of crystalline form-M of methylamine salt compound of formula- 19a comprises of the following steps:

a) Dissolving the crude 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula- 1 in a suitable solvent,

b) adding the methyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent as defined above,

f) drying the compound to get the crystalline form-M of methyl amine salt of 2-[3- cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5 -carboxylic acid compound of formula- 19a. 11 000328

The other embodiment of present invention provides crystalline form-S of tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazoIe-5- carboxylic acid compound o

Formula- 19b

The crystalline form-S of tertiary butyl amine salt compound of formula- 19b of the present invention is characterized by it's powder x-ray diffractogram having the peaks at 5.86, 8.03, 11.54, 13.91,16.08, 16.51, 17.37, 18.13, 19.74, 20.30, 21.35, 22.55, 23.76, 24.96, 26.07, 27.16, 28.51, 31.69 and 45.42 ± 0.2 degrees of 2Θ and substantially as shown in figure-3; its IR spectrum having peaks at about 1283, 2227 and 3385 cm^"1 and substantially as shown in figure-4; The crystalline form-S compound of formula- 19b is useful in the preparation of highly pure febuxostat compound of formula- 1.

A process for the preparation of crystalline form-S of tertiary butylamine salt compound of formula- 19b comprises of the following steps:

a) Dissolving the crude 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5 - carboxylic acid compound of formula- 1 in a suitable solvent,

b) adding the tertiary butyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline form-S of tertiary butyl amine salt of 2-[3- cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 19b.

The thirteenth aspect of the present invention provides novel amine salts of 2- [3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-20 represented by the following structure

Formula-20

The novel amine salts compound of general formula-20 are useful in the preparation of highly pure 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula- 15 as well as febuxostat compound of formula- 1. The fourteenth aspect of the present invention provides a process for the preparation of novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of general formula-20, which comprises of reacting the 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 15, with a suitable organic amine as defined above, in a suitable solvent to provide corresponding amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]- 4-methylthiazole-5-carboxylic acid compound of general formula-20.

The other embodiment of the present invention provides a crystalline form-M of methyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula-20a.

Formula-20a

The crystalline form-M of methyl amine salt compound of formula-20a of the present invention is characterized by it's powder x-ray diffractogram having the characteristic peaks at 7.39, 8.59, 9.04, 12.39, 12.65, 13.76, 14.06, 14.77, 15.10, 17.10, 18.00, 20.87, 22.53, 23.30, 24.77, 25.26, 25.99, 26.68 and 32.11 ± 0.2 degrees of 2Θ and substantially as shown in figure-5; its IR spectrum having peaks at about 1281, 1678 and 3420 cm^"1 and substantially as shown in figure-6; and its DSC thermogram having endotherm peak at about 204.13°C. The crystalline form-M of methyl amine salt compound of formula-20a is useful in the preparation of highly pure compound of formula- 15 and compound of formula- 1.

A process for the preparation of crystalline form-M of methylamine salt compound of formula-20a comprises of the following steps,

a) Dissolving the crude 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula- 15 in a suitable solvent,

b) adding the methyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline form-M of methyl amine salt of 2-[3- formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20a.

The other embodiment of the present invention provides crystalline form-N of n- butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula-20b.

Formula-20b

The crystalline form-N of n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20b of the present invention is characterized by it's powder x-ray diffractogram having the characteristic peaks at 5.73, 7.30, 8.06, 14.28, 15.51, 16.13, 18.13, 20.27, 24.40 and 26.19 ± 0.2 degrees of 2Θ and substantially as shown in figure-7; its IR spectrum having peaks at about 1276, 1700 and 3415 cm^"1 and substantially as shown in figure-8; and its DSC thermogram having endotherm peak at about 191.27°C. The crystalline form-N of n-butyl amine salt compound of formula-20b is useful in the preparation of highly pure compound of formula- 15 and compound of formula- 1.

A process for the preparation of crystalline form-N of n-butylamine salt compound of formula-20b comprises of the following steps,

b) adding the n-butyl amine to the reaction mixture,

c) stirring the reaction mixture up to the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline form-N of n-butyl amine salt of 2- [3- formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20b.

The fifteenth aspect of the present invention provides novel amine salts of 2- [3- ((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid, compound of general formula-21 having the following structural formula,

Formula-21

wherein, R and R are the same or different; selected from hydrogen or alkyl or aryl or aralkyl or substituted aryl;

The novel amine salts compound of general formula-21 of the present invention are useful in the preparation of highly pure 2-[3-((hydroxyimino)methyl)-4-(2- 0328 methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-14 as well as febuxostat compound of formula- 1.

The sixteenth aspect of the present invention provides a process for the preparation of novel salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-

4- methylthiazole-5-carboxylicacid compound of general formula-21, which comprises of reacting the 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl] -4-methy lthiazole-

5- carboxylicacid compound of formula-14, with a suitable organic amine as defined above, in a suitable solvent to provide corresponding amine salt compound of 2-[3- ((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of general formula-21.

The other embodiment of the present invention provides crystalline form-M of methyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5 -carboxylic

Formula-21 a

The crystalline form-M of methyl amine salt of 2-[3-((hydroxyimino)methyl)-4- (2 -methylpropoxy) phenyI]-4-methyIthiazoIe-5-carboxylic acid compound of formula-2 la of the present invention is characterized by it's powder x-ray diffractogram having the characteristic peaks at 7.17, 7.58, 11.70, 14.36, 14.66,14.94, 16.63, 17.90, 18.96, 21.19, 23.55, 29.05, 29.61, 30.36, 31.68 and 45.41 ± 0.2 degrees of 20 and substantially as shown in figure-9; its IR spectrum having peaks at about 970, 1263 and 3258 cm^"1 and substantially as shown in figure- 10; and its DSC thermogram having endotherm peak at about 189.63°C. The crystalline form-M of methyl amine salt compound of formula-2 la of the present invention is useful in the preparation of highly pure compound of formula- 5 and formula- 1. A process for the preparation of crystalline form-M of methylamine salt compound of formula-21a comprises of the following steps:

a) Dissolving the crude 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid of formula- 14 in a suitable solvent,

b) adding the methyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline form-M of methyl amine salt of 2-[3- ((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-21a.

The other embodiment of the present invention provides crystalline form-N of n- butyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5-carboxylic acid compound of formula-21b.

Formula-21b

The crystalline form-N of n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4- (2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-21b of the present invention is characterized by it's powder x-ray dififractogram having the peaks at 6.33, 21.42, 23.61, 26.18, 27.30, 31.67 and 45.40 ± 0.2 degrees of 2Θ and substantially as shown in figure-11 ; its IR spectrum having peaks at about 969, 1263 and 3245 cm^"1 and substantially as shown in figure- 12; and its DSC thermogram having endotherm peak at about 104.57°C. The crystalline form-N of n-butyl amine salt compound of formula-21b of the present invention is useful in the preparation of highly pure compound of formula- 14 and formula- 1.

A process for the preparation of crystalline form-N of n-butylamine compound of formula-21b of the present invention comprises of the following steps: a) Dissolving the crude 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula- 14 in a suitable solvent, b) adding the n-butyl amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline form-N of n-butyl amine salt of 2-[3- ((hydroxyimino)methyl)-4-(2-rnethylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-21 b.

The novel amine salts compound of formula-20 and formula-21 of the present invention further converted into highly pure febuxostat compound of formula- 1 by treating the salt compound of formula-20 or formula-21 with a suitable acid in a suitable solvent to provide corresponding highly pure compound of formula- 15 or formula- 14. The said compound of formula- 15 or formula- 14 is converted into highly pure febuxostat compound of formula- 1 by the conventional methods.

The novel amine salts of compound of general formula- 19 of the present invention further converted into highly pure febuxostat compound of formula- 1 by treating the salt compound of general formula- 19 with a suitable acid in a suitable solvent to provide highly pure compound of formula- 1.

The suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like or organic acids such as acetic acid, trifluoro acetic acid, para toluene sulfuric acid, methane sulfonic acid and the like and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and also mixtures thereof.

The seventeenth aspect of the present invention is to provide a process for the purification of febuxostat compound of formula- 1, 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 eighteenth 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,

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 nineteenth aspect of the present invention is to provide a process for the preparation of crystalline form-G of febuxostat, which comprises of following steps: i) Dissolving the febuxostat compound of formula- 1 in a suitable solvent,

ii) treating it with charcoal,

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

iv) heating the obtained filtrate,

v) adding a suitable antisolvent to it,

vi) cooling the reaction mixture,

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

viii) 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 twentieth 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, 8 e) filtering the precipitated solid and washing with a suitable solvent,

wherein, the suitable solvent is selected from ketone solvents, polar solvents such as water or mixtures 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 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 one is at the wet material obtained by the filtration after neutralization with aqueous hydrochloric acid (crude compound) and another one is after recrystallization of the wet compound in acetone.

The wet material was dried under arial condition and analyzed by PXRD and found that it is matches with the crystalline form-G and having the water content of 2.5- 2.7%. The PXRD of febuxostat obtained after recrystallization of wet material from acetone followed by drying under arial condition is similar to the crystalline form-G having water content of 2.5%. When both the above materials were dried at higher temperature leads to the crystalline form-B, which is having water content up to 0.5% i.e, anhydrous form. One who skilled in the art may know 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):

Ethyl ester impurity

2) Methyl 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate (Methyl ester impurity)

Methyl ester impurity

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

di acid impurity

The present invention is represented schematically as follows: Scheme-I:

Formula-6 ForrauIa-

Scheme-II:

Scheme-Ill:

The related substance of Febuxostat was analyzed by HPLC using the following conditions: A liquid chromatographic system is to be equipped with variable wavelength UV-Detector and integrator and Column: Symmetry C-18 250 x 4.6 mm, 5μπι or Equivalent; Flow rate: 1.0 mL/min; wavelength: 318 nm; Temperature: 25°C; Load: 20 μΐ; Run time: 50 min; Elution: Gradient; and using Buffer: methanol (40: 60 v/v) as a mobile phase (A) and methanol as mobile phase (B); Diluent: Methanol: Water (90:10 v/v); Buffer: aqueous mixture of potassium dihydrogen phosphate and triethylamine and pH was adjusted to 3.0 using dil H3PO4 and filter through 0.45 μπι Nylon membrane filter paper and sonicate to degas it.

Further Febuxostat obtained as per the present invention is further micronized or milled to get the desired particle size. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, with out limitation, ball, roller and hammer mills, and jet mills.

As used herein the term "pure" refers to the compound having purity greater than 99.00%, preferably greater than 99.50% and more preferably greater than 99.95% by HPLC.

PXRD analysis of Febuxostat was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. 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-methylpropoxy)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. The p^H 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 the title compound. Yield: 20 grams.

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

A mixture of 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 (25 g), ethyl 2-chloroacetoacetate 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 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 the title compound. Yield: 20 grams. Example 3: 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 1 -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 4: Preparation of 4-(2-methylpropoxy)-l,3-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 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 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 5: Preparation of 3-bromo-4-hydroxybenzonitrile (FormuIa-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 6: 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 sodium sulfate & distilled off the solvent to get the title compound. Yield: 25 grams.

Example 7: Preparation of 4-(2-methylpropoxy)-l,3-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°C 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

Example 8: 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. The p^H 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 9: 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. The p^H 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 10: Preparation of ethyl 2-[3-formyl-4-(2-methyIpropoxy) phenyl]-4- methylthiazole-5-carboxylate compound of formula-12.

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 11: Preparation of ethyl 2-[3-cyano-4-(2-methyIpropoxy) phenyl]-4- methyIthiazoIe-5-carboxylate compound of formuIa-5.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylate compound of formula-12 (10 gms) in formic acid (40 ml) was 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 12: Preparation of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula-15.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylate (100 gms) in methanol (500 ml) was 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 p^H 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 13: Preparation of ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methyIpropoxy) phenyl]-4-methyIthiazole-5-carboxylate compound of formula-13.

To the solution of ethyl 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylate (10 gms) in methanol (50 ml) was 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 14: Preparation of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula -14. To the solution of ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylate (100 gms) in methanol (500 ml) was 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 p^H 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. 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 15: 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 -14 (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 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 pure title compound. Yield: 8.5 gms. Example 16: Preparation of 2-[3-cyano-4-(2-methyIpropoxy) 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-5 (100 gms) in tetrahydrofuran (500 ml) was 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 17: Preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula-l.

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-thiazole carboxylate (306 mg). It was hydrolyzed with ΙΝ-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 crystals were collected by filtration.

The PXRD of the obtained material was 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.

Example 18: Preparation of methylamine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyI]-4-methylthiazole-5-carboxylic acid compound of formula-19a.

To 10 gms of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid added to ethyl acetate (10 ml) and cyclohexane (10 ml). Stirred the reaction mixture for 10 minutes. Added methanolic methyl amine (0.98 gms) to the reaction mixture and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane (10 ml). Dried the obtained compound to get the title compound.

MR: 185 - 190°C; Yield: 8 gms;

Example 19: Preparation of tertiary butyl amine salt of 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxyIic acid compound of formula- 19b.

To 10 gms of 2-[3-cyano-4-(2 -methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid was added 70 ml of toluene. Stirred the reaction mixture for 10 minutes. Added tertiary butyl amine (2.3 gms) to the reaction mixture and stirred for 10 hours. Filtered the precipitated solid and washed with toluene (10 ml). Dried the obtained compound to get the title compound. MR: 225 - 230°C; Yield: 11.5 gms

Example 20: Preparation of methylamine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-20a.

To 10 gms of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid was added Ethyl acetate (10 ml) and cyclohexane (20 ml). Stirred the reaction mixture for 10 minutes. Added methanolic methyl amine (0.97 gms) to the reaction mixture and stirred for 3 hours. Filtered the precipitated solid and washed with 1 :2 mixture of ethyl acetate and cyclohexane (10 ml). Dried the obtained compound to get the title compound. MR: 190 - 195°C; Yield: 9 gms

Example 21: Preparation of n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methyIthiazoIe-5-carboxylic acid compound of formula-20b.

To 10 gms of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid was added 30 ml of toluene. Stirred the reaction mixture for 10 minutes. Added n-butyl amine (2.3 gms) to the reaction mixture and stirred for 10 hours. Filtered the precipitated solid and washed with toluene (10 ml). Dried the obtained compound to get the title compound. MR: 2 6 - 220°C; Yield: 5 gms.

Example 22: Preparation of methylamine salt of 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula- 21a.

To 10 gms of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylicacid added Ethyl acetate (10 ml) and cyclohexane (20 ml). Stirred the reaction mixture for 10 minutes. Added methanolic methyl amine (0.93 gms) to the reaction mixture and stirred for 3 hours. Filtered the precipitated solid and washed with 1 :2 mixture of ethyl acetate and cyclohexane (10 ml). Dried the obtained compound to get the title compound. MR: 215-22TC; Yield: 7 gms

Example 23: Preparation of n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula- 21b.

To 10 gms of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid was added 50 ml of toluene. Stirred the reaction mixture for 10 minutes. Added n-butyl amine (2.2 gms) to the reaction mixture and stirred for 10 hours. Filtered the precipitated solid and washed with toluene (10 ml). Dried the obtained compound to get the title compound. Yield: 9.5 gms; MR: 95-118°C.

Example 24: 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 25: 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 26: Preparation of crystalline form-B 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 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 27: 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

Claims

We Claim:

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

a) Converting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2 in 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 to provide the febuxostat compound of formula- 1,

d) suspending 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.

2. An improved process for the preparation of febuxostat compound of formula- 1, comprises of:

a) Converting 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2 in 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 a mixture of 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 tetrahydrofuran to provide the febuxostat compound of formula- 1, d) suspending 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.

3. 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-chloroacetoacetate compound of formula-4, characterized in that the said reaction is carried out in a mixture of solvents selected from ketone solvents, ester solvents and polar aprotic solvents.

4. A process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, 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 a suitable solvent to provide 4-hydroxy-l,3-benzendicarbonitrile compound of formula-7,

b) reacting the compound of formula-7 in-situ with 1 -bromo-2-methylpropane in the presence of a suitable base and a suitable catalyst such as potassium iodide in a suitable solvent to provide the compound of formula-2.

5. A process for the preparation of 4-(2-methylpropoxy)-l,3-benzenedicarbonitrile compound of formula-2, 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 and a suitable catalyst such as potassium iodide in a suitable solvent to provide 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 to provide compound of formula-2.

6. A process according to claims 4 & 5, 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 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.

7. A process according to claim 4, the preparation of 4-(2-methylpropoxy)- 1,3 -benzene dicarbonitrile compound of formula-2, 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 to provide 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.

8. A process according to claim 5, the preparation of 4-(2-methylpropoxy)-l,3- benzenedicarbonitrile compound of formula-2, comprises of:

a) Brominating the 4-cyano phenol compound of formula-8 with N-bromo succinamide in the presence of trifluoro methane 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 to provide 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 to provide compound of formula-2.

9. 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-5, 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,

10. A process according to claim 9, 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. 1. An improved process for the preparation of 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy)phenyl]-4-methyl thiazole-5-carboxylic acid compound of formula- 14, comprises of:

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula-11, with l-bromo-2-methylpropane 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- 12,

b) reacting the compound of formula- 12 with hydroxylamine hydrochloride in a suitable solvent to provide ethyl 2-[3-((hydroxyimino) methyl)-4-(2-methyl propoxy) phenyl] -4-methyl thiazole-5-carboxylate compound of formula- 13, c) hydrolyzing the compound of formula- 13 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- 14.

12. 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-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid compound of formula- 14, 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,

13. A process according to claim 11, wherein,

in step a) the suitable base is selected from inorganic bases like alkali metal d hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates anorganic 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.

14. The compound of formula- 1, according to the process of claim 12, contains less than 0.2 %, preferably less than 0.15 %, more preferably less than 0.1 % of amide impurity.

15. A process for the preparation of 2-[3-formyl-4-(2-methylpropoxy)phenyI]-4- methylthiazole-5-carboxylic acid compound of formula-15, comprises of:

a) Reacting ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate compound of formula- 11 , with 1 -bromo-2-methylpropane in presence of a suitable base in a suitable solvent to provide ethyl 2-[3-formyl-4-(2-methyl propoxy) phenyl]-4-methylthiazole-5-carboxylate compound of formula- 12, b) hydrolyzing the compound of formula- 12, 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- 15.

16. 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-15, 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.

17. A process according to claim 15, wherein,

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. 18. A process for the preparation of novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-19, comprises of, reacting the 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methy lthiazole- 5-carboxylic acid compound of formula- 1, with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-19.

19. A process for the preparation of crystalline organic amine salt compound of general formula-19 comprises of:

a) Dissolving the crude 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methylthiazole 5-carboxylic acid compound of formula- 1 in a suitable solvent,

b) adding the organic amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline organic amine salt of 2-[3-cyano-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula- 19.

20. Novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of eneral formula- 19,

Formula- 19

21. A process for the preparation of novel amine salts of 2-[3-formyl-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-20, comprises of reacting the 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxyIic acid compound of formula- 15, with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 2-[3-formyl-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-20.

22. A process for the preparation of crystalline organic amine salt compound of general formula-20, comprises of:

a) Dissolving the crude 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl thiazole- 5-carboxylic acid compound of formula- 15 in a suitable solvent,

b) adding the organic amine to the reaction mixture,

c) stirring the reaction mixture up to the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline organic amine salt of 2-[3-formyl-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of general formula-20.

23. Novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl] -4-methylthiazole 5- carboxylic acid compound of eneral formula-20,

Formula-20

24. A process for the preparation of novel amine salts of 2-[3-((hydroxyimino)methyl)-4- (2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of general formula-21, comprises of, reacting the 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula- 14 with a suitable organic amine in a suitable solvent to provide corresponding amine salt of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl] -4-methy lthiazole- 5-carboxylicacid compound of general formula-21.

25. A process for the preparation of crystalline organic amine salt of general formula-21 comprises of:

a) Dissolving the crude 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]- 4-methylthiazole-5-carboxylic acid of formula- 14 in a suitable solvent,

b) adding the organic amine to the reaction mixture,

c) stirring the reaction mixture upto the completion of reaction,

d) filtering the precipitated solid,

e) washing the solid with a suitable solvent,

f) drying the compound to get the crystalline organic amine salt of 2-[3- ((hydroxylimino) methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of general formula-21.

26. Novel amine salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carbo ,

Formula-21

27. A process according to the claims 18-26, wherein the suitable organic amine (RNHR¹) is selected from ammonia, methyl amine, ethyl amine, dimethyl amine, trimethyl amine, diethyl amine, triethyl amine, n-propyl amine, isopropyl amine, n- butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, Octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, Ν,Ν-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methyl benzyl amine, tribenzyl amine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, Ν,Ν-dimethyl cyclo hexyl amine, N,N-diethylcycloheptylamine; preferably methyl amine, n-butyl amine, tertiary butyl amine; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents; preferably ester solvents, hydrocarbon solvents.

28. 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid methyl amine salt compound of formula- 19a. 29. 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid tertiary butyl amine salt compound of formula- 19b.

30. 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid methyl amine salt compound of formula-20a.

31. 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid n-butyl amine salt compound of formula-20b.

32. 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylic acid methyl amine salt compound of formula-21a.

33. 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5- carboxylic acid n-butyl amine salt compound of formula-21b.

34. Crystalline form-M of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5- carboxylic acid methyl amine salt compound of formula- 19a,

Formula- 19a

characterized by it's:

i) powder x-ray diffractogram having the peaks at 8.89, 13.18, 14.33, 17.84, 18.92, 21.37, 21.76, 23.42, 24.76, 26.53, 26.93, 27.64, 28.95, 29.38, 31.67, 32.83 and 45.41 ± 0.2 degrees of 2Θ;

ii) IR spectrum having peaks at about 1270, 2234 and 3402 cm^"1.

35. Crystalline form-S of 2-[3-cyano-4-(2- methyl propoxy) phenyl]-4-methyl thiazole-5- carboxylic acid tertiary b,

Formula- 19b

characterized by it's:

i) powder x-ray diffractogram having the peaks at 5.86, 8.03, 11.54, 13.91,16.08,

16.51 , 17.37, 18.13, 19.74, 20.30, 21.35, 22.55, 23.76, 24.96, 26.07, 27.16, 28.51,

31.69 and 45.42 ± 0.2 degrees of 2Θ;

ii) IR spectrum having peaks at about 1283, 2227 and 3385 cm^"1.

36. Crystalline form-M of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methyl thiazole-5- carboxylic acid methyl amine salt compound of formula-20a,

Formula-20a

characterized by it's:

i) powder x-ray diffractogram having the characteristic peaks at 7.39, 8.59, 9.04, 12.39, 12.65, 13.76, 14.06, 14.77, 15.10, 17.10, 18.00, 20.87, 22.53, 23.30, 24.77, 25.26, 25.99, 26.68 and 32.11 ± 0.2 degrees of 2Θ;

ii) IR spectrum having peaks at about 1281, 1678 and 3420 cm^"1.

37. Crystalline form-N of 2-[3-formyl-4-(2-methylpropoxy) phenyl] -4-methyl thiazole-5- carboxylic acid n-butyl amine salt compound of formula-20b,

Formula-20b

characterized by it's:

i) powder x-ray diffractogram having the characteristic peaks at 5.73, 7.30, 8.06, 14.28, 15.51, 16.13, 18.13, 20.27, 24.40 and 26.19 ± 0.2 degrees of 29;

ii) IR spectrum having peaks at about 1276, 1700 and 3415 cm^"1.

38. Crystalline form-M of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid methyl amine salt compound of formula-21a,

Formula-21a

characterized by it's:

i) Powder x-ray diffractogram having the characteristic peaks at 7.17, 7.58, 11.70, 14.36, 14.66,14.94, 16.63, 17.90, 18.96, 21.19, 23.55, 29.05, 29.61, 30.36, 31.68 and 45.41 ± 0.2 degrees of 2Θ;

ii) IR spectrum having peaks at about 970, 1263 and 3258 cm^"1.

39. Crystalline form-N of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid n-butyl amine salt compound of formula-21b,

characterized by it's:

i) powder x-ray diffractogram having the peaks at 6.33, 21.42, 23.61, 26.18, 27.30,

31.67 and 45.40 ± 0.2 degrees of 2Θ;

ii) IR spectrum having peaks at about 969, 1263 and 3245 cm^"1.

40. A process for the purification of febuxostat compound of formula- 1, comprises of: 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.

41. A process for the preparation of crystalline form-B of febuxostat compound of formula- 1, comprises of:

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 at 60-70°C to get the crystalline form-B of febuxostat compound of formula- 1.

42. A process for the preparation of crystalline form-G of febuxostat compound of formula-1, comprises of:

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 at 40-45°C to get the crystalline form-G of febuxostat compound of formula-1.

43. A process according to claim 34-36, 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; the suitable antisolvent is water.

44. A process for the preparation of crystalline form- A of febuxostat, 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 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 and polar protic solvent like water or mixture thereof.

45. Use of novel amine salts of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of general formula- 19 for the preparation of pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1.

46. Use of compounds of formula- 19a and 19b for the preparation of pure 2-[3-cyano-4- (2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1. 47. Use of crystalline form-M of methyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-19a and crystalline form-S of tertiary butyl amine salt of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula-19b for the preparation of pure 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1.

48. Use of novel amine salts of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of general formula-20 for the preparation of highly pure 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5- carboxylic acid compound of formula- 15 as well as 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1.

49. Use of compounds of formula-20a and 20b for the preparation of highly pure 2-[3- formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-15 as well as 2-[3-cyano-4-(2-methylpropoxy) phenyl] -4-methy lthiazole- 5-carboxylic acid compound of formula- 1. 50. Use of crystalline form-M of methyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl] -4-methylthiazole-5-carboxyIic acid compound of formula- 20a and crystalline form-N of n-butyl amine salt of 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula-20b for the preparation of highly pure 2-[3-formyl-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-15 as well as 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula- 1.

51. Use of novel amine salts of 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of general formula-21 for the preparation of highly pure 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula- 14 as well as 2-[3- cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1. 52. Use of compounds of formula-21 a and 21b for the preparation of highly pure 2-[3- ((hy droxy imino)methyl)-4-(2-methy lpropoxy) phenyl] -4-methy lthiazole- 5 -carboxylic acid compound of formula-14 as well as 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4- methylthiazole-5-carboxylic acid compound of formula- 1. 53. Use of crystalline form-M of methyl amine salt of 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 21 a and crystalline form-N of n-butyl amine salt of 2-[3-((hydroxyimino)methyl)-4- (2-methylpropoxy) phenyl] -4-methyl thiazole-5-carboxylic acid compound of formula-21b for the preparation of highly pure 2-[3-((hydroxyimino)methyl)-4-(2- methylpropoxy) phenyl]-4-methylthiazole-5-carboxylicacid compound of formula-14 as well as 2- [3 -cyano-4-(2 -methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1.

4. 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula- 1 obtained by any one of the preceding claims having purity greater than 99.00% by HPLC, preferably greater than 99.50% by HPLC, more preferably greater than 99.95% by HPLC.