WO2012073259A1

WO2012073259A1 - Novel process for the preparation of febuxostat

Info

Publication number: WO2012073259A1
Application number: PCT/IN2011/000823
Authority: WO
Inventors: Mangesh Narayan Rajadhyaksha; Vidyadhar Kashinath Jadhav; Nilesh Balkrishna Shrigadi; Aditi Milind Panandikar
Original assignee: Indoco Remedies Limited
Priority date: 2010-12-02
Filing date: 2011-12-02
Publication date: 2012-06-07

Abstract

Disclosed herein is a novel process for the preparation of 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and novel intermediates thereof.

Description

NOVEL PROCESS FOR THE PREPARATION OF FEBUXOSTAT

FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and novel intermediates thereof.

BACKGROUND AND PRIOR ART:

The compound 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I having an international non-proprietary name Febuxostat is a non- purine selective inhibitor of Xanthine oxidase useful for the treatment of hyperuricemia and gout.

Formula I

The US patent US5614520 discloses the preparation of the compound 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, wherein the compound 4- hydroxy-3-nitrobenzaldehyde of Formula IA is heated with hydroxylamine hydrochloride and sodium formate _, in presence of formic acid to get the compound 4-hydroxy-3- nitrobenzonitrile of Formula IB, which on reaction with thioacetamide in presence of hydrogen chloride in Ν,Ν-dimethylformamide yields the compound 4-hydroxy-3- nitrobenzthioamide of Formula IC. The compound of Formula IC on reaction with ethyl 2-chloroacetoacetate undergoes cyclisation to yield the compound ethyl 2-(4-hydroxy-3- nitrophenyl)-4-methyl-5-thiazolecarboxylate of Formula ID. The compound of Formula ID on O-alkylation with l-bromo-2-methylpropane in presence of N,N- dimethylformamide, potassium iodide and potassium carbonate results in the compound ethyl 2-[4-(2-methylpropoxy)-3-nitrophenyl]-4-methyl-5-thiazolecarboxylate of Formula IE, which after crystallization from ethanol taken for the next stage. The nitro compound of Formula IE is reduced using hydrogen in presence of Pd/C in mixed solvent of ethyl acetate and ethanol to give compound ethyl 2-[3-amino-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylate of Formula IF. The amino compound of Formula IF is diazotized and reacted with potassium cyanide in presence of cuprous cyanide, which after decomposition and work up is purified using silica gel column chromatography to yield the compound ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5- thiazolecarboxylate of Formula II. The compound of Formula II is taken in mixture of solvents ethanol and tetrahydrofuran to carry out hydrolysis using aqueous solution of sodium hydroxide. The reaction mixture is concentrated, adjusted the pH to acidic and extracted in solvent which on concentration and crystallization yields pure compound 2- [3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I. The reaction sequence is as shown in Scheme 1 below;

Formula IA Formula IB Formula IC

Scheme 1

The draw backs in the above process are; i. handling of highly toxic cyanating agents such as cuprous cyanide and potassium cyanide.

ii. the purification of the intermediates and the final product requires column chromatography which is not feasible to implement on industrial scale.

Another patent JP 06329647, discloses two methods for preparation of the penultimate intermediate ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate of Formula II. The first method discloses formylation of ethyl 2-(4-hydroxyphenyl)-4- methylthiazole-5-carboxylate of Formula IIA with hexamethylenetetramine and trifluoroacetic acid to give ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5- carboxylate of Formula IIB. The compound of Formula IIB is reacted with hydroxylamine hydrochloride in the presence of formic acid and sodium formate to get ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate of Formula IIC. The compound of formula IIC on O-alkylation with l-bromo-2-methylpropane in presence of solvent Ν,Ν-dimethylformamide, potassium carbonate as base and potassium iodide yields the compound ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4_rmethylthiazole-5- carboxylate of Formula II. In the second method the compound ethyl 2-(4- hydroxyphenyl)-4-methylthiazole-5-carboxylate of Formula IIA after formylation is first subjected to O-alkylation, followed by reaction with hydroxylamine hydrochloride, formic acid and sodium formate yields the compound ethyl 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate of Formula II. The reaction seq

Scheme 2 In the above process it is observed during formylation, the ester moiety of the compound of Formula IIA gets partially hydrolysed resulting in the formation of free carboxylic acid compound of Formula HE as impurity which is required to be removed before O- alkylation reaction;

Formula HE

Further the above process requires column chromatography to purify the product, resulting in a process that is expensive and not feasible to implement on industrial scale.

Another Patent Application CN 101386604 discloses the preparation of Febuxostat of Formula I starting from the compound ethyl 4-nitrobenzoate of Formula III which on cyanation with sodium cyanide followed by alkylation with l-bromo-2-methylpropane results in the compound ethyl 3-cyano-4-(2-methylpropoxy)benzoate; of Formula IIIA. Hydrolysis of the compound of Formula IIIA followed by amidation yields the compound 3-cyano-4-(2-methylpropoxy)benzamide of Formula IIIB which on reaction with phosphorus pentasulfide gives 3-cyano-4-(2-methylpropoxy)benzothioamide of Formula IIIC. Reaction of the compound of Formula IIIC with ethyl 2-chloroacetoacetate results in the cyclised compound ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole- 5-carboxylate of Formula II. Alkaline hydrolysis of the compound of Formula II yields Febuxostat of Formula I. The reaction sequence is as described in Scheme 3 below;

Scheme 3 The drawbacks of the above process are;

i. the process requires use of highly toxic sodium cyanide for cyanation reaction; ii. use of phosphorus pentasulfide in aqueous medium leads to evolution of toxic hydrogen sulfide gas which causes respiratory problems, thus posing a safety hazard on industrial scale production.

Therefore, the present inventors have come out with a novel process to prepare 2-[3- cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I which avoids the use of hazardous reagents, chromatographic purification of intermediates and the product is substantially devoid of the impurity by using the novel carboxamide derivative 2-(4-hydroxyphenyl)-4-methylthiazole of Formula IV.

Formula IV

OBJECTIVE OF THE INVENTION:

The objective of the present invention is to prepare 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I, by a novel process which is safe, rigid, industrially viable and substantially devoid of any impurity.

Another objective of the present invention is to prepare 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula 1 by using novel compound 2-(4-hydroxyphenyl)-N,N,4-trimethylthiazole-5-carboxamide of Formula IV.

Yet another objective of the present .invention is to provide novel intermediate compound 2-(3-formyl-4-hydroxyphenyl)-N,N,4-trimethylthiazole-5-carboxamide of Formula V.

Another objective of the present invention is to provide novel intermediate compound 2- [3-formyl-4-(2-methylpropoxy)phenyl]-N,N,4-trimethylthiazole-5-carboxamide of Formula VI. Another objective of the present invention is to provide novel intermediate compound 2- [3-cyano-4-(2-methylpropoxy)phenyl]-N,N,4-trimethylthiazole-5-carboxamide of Formula VII.

Another objective of the present invention is to provide novel intermediate compound 2- (3-cyano-4-hydroxyphenyl)-N,N,4-trimethylthiazole-5-carboxamide of Formula VIII.

Another objective of the present invention is to provide novel intermediate compound 2- [3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula IX.

SUMMARY OF THE INVENTION:

Accordingly the present invention provides a process for the preparation of 2-[3-cyano-4- (2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I;

Formula I

comprising the steps of;

i. formylating the compound of Formula IV

Formula IV

wherein, the groups Rj and R₂ are same, or different; and are independently refers to hydrogen or lower alkyl groups of straight or branched chain of C to C₅ carbon atoms, with polyphosphoric acid in presence of hexamine to obtain the compound of Formula V;

Formula V

wherein, the groups Ri and R₂ are same as defined above,

ii. alkylating the compound of Formula V with the compound .

wherein, X is a halogen atom selected from chlorine, bromine or iodine atom, in presence of a base, an organic solvent and catalyst to obtain the compound of Formula VI;

Formula VI

wherein, the groups Ri and R₂ are same as defined above,

iii. reacting the compound of Formula VI with hydroxyl amine in presence of sodium formate and formic acid to get the compound of Formula VII;

Formula VII

wherein, the groups Ri and R₂ are same as defined above,

which undergoes in-situ hydrolysis to result in compound of Formula I. In another aspect, the present invention provides a process for the preparation of 2-[3- cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I;

Formula I comprising the steps of;

i. reacting the compound of

Formula V

wherein, the groups Rl and R2 are same, or different; and are independently refers to hydrogen or lower alkyl groups of straight or branched chain of CI to C5 carbon atoms

with hydroxylamine in presence of sodium formate and formic acid to get the compound of Formula VIII

Formula VIII

wherein the groups Ri and R₂ are same as defined above, ii. alkylating the compound of Formula VIII with the compound,

wherein X is a halogen atom selected from chlorine, bromine or iodine atom in presence of a base, an organic solvent and catalyst to obtain the compound of Formula VII;

Formula VII

wherein the groups Ri and R₂ are same as defined above,

iii. hydrolyzing the compound of Formula VII using base in presence of solvent and adjusting the pH with dilute acid to result in compound of Formula I.

In yet another aspect, the present invention provides a process for the preparation of 2- [3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of FoiTnula I;

Formula I

comprising the steps of;

a. hydrolyzing the compound of Formula VI,

Formula VI wherein, the groups Ri and R₂ are same, or different; and are independently refer to hydrogen or lower alkyl groups of straight or branched chain of d to C₅ carbon atoms,

using base in presence of organic solvent to isolate the compound of Formula IX,

Formula IX

b. reacting the compound of Formula IX with hydroxylamine in presence of sodium formate and formic acid to isolate the compound of Formula I; and optionally

c. purifying compound of Formula I.

DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a process for the preparation of 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I using novel carboxamide derivative of 2-(4- iazole of Formula IV.

Formula IV

The advantage in using the novel compound of Formula IV is that the carboxamide group is stable and does not get hydrolysed during the formylation reaction with hexamine in presence of polyphosphoric acid, thus avoiding the formation of carboxylic acid impurity. Another advantage of the carboxamide derivative is that it reduces the hydrolysis step by undergoing simultaneous hydrolysis during the preparation of cyano compound using hydroxylamine, sodium formate and formic acid.

In one of the embodiment of the present invention, the carboxamide derivative of 2-(4- hydroxyphenyl)-4-methylthiazole of Formula IV (wherein the groups R\ and R₂ are same as defined above) on formylation reaction with hexamine in presence of polyphosphoric acid results in the carboxamide derivative of 2-(3-formyl-4-hydroxyphenyl)-4- methylthiazole of Formula V. R\ and R₂ as referred in in the compound of Formula IV and Formula V are either hydrogen or the lower alkyl groups of straight or branched chain of Ci to C₅ carbon atoms such as a methyl group, an ethyl group, n-propyl group, an iso-propyl group, n-butyl group, a sec-butyl group, an iso-butyl group, a tert-butyl group, n-pentyl group, etc. The preferred compound of Formula IV and Formula V are where R| and R₂ both are methyl groups.

The formylation reaction is carried out at a temperature in the range of 60°C to 85°C, wherein the preferred temperature for the reaction is 70°C to 80°C and the most preferred temperature for the reaction is 75°C to 80°C. The strength of polyphosphoric acid used ^; for the formylation reaction is 100% to 120%, wherein the preferred strength of polyphosphoric acid used for the reaction is 104% to 112% and the most preferred strength of polyphosphoric acid used is 104% to 107%. Addition of hexamine to the reaction mass is exothermic, so to control the exothermicity, hexamine is added lot wise maintaining the temperature of the reaction in the range of 60°C to 85 °C. After completion of the reaction, the reaction mass is quenched with a mixture of acetic acid and water in the ratio of 1 :28. The reaction mass is cooled and extracted with the organic solvents selected from ethyl acetate, dichloro methane and toluene. The preferred solvent used for the extraction is ethyl acetate. The ethyl acetate layer is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure maintaining the temperature below 60°C to isolate the carboxamide derivative of 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole of Formula V. The starting material, carboxamide derivative of 2-(4-hydroxyphenyl)-4-methylthiazole of Formula IV (wherein the groups Ri and R₂ are methyl) is prepared by reacting 4- hydroxybenzenethioacetamide and N,N-dimethyl-2-chloroacetoacetamide in presence of an organic solvent. The starting compound of Formula IV can also be prepared from ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate. The ester group is hydrolysed using an aqueous solution of sodium hydroxide, isolating the free acid and converting it to corresponding chlorocompound before reacting with dimethyl amine to obtain carboxamide derivative of 2-(4-hydroxyphenyl)-4-methylthiazole of Formula IV (wherein the groups Ri and R₂ are methyl).

In another embodiment of the present invention, the carboxamide derivative of 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole of Formula V is alkylated with a halogen derivative of 2-methylpropane at a temperature in the range of 20°C to 80°C in presence of an organic solvent, a base and catalyst to get the carboxamide derivative of 2-[3- formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole of Formula VI. R_\ and R₂ as referred in in the compound of Formula V and Formula VI are either hydrogen or the lower alkyl groups of straight or branched chain of C_\ to C₅ carbon atoms such as a methyl group, an ethyl group, n-propyl group, an iso-propyl group, n-butyl group, a sec- butyl group, an iso-butyl group, a tert-butyl group, n-pentyl group, etc. The preferred compound of Formula V and Formula VI are where R_\ and R₂ both are methyl groups.

The halogen derivative of 2-methylpropane used in the reaction is selected from 1 - chloro-2-methylpropane, l-bromo-2-methylpropane and l-iodo-2-methylpropane, wherein the preferred compound used for alkylation is l-bromo-2-methylpropane. The base used for the alkylation reaction is selected from sodium carbonate, potassium carbonate and cesium carbonate, wherein the preferred base used for the reaction is potassium carbonate. The catalyst used for the alkylation reaction is selected from potassium iodide, polyethyleneglycol-400, 18-crown-6, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, tetra-butylammonium bromide, tetraamylammonium bromide, trimethylvinylammonium bromide, tetramethylammonium bromide, tetrabutylammonium chloride and trimethylphenylammonium chloride either alone or mixture thereof. The preferred catalyst used for the alkylation reaction is selected from potassium iodide and tetrabutylammonium bromide either alone or mixture thereof, wherein the most preferred catalyst used for the alkylation reaction is potassium iodide.

The organic solvent used for the alkylation reaction is selected from acetone, dimethyl sulfoxide, N,N-dimethylacetamide, Ν,Ν-dimethylformamide, acetonitrile, toluene and tetrahydrofuran, wherein the preferred solvent used for the reaction is acetone, N,N- dimethylformamide and tetrahydrofuran. The preferred temperature for the alkylation reaction is 60°C to 80°C, wherein the most preferred temperature for the reaction is 70°C to 75°C.

In another embodiment of the present invention the carboxamide derivative of 2-[3- formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole of Formula VI is reacted with hydroxylamine in presence of formic acid and sodium formate at temperature in the range of 80°C to 1 15°C for 25 to 45 hours, undergoes simultaneous hydrolysis with the formation of cyano compound to yield 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid of Formula I [Febuxostat]. If desired the compound of Formula I is further purified with hot hexane.

The compound hydroxylamine used in the reaction is in its salt form selected from hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate, wherein the preferred salt used for the reaction is hydroxylamine hydrochloride. Ri and R₂ in the compound of Formula VI is either hydrogen or the lower alkyl groups of straight or branched chain of Q to C₅ carbon atoms such as a methyl group, an ethyl group, n- propyl group, an iso-propyl group, n-butyl group, a sec-butyl group, an iso-butyl group, a tert-butyl group, n-pentyl group, etc. The preferred compound of Formula VI is where Ri and R₂ both are methyl groups. The advantage of the reaction is that the cyanation and the hydrolysis of carboxamide group takes place simultaneously in one step thus reducing the number of steps as well as avoiding the treatment of the intermediate compound with alkali to carry out the hydrolysis of the carboxamide group.

The reaction sequence of the present invention can be represented as shown in Scheme 4 below;

ormu a

Scheme 4

In another embodiment of the present invention, the carboxamide derivative of 2-[3- formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole of Formula VI is reacted with hydroxylamine in presence of formic acid and sodium formate maintaining the temperature in the range of 80°C to 115°C for 3 to 8 hours to form the intermediate carboxamide derivative 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole of Formula VII, which on alkaline hydrolysis in presence of solvent followed by acidification of the reaction mass yields the compound 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I [Febuxostat]. The compound hydroxylamine used in the reaction is in its salt form selected from hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate, wherein the preferred salt used for the reaction is hydroxylamine hydrochloride.

Accordingly the compound of Formula VI is charged in formic acid solution and stirred. The compound hydroxylamine hydrochloride and sodium formate are charged in one lot, stirred and raised the temperature to 100°C to 110°C. Maintained the reaction mixture at 100°C to 110°C for 3 to 5 hours monitoring for complete conversion of carboxamide derivative of Formula VI. After completion of the reaction, cooled the reaction mass and concentrated the reaction mass to remove formic acid under reduced pressure maintaining temperature of the reaction below 65°C.Diluted the residual reaction mass with mixture of solvents of tetrahydroftiran and methanol. The ratio of the mixture of solvents tetrahydroftiran and methanol used is in the range of 2:0.5 to 0.5:2, wherein the preferred ratio of tetrahydroftiran and methanol used is 1 :0.75. Stirred the reaction mass at 25°C to 30°C and charged dilute aqueous solution of sodium hydroxide. The hydrolysis of the carboxamide group is carried out at temperature in the range of 55°C to 60°C. The time taken for the complete hydrolysis of the carboxamide group is between 14 to 20 hours. Concentrated the reaction mass after the complete hydrolysis and diluted the reaction mass with water. Adjusted the pH of the reaction mass to 2 with dilute hydrochloric acid and stirred at 20°C to 30°C. Filtered the precipitated solid compound 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I [Febuxostat] and dried at 65° to 70°C till constant weight.

In another embodiment of the present invention, the carboxamide derivative of 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole of Formula V is reacted with hydroxylamine in presence of formic acid and sodium formate maintaining the temperature in the range of 80°C to 115°C for 3 to 8 hours to isolate the carboxamide derivative 2-(3-cyano-4- hydroxyphenyl)-4-methylthiazole of Formula VIII. Ri and R₂ in the compound of Formula V and Formula VIII is either hydrogen or the lower alkyl groups of straight or branched chain of Cj to C₅ carbon atoms such as a methyl group, an ethyl group, n-propyl group, an iso-propyl group, n-butyl group, a sec-butyl group, an iso-butyl group, a tert- butyl group, n-pentyl group, etc. The preferred compound of Formula V and Formula VIII is where Rj and R₂ both are methyl groups. The compound hydroxylamine used in the reaction is in its salt form selected from hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate, wherein the preferred salt used for the reaction is hydroxylamine hydrochloride. The preferred temperature range for the reaction is 80°C to 100°C, wherein the most preferred temperature for the reaction is between 85°C to 90°C.

In another embodiment of the present invention, the carboxamide derivative 2-(3-cyano- 4-hydroxyphenyl)-4-methylthiazole of Formula VIII is alkylated with a halogen derivative of 2-methylpropane at a temperature in the range of 20°C to 80°C in presence of an organic solvent, a base and catalyst to get the carboxamide derivative of 2-[3-cyano- 4-(2-methylpropoxy)phenyl]-4-methylthiazole of Formula VII. Ri and R₂ in the compound of Formula VII and Formula VIII are either hydrogen or the lower a!kyl groups of straight or branched chain of C\ to C₅ carbon atoms such as a methyl group, an ethyl group, n-propyl group, an iso-propyl group, n-butyl group, a sec-butyl group, an iso- butyl group, a tert-butyl group, n-pentyl group, etc. The preferred compound of Formula VII and Formula VIII are where Ri and R₂ both are methyl groups.

The halogen derivative of 2-methylpropane used in the reaction is selected from 1-chloro- 2-methylpropane, l-bromo-2-methylpropane and l-iodo-2-methylpropane; wherein the preferred compound used for alkylation is l-bromo-2-methylpropane. The base used for the alkylation reaction is selected from sodium carbonate, potassium carbonate and cesium carbonate, wherein the preferred base used for the reaction is potassium carbonate. The catalyst used for the alkylation reaction is selected from potassium iodide, polyethyleneglycol-400, 18-crown-6, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, tetra-butylammonium bromide, tetraamylammonium bromide, trimethylvinylammonium bromide, tetramethylammonium bromide, tetrabutylammonium chloride and trimethylphenylammonium chloride either alone or mixture thereof. The preferred catalyst used for the alkylation reaction is potassium iodide and tetrabutylammonium bromide either alone or mixture thereof, wherein the most preferred catalyst used for the alkylation reaction is potassium iodide.

The organic solvent used for the alkylation reaction is selected from acetone, dimethyl sulfoxide, N,N-Dimethylacetamide, Ν,Ν-dimethylformamide, acetonitrile, toluene and tetrahydrofuran, wherein the preferred solvent used for the reaction is acetone, N,N- dimethylformamide and tetrahydrofuran.The preferred temperature range for the alkylation reaction is 60°C to 80°C, wherein the most preferred temperature for the reaction is 70°C to 75°C.

The compound carboxamide derivative of 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4- trimethylthiazole of Formula VII is subjected to alkaline hydrolysis in the mixture of solvents tetrahydrofuran and methanol to obtain 2-[3-cyano-4-(2-methylpropoxy)phenyl]* 4-methylthiazole-5-carboxylic acid of Formula I [Febuxostat]. The mixture of solvents used is tetrahydrofuran and methanol in the ratio of 2:0.5 to 0.5:2, wherein the preferred ratio of tetrahydrofuran and methanol used is 1 :0.75. Stirred the reaction mass at 25°C to 30°C and charged dilute aqueous solution of sodium hydroxide. The hydrolysis of the carboxamide group is carried out at temperature in the range of 55°C to 60°C. The time taken for the complete hydrolysis of the carboxamide group is between 14 to 20 hours. Concentrated the reaction mass after the complete hydrolysis and diluted the reaction mass with water. Adjusted the pH of the reaction mass to 2 with dilute hydrochloric acid and stirred at 20°C to 30°C. Filtered the precipitated solid compound 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I [Febuxostat] and dried at 65°C to 70°C till constant weight.

The reaction sequence of the present invention can be represented as shown in Scheme 5 below;

Scheme 5

In yet another embodiment of the present invention, the carboxamide derivative of 2- [3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole of Formula VI is subjected to alkaline hydrolysis to isolate 2-[3-formyl-4-(2-methylpropoxy)-phenyl]-4-methylthiazole- 5-carboxylic acid of Formula IX. Ri and R₂ in the compound of Formula VI is either hydrogen or the lower alkyl groups of straight or branched chain of Ci to C₅ carbon atoms such as a methyl group, an ethyl group, n-propyl group, an iso-propyl group, n -butyl group, a sec-butyl group, an iso-butyl group, a tert-butyl group, n-pentyl group, etc. The preferred compound of Formula VI is where Ri and R₂ both are methyl groups. The alkali used for the hydrolysis reaction is aqueous solution of metal hydroxide selected from sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide. The preferred alkali used for hydrolysis is aqueous solution of sodium hydroxide. The hydrolysis reaction is carried out in solvent media selected from methanol, ethanol, propanol, isopropanol, toluene, hexane, cyclohexane and tetrahydrofuran either alone or mixture thereof. The preferred solvent used for the hydrolysis reaction is mixture of tetrahydrofuran and methanol. The ratio of the mixture of solvents tetrahydrofuran and methanol is 2: 0.5 to 0.5: 2, wherein the preferred ratio of tetrahydrofuran and methanol used is 1: 0.75. The hydrolysis of the carboxamide group is carried out at temperature in the range of 55°C to 60°C. The time taken for the complete hydrolysis of the carboxamide group is between 14 to 20 hours. To isolate the carboxylic acid compound, concentrated the reaction mass after the complete hydrolysis and diluted the residual mass with water. Adjusted the pH of the reaction mass to 2 with dilute hydrochloric acid and stirred at 20°C to 30°C. Filtered the precipitated solid compound 2-[3-formyl-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula IX and dried at 65°C to 70°C till constant weight.

In yet another embodiment of the present invention, the compound 2-[3-formyl-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula IX is reacted with hydroxylamine in presence of formic acid and sodium formate maintaining the temperature in the range of 80°C to 115°C for 3 to 8 hours to isolate the compound 2-[3- cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid of Formula I [Febuxostaf]. The compound hydroxylamine used in the reaction is in its salt form selected from hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate, wherein the preferred salt used for the reaction is hydroxylamine hydrochloride. The preferred temperature range for the reaction is 80°C to 100°C, wherein the most preferred temperature for the reaction is between 85°C to 90°C.

The reaction sequence of the present invention can be represented as shown in Scheme 6 below;

Scheme 6

The process according to the present invention provides a novel intermediate of formula IV;

Formula IV

wherein, Rj and R₂ are as defined above.

Also disclosed herein, is a novel intermediate of Formula V;

Formula V

wherein, R] and R₂ are as defined above. Also disclosed herein, is a novel intermediate of Formula VI;

Formula VI

wherein, Rj and R₂ are as defined above.

Also disclosed herein, is a novel intermediate of Formula VII;

Formula VII

wherein, Ri and R₂ are as defined above.Also disclosed herein, is a novel intermediate of Formula VII

Formula VIII

wherein, Ri and R₂ are as defined above.

Certain specific aspects and embodiments of the present invention is further illustrated in detail with reference to the following examples, which are provided solely for the purpose of illustration and are not to be construed as limiting the scope of the invention in any manner. EXAMPLES:

Example 1: Preparation of 2-(4-hydroxyphenyl)-N,N-4-trimethylthiazole-5- carboxamide:

Charged 4-hydroxybenzenethioacetamide (10.0 gm) and N,N-dimethyl 2- chloroacetoacetamide (11.7 gm) in isopropyl alcohol (100 ml) at 25°-30°C under stirring. Raised the reaction temperature to reflux and maintained. After complete conversion of starting material, cooled the reaction mixture to 5°-10°C and maintained under stirring for 30 minutes at 5°-10°C. Filtered the solid and washed with cold isopropyl alcohol (50 ml) and dried at 60°-65°C till constant weight. m. p.: 139.6°-139.8°C.

Ή-NMR (DMSO-d₆) 400 MHz: δ (ppm) 2.36 (s, 3 H), 2.98 (s, 6 H), 6.84 (d, 2H), 6.84 (d, 2H, J=8.8 Hz), 7.73 (d, 2H, J=8.4 Hz), 10.07 (bs, lH); ^,3C-NMR (DMSO-d₆): δ (ppm) 16.80, 116.46, 124.04, 124.25, 128.47, 152.02, 160.38, 163.19, 167.01.

IR (cm^-1): 2962.4, 2804.6, 1585.3, 1425.2.

MS (M+l): 263.2.

Yield = 14.55 gm

% yield = 86.7

Example 2: Preparation of 2-(3-formyl-4-hydroxyphenyl)-N,N-4-trimethyIthiazoIe- 5-carboxamide:

Charged polyphosphoric acid (140.0 gm of 105% strength) and 2-(4-hydroxyphenyl)- N,N-4-trimethylthiazole-5-carboxamide (20 gm) in a dry flask. Raised the temperature of the mixture under stirring to 70°-72°C and maintained for 30 minutes. To the clear solution charged hexamine (21.3 gm) in lots maintaining temperature at 70°-72°C. After complete addition, raised the temperature of the reaction mixture to 75°-78°C and maintained for 4-5 hours. Monitored the reaction on TLC for complete conversion of starting material. After completion of the reaction charged mixture of acetic acid: water (290 ml, 1:28) to the reaction mixture maintaining temperature at 75°-78°C. Reaction mixture was stirred and gradually cooled to 30°-35°C. Extracted the reaction mixture using ethyl acetate (3x150 ml). Combined ethyl acetate layers, washed with aqueous sodium bicarbonate solution (150 ml), dried over anhydrous sodium sulfate and filtered. Concentrated the filtrate under vacuum below 55°C to get the solid product of 2-(3- formyl-4-hydroxyphenyl)-N,N-4-trimethylthiazole-5-carboxamide. m. p.: 125.8°-127.0°C.

!H-NMR (DMSO-d₆) 400 MHz: δ (ppm) 2.35 (s, 3H), 2.98 (s, 6H), 7.10 (d, 1H, J=8.8 Hz), 8.03 (dd, 1H, J=2.0 Hz, J=8.8 Hz), 8.14 (d, 1H, J=2.0 Hz), 10.30 (s, 1H); ¹³C- NMR (DMSO-d₆): δ (ppm) 16.74, 118.84, 123.07, 124.59, 124.87, 126.92, 134.22, 152.27, 162.96, 165.66, 191.0.

IR icm ): 3020.1, 2925.5, 1666.4, 1630.9, 1292.9.

MS (M+1): 291.2.

Yield = 18.0 gm

% yield = 81.3

Example 3: Preparation of 2-[3-formyl-4-(2-methyIpropoxy)phenyl]-N,N-4- triniethylthiazole-5-carboxamide:

Charged 2-(3-formyl-4-hydroxyphenyl)-N,N-4-trimethylthiazole-5-carboxamide (20 gm) and dimethylformamide (100 ml) at 25°-30°C and stirred for 15 minutes. Charged potassium carbonate (38.0 gm) and potassium iodide (4.5 gm) to the reaction mixture and raised the temperature of reaction mixture to 70°-72°C. Added l-bromo-2-methylpropane solution in dimethylformamide (37.6 gm in 40 ml) maintaining temperature at 70°-72°C. Further maintain the reaction mixture at 70°-72°C for 4-5 hours. Monitored the reaction on TLC for complete conversion of starting material. Cooled the reaction mixture to 25°- 30°C and charged with water (300 ml) and ethyl acetate (50 ml). Extracted the aqueous layer with ethyl acetate (2x150 ml). Combined ethyl acetate layers, washed with saturated sodium chloride solution (150 ml), dried over anhydrous sodium sulfate and filtered. Concentrated the filtrate under vacuum to obtain the solid product of 2-[3-formyl-4-(2- methylpropoxy)phenyl]-N,N-4-trimethylthiazole-5-carboxamide. m. p.: 95.5°-99.5°C.

'H-NMR (DMSO-d₆) 400 MHz: δ (ppm) 1.01 (d, 6H, J=6.4 Hz), 2.10 (m, 1H), 2.36 (s, 3H), 2.99 (s, 6H), 3.97 (d, 2H, J=6.4 Hz), 7.32 (d, 1H, J=8.8 Hz), 8.11 (d, 1H, J=2.0 Hz), 8.14 (s, 1H), 10.39 (s, 1H); ¹³C-NMR (DMSO-d₆): δ (pppm) 16.68, 19.33, 28.18, 75.17, 114.78, 124.78, 125.18, 125.46, 125.70, 134.11, 152.34, 162.79, 165.23, 188.92.

IR (cm ¹): 3075.2, 2957.4, 2852.9, 1686.1, 1630.7, 1602.9.

MS (M+l): 347.1.

Yield = 22.0 gm

% yield = 92.2

Example 4: Preparation of 2-[3-formyl-4-(2-methylpropoxy)phenyl]-N,N-4- trimethylthiazole-5-carboxamide:

Charged 2-(3-formyl-4-hydroxyphenyl)-N,N-4-trimethylthiazole-5-carboxamide (20.0 gm) and dimethylformamide (100 ml) at 25°-30°C and stirred for 15 minutes. Charged potassium carbonate (38.0 gm), tetrabutylammonium bromide (2.3 gm) and potassium iodide (4.5 gm) to the reaction mixture, stirred and raised the temperature of reaction mixture to 55°-60°C. Added l-bromo-2-methylpropane solution in tetrahydrofuran (19 gm in 19 ml) maintaining temperature at 55°-60°C. Further maintain the reaction mixture at 62°-65°C for 6-8 hours. Monitored the reaction on TLC for complete conversion of starting material. Concentrated the reaction mixture under reduced pressure maintaining temperature below 40°C till one to two volume of solvent remained in the reaction. Cooled the reaction mixture to 25°-30°C and diluted the residual mixture with water (50 ml) and ethyl acetate (50ml). Extracted the aqueous layer with ethyl acetate (2x50 ml). Combined ethyl acetate layers, washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get the solid product of 2-[3-formyl-4-(2-methylpropoxy)phenyl]-N,N-4-trimethylthiazole-5- carboxamide.

Yield = 22.2 gm

% yield = 93.1

Example 5: Preparation of 2-[3-cyano-4-(2-methyIpropoxy)phenyl]-4- methyIthiazole-5-carboxylic acid [Febuxostat]:

Charged 2-[3-formyl-4-(2-methylpropoxy)phenyl]-N,N-4-trimethylthiazole-5- carboxamide (10 gm) and formic acid (60 ml) at 25°-30°C, stirred for 15 minutes. To the reaction mixture, under stirring, charged hydroxylamine hydrochloride (2.1 gm) and sodium formate (2.9 gm). Raised the temperature of reaction mixture to 100°-105°C and maintained. Monitored the reaction progress on TLC for the absence of nitrile intermediate formed during the reaction. After completion, the reaction mixture was cooled to 25°-30°C and charged water (100 ml). Stirred the reaction mixture for 1 hour and filtered the crude solid mass. Purified the crude solid mass with hot hexane to get the pure Febuxostat.

Yield = 6.90 gm

% yield = 75.6

Example 6: Preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid [Febuxostat]:

Charged 2-[3-formyl-4-(2-methylpropoxy)phenyl]-N,N-4-trimethylthiazole-5- carboxamide (10 gm) and formic acid (60 ml) at 25°-30°C, stirred for 15 minutes. To the reaction mixture, under stirring, charged hydroxylamine hydrochloride (2.1 gm) and sodium formate (2.9 gm). Raised the temperature of reaction mixture to 100°-105°C and maintained for 3-5 hours. Monitored the reaction progress on TLC for the absence of oxime intermediate formed during the reaction. Cooled the reaction mixture to 60°-65°C and concentrated under reduced pressure to remove formic acid below 45°C. Diluted the residual mass with mixture of tetrahydrofuran and methanol (10 ml: 7.5 ml). Charged aqueous sodium hydroxide solution (7.0 ml, IN) to the reaction mixture and raised the temperature to 55°-60°C. Maintained the reaction for 15-18 hours at 55°-60°C and monitored on TLC for the absence of starting material. Concentrated the reaction mass under reduced pressure below 45°C and diluted the reaction mass with water (150 ml). Adjusted the pH of the reaction mass to 2 with 1: 1 aqueous hydrochloric acid and stirred at 20°-30°C. Filtered the precipitated solid mass to get 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid [Febuxostat].

Yield = 7.00 gm

% yield = 76.7 Example 7: Preparation of 2-(3-cyano-4-hydroxyphenyl)-N,N-4-trimethylthiazole-5- carboxamide:

Charged 2-(3-formyl-4-hydroxyphenyl)-N,N-4-trimethylthiazole-5-carboxamide (3.0 gm) and formic acid (18 ml) at 25°-30°C, stirred for 15 minutes. To the reaction mixture under stirring charged hydroxylamine hydrochloride (0.79 gm) and sodium formate (1.05 gm). Raised the temperature of the reaction mixture to 85°-90°C and maintained for 3-5 hours. Monitored the reaction progress on TLC for the absence of oxime intermediate formed during the reaction. Cooled the reaction mixture to 25°-30°C and charged water (50 ml). Stirred the reaction mixture for 1 hour and filtered the solid mass to obtain 2-(3-cyano-4- hydroxyphenyl)-N,N-4-trimethylthiazole-5-carboxamide. m. p.: 228.4°-228.8°C.

Ή-NMR (DMSO-d₆) 400 MHz: δ (ppm) 2.36 (s, 3H), 3.00 (s, 6H), 7.13 (d, 1H, J=8.0 Hz), 8.06 (dd, 1H, J=4, 8 Hz), 8.12 (m, 1H), 11.78 (bs, 1H); ¹³C-NMR (DMSO-d₆): δ (ppm) 16.7, 100.2, 1 16.6, 117.5, 124.8, 125.3, 131.5, 133.0, 152.1, 162.4, 162.8, 164.7. IR (cm^-1): 2935.8, 2741.9, 2232.0, 1600.3, 1449.5, 1408.8.

MS (M+1): 288.1.

Yield = 2.30 gm

% yield = 77.4

Example 8: Preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-N,N-4- trimethyIthiazole-5-carboxamide:

Charged 2-(3-cyano-4-hydroxyphenyl)-N,N-4-trimethylthiazole-5-carboxamide (5.0 gm) and dimethyl formamide (25 ml) at 25°-30°C, stirred for 15 minutes. Charged potassium carbonate (9.6 gm) and potassium iodide (1.2 gm) to the reaction mixture, and raised the temperature under stirring to 70°-72°C. Added solution of 1-bromo 2-methylpropane in dimethylformamide (9.5 gm in 10 ml) maintaining temperature at 70°-72°C. Maintained the reaction at 70°-72°C for 4-5 hours. Monitored the reaction on TLC for complete conversion of starting material. Cooled the reaction mixture to 25°-30°C and charged water (150 ml) and ethyl acetate (150 ml). Extracted the aqueous layer with ethyl acetate (2x75 ml). Combined ethyl acetate layers, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate and filtered. Concentrated the filtrate under vacuum to obtain solid product of 2-[3-cyano-4-(2-methylpropoxy)phenyl]- N,N-4-trimethylthiazole-5-carboxamide. m. p.: 95.5°-99.5°C.

1H-NMR (DMSO-de) 400 MHz: δ (ppm) 1.00 (d, 6H, J=6.4 Hz), 2.07 (m, IH), 2.36 (s, 3H), 2.99 (s, 6H), 3.97 (d, 2H, J=6.4 Hz), 7.35 (d, IH, J=8.8 Hz), 8.16 (dd, IH, J=2.0 Hz, J=8.0 Hz), 8.21 (s, IH); ¹³C-NMR (DMSO-d₆): δ (ppm) 16.66, 19.15, 28.06, 75.52, 101.94, 114.27, 115.88, 125.76, 125.95, 131.56, 133.11, 152.21, 162.10, 162.74, 164.29. IR (cm-¹): 2963.87, 1227.51, 1608.84, 1570.37, 1280.74.

MS (M+1): 344.1.

Yield = 5.50 gm

% yield = 92.0

Example 9: Preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methyIthiazole-5-carboxyIic acid [Febuxostat]:

Charged 2-[3-cyano-4-(2-methylpropoxy)phenyl]-N,N-4-trimethylthiazole-5- carboxamide (10 gm), in solvent mixture of tetrahydrofuran and methanol (100 ml: 75 ml). Stirred at 25°-30°C and charged aqueous sodium hydroxide solution (50 ml, IN) to the reaction mixture and raised the temperature to 55°-60°C. Maintained the reaction for 15-18 hours at 55°-60°C and monitored on TLC for the absence of starting material. Concentrated the reaction mass under reduced pressure below 55°C and diluted the residual mass with water (200 ml). Adjusted the pH of the reaction mixture to 2 with 1 :1 aqueous hydrochloric acid and stirred at 20°-30°C. Filtered the precipitated solid mass to get 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid [Febuxostat].

Yield = 7.60 gm

% yield = 82.5

Example 10: Preparation of 2-[3-formyl-4-(2-methylpropoxy)phenyl]-N,N-4- trimethylthiazole-5-carboxylic acid:

Charged 2-[3-formyl-4-(2-methylpropoxy)phenyl]-N,N-4-trimethylthiazole-5- carboxamide (10.0 gm), in solvent mixture of tetrahydrofuran and methanol (1.0 ml: 7.5 ml). Stirred at 25°-30°C and charged aqueous sodium hydroxide solution (7 ml, IN) to the reaction mixture, raised the temperature to 55°-60°C. Maintained the reaction for 15- 18 hours at 55°-60°C and monitored on TLC for the absence of starting material. Concentrated the reaction mass under reduced pressure below 45°C and diluted the residual mass with water (150 ml). Adjusted the pH of the reaction mixture to 2 with 1:1 aqueous hydrochloric acid and stirred at 20°-30°C. Filtered the precipitated solid mass to get 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid. m. p. = 215.0°-219.0°C.

'H-NMR (DMSO-d₆) 400 MHz: δ (ppm) 0.95 (d, 6H, J=6.6 Hz), 0.96 (s, 3H), 2.00 (m, 1H), 2.53 (s, 3H), 3.96 (d, 2H, J=6.4 Hz), 7.30 (d, 2H, J=8.7 Hz), 8.13-8.17 (m, 2H), 10.38 (s, 1H), 103.36 (bs, 1H); ¹³C-NM (DMSO-d₆): δ (ppm) 17.06, 18.93, 27.73, 74.79, 114.42, 122.39, 124.33, 124.84, 125.67, 134.06, 159.61, 162.73, 162.88, 167.14, 188.55.

IR (cm-'): 2963.2, 2873.6, 1678.7, 1606.5, 1285.5

MS (M+l): 320.0.

Yield = 8.55 gm

% yield = 92.7

Example 11: Preparation of 2-[3-cyano-4-(2-methylpropoxy)pb.enyI]-4- methylthiazole-5-carboxylic acid [Febuxostat]:

Charged 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (8.0 gm) and formic acid (48 ml) at 25°-30°C, stirred for 15 minutes. To the reaction mixture under stirring charged hydroxylamine hydrochloride (2.06 gm) and sodium formate (2.68 gm). Raised the temperature of the reaction mixture to 100°-105°C and maintained for 2-3 hours. Monitored the reaction progress on TLC for the absence of aldoxime intermediate formed during the reaction. Cooled the reaction mixture to 25°- 30°C and charged water (200 ml). Stirred the reaction mixture for 1 hour and filtered the solid mass to obtain 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5- carboxylic acid [Febuxostat].

Yield = 7.20 gm

% yield = 90.9

Claims

We Claim,

1. A process for preparation of ^'2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid of Formula-I;

Formula I

comprising the steps of;

formylating the compound of Formula IV

Formula IV

wherein the groups i and R₂ are same, or different; and are independently refer to hydrogen or lower alkyl groups of straight or branched chain of Q to C₅ carbon atoms,

with hexamine in presence of polyphosphoric acid to obtain the compound of Formula V;

Formula V

wherein the groups Ri and R₂ are same as defined above,

b. alkylating the compound of Formula V with an alkylating agent

H₃C

/ \

H₃C X

wherein X is a halogen atom selected from chlorine, bromine or iodine atom, in presence of a base, an organic solvent and catalyst to obtain the compound of Formula VI;

Formula VI

wherein the groups Ri and R₂ are same as defined above,

reacting the compound of Formula VI with hydroxyl amine in presence of formate and formic acid mixture to get the compound of Formula VII;

Formula VII

wherein, the groups Ri and R₂ are same as defined above,

which undergoes in-situ hydrolysis to result in compound of Formula 1; and optionally

purifying the compound of Formula I.

The process according to claim 1 ; wherein the polyphosphoric acid used in step (a) has strength in the range of 100% to 120%.

The process according to claim 1 ; wherein the alkylating agent used for alkylation reaction in step (b) is selected from l-chloro-2-methylpropane, l-bromo-2- methylpropane and l-iodo-2-methylpropane.

The process according to claim 3; wherein the alkylating agent used for the alkylation reaction is l-bromo-2-methylpropane.

The process according to claim 1 ; wherein the organic solvent used for the alkylation reaction in step (b) is selected from acetone, dimethyl sulfoxide, N,N- dimethylacetamide, Ν,Ν-dimethylformamide, acetonitrile, toluene and tetrahydrofuran.

6. The process according to claim 1; wherein the catalyst used for the alkylation reaction in step (b) is selected from potassium iodide, polyethyleneglycol-400, 18- crown-6, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, tetrabutylammonium bromide, tetraamylammonium bromide, trimethylvinylammonium bromide, tetramethylammonium bromide, tetrabutylammonium chloride and trimethylphenylammonium chloride either alone or in mixture thereof.

7. The process according to claim 6; wherein the preferred catalyst used for the reaction is potassium iodide and tetrabutylammonium bromide either alone or in mixture thereof.

8. The process according to claim 1 ; wherein R_\ and R₂ are methyl.

9. A process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid of Formula-I;

Formula-I comprising the steps of;

a. formylating the compound of Formula IV

Formula IV

wherein, the groups Rj and R₂ are same or different and are independently refer to hydrogen or lower alkyl groups of straight or branched chain of C\ to C₅ carbon atoms, with hexamine in presence of polyphosphoric acid to obtain the compound of Formula V

Formula V

wherein, the groups Ri and R₂ are same as defined above,

reacting the compound of Formula V with hydroxylamine in presence of sodium formate and formic acid mixture to get the compound of Formula VIII;

Formula VIII

wherein, the groups Ri and R₂ are same as defined above,

alkylating the compound of Formula VIII with an alkylating agent,

wherein, X is a halogen atom selected from chlorine, bromine or iodine atom, in presence of a base, an organic solvent and catalyst to obtain the compound of Formula VII;

Formula VII

wherein, the groups Ri and R₂ are same as defined above,

hydrolyzing the compound of Formula VII using base in presence of solvent to result in the compound of Formula I.

10. The process according to claim 9; wherein the polyphosphoric acid used in step (a) has strength in the range of 100% to 120%.

11. The process according to claim 9; wherein the alkylating agent used for alkylation reaction in step (c) is selected from l-chloro-2-methylpropane, l-bromo-2- methylpropane and l-iodo-2-methylpropane.

12. The process according to claim 11; wherein the preferred alkylating agent used for the alkylation reaction is l-bromo-2-methylpropane.

13. The process according to claim 9; wherein the organic solvent used for the alkylation reaction in step (c) is selected from acetone, dimethyl sulfoxide, N,N- dimethylacetamide, Ν,Ν-dimethylformamide, acetonitrile, toluene and tetrahydrofuran.

14. The process according to claim 9; wherein the catalyst used for the alkylation reaction in step (c) is selected from potassium iodide, polyethyleneglycol-400, 18- crown-6, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, tetrabutylammonium bromide, tetraamylammonium bromide, trimethylvinylammonium bromide, tetramethylammonium bromide, tetrabutylammonium chloride and trimethylphenylammonium chloride either alone or in mixture thereof.

15. The process according to claim 14; wherein the preferred catalyst used for the reaction is potassium iodide and tetrabutylammonium bromide either alone or in mixture thereof.

16. The process according to claim 9; wherein the base used in step (d) for the hydrolysis reaction is aqueous sodium hydroxide.

17. The process according to claim 9; wherein the solvent used in step (d) for the hydrolysis reaction is mixture of tetrahydrofuran and methanol.

18. The process according to claim 17; wherein the ratio of solvent tetrahydrofuran and methanol is 2:0.5 to 0.5:2.

19. The process according to claim 9; wherein the hydrolysis reaction in step (d) is carried out at temperature of 55°C to 60°C.

20. The process according to claim 9; wherein the compound of Formula I in step (d) is isolated by adjusting pH upto 2 with dilute mineral acid.

21. The process according to claim 20; wherein the dilute mineral acid is dilute hydrochloric acid.

22. The process according to claim 9; wherein Ri and R₂ are methyl.

23. A process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4- methylthiazole-5-carboxylic acid of Formula-I;

comprising the steps of;

a. hydrolysing the compound of Formula VI

Formula VI

wherein, the groups Ri and R₂ are same, or different; and are independently refers to hydrogen or lower alkyl groups of straight or branched chain of Ci to C₅ carbon atoms,

using base in presence of organic solvent to isolate the compound of Formula IX;

Formula IX

reacting the compound of Formula IX with hydroxylamine in presence sodium formate and formic acid to isolate the compound of Formula I; and optionally purifying compound of Formula I.

24. The process according to claim 23; wherein the base used in step (a) for the hydrolysis reaction is aqueous sodium hydroxide.

25. The process according to claim 23; wherein the organic solvent used in step (a) for the hydrolysis reaction is mixture of tetrahydrofuran and methanol.

26. The process according to claim 25; wherein the ratio of solvent tetrahydrofuran and methanol is 2:0.5 to 0.5:2.

27. The process according to claim 23; wherein the hydrolysis reaction in step (a) is carried out at temperature of 55°C to 60°C.

28. The process according to claim 23; wherein the compound of Formula IX in step (a) is isolated by adjusting pH up to 2 with dilute mineral acid.

29. The process according to claim 28; wherein the dilute mineral acid is dilute hydrochloric acid.

30. The process according to claim 23; wherein Ri and R₂ are methyl.

31. A novel intermediate compound of formula IV;

Formula IV

wherein Ri and R₂ are same, or different; and are independently refer to hydrogen lower alkyl groups of straight or branched chain of CI to C5 carbon atoms.

A novel intermediate compound of formula V,

Formula V

where Ri and R₂ are same, or different; and are independently refer to hydrogen or lower alkyl groups of straight or branched chain of CI to C5 carbon atoms.

33. A novel intermediate compound of formula VI;

Formula VI

where Ri and R₂ are same, or different; and are independently refer to hydi lower alkyl groups of straight or branched chain of CI to C5 carbon atoms.

A novel intermediate comp

Formula VII

A novel intermediate compound of formula VIII,

Formula VIII

where R\ and R₂ are same, or different; and are independently refer to hydrogen or lower alkyl groups of straight or branched chain of CI to C5 carbon atoms.