FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Process for the preparation of 2-aryl thiazole derivative"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mum bai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to one pot process for the preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I.
BACKGROUND AND PRIOR ART:
The compound 2-(3-cyano-4-isobutoxyphenyl)-4-methy]-5-thiazolecarboxylic acid of Formula-I having international non proprietary name febuxostat is used in the treatment of hyperuricemia. Febuxostat is a non-purine selective inhibitor of xanthine oxidase which reduces production of uric acid.

Formula-I The US patent US5614520 discloses the preparation of the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, wherein the compound 4-hydroxy-3-nitrobenzaldehyde of Formula-11 is heated with hydroxylamine hydrochloride and sodium formate in presence of formic acid to get the compound 4-hydroxy-3-nitrobenzonitrile of Formula-Ill, which on reaction with thioacetamide in presence of hydrogen chloride in N,N-dimethylformamide yields the compound 4-hydroxy-3-nitrobenzthioamide of Formula-IV, The compound of Formula-IV on reaction with ethyl 2-chloroacetoacetate undergoes cyclisation to yield the compound ethyl 2-(4-hydroxy-3-nitropheny])-4-methyl-5-thiazolecarboxylate of Formula-V. The compound of Formula-V on O-alkylation with 1 -bromo-2-methylpropane in presence of dimethylformamide, potassium iodide and potassium carbonate results in the compound ethyl 2-(4-isobutoxy-3-nitro-phenyl)-4-methyl-5-thiazolecarboxylate of Formula-VI, which after crystallization from ethanol taken for the next stage. The nitro compound of Formula-VI 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-isobutoxyphenyl)-4-methylthiazole-5-carboxylate of Formula-VII. The amino compound of Formula-Vli 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-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate of Formula-VIII. The compound of Formula-VIII is taken in mixture of solvents ethanol and tetrahydrfuran 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-isobutoxyphenyl)-4-methyl-5-thiazoIecarboxylic acid of Formula-I. The reaction sequence is as shown in Scheme-1 below;

Scheme-1 The drawbacks of the above process are;
i. use of hazardous potassium cyanide for introduction of -CN group which is
poisonous and unsafe to handle on large scale; ii. it involves column chromatography for purification of intermediates;

iii. uses mixture of organic solvents ethanol and tetrahydrofuran for ester hydrolysis to isolate the compound of Formula-I.
It is evident from the prior art that there remains a need for an improved process to prepare the compound 2-(3-cyano-4-isobutoxypheny])-4-methyl-5-thiazolecarboxyIic acid of Formula-I, overcoming the use of hazardous chemicals, limitations of column chromatography for purification of intermediates, mixture of solvents and multiple process steps to obtain the compound of Formula-I by providing cost effective and industrially useful process.
Therefore it becomes the objective of the present invention to prepare the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I by avoiding the use of hazardous chemical and carrying out both alkylation and hydrolysis reactions in one pot reducing the number of steps.
It is also the objective of the present invention to prepare pure compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I with cost effective and industrially useful process.
Yet another objective of the present invention is to carry out hydrolysis of the compound of Formula-VIII in single solvent to get the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I.
SUMMARY OF THE INVENTION:

Formula-I
comprising the steps of;
Accordingly the present invention provides a process for preparation of the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I;



i. O-alkylation of the compound ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylate of Formula-IX ;
Formula-IX with halo derivative 2-methylpropane of Formula-X
Where X = CI, Br or 1.
ii. followed by in-situ hydrolysis of the intermediate compound ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate of Formula-VIII to isolate the compound of Formula-I.
In another aspect of the present invention provides a process for preparation of compound of formula I by O-alkylation of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-mefhyl-thiazole-5-carboxylate of Formula-IX with 2- methyl halo propane of Formula-X to obtain compound of formula VIII. The compound of formula VIII thus obtained is isolated and further hydrolyzed to obtain compound of formula I.
The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the appended examples and claims.
DESCRIPTION OF THE INVENTION:
Accordingly the present invention describes a process for the preparation of the
compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid
(Febuxostat) of Formula-I by carrying out O-alkylation of compound of Formula-IX and ester hydrolysis of the compound of Formula-VII in one-pot process using single solvent.

In one embodiment of the present invention the compound ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazoIe-5-carboxylate of Formula-IX is reacted with halo derivative of 2-methyIpropane in presence of polar aprotic solvent, potassium iodide and base at the temperature in the range of 40°C - 800C. The halo derivative of 2-methylpropane is selected from chloro, bromo and iodo compound wherein the preferred halo derivative used is l-bromo-2-methylpropane. The polar aprotic solvent used for the O-alkylation reaction is selected from N,N-dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, wherein the preferred solvent used is N,N-dimethylacetamide and N-methyl-2-pyrrolidone. The most preferred solvent used for the alkylation reaction is N-methyl-2-pyrroIidone. The reaction is carried out at preferred temperature of 60°C -80°C, wherein the most preferred temperature used for the reaction is 70°C - 75°C.
The compound ethyl 2-(3-cyano-4-hydroxyphenyl)-4-rnethyithiazole-5-carboxylate of Formula-IX used as starting material can be prepared as per the processes disclosed in Japanese publication 3P06S29647.
Accordingly the compound ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate of Formula-IX is taken in the preferred polar aprotic solvent containing the base potassium carbonate and catalytic amount of potassium iodide. The temperature of the reaction mixture is raised to 70°C. Addition of solution of halo derivative of 2-methyipropane prepared in the same solvent is carried out maintaining the temperature at 70°-75°C. The reaction is maintained at the temperature of 70°-75°C for 3-5 hours. After completion of reaction, cooled the reaction mixture to 25°-35°C and charged aqueous solution of sodium hydroxide. Raised the temperature and maintained the reaction mixture at 60°-65°C for 1-2 hours. After completion of the hydrolysis, the reaction mass is cooled to 25°-30°C and adjusted the pH of the reaction mixture to 1-2 using dilute hydrochloric acid. Stirred and filtered the solid to isolate the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I. The compound is optionally purified in ethanol to get the pure compound 2-(3-cyano-4-isobutoxyphenyI)-4-methyl-5-thiazolecarboxylic acid of Formula-I. The reaction sequence of this embodiment can be represented as per the Scheme-2 below;


The reaction of O-alkylation and hydrolysis of the ester group in the preferred polar aprotic solvents gives the advantage of one-pot reaction, avoids the isolation of the intermediate compound, easy isolation of product avoiding solvent extraction and concentration of solvent and reduces one step of processing, This makes the process economical and rigid at industrial scale preparation of the compound. This is not feasible when the reaction of O-alkylation is carried out in the disclosed polar aprotic solvent used in prior art, where one has to isolate the intermediate compound before taking for hydrolysis.
Alternatively, in another embodiment of the present invention the compound ethyl 2-(3-cyano-4-hydroxy-phenyl)-4-methylthiazole-5-carboxylate of Formula-IX is alkylated to give the compound ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate of Formulau-IIII, which is isolated and hydrolysed in single solvent yields the compound 2-(3-cyano-4-isobutyl-oxyphenyI)-4-methyl-5-thiazoIecarboxylic acid of FormuIa-I. Accordingly the compound ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthaizole-5-carboxylate of Formula-IX is taken in the preferred polar aprotic solvent containing the base potassium carbonate and catalytic amount of potassium iodide. The temperature of :he reaction mixture is raised to 70°C. Addition of solution of halo derivative of 2-methylpropane in the same solvent is carried out maintaining the temperature at 70°-75°C. The reaction is maintained at temperature of 70°-75°C for 3-5 hours. After completion of the reaction, reaction mixture is cooled to 25°-30°C and water is added as liluent. Stirred the reaction mass for 30 minutes to one hour. The solid separated is iltered to isolate the alkylated compound ethyl 2-(3-cyano-4-isobutoxypheny])-4-nethylthiazole-5-carboxylate of Formula-VIII.

As per the embodiment of the present invention the isolated compound of Formula-VIII is taken in the single solvent selected from acetone, methyl ethyl ketone, acetonitrile, N,N-dim ethyl acetamide and N-methyl-2-pyrrolidone. Aqueous solution of sodium hydroxide is charged and the reaction mixture is heated to 55°-60°C and further maintained for one hour. After the complete hydrolysis the reaction mixture is cooled to 45°C and concentrated under reduced pressure to get the residual mass. Water is charged to the residual mass and adjusted the pH to 1-2 using dilute hydrochloric acid to precipitate the solid. Filtered the solid product to isolate the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-]. The compound is optionally purified in ethanol to get the pure compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I. The reaction sequence of this embodiment can be represented as per the Scheme-3 below;

Scheme-3
The present invention is further illustrated in detail with reference to the following examples. It is desired that the example be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
EXAMPLES:
Example 1: Preparation of 2-(3-cyano-4-isobotoxyphenyl)-4-methyl-5-thiazoIe carboxylic acid of Formula-I [Febuxostat; One-pot reaction]
In a dry flask charged N-methyl-2-pyrrolidone (40.0 ml), ethyl 2-(3-cyano-4-hydroxyphenyI)-4-methylthiazole-5-carboxylate (5.0 gm) potassium iodide (1.14 gm), stirred and charged potassium carbonate (9.55 gm). Raised the temperature of the reaction mixture to 70°-72°C and stirred for 5 mins. Added drop wise solution of l-bromo-2-methy]propane in N-methyl-2-pyrrolidone (7.11 gm in 10 ml) to the reaction mixture and

maintained at 70°-72°C under stirring for 3 hours. After complete conversion of starting
material monitoring on TLC/ HPLC, cooled the reaction mixture to 30°-35°C and charged
aqueous solution of sodium hydroxide (2.42 gm in 35 ml) to the reaction mixture.
Maintained the reaction mixture for 1 hour under stirring at 60°-65°C. Monitored the
reaction by TLC, after complete hydrolysis of the starting material, stopped heating and
cooled the reaction mixture to 25°-30°C. Adjusted pH of the reaction to 1-2 with aqueous
hydrochloric acid (1:1, 15 ml). Stirred the reaction mixture at 25°-30°C for 30
minutes and filtered the solid, washed with water and dried till constant weight to get the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazole-carboxylic acid. Yield = 4.20 gm % yield = 76.5
Example 2: Preparation of ethyl 2-(3-cyano-4-isobatoxyphenyl)-4-methylthaizole-5-carboxylate
In a dry flask charged N-methyl-2-pyrrolidone (105 ml), ethyl 2-(3-cyano-4-
hydroxyphenyl)-4-methylthiazole-5-carboxylate (15.0 gm), potassium iodide (1.14 gm),
stirred and charged potassium carbonate (28.7 gm). Raised the temperature of the reaction
mixture to 70°-72°C and stirred for 5 mins. Added drop wise solution of 1-bromo-
2-methylpropane in N-methyl-2-pyrrolidone (28.5 gm in 30 ml) to the reaction mixture and maintained at 70°-72°C under stirring for 3 hours. Monitored the reaction by TLC, after completion of reaction, stopped heating and cooled the reaction mixture to 25°-30°C. Charged water (330 ml) and stirred the reaction mixture at 25°-30°C for 30 minutes. Filtered the solid and washed with water, dried at 65°-70°C till constant weight to get the compound ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthaizole-5-carboxylate. Yield =17.6 gm % yield = 98.21
Example 3: Preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazoIe carboxylic acid of Formula-I [Febuxostai]
In a flask charged acetone (50 ml) and ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-. methylthaizoIe-5-carboxylate (5 gm). Charged under stirring aqueous solution of sodium hydroxide solution (1N, 25 ml). Raised the reaction temperature to 55°-60°C and

maintained under stirring for 1 hour. Monitored the reaction by TLC, after complete hydrolysis of the starting material, stopped heating and cooled the reaction mixture to 40o-45°C. Concentrated the reaction mixture under vacuum below 40°-45°C, charged water (100 ml) to the residual mass and stirred the reaction to adjust the pH of the reaction to 1-2 with aqueous hydrochloric acid (1:1, 6 ml). Stirred the reaction mixture at 25°-30°C for 30 minutes and filtered the solid, washed with water and dried till constant weight to get the compound 2-(3-cyano-4-isobutoxyphenyl)-4-methyI-5-thiazole-carboxylic acid. Yield = 4.25 gm % yield = 92.59

We claim,
1. A process for preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid of Formula-I;

Formula-IX with halo derivative 2-methylpropane of Formula-X in presence of catalyst potassium iodide, a base and polar aprotic solvent selected from N,N-dimethylacetamide, N-methyl-2-pyrroIidone and dimethyl sulfoxide,

Formula-X Where X = CI, Br or 1. ii. in-situ hydrolysis of the intermediate compound ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate of FormuIa-VIII, to isolate the compound of Formula-I. 2. The process according to claim 1, wherein preferred polar aprotic solvent used are N,N-dimethylacetamide or N-methyl-2-pyrrolidone.

The process according to claim 1, wherein said base is potassium carbonate.
The process according to claim 1, wherein said reaction is carried out at a
temperature range of 40°C - 80°C.
A process for preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-
thiazolecarboxylic acid of Formula-l;

rormuia-i comprising the steps of;
i. O-alkylating the compound ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-e of th iazole-S-carboxylatFormula -IX;

FormuIa-IX with halo derivative 2-methylpropane of Form.ula-X in presence of catalytic amount of potassium iodide, a base and polar aprotic solvent selected from N,N-dimethylacetamide, N-methy!-2-pyrroiidone and cijmethyl sulfoxide,

Where X = CI, Br or I. to obtain the compound ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate of Formula-VIII; and


ii. hydrolysing the compound ethyl 2-(3-cyano-4-isobutoxyphenyI)-4-methylthiazoIe -5-carboxylate of Formula-VIII in presence of a single solvent to isolate the compound of Formula-I.
6. The process according to claim 5, wherein said base is potassium carbonate.
7. The process according to claim 5, wherein said single solvent used is selected from acetone, methyl ethyl ketone, acetonitrile, N,N-dimethylacetamide and N-methyl-2-pyrrolidone.
8. The process according to claim 5, wherein O-alkylation is conducted at a temperature of 70°C - 75°C.
9. The process according to claim 5, wherein, hydrolysis is conducted at a temperature of55°C-60°C.