Claims:WE CLAIM:

1. A process for the preparation of Febuxostat compound of formula (I) comprising the steps of;
a) 4-hydroxythiobenzamide of formula (XV) is reacted with ethyl-2-chloroacetoacetate to obtain 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI).

b) The product of step a) undergoes formylation in presence of Phosphorus pentoxide / methane sulfonic acid and Hexamethylenetetramine to obtain 2-(3-formyl-4-hydroxy phenyl)-4-methylthiazole-5-carboxylicacid ethyl ester (XVII).

c) The product of step b) is reacted with the isobutyl bromide in presence of K2CO3 / KI to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII).

d) The product of step c) undergoes cyanation in presence of Hydroxylamine hydrochloride / DMSO and water to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII).

e) The product of step d) converts into pure Febuxostat in presence of NaOH / hydrochloric acid.

2. The process as claimed in claim 1 step d), where in the reaction is carried out at 70 to 90°C for 4-6 hrs to obtain the compound of formula (VIII).

3. The process as claimed in claim 1, where in the reaction carried out in solvent is selected from dimethyl sulfoxide, acetone, tetrahydrofuran, dimethylformamide, acetonitrile and ethyl acetate, cyclohexane, dichloromethane, acetic acid, methanol, ethanol, isopropanol and water;

4. The process as claimed in claim 1, where in the base is selected from potassium carbonate, sodium carbonate, potassium iodide, ammonia, potassium hydroxide and sodium hydroxide.

, Description:BACKGROUND OF THE INVENTION

Febuxostat is a non-purine xanthine inhibitor known from US 5,614,520. It is chemically designated as 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid as represented by Formula I.

Febuxostat is marketed in the United States under the brand name Uloric® and in Europe under the brand name Adenuric® for the chronic management of hyperuricemia in patients with gout. It works by non-competitively blocking the channel leading to the active site on xanthine oxidase. xanthine oxidase is needed to successively oxidate both hypoxanthine and xanthine to uric acid. Hence, Febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid.

Febuxostat and its intermediates processes are disclosed in EP 0513379 B1, converting the compound of formula (II) to compound of formula (III) in presence of Hydroxylamine hydrochloride / HCOONa. The compound of formula (III) is reacted with CH3C(S)NH2 in presence of HCl to get the compound of formula (IV) and it allows to react with ethyl 2-chloroacetoacetate to get the compound of formula (V). The compound of formula (V) is reacted with isobutyl bromide in presence of K2CO3 to get the compound of formula (VI) and it undergoes reduction, followed by cyanation to get the compound of formula (VIII) and further it is treated with NaOH to produce Febuxostat (I).

The above process is schematically shown as below:

Scheme-I

US 20130172571 of Natco describes a process for the preparation of Febuxostat, reacting the compound of formula (IX) with Hydroxylamine / formic acid to get the compound of formula (X). The compound of formula (X) is reacted with MeCSNH2 in presence of HCl to get the compound of formula (XI). The compound of formula (XI) is reacted with ethyl-2-chloroacetoacetate to get the compound of formula (XII), further it is reacted with isobutyl bromide to get the compound of formula (XIII) followed by cyanation to get Febuxostat (I).

The above process is schematically shown as below:

Scheme-II

This particular process suffers from major drawbacks including several steps from the starting material to the final product, but, most importantly, it employs the use of cyanides, which are extremely toxic reagents. Cyanide salts are likely to generate hydrocyanide, which sets a high amount of risk in an industrial scale process.

CN102070559 A of Jiangsu Tohope describes a process for the preparation of 2-(3-cyano-4-iso butoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII) (Febuxostat intermediate), reacting p-cyano phenol (XIV) with thioacetamide in presence of DMF / HCl and water to get 4-hydroxythiobenzamide (XV). The compound of formula (XV) is reacted with ethyl 2-chloro acetoacetate in presence of ethanol to get 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI). The compound of formula (XVI) is reacted with paraformaldehyde in presence of 2-methyl-THF / MgCl2 / TEA / HCl and water to get 2-(3-formyl-4-hydroxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester (XVII) and it is reacted with bromoisobutane in presence of DMF / K2CO3 and KI to get 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII). The compound of formula (XVIII) is reacted with NH2OH.HCl in presence of DMF and water to get 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII).

The above process is schematically shown as below:

Scheme-III:

According to the above prior art process for the preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester (VIII) from the compound 2-(3-formyl-4-isobutoxy phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester in presence of Hydroxylamine hydrochloride / Dimethyl formamide and water. The reaction was carried out for 18 hrs causes low yield and high impurity profile, and which enhance the cost and time.

DMF is a dangerous solvent, it is classified as reprotoxic and has a regulated use in Europe (substance of very high concern and inscribed on the candidate list for authorisation according to EC1907/2006 regulation). DMSO is a non-dangerous and highly biocompatible solvent.

The present invention which involves DMSO as a solvent in cyanation reaction to affords 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester with high purity, high yield and less impurity.

In view of the foregoing, the present inventors have result of extensive studies, the efficiency is extremely only the process for the preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylic acid ethyl ester (VIII) from the compound 2-(3-formyl-4-isobutoxy phenyl) -4-methylthiazole-5-carboxylic acid ethyl ester (XVIII) in presence of Hydroxylamine hydrochloride / DMSO/ water and the reaction was carried out for 4-6 hrs. Further converts into Febuxostat with high yield and purity with advantages of cost effective and time reducing process.

SUMMARY OF THE INVENTION

The present invention relates to process for the preparation of Febuxostat (I).

In one aspect of the present invention, provides an improved process for the preparation of Febuxostat (I), comprising the steps of:

a) 4-hydroxythiobenzamide of formula (XV) is reacted with ethyl-2-chloroacetoacetate to obtain 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI).

b) The product of step a) undergoes formylation in presence of Phosphorus pentoxide / methane sulfonic acid / Hexamethylenetetramine to obtain 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylicacid ethyl ester (XVII).

c) The product of step b) is reacted with the isobutyl bromide in presence of K2CO3 / KI to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII).

d) The product of step c) undergoes cyanation in presence of Hydroxylamine hydrochloride / DMSO and water to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII), and

e) The product of step d) converts into Febuxostat in presence of NaOH / hydrochloric acid.

In another aspect of the present invention provides an improved process for the preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII) from 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII) in presence of Hydroxylamine hydrochloride / DMSO / water.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to process for the preparation of Febuxostat with cost effective and industrial applicable process.

In one embodiment of the present invention relates to an improved process for the preparation of Febuxostat (I), comprising the steps of:

a) 4-hydroxythiobenzamide of formula (XV) is reacted with ethyl-2-chloroacetoacetate to obtain 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI).

b) The product of step a) undergoes formylation in presence of Phosphorus pentoxide / methane sulfonic acid and Hexamethylenetetramine to obtain 2-(3-formyl-4-hydroxy phenyl)-4-methylthiazole-5-carboxylicacid ethyl ester (XVII).

c) The product of step b) is reacted with the isobutyl bromide in presence of K2CO3 / KI to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII).

d) The product of step c) undergoes cyanation in presence of Hydroxylamine hydrochloride / DMSO and water to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII).

e) The product of step d) converts into Febuxostat in presence of NaOH / Hydrochloric acid.

In an embodiment of the present invention, wherein reacting the compound 4-hydroxy thiobenzamide (XV) is reacted with ethyl-2-chloroacetoacetate in presence of ethanol / purified water, the reaction mixture was stirred at reflux for 5 hrs to obtain 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI). The compound of formula (XVI) undergoes formylation in presence of Phosphorus pentoxide / methane sulfonic acid, heated at 80-100ºC for 2-5 hrs preferably 85-90°C for 3 hrs, followed by addition of Hexamethylenetetramine / water and EtOAc to obtain 2-(3-formyl-4-hydroxyphenyl)-4-methyl thiazole-5-carboxylicacid ethyl ester (XVII). The compound of formula (XVII) is reacted with the isobutyl bromide in presence of K2CO3 and KI to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII), followed by cyanation in presence of Hydroxylamine hydrochloride / DMSO / water and the reaction was carried out at 70-90ºC for 4-6 hrs to obtain 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII), further it is treated with NaOH in presence of methanol to produce Febuxostat (I).

In an embodiment of the present invention, suitable solvents that may be used in the process include, but are not limited to, alcohol solvents; ketone solvents; halogenated hydrocarbon solvents; ester solvents; nitrile solvents; polar aprotic solvents; water or mixtures thereof.

wherein the solvents are selected from group comprising of ethyl acetate, cyclohexane, dimethyl sulfoxide (DMSO), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, ethyl acetate, dichloromethane, acetic acid, methanol, ethanol, isopropanol and water;

In an embodiment of the present invention, the bases are selected from bases like potassium carbonate, sodium carbonate, potassium iodide, ammonia, potassium hydroxide, sodium hydroxide, barium hydroxide and calcium hydroxide.

In an embodiment of the present invention provides an improved process for the preparation of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (VIII) from 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII) in presence of Hydroxylamine hydrochloride / DMSO / water and the reaction is carried out at 70 to 90ºC for 4-6 hrs.

Hence, the present inventors are concluded that an improved process for the preparation of Febuxostat from compound of formula (VIII) and its undergoes cyanation in presence of Hydroxylamine hydrochloride / DMSO and water and the reaction was carried out at 70 to 90ºC for 4-6 hrs to get the compound of formula (VIII), further it is treated with NaOH in presence of solvent to produce Febuxostat(I).

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:

Preparation of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate:

4-hydroxybenzothioamide (100.0 g) and 2-chloroethyl acetoacetate (150.0 g) were added to ethanol (100 ml). The reaction mixture was stirred at reflux for 5 hrs. Upon completion of the reaction, monitored by thin-layer chromatography (TLC), the mixture was cooled to room temperature. The resultant product was separated by filtration, washed with water and dried at 55 to 60°C to get title compound.

Purity: 99.5%

Yield: 92 %.

1H NMR, (DMSO-d6): d 1.29 (t, J=7.1 Hz, 3H), 2.65 (s, 3H), 4.27 (q, J=7.1 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 10.21 (s, 1H).

Example-2:

Preparation of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate:

A mixture of methane sulfonic acid (30 ml) and phosphorus pentoxide (30.0 g) were heated at 85 to 90°C for 3 hrs to get clear solution, followed by portion wise addition of Hexamethylenetetramine (55.6) and maintaining the reaction mass temperature below 90ºC. Charge stage-1 (90.0g) was added to the reaction mass and heated 85 to 90°C for 6 to 8 hrs. The reaction mixture was brought at 50 to 70°C and quenched slowly in chilled water (2000 litres) at 5-10°C. The resultant material was extracted with ethyl acetate (700 ml), after adjusting the reaction mass pH at 8.0 with sodium carbonate, ethyl acetate layer was distilled completely at 60 to 65°C under vacuum to afford title compound.

Purity: 90%

Yield: 86 %.

1H NMR ((DMSO-d6): d 1.30 (t, J=7.1 Hz, 3 H), 2.65 (s, 3 H), 4.28 (q, J=7.1 Hz, 2 H), 7.10 (d, J=8.7 Hz, 1 H), 8.08 (dd, 2J=6.3 Hz & 2.4 Hz, 1 H), 8.21 (d, J=2.4 Hz, 1 H), 10.31 (s, 1H).

Example-3:

Preparation of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate:

A mixture of Stage-2 (70.0 g), DMF (300 ml), potassium carbonate (85.0 g) and potassium iodide (10.0 g) are cooled to 5-10°C, added Isobutyl bromide (85.0 g) and heated to 70-90°C for 8 to 10 hrs. The reaction mass was cooled to 25-30°C and quenched slowly in chilled water (1500 mL) at same temperature. The resultant mass was stir for 1 hour, filtered and then washed with water (100 ml). The obtain wet cake was dried at 55 to 60°C to get title compound.

Purity: 98%

Yield: 88 %.

1H NMR (DMSO-d6): d 1.03 (d, J=6.7 Hz, 6 H), 1.30 (t, J=7.1 Hz, 3 H), 2.12 (m, 1 H), 2.68 (s, 3 H), 4.01 (d, J=6.4 Hz, 2 H), 4.27-4.32 (m, 2 H), 8.22-8.25(m, 2 H), 10.41 (s, 1H)

Example-4:

Preparation of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate:

Stage-3 (50 g) and Hydroxylamine hydrochloride (25 g) were added to DMSO (500 ml). The reaction mass was heated at 70 to 90°C for 4 to 6 hours and then slowly cooled to 70 to 75°C, followed by quenching in chilled water (1000 ml) at 10 to 30°C. After stirring at 25 to 30°C for 1 hr, the reaction mixture was filtered and washed with water (50.0 ml). The resultant wet cake was dried at 55 to 60°C to get title compound.

Purity: 99%

Yield: 95%.

1H NMR (DMSO-d6): d 1.02 (d, J=6.7 Hz, 6 H), 1.31 (t, J=7.1 Hz, 3 H), 2.09 (m, 1 H),2.68 (s, 3 H), 4.00 (d, J=6.5 Hz, 2 H), 4.30 (q, J=7.1 Hz, 2 H),7.37 (d, J=9.0 Hz, 1H), 8.24 (dd, 2J=6.5 Hz & 2.3 Hz, 1 H), 8.30 (d, J=2.3 Hz, 1 H).

Example-5:

Preparation of Febuxostat:

Methanolic solution of Stage-4 (100 g in 400 ml methanol), THF (100 ml) and aqueous sodium hydroxide solution (9 g dissolved in 90 mL water) were added and stirred at 50 to 55°C for 5 to 6 hrs. The reaction mixture was cooled to 10-15°C, pH was adjusted 4.0 to 5.0 by using HCl and the precipitate material was filtered. The obtain wet material was taken in ethyl acetate (500 ml) and heated to 65-70°C to get clear solution. The reaction mixture was allow to cool at 25 to 30°C, the obtain product was filtered, washed with Ethyl acetate (100 ml) and dried at 55 to 60°C to afford Febuxostat with 99.5% purity.

Yield: 82%

1H NMR (DMSO-d6): d 1.01 (d, J=6.7 Hz, 6 H), 2.09 (m, 1 H), 2.65 (s, 3 H), 3.99 (d, J=6.5 Hz, 2 H), 7.35 (d, J=9.0 Hz, 1H), 8.20 (dd, 2J=6.6 Hz & 2.3 Hz, 1 H), 8.26 (d, J=2.3 Hz, 1 H), 13.41 (brs, 1 H)