ES2772131T3 - A new process for the preparation of Febuxostat - Google Patents

Abstract

A process that comprises the conversion of the formyl group of the compound of formula II into a cyano group, to produce the compound of formula III, in the presence of ammonia, oxygen and a metallic catalyst, where the temperature range is 60-120 ° C , ** (See formula) ** where R1 is a hydrogen atom, an alkyl, alkenyl or alkynyl group where the chain group is straight or branched with 1 to 15 carbon atoms and R2 is an alkyl, alkenyl group or alkynyl where the chain group is straight or branched with 1 to 15 carbon atoms.

Description

DESCRIPTION

A new process for the preparation of Febuxostat

Technical field of the invention

The present invention relates to a novel method of preparation for 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylic acid (Febuxostat) by new and high-yield conversion from a formyl group into a cyano group.

Background of the invention

Febuxostat (Formula I) is a xanthine oxidase inhibitor, which was discovered by the Japanese company Teijin Pharma Ltd and is indicated for use in the treatment of hyperuricemia and chronic gout. Its chemical name is 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylic acid. It is marketed under the brands Adenuric in Europe, Feburic in Japan and Uloric in the United States and Canada.

In EP0513379B1 Febuxostat is prepared from 4-hydroxy-3-nitrobenzaldehyde, according to the following scheme.

This particular process has major drawbacks. Not only is it very long, including seven steps from starting material to final product, but more importantly, it employs the use of cyanides, which are extremely toxic reagents. Cyanide salts are likely to generate hydrocyanide, which establishes a high risk in an industrial scale process.

In Japanese patent JP06345724A (JP2706037B) the intermediate Febuxostat ethyl ester is prepared from p-cyano-nitrobenzene, in three steps. Febuxostat can then be prepared by alkaline hydrolysis, according to the prior art.

The use of extremely toxic potassium cyanide makes this process unsuitable for manufacturing purposes.

In Japanese patent JP3202607B the ethyl ester of Febuxostat is prepared, according to the above scheme, through two similar routes. Route A uses flash column chromatography for the purification of the hydroxylamine reaction product, while route B suffers from low yield and the use of chlorinated solvents for recrystallization. In addition, the reaction solvent is in both cases formic acid which causes severe skin burns and eye damage in humans. Formic acid is also corrosive to metal-based building materials (MOCs) such as stainless steel and nickel alloys, essentially limiting the options to glass vessels or reactors. The drawbacks of using this solvent are also related to the high volumes of formic acid required per batch, which makes waste treatment difficult.

Similarly, according to example 11 in WO2011141933, the hydroxylamine reaction uses formic acid in high proportion and temperature, which makes the process problematic on a large scale, in terms of equipment selection, safety and waste management .

In CN101723915B emphasis is placed on improving the hydroxylamine reaction. Formic acid is replaced with dimethylformamide (DMF) and other solvents. However, according to widely used organic chemistry textbooks, such as March's Advanced Organic Chemistry, p1287, 6th ed., MB Smith and J. March, ISBN 0 471-72091-7, the mechanism of the reaction involves the formation of an oxime, on the action of hydroxylamine, which is dehydrated to form a nitrile, with the help of a suitable reagent, for example, formic acid or acetic anhydride. In the absence of such a reagent, it is expected that the reaction will, at least, not lead to completion, leading to low yields and levels of unwanted impurities, i.e., the intermediate oxime. Such impurities, arising from process reactions and exhibiting a similar structure to the desired product, are often difficult to remove with common industrial techniques, e.g. eg, crystallization.

Similarly, WO2012066561 performs the hydroxylamine reaction in polar aprotic solvents, preferably DMF solvent, with the addition of acetyl chloride, thus avoiding the use of formic acid.

In WO2010142653A1 the intermediate Febuxostat ethyl ester is prepared from 4-cyanophenol, through a five-stage process. Febuxostat can be prepared from its respective ethyl ester by alkaline hydrolysis, as in the previous case.

The process employs, in the final stage, the use of palladium catalyst and, in addition, the reaction is carried out at elevated temperatures (145 ° C) for 48 hours, conditions that increase the cost of energy and, in general, are difficult. to transfer on an industrial scale.

WO2005095400 describes a method for transforming an orthosubstituted aromatic methoxy-formyl compound into the corresponding nitrile analog, using molecular iodine and ammonia. The same methodology was described by Talukdar et al. cabbage. in Tetrahedron Letters, 42, 6, 2001, pp 1103-1105 for aromatic, heterocyclic, aliphatic, conjugated and polyhydroxylated aldehydes.

A transformation similar to the key reaction of the present invention, that is, the oxidation of aldehydes to nitriles is described by Tao et al., In Organic and Biomolecular Chemistry, 11,20, 2013, p 3349, although the main object of its The study was the aerobic oxidative synthesis of aryl nitriles from the corresponding benzyl alcohols. The authors evaluated the transformation of aryl aldehydes into aryl nitriles using Cu (NO3) 2 / NH3 / O2 and concluded that the yields were highly dependent on the nature of the substitution of the aryl group, in terms of its electron extraction capacity and varied from a low 5% to 89%. No experimental evidence or even reference is provided that the same reaction conditions could be applied to achieve, with acceptable yields in manufacturing on an industrial scale, the transformation of aromatic aldehydes bearing an ester group as will be shown in the present invention. Consequently, there is still a need for a suitable process to produce Febuxostat compound with higher yields, which presents a chemical purity that meets the standards of national or international authorities, with an industrially viable, convenient and safe method.

Summary of the invention

The invention provides a process for the conversion of a formyl group of the compound of formula II into a cyano group of the compound of formula III, wherein R ¹ is a hydrogen atom, an alkyl, alkenyl or alkynyl group and R ² is a group alkyl, alkenyl or alkynyl, in the presence of ammonia and oxygen and metal catalyst, where the temperature range is 60-120 ° C.

Another object of this invention is to provide a novel process for the preparation of Febuxostat, which exhibits improved performance, safe reagents, and industrially applicable techniques.

A further object of the invention is a process for the production of Febuxostat, which comprises the following steps:

a) alkylation of the compound of formula IIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group to form a compound of formula IIb where R ¹ is iso-butyl and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group;

b) conversion of the formyl group of the compound of formula IIb into a cyano group, to produce the compound of formula IIIb, in the presence of: ammonia, oxygen and a metal catalyst where the temperature range is 60-120 ° C;

c) hydrolysis of the ester group of the compound of formula IIIb to produce Febuxostat, or a salt thereof;

It has been found that the above route will also work well when steps a) and b) are reversed. Therefore, it is another object of the present invention to provide an alternative route for the production of Febuxostat, which comprises:

a) Conversion of the formyl group of the compound of formula IIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group to a cyano group, to produce the compound of formula IIIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group, in the presence of ammonia, oxygen and a metal catalyst;

b) alkylation of the compound of formula IIIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group to the compound of formula IIIb where R ¹ is iso-butyl and R ² is a group alkyl, alkenyl or alkynyl, preferably an ethyl group;

c) hydrolysis of the ester group of the compound of formula IIIb to produce Febuxostat, or a salt thereof.

According to the present invention, the transformation of the formyl group into a cyano group in a compound of formula II, in any of the processes described above, is carried out in the presence of ammonia, oxygen, and a metallic catalyst where the temperature range is 60- 120 ° C.

Another object of the present invention is a process for the preparation of Febuxostat, which comprises the conversion of the formyl group of the compound of general formula II, into the cyano group of the compound of formula III, in the presence of ammonia, oxygen and a metallic catalyst wherein the temperature range is 60-120 ° C, and the subsequent conversion of the compound of general formula III in Febuxostat. Conversion of the compound of general formula III to Febuxostat is easily achieved when R ² is other than hydrogen by removing the alkyl, alkenyl or alkynyl group and, where R ¹ is other than iso-butyl, converting R ¹ to iso-butyl.

Detailed description of the invention

In the present invention, a new way is demonstrated for the conversion of the formyl group of the compound of formula II into the cyano group of the compound of formula III, where R ¹ is a hydrogen atom, an alkyl, alkenyl or alkynyl group and R ² It is an alkyl, alkenyl or alkynyl group, preferably an ethyl group in the presence of ammonia, oxygen and metal catalyst, where the temperature range is 60-120 ° C.

The present invention also encompasses the preparation of Febuxostat or salts thereof, through this new transformation, included in the process in the following scheme. The process is advantageous over prior art methods, because it has high reaction yields, leads to compounds with suitable chemical purities for pharmaceutical purposes, uses safer reagents, and possesses characteristics suitable for industrialization.

A particular object of the invention is to provide a process for the preparation of Febuxostat, which comprises the following steps:

a) alkylation of the compound of formula IIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group to the compound of formula IIb where R ¹ is an iso-butyl group and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group;

b) conversion of the formyl group of the compound of formula IIb into a cyano group, to produce the compound of formula IIIb, in the presence of ammonia, oxygen and a metal catalyst, where the temperature range is 60-120 ° C;

c) hydrolysis of the ester group of the compound of formula IIIb to produce Febuxostat, or a salt thereof.

Suitable ester groups for the preparation of Febuxostat are methyl, ethyl, propyl, Y ^or as / propyl, butyl, ^iso -butyl, te / i-butyl, preferably an ethyl ester group.

In step a, the etherification reaction is carried out with an isobutyl halide, preferably isobutyl bromide, in the presence of a base. The base can be an inorganic base. Preferable inorganic bases are metal hydroxides and carbonates. The most preferable inorganic bases are potassium carbonate, sodium carbonate, lithium carbonate. The base can also be an organic base. Preferable organic bases are amines. The most preferable organic bases are trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, N, N- dimethylaminopyridine. The reaction is carried out at temperatures that vary between 25-100 ° C. Preferable temperatures are 50-80 ° C. Suitable solvents for the reaction are polar aprotic solvents. Preferable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, acetone, t-butyl methyl ether.

In step b, the conversion of the formyl group to the cyano group is carried out with ammonia, an oxygen source and a metal catalyst. As the metal catalyst, various metal compounds can be used. Non-limiting examples of metals are copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium, and rhenium. The preferred metals are copper, iron, ruthenium, palladium, iridium, and silver. The most preferred metals are copper, iron, and ruthenium. Non-limiting examples of metal catalysts are oxides, hydroxides, salts of metals with the conjugate base of strong acids, such as hydrohalides, sulfuric acid, nitric acid, or organic acids, such as triflic acid and acetic acid.

The amount of ammonia used in the reaction can vary, depending on the scale of the reaction and the conditions used for it. Typically, in reactions involving such volatile reagents, the latter are used in large excess. Also, the amount of ammonia used in the reaction depends on the form in which the reagent is available. Non-limiting examples are aqueous solutions of ammonia and ammonia gas. The solvent can be a typical organic solvent. Preferable organic solvents are polar aprotic solvents. Preferable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, n- methylpyrrolidone, tetrahydrofuran, acetonitrile, acetone, i-butylmethyl ether. The temperature, at which the reaction is carried out, can vary from room temperature to the boiling point of the respective solvent.

In step c, the hydrolysis of the ester can be carried out under basic conditions. Such conditions imply a strong inorganic base. The preferable bases are metal oxides, hydroxides and carbonates. The most preferable bases are the alkali and alkaline earth metal oxides, hydroxides and carbonates. The most preferable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, barium oxide, sodium carbonate, potassium carbonate, and lithium carbonate. The reaction can be carried out in a variety of solvents, depending mainly on the nature of the base used in it. Typical organic solvents suitable for this reaction are polar protic and aprotic solvents, as well as their mixtures with water. Preferred polar aprotic solvents are tetrahydrofuran, acetone, t-butyl methyl ether, ethyl acetate. The preferred polar protic solvents are lower alcohols. The most preferable solvents are methanol, ethanol, n-propanol and I -as-propanol. The reaction can be carried out at room temperature up to the boiling point of the solvent used. The preferable temperature range is 20 to 80 ° C.

We have found that the above route will also work when steps a) and b) are performed in reverse sequence. Conditions and preferred conditions apply equally. Therefore, another object of the invention is to provide an alternative process for the preparation of Febuxostat, comprising the following steps:

a) Conversion of the formyl group of the compound of formula IIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group to a cyano group, to produce the compound of formula IIIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group, in the presence of ammonia, oxygen and a metal catalyst, where the temperature range is 60-120 ° C;

b) alkylation of the compound of formula IIIa where R ¹ is a hydrogen atom and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group to the compound of formula IIIb where R ¹ is an iso-butyl group and R ² is an alkyl, alkenyl or alkynyl group, preferably an ethyl group;

c) hydrolysis of the ester group of the compound of formula IIIb to produce Febuxostat, or a salt thereof.

The first step in this sequence is only in accordance with the invention when the compound of formula IIa is reacted with ammonia, oxygen and the metal catalyst as defined in step a) of the above scheme. The use of ammonia and iodine is not according to the invention but only for reference. The preferred conditions for the individual process steps are as already described above.

In yet another embodiment of the present invention, the metal catalyst used in step b is a copper catalyst, an iron catalyst, or a ruthenium catalyst.

In yet another embodiment of the invention, the metal catalyst is a copper catalyst. The copper catalyst can be selected from inorganic compounds and copper salts, oxidative state (I) or (II). Preferable compounds and salts are copper halides, copper nitrate, copper acetate, copper sulfate, copper triflate, copper oxide and their hydrates.

In the present invention, the conversion of the formyl group of formula II to the cyano group of formula III is carried out in the presence of ammonia, an oxygen source and a metal catalyst.

In a preferred embodiment of the present invention, the conversion described above is carried out in a polar aprotic solvent. The preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, W-methylpyrrolidone, and tetrahydrofuran.

In the present invention, the above-described conversion of the formyl group of formula II to the cyano group of formula III is carried out at temperatures ranging from 60-120 ° C. Preferably, the temperature range is 70-110 ° C.

In yet another embodiment of the invention, said conversion of the formyl group of formula II to the cyano group of formula III is carried out under an oxygen atmosphere. The percentage of oxygen that is present in the reaction atmosphere can vary from 1% to 100%. The preferable range is 5% to 100%. The most preferable range is 20% to 100%. It will be recognized by those skilled in the art that when the reaction atmosphere is less than 100%, the remaining percentage may express other gases. Non-limiting examples are nitrogen, noble gases, methane, hydrogen, and carbon dioxide. Therefore, the definition can be interpreted as including the composition of atmospheric air as well.

Furthermore, the person skilled in the art will recognize that the reaction time may vary depending on the percentage of oxygen present in the air supply, used in the reaction. The reaction time can also vary, depending on the pressure developed or applied to the reaction.

Another object of the present invention is a process for the preparation of Febuxostat, as described above, which comprises the conversion of the formyl group of the compound of formula II into a nitrile group of the compound of formula III, which comprises ammonia, oxygen and a catalyst metallic, where the temperature range is 60-120 ° C and subsequently converts the compound of formula III into Febuxostat.

Experimental

EXAMPLE 1: Preparation of the compound of formula I Ib

14.14 g of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate (Formula III) are dissolved in 55 ml of dimethylformamide, at room temperature. 40 g of potassium carbonate are added, together with 15.9 ml of isobutyl bromide. Heat the reaction to 75-80 ° C and stir for 4 hours. It is cooled to 25-30 ° C, while adding 165 ml of process water. It is then cooled to 0-5 ° C and stirred for 30 minutes at this temperature. The precipitated solid is filtered and the filter cake is washed with 55 ml of process water. The wet cake is dried under vacuum at 40 ° C for 7 hours, to collect 16.43 g of ethyl 2- (3-formyl-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate (Formula IIb).

EXAMPLE 2: Preparation of the compound of formula IIIb

In a 25 ml round bottom flask, with stirring at 25-30 ° C, 1.0 g (2.88 mmol) of 2- (3-formyl-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate is charged of ethyl in 3.0 ml of dimethylformamide. 34 mg (0.19 mmol) of copper acetate are added with stirring at 25-30 ° C. Rinse with oxygen (O ² ) and add 0.66 ml (34.92 mmol) of 25% aqueous ammonia. It is rinsed again with O ² . The reaction mixture is heated to 80-82 ° C overnight. The progress of the reaction is checked by TLC (cyclohexane: ethyl acetate 3: 1). Cool the reaction mass to 25-30 ° C. 25 ml of ethyl acetate and 25 ml of brine are added to the reaction mass, the organic layer is separated and the aqueous layer is extracted twice with 25 ml of ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue is purified with column chromatography (cyclohexane: ethyl acetate 9: 1). 0.754 g of ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate are collected (Formula IIIb) Yield: 75.4%.

EXAMPLE 3 (for reference only): Preparation of compound of formula IIIb

In a 25 ml round bottom flask, 0.17 g (0.49 mmol) of 2- (3-formyl-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate is charged with stirring at 25-30 ° C of ethyl in 2.5 ml of tetrahydrofuran. 2.9 ml (153.43 mmol) of 25% aqueous ammonia are added, with stirring at 25-30 ° C. 137 mg (0.54 mmol) of iodine (I ² ) are added to the reaction mass, the reaction mixture is stirred at 25-30 ° C for 15-30 min. The progress of the reaction is checked by TLC (cyclohexane: ethyl acetate 3: 1). Starting material is consumed. 2.5 ml of 5% w / v aqueous sodium thiosulfate Na2S2O3 and 15 ml of ethyl acetate are added to the reaction mass, the organic layer is separated and the aqueous layer is extracted twice with 15 ml of acetate of ethyl. The organic layers are combined, dried over sodium sulfate anhydrous, filtered and concentrated to dryness. 0.158 g of ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate are collected (Formula IIIb).

EXAMPLE 4: Preparation of Febuxostat

2.407 g of ethyl-2- (3-cyano-4-isobutoxyphenyl) -4-methylhiazole-carboxylate in 20 ml of tetrahydrofuran with stirring, at 25-35 °, are charged to a 100 ml 2-neck round bottom flask. C, 0.748 g of sodium hydroxide and heat reaction mass at 60-65 ° C for about 8 hours. The progress of the reaction is checked by TLC (cyclohexane: ethyl acetate 3: 1). The reaction mass is cooled to 0-5 ° C and 50 ml of process water is added keeping the temperature within 0-5 ° C. Adjust the pH to 1-2 with 4.5 ml of 6N hydrochloric acid, keeping the temperature within 0-5 ° C. The reaction mass is heated to 25-30 ° C and the reaction mass is stirred at the above temperature for 15 min. The precipitated solid is filtered through the Buchner funnel under reduced pressure, washed with 2 ml of process water and dried under suction for 20-30 minutes. The crude solid is transferred into a 50 ml round bottom flask, 12 ml of process water and 12 ml of acetone are charged at 25-30 ° C. Heat the reaction mass at 50-60 ° C for 60 min. Cool the reaction mass to 0-5 ° C and stir for 60 minutes at the above temperature. The precipitated solid is filtered through a Buchner funnel under reduced pressure, washed with 2 ml of a 1: 1 mixture of acetone and process water and dried for 30-45 min. Dry in vacuo at 60 ° C. 1.821 g of Febuxostat (compound I) are collected, Purity: 82.6%, Yield: 0.62 w / w.

EXAMPLE 5 (for reference only): Preparation of compound of formula IIIa

In a 50 ml round bottom flask, charge 0.5 g (1.72 mmol) of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate under stirring in 8.6 ml of THF, at 25-30 ° C. 10.3 ml (544.94 mmol) of 25% aqueous ammonia are added, with stirring at 25-30 ° C. 480 mg (1.89 mmol) of iodine (I ² ) are added to the reaction mass, the reaction mixture is stirred at 25-30 ° C for 15-30 min. The progress of the reaction is checked by TLC (cyclohexane: ethyl acetate 1: 1). Starting material is consumed. 8.6 ml of 5% w / v aqueous thiosulfate and 40 ml of ethyl acetate are added to the reaction mass, the organic layer is separated and the aqueous layer is extracted twice with 40 ml of ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Purification of the residue with column chromatography (cyclohexane: ethyl acetate 3: 1) collected 0.213 g of ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate (Formula IIIa). Yield: 42.6%.

EXAMPLE 6: Preparation of compound IIIb

2.2 g of ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate (Formula VI) are dissolved in 7 ml of dimethylformamide and 6.6 g of ethyl carbonate are added to this mixture. potassium and 3.14 g of isobutyl bromide. The reaction is stirred at 75 ° C for 15 hours and then cooled to 40 ° C. 15 ml of process water are added and it is cooled to 0 5 ° C. The precipitated solid is filtered and washed with 15 ml of process water, which, after drying, collects 2.28 g of ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate. (Formula IIIb).

EXAMPLE 7: Preparation of compound I (Febuxostat)

2.131 g of ethyl-2 (3-cyano-4-isobutoxyphenyl) -4-methylhiazole-carboxylate, 64 ml of methanol and 2.5 ml of process water are charged to a 100 ml 2-neck round bottom flask with stirring at 25-35 ° C. 1.718 g of potassium carbonate and heat reaction mass are added under reflux for about 2-3 hours. The progress of the reaction is checked by TLC (cyclohexane: ethyl acetate 3: 1). The reaction mass is cooled to 20-25 ° C. The solvent is concentrated below 40 ° C. To the residue, 43 ml of process water, 21 ml of ethyl acetate are added and the mixture is stirred for 30 minutes at 25-35 ° C. The layers are separated and the aqueous layer is transferred into a 100 ml round bottom flask. The pH is adjusted to 2.3-2.7 with 25 ml of 1N hydrochloric acid, at 25-35 ° C. The reaction mass is heated to 40 ° C and the reaction mass is stirred at this temperature for 60-90 min. Cool the reaction mass to 25-35 ° C. The precipitated solid is filtered through the Buchner funnel under reduced pressure, washed with 5 ml of process water and dried under suction for 30-45 min. Dry in vacuo at 60 ° C. 1.708 g of Febuxostat (compound I) are collected, Purity: 86.7%, Yield: 0.69 w / w.

EXAMPLE 8: Preparation of the crystalline form of Febuxostat III

In a 250 ml round bottom flask, charge at 25-30 ° C, 10 g of crude 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylic acid (Febuxostat) with stirring at 200 ml of ethyl acetate. Heat the reaction mass to reflux and stir for 30 min. Cool the reaction mass to 25-30 ° C. Reheat the reaction mass and partially distill the solvent from the reaction mass at a temperature below 40 ° C under reduced pressure. Cool the reaction mass to 25-30 ° C. The precipitated solid is filtered through the Buchner funnel under reduced pressure and spray washed with 10 ml of ethyl acetate. Dry in vacuo at 60 ° C. 8.5 g of Febuxostat are collected. Yield: 85% w / w. The XRPD of the crystalline compound is in accordance with that reported in Chinese patent CN101412700B.

Claims (9)

1. A process that comprises the conversion of the formyl group of the compound of formula II into a cyano group, to produce the compound of formula III, in the presence of ammonia, oxygen and a metallic catalyst, where the temperature range is 60-120 ° C,

where R ¹ is a hydrogen atom, an alkyl, alkenyl or alkynyl group where the chain group is straight or branched with 1 to 15 carbon atoms and R ² is an alkyl, alkenyl or alkynyl group where the group of chain is straight or branched with 1 to 15 carbon atoms. 2. A process for the production of Febuxostat that comprises the following stages: a) Conversion of the formyl group of the compound of formula IIb where R ¹ is a group is ^or butyl and R ² is as defined in claim 1 for the cyano group, to produce the compound of formula IIIb, in the presence of ammonia, oxygen and a metal catalyst, where the temperature range is 60-120 ° C,

b) group hydrolysis

of the same.

3. A process for the production of Febuxostat that comprises the following stages: a) Conversion of the formyl group of the compound of formula IIa where R ¹ is a hydrogen atom and R ² is as defined in claim 1 for the cyano group, to produce the compound of formula IIIa, in the presence of ammonia, oxygen and a metal catalyst, where the temperature range is 60-120 ° C,

b) alkylation of the compound of formula IIIa to the compound of formula IIIb wherein R ¹ is an iso-butyl group and R ² is as defined in claim 1;

c) hydrolysis of the ester group of the compound of formula IIIb to produce Febuxostat, or a salt thereof.

4. A process according to claim 2 or 3, wherein R ² is an ethyl group. 5. A process according to claims 1-3, wherein the metal catalyst is a copper, iron or ruthenium catalyst. 6. A process according to claim 5, wherein the metal catalyst is preferably a copper catalyst, preferably copper (I) or (II) halide, copper (I) or (II) nitrate, copper (I) or (II) acetate, copper (I) or (II) sulfate, copper (I) or (II) triflate, copper (I) or oxide (II) and their hydrates. 7. A process according to claims 1-3, wherein the reaction is carried out in a polar aprotic solvent, preferably acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, non / te-methylpyrrolidone or tetrahydrofuran. 8. A process according to claims 1-3, wherein the reaction is carried out under an atmosphere with a composition comprising oxygen in a range of 1-100%, under a pressure of 101.325 KPa to 20265 KPa. 9. A process according to claim 8, wherein the reaction is carried out under a composition and pressure of normal atmosphere.