WO2015018507A2

WO2015018507A2 - A novel process for the preparation of febuxostat

Info

Publication number: WO2015018507A2
Application number: PCT/EP2014/002079
Authority: WO
Inventors: Theocharis V. KOFTIS; Efstratios Neokosmidis; Sakellarios TRAKOSSAS; Theodoros Panagiotidis; Thanos Andreou; Anastasia-Aikaterini VARVOGLI
Original assignee: Pharmathen S.A.
Priority date: 2013-08-07
Filing date: 2014-07-30
Publication date: 2015-02-12
Also published as: CN105452228B; JP2017509581A; JP2019194203A; WO2015018507A3; JP6585044B2; ES2772131T3; CN105452228A

Abstract

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

Description

A NOVEL PROCESS FOR THE PREPARATION OF FEBUXOSTAT

TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel preparation method for 2-(3-cyano-4-isobutoxyphenyl)- 4-methyl-l,3-thiazole-5-carboxylic acid (Febuxostat) via novel and high yielded conversion of a formyl group in to a cyano group.

BACKGROUND OF THE INVENTION

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

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

This particular process suffers from major drawbacks. Not only it is very long, including seven 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.

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

MeCSNH,

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

Route A

In Japanese patent JP3202607B Febuxostat ethyl ester 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 to humans. Formic acid is also corrosive towards metal-based materials of construction (MOC), like stainless steel and nickel alloys, limiting the options, essentially, to glass reactors or vessels. The drawbacks of using this solvent are also related to the high volumes of formic acid required per batch, which hinder the waste treatment.

In CN101723915B focus is made to the improvement of 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, pi 287, 6^th edition, M. B. Smith and J. March, ISBN 0-471-72091-7, the mechanism of the reaction involves the formation of an oxime, upon the action of hydroxylamine, which further dehydrates to form a nitrile, with the aid 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, thereby leading to low yields and undesired impurity levels, namely the intermediate oxime. Such impurities, arising from the reactions of the process and which exhibit similar structure of the desired product, are often difficult to remove with common industrial techniques, e.g. crystallization.

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

OH

The process employs, in the final step, the use of palladium catalyst and, moreover, the reaction is performed at elevated temperatures (145 °C) for 48 hours, conditions that raise the energy cost and are, in general, difficult to transfer in industrial scale.

Accordingly, there is still a need for a process suitable to produce Febuxostat compound in higher yields, exhibiting a chemical purity that meets national or international authorities standards, with an industrially viable, convenient and safe method. SUMMARY OF THE INVENTION

The invention provides a process for the convertion of a formyl group of compound of formula II into a cyano group of compound of formula III, wherein R_\ is a hydrogen atom, an alkyl, alkenyl, or alkynyl group and R₂ is an alkyl, alkenyl, or alkynyl group, in the presence of ammonia and either oxygen and metal catalyst or iodine.

N JIi

Another object of this invention is to provide a novel process for the preparation of Febuxostat, exhibiting improved yield, safe reagents and industrially applicable techniques. A further object of the invention is a process for the production of Febuxostat, comprising the following steps: a) alkylation of compound of formula Ila where Ri is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to form a compound of formula lib where Ri is wo-butyl and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group;

conversion of the formyl group of compound of formula lib to cyano group, to produce compound of formula Illb, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine;

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

We have found that the route above will also perform as well when the steps a) and b) are reversed. Therefore, it is another object of the present invention, to provide an alternate route for the production of Febuxostat, comprising:

a) conversion of formyl group of compound of formula Ila where R_\ is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to cyano group, to produce compound of formula Ilia where Ri is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine;

b) alkylation of compound of formula Ilia where R_\ is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to compound of formula Illb where R_\ is wo-butyl and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group;

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

According to a preferred embodiment of the present invention, the transformation of the formyl group to cyano group in a compound of formula II, in either of the processes described above, is performed in the presence of i) ammonia, oxygen, and a metal catalyst or ii) ammonia and iodine.

Another object of the present invention is a process, for the preparation of Febuxostat, comprising the conversion of the formyl group of compound of general formula II, to cyano group of compound of formula III, in the presence of: i) ammonia, oxygen and a metal catalyst, or, ii) ammonia and iodine, and subsequent conversion of the compound of general formula III to Febuxostat. Conversion of the compound of general formula III to Febuxostat is readily achieved when R₂ is other than hydrogen by removing the alkyl, alkenyl, or alkynyl group and, where Ri is other than z^'so-butyl, converting R_t to so-butyl.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention a novel pathway for the conversion, of the formyl group of compound of formula II into the cyano group of compound of formula III, is demonstrated, where Rj is a hydrogen atom, an alkyl, alkenyl, or alkynyl group and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group in the presence of ammonia and either oxygen and metal catalyst or iodine.

NH3/0₂ metal catalyst

NH3 I2

The present invention also encompasses the preparation of Febuxostat or salts thereof, through this novel transformation, included in the process in the below scheme. The process is advantageous over prior art methods, due to the fact that it features high reaction yields, leads to compounds with chemical purities suitable for pharmaceutical purposes, uses more safe reagents and possesses characteristics suitable for industrialization.

A particular object of the invention is to provide a process for the preparation of Febuxostat, comprising the following steps: a) alkylation of compound of formula Ila where Ri is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to compound of formula lib where Ri is an /^'so-butyl group and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group;

conversion of the formyl group of compound of formula lib to cyano group, to produce compound of formula Illb, in the presence of : i) ammonia, oxygen and a metal catalyst, or, ii) ammonia and iodine;

Suitable ester groups for preparation of Febuxostat are methyl, ethyl, propyl, /so-propyl, butyl, wo-butyl, tert-butyl preferably an ethyl ester group.

In step a, the etherification reaction is performed 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. More preferable inorganic bases are potassium carbonate, sodium carbonate, lithium carbonate. The base may also be an organic base. Preferable organic bases are amines. More preferable organic bases are trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, NN-dimethylaminopyridine. The reaction is performed at temperatures that range between 25-100 °C. Preferable temperatures are 50-80 °C. Solvents suitable 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 cyano group is performed with ammonia, an oxygen source and a metal catalyst. As a metal catalyst various compounds of metals may be used. Non-limiting examples of metals are copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium. Preferred metals are copper, iron, ruthenium, palladium, iridium and silver. More preferred metals are copper, iron and ruthenium. Non-limiting examples of metal catalysts are oxides, hydroxides, salts of metals with the conjugated base of either strong acids, such as hydrohalides, sulfuric acid, nitric acid, or organic acids, such as triflic acid and acetic acid. The amount of ammonia used at the reaction may well vary, depending on the scale of the reaction and the conditions employed to it. Normally, at reactions involving such volatile reagents, the latter are used in great excess. Moreover, 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 gaseous ammonia. 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, /-butylmethylether. The temperature, at which the reaction is performed, may range from room temperature to the boiling point of the respective solvent. Alternatively, step b is performed with ammonia and molecular iodine. For the course of the reaction, typical organic solvents can be used, preferably polar aprotic solvents, as defined above. Again, the amount of ammonia is according to the nature of the reagent, as defined above. The temperature at which the reaction is performed may range from 0 °C to the boiling point of the respective solvent.

In step c, the hydrolysis of the ester may be performed under basic conditions. Such conditions involve a strong inorganic base. Preferable bases are metal oxides, hydroxides and carbonates. More preferable bases are alkali metal and alkaline earth oxides, hydroxides and carbonates. More preferable bases are sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, barium oxide, sodium carbonate, potassium carbonate and lithium carbonate. The reaction may be performed in a variety of solvents, depending mainly on the nature of the base used at it. Typical organic solvents suitable for this reaction are polar protic and aprotic solvents, as well as mixtures of them with water. Preferred polar aprotic solvents are tetrahydrofuran, acetone, t-butyl methyl ether, ethyl acetate. Preferred polar protic solvents are lower alcohols. More preferable solvents are methanol, ethanol, n-propanol and z^'sO-propanol. The reaction can be performed at room temperature to the boiling point of used solvent. Preferable temperature range is from 20 to 80 °C.

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

a) conversion of formyl group of compound of formula Ila where Rj is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to cyano group, to produce compound of formula Ilia where R_\ is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine;

b) alkylation of compound of formula Ilia where R] is a hydrogen atom and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group to compound of formula Illb where R] is an /so-butyl group and R₂ is an alkyl, alkenyl, or alkynyl group, preferably an ethyl group;

Preferred conditions for individual steps of the process 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 still another embodiment of the invention, the metal catalyst is a copper catalyst. The copper catalyst may be selected from inorganic compounds and salts of copper, of 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 a preferred embodiment of the present invention, the conversion of the formyl group of formula II to cyano group of formula III is carried out in the presence of ammonia, an oxygen source and a metal catalyst.

In yet another preferred embodiment of the present invention, the above described conversion is carried out in a polar aprotic solvent. Preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone and tetrahydrofuran.

In yet another preferred embodiment of the present invention, the above described conversion of the formyl group of formula II to cyano group of formula III is carried out in temperatures ranging from 20 °C to the boiling point of the solvent, wherein the reaction is performed. Preferable temperature range is 50-140 °C. More preferable temperature range is 60-120 °C. Even more preferable temperature range is 70-1 10 °C.

In still another embodiment of the invention, said conversion of the formyl group of formula II to cyano group of formula III is performed under oxygen atmosphere. The percentage of the oxygen which is present in the reaction atmosphere may range from 1% to 100%. Preferable range is 5% to 100%. More preferable range is 20% to 100%.

It will be acknowledged, from the person skilled to the art, that, when the atmosphere of the reaction 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 may be interpreted as including the composition of atmospheric air as well. It will further be acknowledged, from the person skilled to the art, that the reaction time may vary depending on the percentage of oxygen present in the air supply, used in the reaction. The reaction time may also vary, depending on the pressure developed or applied to the reaction.

In still another embodiment of the invention, the conversion of the formyl group of formula II to cyano group of formula III may also be achieved with ammonia and iodine. In a preferred embodiment of the present invention, said conversion is carried out in a polar aprotic solvent. Preferred aprotic solvents are dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, acetonitrile and tetrahydrofuran.

In yet another preferred embodiment of the present invention, the above mentioned conversion of the formyl group of formula II to cyano group of formula III is carried out in temperatures ranging from 0 °C to the boiling point of the solvent, wherein the reaction is performed. Preferable temperature range is 0-100 °C. More preferable temperature range is 10-60 °C. Even more preferable temperature range is 10-40 °C.

In still another embodiment of the invention, the above mentioned conversion of the formyl group of formula II to cyano group of formula III is performed under normal atmosphere conditions. The person skilled to the art will acknowledge that this feature does not limit the scope of the invention.

Another object of the present invention is a process for the preparation of Febuxostat, as described above, comprising the conversion of the formyl group of compound of formula II, to nitrile group of compound of formula III, comprising: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine, and subsequently converting the compound of formula III to Febuxostat.

EXPERIMENTAL of compound of formula lib

Dissolve 14.14g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula III) in 55 ml dimethylformamide, at ambient temperature. Add 40g of potassium carbonate, along with 15.9 ml isobutyl bromide. Heat the reaction to 75-80 °C and stir for 4 hours. Cool to 25-30 °C, while 165 ml process water is added. Further cool to 0-5 °C and stir for 30 minutes at this temperature. Filter off the precipitated solid and wash the filter cake with 55 ml process water. The wet cake is dried under vacuum at 40 °C for 7 hours, to furnish 16.43 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula lib). of compound of formula Illb

In a 25 mL round-bottomed flask charge under stirring at 25-30 °C, 1.0 g (2.88 mmol) of ethyl 2- (3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in 3.0 mL dimethylformamide. Add 34 mg (0.19 mmol) copper acetate under stirring at 25-30 °C. Flush with oxygen (0₂) and add 0.66 ml (34.92 mmol) 25% aqueous ammonia. Flush again with 0₂. Heat the reaction mixture to 80-82 °C overnight. Check the progress of the reaction by TLC (cyclohexanerethyl acetate 3:1). Cool reaction mass to 25-30 °C. Add 25mL ethyl acetate and 25mL brine at the reaction mass, separate organic layer and extract aqueous layer twice with 25mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate till dry. The residue is purified with column chromatography (cyclohexane:ethyl acetate 9:1). afforded 0.754g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb) Yield: 75.4%.

EXAMPLE 3: Preparation of compound of formula Illb

In a 25 mL round-bottomed flask charge under stirring at 25-30 °C, 0.17 g (0.49 mmol) of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate in 2.5 mL tetrahydrofuran. Add 2.9 mL (153.43 mmol) 25% aqueous ammonia, under stirring at 25-30 °C. Add 137 mg (0.54 mmol) iodine (I₂) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 3:1). Starting material is consumed. Add 2.5 mL 5% w/v aqueous sodium thiosulfate Na₂S₂0₃ and 15mL ethyl acetate at the reaction mass, separate organic layer and extract twice aqueous layer with 15mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate till dry. 0.158g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula Illb) are collected.

EXAMPLE 4: Preparation of Febuxostat

In a 100 ml 2-neck round-bottomed flask charge 2.407g of ethyl-2-(3-cyano-4-isobutoxyphenyl)- 4-methylhiazole-carboxylate in 20ml tetrahydrofuran under stirring, at 25-35 °C, 0.748g of sodium hydroxide and heat reaction mass to 60-65 °C for approximately 8 hrs. Check the progress of the reaction by TLC (cyclohexane:ethyl acetate 3:1). Cool reaction mass to 0-5 °C and add 50 ml process water keeping temperature within 0-5 °C. Adjust pH to 1-2 with 4.5 ml 6 N hydrochloric acid, keeping temperature within 0-5 °C. Warm up reaction mass to 25-30 °C and stir reaction mass at the above temperature for 15 min. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 2 ml process water and suck dry for 20- 30 min. Transfer the crude solid in a 50 ml round-bottomed flask, charge 12 ml process water and 12 ml acetone at 25-30°C. Heat the reaction mass to 50-60 °C for 60 min. Cool down reaction mass to 0-5 °C and stir for 60 min at the above temperature. Filter off the precipitated solid though Buchner funnel under reduced pressure, spray wash with 2 ml of a 1 : 1 mixture of acetone and process water and suck dry for 30-45 min. Dry under vacuum at 60 °C. 1.821g of (compound I) Febuxostat are collected, Purity: 82.6%, Yield: 0.62w/w. on of compound of formula Ilia

In a 50 mL round-bottomed flask charge under stirring 0.5g (1.72 mmol) of ethyl 2-(3-formyl-4- hydroxyphenyl)-4-methylthiazole-5-carboxylate in 8.6 mL THF, at 25-30 °C. Add 10.3 mL (544.94 mmol) 25% aqueous ammonia, under stirring at 25-30 °C. Add 480 mg (1.89 mmol) iodine (I₂) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 1 :1). Starting material is consumed. Add 8.6 mL 5% w/v aqueous thiosulfate and 40 mL ethyl acetate at the reaction mass, separate organic layer and extract aqueous layer twice with 40 mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate to dryness. Purification of the residue with column chromatography (cyclohexane: ethyl acetate 3: 1) afforded 0.213 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula Ilia). Yield : 42.6%. EXAMPLE 6: Preparation of compound Illb

Dissolve 2.2 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula VI) in 7 ml dimethylformamide and to this mixture add 6.6 g of potassium carbonate and 3.14 g of isobutyl bromide. Stir the reaction at 75 °C for 15 hours and then cool to 40 °C. Add 15 ml process water and cool to 0-5 °C. Filter the precipitated solid off and wash with 15 ml process water, which, after drying, affords 2.28 g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4- methylthiazole-5-carboxylate (Formula Illb).

EXAMPLE 7: Preparation of compound I (Febuxostat)

In a 100 ml 2-neck round-bottomed flask charge 2.131 g of ethyl-2(3-cyano-4-isobutoxyphenyl)- 4-methylhiazole-carboxylate, 64 ml methanol and 2.5 ml process water are added under stirring at 25-35 °C. Add 1.718 g potassium carbonate and heat reaction mass to reflux for approximately 2-3 hrs. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 3:1). Cool reaction mass to 20-25 °C. Concentrate solvent at below 40 °C. To the residue add 43 ml process water, 21 ml ethyl acetate and stir for 30 min at 25-35 °C. Separate layers and transfer aqueous layer in a 100 ml round-bottomed flask. Adjust pH to 2.3-2.7 with 25 ml 1 N hydrochloric acid, at 25-35 °C. Warm up reaction mass to 40 °C and stir reaction mass at this temperature for 60-90 min. Cool down reaction mass to 25-35 °C. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 5 ml process water and suck dry for 30-45 min. Dry under vacuum at 60 °C. 1.708g of (compound I) Febuxostat are collected, Purity: 86.7%, Yield: 0.69w/w.

EXAMPLE 8: Preparation of Febuxostat crystalline form III

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

Claims

1. A process comprising conversion of formyl group of compound of formula II to cyano group, to produce compound of formula III, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine

wherein R_\ is a hydrogen atom, an alkyl, alkenyl, or alkynyl group wherein chain group is either straight or branched with 1 to 15 carbon atoms and R₂ is an alkyl, alkenyl, or alkynyl group wherein chain group is either straight or branched with 1 to 15 carbon atoms.

2. A process for the production of Febuxostat comprising the following steps:

a) conversion of formyl group of compound of formula lib wherein Ri is an wo-butyl group and R₂ is as defined in claim 1 to cyano group, to produce compound of formula Illb, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine

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

A process for the production of Febuxostat comprising the following steps:

conversion of formyl group of compound of formula Ila wherein R_\ is a hydrogen atom and R₂ is as defined in claim 1 to cyano group, to produce compound of formula Ilia, in the presence of: i) ammonia, oxygen, and a metal catalyst, or, ii) ammonia and iodine

b) alkylation of compound of formula Ilia to compound of formula Illb wherein wherein Ri is an /so-butyl group and R₂ is as defined in claim 1 ;

4. A process according to claims 2 or 3 wherein R₂ is an ethyl group.

5. A process, according to claims 1, 2 or 3, wherein the transformation of the formyl group to cyano group is performed with ammonia, oxygen and a metal catalyst.

6. A process, according to claims 1, 2 or 3, wherein the transformation of the formyl group to cyano group is performed with ammonia and iodine.

7. A process, according to claim 5, wherein the metal catalyst is a copper, iron or ruthenium catalyst.

8. A process, according to claim 7, 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 (II) oxide and their hydrates.

9. A process, according to claim 5, wherein the reaction is performed in a polar aprotic solvent, preferably dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone or tetrahydrofuran.

10. A process, according to claim 5, wherein the reaction is performed under an atmosphere with a composition comprising oxygen in a range 1-100%, under 1 arm pressure to 200 arm.

1 1. A process, according to claim 10, wherein the reaction is performed under normal atmosphere composition and pressure.

12. A process, according to claim 6, wherein the reaction is performed in a polar aprotic solvent, preferably dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone or tetrahydrofuran.

13. A process for the production of Febuxostat comprising conversion of the compound of general formula III prepared according to claim 1 to Febuxostat.

14. A process for the preparation of Febuxostat crystalline Form III comprising the steps of: a) dissolving Febuxostat as prepared in claims 2 and 3 in ethyl acetate; b) heating the reaction mass up to 75-80°C; c) cooling the reaction mass at 25-30°C d) partially removal of the solvent; e) cooling the reaction mass; f) filtering, washing with ethyl acetate and isolating pure crystalline Form III of Febuxostat.