WO2012131590A1 - An improved process for preparation of febuxostat and its polymorphic crystalline form c thereof - Google Patents
An improved process for preparation of febuxostat and its polymorphic crystalline form c thereof Download PDFInfo
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- WO2012131590A1 WO2012131590A1 PCT/IB2012/051475 IB2012051475W WO2012131590A1 WO 2012131590 A1 WO2012131590 A1 WO 2012131590A1 IB 2012051475 W IB2012051475 W IB 2012051475W WO 2012131590 A1 WO2012131590 A1 WO 2012131590A1
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- 0 CCO*(C1=C(C)NC(c(cc2)cc(C=O)c2OCC(C)C)S1)=O Chemical compound CCO*(C1=C(C)NC(c(cc2)cc(C=O)c2OCC(C)C)S1)=O 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the present invention relates to a process of preparation of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat).
- the present invention in particular relates to an efficient and easily to operate scalable process of manufacturing of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) of Formula I and its olymorphic crystalline form C thereof.
- Febuxostat is the compound of formula (I) chemically known as 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, which is disclosed in EP 0 513 379.
- Febuxostat disclosed in EP 0 513 379 involves condensation of 4- hydroxy-3-nitrobenzaldehyde with hydroxylamine hydrochloride in the presence of sodium formate to give 4-hydroxy-3-nitrobenzonitrile. Conversion of the cyano group into a thioamide and subsequent reaction with ethyl 2-chloroacetoacetate provides ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate. Alkylation of the 4- hydroxyl group with isobutyl bromide, and catalytic hydrogenation of the 3-nitro moiety provides ethyl-2-(3-amino-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate.
- JP1998045733 JP10045733 describes formylation of 2-(4-hydroxyphenyl)-4-methyl- thiazole-5-carboxylic acid ethyl ester to obtain 2-(3-formyl-4-hydroxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester which on alkylation gives 2-(3-formyl-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester which is converted into 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester.
- the said manufacturing process involves isolation of intermediate product at the end of all the steps, which is not commercially suitable since many operations are required to carry out and results in lower overall yield. Recrystallization of intermediates is required to meet quality standards resulting in material losses and large amount of solvent consumption. Excessive use of halogenated hydrocarbon such as dichloromethane and isobutyl bromide damages environment.
- CN101781270 discloses an intermediate (FBZC) and method of its preparation.
- EP 1020454 B l discloses polymorphs, theirs transitions and process for the preparation of crystal C.
- Crystal C is produced by solvent-mediated polymorphic transition.
- the solvent used is mixed solution of methanol and water and the ratio of methanol to water preferably is from 70:30 to 60:40 and requires small amount of crystal C (1 to 2% or less). Heating temperature exerts an influence on the completion time of the conversion into the crystal C.
- Reported manufacturing process for Febuxostat requires many process steps which also results in the formation of impurities from starting materials/ intermediates, side reactions, degradation during work-up/ hydrolysis thereby reducing the overall yield of the product. Furthermore the process steps are not environment friendly. Toxic chemicals such as thioacetamide, ethyl 2-chloroacetoacetate and sodium cyanide are used in the processes known in the literature, which are not environment friendly and require stringent reaction conditions.
- the crystal form C of Febuxostat disclosed in EP 1020454 Bl is a stable crystal, however, solvent-mediated polymorphic transition into this crystal form usually requires several days and it is difficult to produce the crystal C of Febuxostat in an industrially good reproducible manner.
- the present inventors have found that the Duff reaction of said improved processes using hexamethyleneteteramine and trifluoroacetic acid gives better conversion and commercially feasible process in production point of view than reported ones using polyphosphoric acid. Trifluoroacetic acid can be recovered and reused in same step, whereas polyphosphoric acid which is used in the prior art cannot be recovered and reused.
- the present inventors have found that carrying out hydrolysis of the ethyl ester group in the process for preparation of Febuxostat using alkali metal carbonate in methanol or ethanol is facile, unique and does not bear any resemblance with the method described in prior art.
- Hydrolysis employing alkali metal carbonate as a mild base is safe to handle, effective and one of the unique feature of the present invention; it reduces hydrolysis of cyano group which is main side reaction. This reaction is very clean as compared to one with stronger base such as sodium hydroxide, potassium hydroxide which gives low yield and is corrosive in nature.
- Alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate when used in lower alcohol such as methanol or ethanol
- the hydrolysis reaction proceeds smoothly resulting in quantitative yield of the product.
- the present inventors have developed an improved process wherein the cyano group is formed at the end of the process and therefore not exposed to hydrolysis, thereby avoiding the hydrolysis of cyano group which is the main side reaction in the preparation of Febuxostat, is one of the unique features of the present invention.
- the present inventors have surprisingly found that hydrolysis of the ester group using alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate in lower alcohol such as methanol or ethanol yielded hydrolysed product which on further subjecting to functional group transformation (formyl to cyano) by formic acid in presence of hydroxyl amine hydrochloride and sodium formate followed by cooling yielded highly pure crystalline Febuxostat, as a polymorphic form C which does not require further purification by crystallization.
- the present inventors found that the processes of the present invention results in the formation of substantially pure Febuxostat or polymorphic form C of Febuxostat free from all process impurities. Thus purification of Febuxostat by crystallization to deplete these process impurities is not required, which is not easy and leads to heavy losses thereby increasing cost of the product.
- Formula IV iii Converting compound of formula IV to 2-(3-cyano-4-isobutoxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester, compound of formula V by using hydroxylamine hydrochloride and sodium formate in formic acid;
- an improved process for preparing Form C of Febuxostat which comprises the step of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II.
- Formula VA iv. Converting compound of formula VA or its salt thereof to 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula I by using hydroxylamine hydrochloride and sodium formate in formic acid;
- an improved process for the preparation of the compound of formula VA comprising the steps of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
- the present invention relate to an improved scalable process for the preparation of Febuxostat.
- Compound of formula I. (Febuxostat) or its crystalline form C that is industrially feasible and commercially viable.
- Formula V vi Hydrolyzing compound of formula V with alkali metal cabonate in the presence of lower alcohol to obtained 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid of formula I.
- Ethyl 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is converted to Ethyl 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate using hexamethylenetetramine and strong acid through well known Duff reaction.
- Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is alkylated with isobutyl bromide using alkali metal carbonate in dimethyl formamide to give Ethyl 2-(3- formyl-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate.
- Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate is further converted to ethyl 2-3-cyano-4- isobutoxyphenyl)-4-methyl thiazole-5-carboxylate by using hydroxylamine hydrochloride and sodium formate in formic acid.
- 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid is obtained from ethyl 2-3-cyano-4- isobutoxyphenyl)-4-methyl-5- thiazole carboxylate using milder hydrolysis with alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate in lower alcohol such as methanol or ethanol in water.
- alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate in lower alcohol such as methanol or ethanol in water.
- Alkali metal carbonate preferably employed in the process of the present invention is potassium carbonate.
- the present invention also relates to an improved scalable process for the preparation of polymorphic crystalline form C of Febuxostat, compound of Formula I that is industrially feasible, easy to operate and commercially viable.
- an improved process for preparing Form C of Febuxostat which comprises the step of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II.
- Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is alkylated with isobutyl bromide using potassium carbonate in dimethyl formamide to give Ethyl 2- (3- formyl-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate which on hydrolysis in aqueous lower alcohol with alkali metal carbonate such as potassium carbonate or caesium carbonate or sodium carbonate resulted in the formation of 2-(3-formyl-4- isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid or a alkali metal salt thereof, which is further reacted with hydroxylamine hydrochloride in formic acid at reflux to give Febuxostat with impurities well below the ICH limit.
- alkali metal carbonate such as potassium carbonate or caesium carbonate or sodium carbonate
- Ethyl 2-(3-formyl-4- isobutoxyphenyl)-4-methyl thiazole-5-carboxylate (compound of formula IV) is hydrolysis in aqueous lower alcohol with potassium carbonate resulting in the formation of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid potassium salt, Compound of formula VB (corresponding to formula VA in the provisional application 664/KOL/2011 dated 16/20172011) which is further reacted with hydroxylamine hydrochloride in formic acid and reflux to give Febuxostat.
- an improved process for the preparation of the compound of formula VA comprising the steps of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
- Formula VA Alkali metal carbonate used in the process of the present invention is selected from potassium carbonate, caesium carbonate or sodium carbonate.
- Alkali metal carbonate preferably employed is potassium carbonate.
- Lower alcohol used in the process of the present invention is selected from methanol or ethanol.
- Table 1 Comparison of percentage yield and purity of Febuxostat obtained by the process of the present invention vis-a-vis acknowledge prior art JP1998045733. Table 1 :
- Table 2 Comparison of percentage yield and purity of compound of formula V obtained by the process of the present invention vis-a-vis acknowledge prior art CN101781270.
- Table 3 Comparison of percentage yield and purity of polymorphic form C obtained by the process of the present invention vis-a-vis acknowledge prior art EP 1020454.
- Residue obtained was dissolved in 20.0ml of water and added 10.0ml of ethyl acetate. Stirred and separated the aqueous phase. pH of aqueous phase adjusted to 2.5 ⁇ 0.2 by dilute hydrochloric acid solution at 40°C and stirred for l.Ohr. Slurry of the product formed was filtered, washed with water and dried under vacuum to give 0.85gm of Febuxostat.
- Reaction solution was cooled gradually to 25°C and added 50.0ml of water dropwise at 25°C. Slurry formed was stirred for about l.Ohr, filtered, washed with water and dried under vacuum to give 3.76gm of Febuxostat.
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Abstract
The present invention relates to process of preparation of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat). The present invention in particular relates to an efficient and easily to operate scalable process of manufacturing of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) of Formula I and its crystalline polymorphic Form C.
Description
AN IMPROVED PROCESS FOR PREPARATION OF FEBUXOSTAT AND ITS POLYMORPHIC CRYSTALLINE FORM C THEREOF
FIELD OF INVENTION
The present invention relates to a process of preparation of 2-(3-cyano-4- isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat). The present invention in particular relates to an efficient and easily to operate scalable process of manufacturing of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) of Formula I and its olymorphic crystalline form C thereof.
Formula I BACKGROUND OF INVENTION
Prior art literature:
Febuxostat is the compound of formula (I) chemically known as 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, which is disclosed in EP 0 513 379.
The synthesis of Febuxostat disclosed in EP 0 513 379 involves condensation of 4- hydroxy-3-nitrobenzaldehyde with hydroxylamine hydrochloride in the presence of sodium formate to give 4-hydroxy-3-nitrobenzonitrile. Conversion of the cyano group into a thioamide and subsequent reaction with ethyl 2-chloroacetoacetate provides ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate. Alkylation of the 4- hydroxyl group with isobutyl bromide, and catalytic hydrogenation of the 3-nitro moiety provides ethyl-2-(3-amino-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate. Finally, reaction of the latter with sodium nitrite and subsequent hydrolysis of the ethyl carboxylate gives Febuxostat.
JP1998045733 (JP10045733) describes formylation of 2-(4-hydroxyphenyl)-4-methyl- thiazole-5-carboxylic acid ethyl ester to obtain 2-(3-formyl-4-hydroxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester which on alkylation gives 2-(3-formyl-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester which is converted into 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. Finally, the resultant compound is hydrolyzed to give Febuxostat. Alternatively 2-(3-formyl-4- hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester can be treated with formic acid, sodium formate and hydroxylamine hydrochloride to provide to 2-(3-cyano-4- hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, which is then alkylated to give the 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. The said manufacturing process involves isolation of intermediate product at the end of all the steps, which is not commercially suitable since many operations are required to carry out and results in lower overall yield. Recrystallization of intermediates is required to meet quality standards resulting in material losses and large amount of solvent consumption. Excessive use of halogenated hydrocarbon such as dichloromethane and isobutyl bromide damages environment.
An article "A Facile One-pot synthesis of 4-alkoxy-l, 3-Benezendicarbonitrile" by Masaichi Hasegawa of Teijin Institute for Bio-Medical Research Heterocycles, Vol 47, no 2, 1998 discloses synthesis of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid by treating alkoxy 1, 3- benzenedicarbonitrile with thioacetamide followed by cyclization with chloroacetoacetate and hydroxylation. Use of toxic reagents/ solvents such as potassium cyanide and dimethylsulfoxide during formation of 4-alkoxy- 1, 3-Benezendicarbonitrile. Industrially non feasible column chromatography technique is used to get required quality of the intermediates such as 4-alkoxy-l, 3- benezendicarbonitrile and 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. Intermediate isolation involves solvent extraction, concentration followed by isolation which consumes high amount of solvents and gives lower yields. Final hydrolysis step yield is very poor ~ 35%, isolation of quality product with such poor yielding step is not an easy task.
CN101781270 discloses an intermediate (FBZC) and method of its preparation.
It further discloses method of preparation of 2-[3-formyl-4-(2-methylpropyloxy) phenyl] - 4-methyl-5-thiazole formic acid (FBZC), comprising the step of converting 2-[3-formyl- 4-(2-methylpropyloxy) phenyl] -4-methyl-5-thiazole ethyl formate or methyl ester to intermediate FBZC by hydrolysis in the mixed solution of alkali and organic solvent.
EP 1020454 B l discloses polymorphs, theirs transitions and process for the preparation of crystal C. Crystal C is produced by solvent-mediated polymorphic transition. The solvent used is mixed solution of methanol and water and the ratio of methanol to water preferably is from 70:30 to 60:40 and requires small amount of crystal C (1 to 2% or less). Heating temperature exerts an influence on the completion time of the conversion into the crystal C. Drawbacks of the Prior art:
Reported manufacturing process for Febuxostat requires many process steps which also results in the formation of impurities from starting materials/ intermediates, side reactions, degradation during work-up/ hydrolysis thereby reducing the overall yield of the product. Furthermore the process steps are not environment friendly. Toxic chemicals such as thioacetamide, ethyl 2-chloroacetoacetate and sodium cyanide are used in the processes known in the literature, which are not environment friendly and require stringent reaction conditions.
When the hydrolysis reaction in the process for preparation of Febuxostat is carried out using excess strong base i.e sodium hydroxide as disclosed in CN101781270, poor yield of the product is obtained against reported -43% yield and reaction is non-reproducible indicating degradation of the starting material under the condition disclosed.
The active substance prepared by the processes known until now can be obtained after running through a large number of process steps. The main drawbacks associated with the known synthesis are harsh conditions, the toxic reagents to form the thioamide and the highly toxic cyanides. Therefore the need for an alternative synthesis for the industrial preparation of Febuxostat, which makes use of commercially available, cheaper and non toxic reagents. Hydrolysis with strong bases such as sodium hydroxide, potassium hydroxide gives low yield due to hydrolysis of the cyano functional group and is corrosive in nature. Removal of structurally similar Impurity by crystallization of the final compound is not an easy task and also results in overall cost increase of the product.
Processes known in the prior art result in lower yield of the product obtained after the hydrolysis step; last step governs the overall costs of the process. Hydrolysis of ethyl ester group using strong base also results in side reaction i.e. hydrolysis of cyano group of the compound to give amide impurity. This also lowers the yield of the product. Febuxostat produced using strong base requires additional purification step to get product meeting ICH quality.
Other reported methods for introducing formyl group in phenol derivatives use toxic raw material, or has problems, viz expensive, highly corrosive raw materials, which are not methods of choice for industrial scale.
The crystal form C of Febuxostat disclosed in EP 1020454 Bl is a stable crystal, however, solvent-mediated polymorphic transition into this crystal form usually requires several days and it is difficult to produce the crystal C of Febuxostat in an industrially good reproducible manner.
The processes of the present invention offers several advantages over previous methods of making Febuxostat known in prior literature, and its industrial preparation thereof and also overcome the drawbacks related to the same.
The present inventors have found that the Duff reaction of said improved processes using hexamethyleneteteramine and trifluoroacetic acid gives better conversion and commercially feasible process in production point of view than reported ones using
polyphosphoric acid. Trifluoroacetic acid can be recovered and reused in same step, whereas polyphosphoric acid which is used in the prior art cannot be recovered and reused. The present inventors have found that carrying out hydrolysis of the ethyl ester group in the process for preparation of Febuxostat using alkali metal carbonate in methanol or ethanol is facile, unique and does not bear any resemblance with the method described in prior art. Hydrolysis employing alkali metal carbonate as a mild base is safe to handle, effective and one of the unique feature of the present invention; it reduces hydrolysis of cyano group which is main side reaction. This reaction is very clean as compared to one with stronger base such as sodium hydroxide, potassium hydroxide which gives low yield and is corrosive in nature.
Alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate when used in lower alcohol such as methanol or ethanol, the hydrolysis reaction proceeds smoothly resulting in quantitative yield of the product. In an embodiments of the present invention, the present inventors have developed an improved process wherein the cyano group is formed at the end of the process and therefore not exposed to hydrolysis, thereby avoiding the hydrolysis of cyano group which is the main side reaction in the preparation of Febuxostat, is one of the unique features of the present invention.
The present inventors have surprisingly found that hydrolysis of the ester group using alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate in lower alcohol such as methanol or ethanol yielded hydrolysed product which on further subjecting to functional group transformation (formyl to cyano) by formic acid in presence of hydroxyl amine hydrochloride and sodium formate followed by cooling yielded highly pure crystalline Febuxostat, as a polymorphic form C which does not require further purification by crystallization.
The present inventors found that the processes of the present invention results in the formation of substantially pure Febuxostat or polymorphic form C of Febuxostat free from all process impurities. Thus purification of Febuxostat by crystallization to deplete these process impurities is not required, which is not easy and leads to heavy losses thereby increasing cost of the product.
OBJECT OF THE INVENTION
It is an object of the present invention to provide improved, efficient, economic environment friendly, easy to scale-up and commercially useful process for the manufacture of compound of formula I or its crystalline polymorphic form C that is devoid of drawbacks of prior art processes.
It is another object of the present invention to provide an improved process for the preparation of compound of formula I or its crystalline polymorphic form C that does not employ any hazardous reagents and condition is safer to carry out.
It is another object of the present invention to provide an improved process for the preparation of compound of formula I or its crystalline polymorphic form C in high yield. It is yet another object of the present invention to provide an improved process which yields substantially pure compound of formula I or its crystalline polymorphic form C.
It is yet another object of the present invention to provide an improved process for the preparation of compound of formula I or its crystalline polymorphic form C that is easy to commercialize and provide product free from impurities.
It is a further object of the present invention to provide an improved process for the preparation of compound of formula VA. (corresponding to formula V in the provisional application 664/KOL/2011 dated 16/05/2011).
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided an improved process for preparing Febuxostat, compound of formula I).
Formula (I)
which comprises the step of:
i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
Formula II with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
ii. Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Formula IV iii. Converting compound of formula IV to 2-(3-cyano-4-isobutoxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester, compound of formula V by using hydroxylamine hydrochloride and sodium formate in formic acid;
Formula V
Hydrolyzing compound of formula V with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid of formula I.
Formula I
According to another aspect of the present invention there is provided an improved process for preparing Form C of Febuxostat, which comprises the step of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II.
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
ii. Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Formula IV
iii. Hydrolyzing compound of formula IV with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid, compound of formula VA or its salt thereof;
Formula VA iv. Converting compound of formula VA or its salt thereof to 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula I by using hydroxylamine hydrochloride and sodium formate in formic acid;
Formula I
v. Isolation of pure compound of formula I with polymorphic form C from reaction mixture as obtained in step iv by addition of water above 60°C and cooling to room temperature.
According to yet another aspect of the present invention there is provided an improved process for the preparation of the compound of formula VA comprising the steps of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Hydrolyzing compound of formula IV with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid, com ound of formula VA or its salt thereof.
Formula VA
DETAILED DESCRIPTION
The present invention relate to an improved scalable process for the preparation of Febuxostat. Compound of formula I. (Febuxostat) or its crystalline form C that is industrially feasible and commercially viable.
In an embodiment of the present invention there is provided an improved process for preparing Febuxostat of formula I).
Formula (I)
which comprises the step of:
i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, Compound of Formula II.
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III.
Formula III ii. Treating the compound of formula III with isobutyl bromide to obtained 2-(3- formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV.
Formula IV
iii. Converting compound of formula IV to 2-(3-cyano-4-isobutoxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester, compound of formula V by using hydroxylamine hydrochloride and sodium formate in formic acid.
Formula V vi. Hydrolyzing compound of formula V with alkali metal cabonate in the presence of lower alcohol to obtained 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid of formula I.
Formula I Ethyl 2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is converted to Ethyl 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate using hexamethylenetetramine and strong acid through well known Duff reaction.
Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is alkylated with isobutyl bromide using alkali metal carbonate in dimethyl formamide to give Ethyl 2-(3- formyl-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate.
Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate is further converted to ethyl 2-3-cyano-4- isobutoxyphenyl)-4-methyl thiazole-5-carboxylate by using hydroxylamine hydrochloride and sodium formate in formic acid. 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (Febuxostat) is obtained from ethyl 2-3-cyano-4- isobutoxyphenyl)-4-methyl-5- thiazole carboxylate using milder hydrolysis with alkali metal carbonate such as potassium carbonate, caesium carbonate or sodium carbonate in lower alcohol such as methanol or ethanol in water. Alkali metal carbonate preferably employed in the process of the present invention is potassium carbonate.
The process of the present invention can be represented in scheme I as follows:
Scheme I:
ormu a
The present invention also relates to an improved scalable process for the preparation of polymorphic crystalline form C of Febuxostat, compound of Formula I that is industrially feasible, easy to operate and commercially viable.
In other embodiment of the present invention there is provided an improved process for preparing Form C of Febuxostat which comprises the step of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II.
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III.
Formula III
ii. Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV.
Formula IV iii. Hydrolyzing compound of formula IV with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-thiazole-5- carboxylic acid, compound of formula VA or its salt thereof.
iv. Converting compound of formula VA or its salt thereof to 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula I by using hydroxylamine hydrochloride and sodium formate in formic acid.
Formula I v. Isolation of pure compound of formula I having polymorphic form C from reaction mixture as obtained in step iv by addition of water above 60°C and cooling to room temperature. Ethyl-2-(4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is converted to Efhyl-2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate using hexamethylenetetramine and strong acid through well known Duff reaction.
Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl thiazole-5-carboxylate is alkylated with isobutyl bromide using potassium carbonate in dimethyl formamide to give Ethyl 2- (3- formyl-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate which on hydrolysis in aqueous lower alcohol with alkali metal carbonate such as potassium carbonate or caesium carbonate or sodium carbonate resulted in the formation of 2-(3-formyl-4- isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid or a alkali metal salt thereof, which
is further reacted with hydroxylamine hydrochloride in formic acid at reflux to give Febuxostat with impurities well below the ICH limit.
In a preferred embodiment of the present invention Ethyl 2-(3-formyl-4- isobutoxyphenyl)-4-methyl thiazole-5-carboxylate (compound of formula IV) is hydrolysis in aqueous lower alcohol with potassium carbonate resulting in the formation of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid potassium salt, Compound of formula VB (corresponding to formula VA in the provisional application 664/KOL/2011 dated 16/05/2011) which is further reacted with hydroxylamine hydrochloride in formic acid and reflux to give Febuxostat.
Formula VB
In another embodiment of the present there is provided an improved process for the preparation of the compound of formula VA comprising the steps of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
ii. Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Formula IV
iii. Hydrolyzing compound of formula IV with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid compound of formula VA or its salt thereof.
Formula VA
In yet another embodiment of the present invention there is provided a compound of formula VA prepared according to the process of the present invention.
Formula VA
Alkali metal carbonate used in the process of the present invention is selected from potassium carbonate, caesium carbonate or sodium carbonate.
Alkali metal carbonate preferably employed is potassium carbonate.
Lower alcohol used in the process of the present invention is selected from methanol or ethanol.
The process of the present invention can be represented in scheme II as follows:
Scheme II:
Formula II Formula I
Formula IV
Comparative data:
Table 1: Comparison of percentage yield and purity of Febuxostat obtained by the process of the present invention vis-a-vis acknowledge prior art JP1998045733.
Table 1 :
Table 2: Comparison of percentage yield and purity of compound of formula V obtained by the process of the present invention vis-a-vis acknowledge prior art CN101781270.
Table 2:
The following examples are meant to illustrate the present invention. The examples are presented to exemplify the invention and are not to be considered as limiting the scope of the invention.
EXAMPLES
Example 1
Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) TCompound of formula II. a) Preparation of Ethyl 2-(3-formyl-4-hvdroxyphenyl)-4-methyl-5-thiazolecarboxylate
[Compound of formula
lO.Ogm of Ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate, [Compound of formula II] and 5.86gm of hexamethylenetetramine was added to 100.0ml of trifluoroacetic acid. Reaction mixture was heated to reflux under stirring for 40 hr. Trifluoroacetic acid was distilled out at 80 ± 3°C. Residue obtained was cooled to 25°C and slowly added 100 ml of water. Slurry formed was stirred for 2.0hr. Slurry of the product was filtered, washed and dried under vacuum to give 9.6 gm of titled compound. b) Preparation of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate [Compound of formula IV1.
350.0gm of Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula III] 332. Ogm of potassium carbonate and 330.0gm of isobutyl bromide were added to 1.751tr of DMF. Reaction mixture was heated to 90 ± 3°C and stirred for 4 hr. Reaction mixture was cooled to 25°C and slowly added 10.50 ltr of water. Slurry of the product formed was stirred for 2.0hr, filtered, washed and dried under vacuum to give 389 gm of titled compound.
Analytical Data- · ^NMR (CDC13, 400 MHz) : δ 1.079-1.101 (doublet, 6H); δ 1.366-1.413 (triplet,
3H); δ 2.185-2.230 (multiplet, 1H); δ 2.769 (singlet, 3H); δ 3.914-3.935 (doublet, 2H); δ 4.316-4.387 (quartet, 2H); δ 7.045-7.074 (doublet, 1H); δ 8.188-8.225 (doublet of doublet, 1H); δ 8.353-8.361 (doublet, 1H).
• Mass (m/e): 348.3 c) Preparation of Ethyl 2-(3-cvano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate [Compound of formula V]. 350.0gm of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula IV] 123.0gm of sodium formate followed by 84.0gm of hydroxylamine hydrochloride were added to 1.4 ltr of formic acid. Reaction mixture was heated to reflux and stirred for 5hr to complete the reaction. Reaction solution was cooled
to 25°C. Slowly added 2.8 ltr of water at 25°C. Slurry formed was stirred for about l.Ohr, filtered, washed with water and dried under vacuum to give 321.0gm of titled compound.
Analytical Data- · ^NMR (CDC13, 400 MHz) : δ 1.053-1.104 (doublet, 6H); δ 1.368-1.416 (triplet,
3H); δ 2.164-2.253 (multiplet, 1H); δ 2.768 (singlet, 3H); δ 3.890-3.911 (doublet, 2H); δ 4.324-4.395 (quartet, 2H); δ 6.998-7.027 (doublet, 1H); δ 8.075-8.112 (doublet of doublet, 1H); δ 8.175-8.182 (doublet, 1H).
• Mass (m/e) : 345.2 d) Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) [Compound of formula Π.
250.0gm of Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula V] and then 200.0gm of potassium carbonate were added to the mixture of 7.51tr of methanol and 250.0ml water. Heated the solution to reflux under stirring for 3hr to complete the reaction. Cooled the clear solution formed and applied vacuum to distill out the solvent to maximum extent below 40°C. To the residue 5.01tr of water was added and stirred to obtain solution. Added 2.51tr of ethyl acetate, stirred and layers separated. pH of aqueous solution adjusted to 2.5 ± 0.2 by addition of dil. hydrochloric acid solution at 40°C and stirred for about l.Ohr. Slurry of the product was filtered, washed with water and dried under vacuum to give 215.0gm of Febuxostat.
Analytical Data- · ^NMR (CDCI3, 400 MHz): δ 0.992-1.067 (doublet, 6H); δ 2.029-2.117
(multiplet, 1H); δ 2.636 (singlet, 3H); δ 3.963-3.985 (doublet, 2H); δ 7.317-7.347 (doublet, 1H); δ 8.160-8.197 (doublet of doublet, 1H); δ 8.238-8.245 (doublet, 1H); δ 13.397 (Broad singlet, 1H).
• Mass (m/e) : 317.1
Example 2
Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) [Compound of formula Π. l.Ogm of Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula V] and 1.9gm of caesium carbonate were added to the mixture of 30.0ml of methanol and 1.0ml water. Raised the temperature of reaction mixture to reflux under stirring and refluxed for 3hr to complete the reaction. Clear solution formed was cooled to 40°C and applied vacuum to distill out the solvent to the maximum extent at 40°C. Residue obtained was dissolved in 20.0ml of water and added 10.0ml of ethyl acetate. Stirred and separated the aqueous phase. pH of aqueous phase adjusted to 2.5 ± 0.2 by dilute hydrochloric acid solution at 40°C and stirred for l.Ohr. Slurry of the product formed was filtered, washed with water and dried under vacuum to give 0.85gm of Febuxostat.
Example 3.
l.Ogm of Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula V] and 0.6gm of sodium carbonate were added to the mixture of 30.0ml methanol and 1.0ml of water. Temperature of mixture raised to reflux and stirred at reflux for 36 hr. Clear solution formed was cooled to 40°C and applied vacuum to distill out the solvent to the maximum extent maintaining temperature below 40°C. Residue obtained after distillation was dissolved in 20.0ml of water and 10.0ml of ethyl acetate. Stirred and aqueous phase separated. pH of the aqueous phase was adjusted to 2.5 ± 0.2 by dil. hydrochloric acid at 40°C and stirred for l.Ohr. Slurry of the product formed was filtered and washed with water and dried under vacuum to give 0.59 gm of Febuxostat.
Example 4
Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) rCompound of formula II.
a) Preparation of Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate [Compound of formula lO.Ogm of Ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate, [compound of formula II] and 5.32gm of hexamethylenetetramine was added to 100.0ml of trifluoroacetic acid. Reaction mixture was heated to reflux under stirring for 40 hr. Trifluoroacetic acid was distilled out. Residue obtained was cooled to 25°C and slowly added 200 ml of water. Slurry formed was stirred for 4.0hr. Slurry of the product was filtered, washed and dried under vacuum to give 7.67 gm of title compound. b) Preparation of 2-(3-formyl-4-isobutoxyphenyl)-4-methyl- 5- thiazolecarboxylic acid [Compound of formula VA1.
Process A:
25.0gm of Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, 24.0gm of potassium carbonate and 24.0gm of isobutyl bromide were added to 125 ml of DMF. Reaction mixture was heated to 90 ± 3°C and stirred for 4 hr. Reaction mixture was cooled to 25°C and slowly added 3.01tr of water. Slurry of the product formed was stirred for l.Ohr, filtered, washed and unloaded to give 64.5 gm of wet Ethyl 2-(3-formyl-4- isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate.
61.0gm of above wet compound and 24.0gm of potassium carbonate were added to the mixture of 0.7501tr of methanol and 25.0ml water. Solution heated to reflux under stirring for 3hr and methanol distilled out under vacuum below 40°C. Residue cooled to 40°C and 0.51tr of water was added. Stirred for 15.0mins. pH of aqueous solution adjusted to 5.5 ± 0.2 by addition of dil. hydrochloric acid solution at 40°C. Stirred for about 2.0hr. Slurry of the product was filtered, washed with water and dried under vacuum to give 22.32gm of 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid
Process B :
3.0gm of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate and 5.63gm of caesium carbonate were added to the mixture of 30.0ml of methanol and 3.0ml water. Reaction mixture was heated to reflux under stirring and stirred for 4hr. Slurry was
cooled to 25°C and added 60.0ml of water at 25°C. pH of aqueous solution adjusted to 3.0 ± 0.2 by addition of dil. hydrochloric acid at 25°C. Slurry stirred for about l.Ohr. Filtered, washed with water and dried under vacuum to give 2.29gm of 2-(3-formyl-4- isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
Analytical Data-
1HNMR (DMSO-de, 400 MHz): δ 1.026-1.045 (doublet, 6H);
δ 2.093-2.159 (multiplet, IH); δ 2.664 (singlet, 3H); δ 3.989-4.005 (doublet, 2H); δ 7.340-7.362 (doublet, IH); δ 8.176-8.182 (doublet, IH); δ 8.197-8.219 (doublet of doublet, IH); δ 10.409 (singlet, IH); δ 13.389 (broad singlet, IH).
Mass (m/e): 320.2
Process C:
50.0gm of Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, 47.44gm of potassium carbonate and 47.04gm of isobutyl bromide were added to 200 ml of DMF. Reaction mixture was heated to 90 ± 3°C and stirred for 3 hr. Reaction mixture was cooled to 25°C and slowly added 1.501tr of water. Slurry of the product formed was stirred for l.Ohr, filtered, washed and unloaded to give 119.06 gm of wet Ethyl 2-(3- formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate.
Charged above wet compound and 47.44gm of potassium carbonate were added to the mixture of 0.501tr of methanol and 0.0501tr water. Solution heated to reflux under stirring for 4hr and methanol distilled out under vacuum below 40°C. Residue cooled to 25°C and 2.01tr of water was added. Stirred for 15.0mins. pH of aqueous solution adjusted to 3.0 ± 0.2 by addition of dil. hydrochloric acid solution at 40°C. Stirred for about 30.0mins. Slurry of the product was filtered, washed with water and dried under vacuum to give 46.38gm of 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid d) Preparation of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) [Compound of formula Π as a crystal form C.
20.0gm of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid, 8.52gm of sodium formate followed by 4.57gm of hydroxylamine hydrochloride were
added to 200.0ml of formic acid. Reaction mixture was heated to reflux and stirred for 5hr to complete the reaction. Reaction solution was cooled gradually to 25°C. Slurry formed was stirred for about 2.0hr, filtered, washed with water and dried under vacuum to give 12.8 gm of Febuxostat as a crystal form C.
Analytical Data-
1HNMR (DMSO-de, 400 MHz): δ 1.014-1.030 (doublet, 6H); δ 2.059-2.126 (multiplet, 1H); δ 2.657 (singlet, 3H); δ 3.990-4.006 (doublet, 2H); δ 7.346-7.369 (doublet, 1H); δ 8.191-8.219 (doublet of doublet, 1H); δ 8.266-8.271 (doublet, 1H); δ 13.410 (broad singlet, 1H).
Mass (m/e): 317.2
Crystal C Data-
IR (KBr): 1702.1, 1217.6 cm"1
XRD Pattern (2Θ) - 6.80°, 11.03°, 13.57°, 15.76°, 16.98°, 17.62°, 18.26°, 18.93°, 20.38°, 20.64°, 22.12°, 23.73°, 24.74°, 25.37°, 34.29°, 36.83°, 38.25° e) Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) [Compound of formula Π as a crystal form C.
25.0gm of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid, 10.65. Ogm of sodium formate followed by 5.98gm of hydroxylamine hydrochloride were added to 250.0ml of formic acid. Reaction mixture was heated to reflux and stirred for 5hr to complete the reaction. Slowly added 25.0ml of water to the reaction mixture at reflux. Reaction solution was cooled to 25°C. Slurry formed was stirred for about l.Ohr, filtered, suck dried and washed with water. Dried under vacuum to give 19.68gm of titled compound as Febuxostat as a crystal C.
Crystal C Data-
IR (KBr): 1702.1, 1217.6 cm"1
XRD Pattern (2θ) - 6.83°, 11.05°, 13.59°, 15.77°, 17.03°, 18.30°, 18.97°, 20.14°, 20.69°, 22.15°, 23.77°, 24.77°, 25.05°, 34.34°, 36.86°, 38.30°.
f) Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid
(Febuxostat) [Compound of formula II. 5.0gm of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate and 4.0gm of potassium carbonate were added to the mixture of 50.0ml of methanol and 5.0ml water. Reaction mixture was heated to reflux under stirring for 4hr to complete the reaction. Solvent distilled out under vacuum below 40°C. Residue obtained was cooled to 25°C and added 1.76gm of sodium formate followed by 1.20gm of hydroxylamine hydrochloride and 50.0ml of formic acid. Reaction mixture was heated to reflux and stirred for 5hr. Reaction solution was cooled gradually to 25°C and added 50.0ml of water dropwise at 25°C. Slurry formed was stirred for about l.Ohr, filtered, washed with water and dried under vacuum to give 3.76gm of Febuxostat.
Claims
1. An improved process for reparing Febuxostat, compound of formula (I).
Formula (I)
which comprises the step of:
i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
Formula II with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
ii. Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Formula IV iii. Converting compound of formula IV to 2-(3-cyano-4-isobutoxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester, compound of formula V by using hydroxylamine hydrochloride and sodium formate in formic acid;
Formula V
iv. Hydrolyzing compound of formula V with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid of formula I.
Formula I
2. The process for preparing Febuxostat according to claim 1 wherein the alkali metal carbonate used in step iv is selected from potassium carbonate, caesium carbonate or sodium carbonate.
The process for preparing Febuxostat according to claim 1 wherein the lower alcohol used in step iv is selected from methanol or ethanol.
An improved process for preparing polymorphic Form C of Febuxostat which comprises the step of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
ii. Alkylating compound of formula III with isobutyl bromide to obtain 2-(3- formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Formula IV iii. Hydrolyzing compound of formula IV with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-formyl-4-isobutoxyphenyl)-4- methylthiazole-5-carboxylic acid, compound of formula VA or its salt thereof;
Formula VA iv. Converting compound of formula VA or its salt thereof to 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula I by using hydroxylamine hydrochloride and sodium formate in formic acid;
Formula I v. Isolation of pure compound of formula I with polymorphic form C from reaction mixture as obtained in step iv by addition of water above 60°C and cooling to room temperature.
The process for preparing polymorphic Form C of Febuxostat according to claim 4 wherein the alkali metal carbonate used in step iii is selected from potassium carbonate, caesium carbonate or sodium carbonate.
The process for preparing polymorphic Form C of Febuxostat according to claim 4 wherein the lower alcohol use in step iii is selected from methanol or ethanol.
A process for the preparation of the compound of formula VA comprising the steps of: i. Reacting 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, compound of Formula II
Formula II
with hexamethylenetetramine in the presence of trifluoroacetic acid to obtain 2-(3- formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula III;
Formula III
Alkylating compound of formula III with isobutyl bromide to obtain 2-(3-formyl- 4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, compound of formula IV;
Formula IV iii. Hydrolyzing compound of formula IV with alkali metal carbonate in the presence of lower alcohol to obtained 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid compound of formula VA or its salt thereof.
Formula VA
The process for preparing compound of formula VA according to claim 7 wherein the alkali metal carbonate used in step (iii) is selected from potassium carbonate, caesium carbonate or sodium carbonate.
9. The process for preparing compound of formula VA according to claim 7 wherein the lower alcohol use in step (iii) is selected from methanol or ethanol.
10. The compound of Formula (VA) prepared by the process according to claim 7.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058950A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Preparation method of febuxostat |
| CN108440443A (en) * | 2018-05-16 | 2018-08-24 | 无棣锐新医药化工有限公司 | The preparation method of febuxostat intermediate |
| CN109320474A (en) * | 2018-11-08 | 2019-02-12 | 昆明源瑞制药有限公司 | A kind of preparation method of Febustat |
| CN110057959A (en) * | 2019-05-24 | 2019-07-26 | 山东新华制药股份有限公司 | A kind of analysis method of the high effective liquid chromatography for measuring Febustat intermediate in relation to substance |
| CN110790720A (en) * | 2019-09-09 | 2020-02-14 | 内蒙古京东药业有限公司 | New preparation method of febuxostat intermediate |
| CN111499593A (en) * | 2020-04-29 | 2020-08-07 | 峨眉山宏昇药业股份有限公司 | The synthesis process of febuxostat |
| CN112142685A (en) * | 2019-06-28 | 2020-12-29 | 北京鑫开元医药科技有限公司 | Improved method for synthesizing febuxostat key intermediate |
| CN112961119A (en) * | 2021-01-21 | 2021-06-15 | 廊坊师范学院 | A kind of preparation method of febuxostat impurity |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0513379A1 (en) | 1990-11-30 | 1992-11-19 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| JPH06329647A (en) * | 1993-05-25 | 1994-11-29 | Teijin Ltd | Production of 2-(4-alkoxy-3-cyanophenyl)thiazole derivative and new production intermediate therefor |
| JPH1045733A (en) | 1996-08-01 | 1998-02-17 | Teijin Ltd | Production of 2-(4-alkoxy-3-cyanophenyl)thiazole derivative |
| EP1020454B1 (en) | 1998-06-19 | 2009-11-25 | Teijin Pharma Limited | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN101781270A (en) | 2009-01-20 | 2010-07-21 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
-
2012
- 2012-03-28 WO PCT/IB2012/051475 patent/WO2012131590A1/en not_active Ceased
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0513379A1 (en) | 1990-11-30 | 1992-11-19 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| JPH06329647A (en) * | 1993-05-25 | 1994-11-29 | Teijin Ltd | Production of 2-(4-alkoxy-3-cyanophenyl)thiazole derivative and new production intermediate therefor |
| JPH1045733A (en) | 1996-08-01 | 1998-02-17 | Teijin Ltd | Production of 2-(4-alkoxy-3-cyanophenyl)thiazole derivative |
| EP1020454B1 (en) | 1998-06-19 | 2009-11-25 | Teijin Pharma Limited | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN101781270A (en) | 2009-01-20 | 2010-07-21 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
| US20110282069A1 (en) * | 2009-01-20 | 2011-11-17 | Chongqing Pharmaceutical Research Institute Co/. Ltd. | High-purity febuxostat and the method for preparation |
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
Non-Patent Citations (4)
| Title |
|---|
| KAESTLE ET AL.: "CLEAVAGE OF ESTERS USING CARBONATES AND BICARBONATES OF ALKALI METALS: SYNTHESIS OF THYMOPENTIN", TETRAHEDRON LETT., vol. 32, no. 3, 1991, pages 327 - 330, XP055028570 * |
| LAROCK: "Comprehensive Organic Transformations - A Guide to Functional Group Preparations, 2nd ed.", part Chapter 9.17 1999, WILEY-VCH, New York, ISBN: 0471190314, article "Interconversion of Nitriles, Carboxylic Acids and Derivatives: Esters to Carboxylic Acids", pages: 1959 - 1968, XP002676948 * |
| MASAICHI HASEGAWA: "A Facile One-pot synthesis of 4-alkoxy-1, 3-Benezendicarbonitrile", TEIJIN INSTITUTE FOR BIO-MEDICAL RESEARCH HETEROCYCLES, vol. 47, no. 2, 1998 |
| YAMAGATA ET AL.: "Studies on Heterocyclic Enaminonitriles, XII. Reactions of 4,5-Dihydro-2-morpholino- (and -2-pyrrolidino)-3-furancarbonitriles with Dichlorocarbene", LIEBIGS ANNALEN DER CHEMIE, no. 11, 1 January 1992 (1992-01-01), pages 1109 - 1112, XP055028573, DOI: 10.1002/jlac.1992199201183 * |
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