CN105452228B - Prepare the novel method of Febuxostat - Google Patents
Prepare the novel method of Febuxostat Download PDFInfo
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- CN105452228B CN105452228B CN201480044498.XA CN201480044498A CN105452228B CN 105452228 B CN105452228 B CN 105452228B CN 201480044498 A CN201480044498 A CN 201480044498A CN 105452228 B CN105452228 B CN 105452228B
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- 0 CC(c1cc(-c2nc(C)c(C(*)=O)[s]2)ccc1*C=C(C)C)N Chemical compound CC(c1cc(-c2nc(C)c(C(*)=O)[s]2)ccc1*C=C(C)C)N 0.000 description 8
- OGAZOYHQFBSRMC-UHFFFAOYSA-N CCOC(c1c(C)nc(-c(cc2)cc(C#N)c2OCC(C)C)[s]1)=O Chemical compound CCOC(c1c(C)nc(-c(cc2)cc(C#N)c2OCC(C)C)[s]1)=O OGAZOYHQFBSRMC-UHFFFAOYSA-N 0.000 description 1
- MMMUBYHFXKDDAK-UHFFFAOYSA-N CCOC(c1c(N)nc(-c(cc2)cc([N+]([O-])=O)c2O)[s]1)=O Chemical compound CCOC(c1c(N)nc(-c(cc2)cc([N+]([O-])=O)c2O)[s]1)=O MMMUBYHFXKDDAK-UHFFFAOYSA-N 0.000 description 1
- INBLGVOPOSGVTA-UHFFFAOYSA-N N#Cc(cc1)cc([N+]([O-])=O)c1O Chemical compound N#Cc(cc1)cc([N+]([O-])=O)c1O INBLGVOPOSGVTA-UHFFFAOYSA-N 0.000 description 1
- YTHJCZRFJGXPTL-UHFFFAOYSA-N [O-][N+](c(cc(C=O)cc1)c1O)=O Chemical compound [O-][N+](c(cc(C=O)cc1)c1O)=O YTHJCZRFJGXPTL-UHFFFAOYSA-N 0.000 description 1
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Pain & Pain Management (AREA)
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- Physical Education & Sports Medicine (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This application involves the novel methods that 2 (3 cyano, 4 isobutoxy phenyl) 41,3 thiazole of methyl, 5 formic acid (Febuxostat) is prepared by novel and the formyl basal orientation cyano of high yield conversion.
Description
Technical field
The present invention relates to prepare 2- (3- cyano -4- isobutyls by novel and the formyl basal orientation cyano of high yield conversion
Phenyl) -4- methyl-1s, the novel method of 3- thiazole -5- formic acid (Febuxostat).
Background technology
Febuxostat (Formulas I) is the inhibitor of xanthine oxidase, by Di Ren pharmaceutical Co. Ltds of Japanese firm
(Teijin Pharma Ltd) is found and it is indicated for the treatment of antihyperuricemic and chronic gout.Its chemical name
It is 2- (3- cyano-4-isobutoxy phenyls) -4- methyl-1s, 3- thiazole -5- formic acid.It with European brand name Adenuric,
Japanese brand name Feburic and the U.S. and Canada brand name Uloric are sold.
In EP0513379B1, Febuxostat is prepared by 4- hydroxyl -3- nitrobenzaldehydes according to following scheme.
This specific method has the shortcomings that more.It is not only very long, includes seven from starting material to final product
Step, and most significantly, it takes the use of cyanide, and cyanide is extremely toxic reagent.Cyanide salt is possible to generate
Hydrocyanide, there are a large amount of risks during commercial scale.
In Japan Patent JP06345724A (JP2706037B), the ethyl ester intermediate of Febuxostat is by cyano nitro
Benzene is prepared through three steps.According to the prior art, Febuxostat then can be prepared by alkaline hydrolysis.
Extremely toxic potassium cyanide uses so that this method is not suitable for manufacturing purpose.
In Japan Patent JP3202607B, Febuxostat ethyl ester is carried out according to scheme above via two similar routes
It prepares.Route A uses flash column chromatography azanol reaction product, however route B has low-yield and the chlorine for recrystallization
Change the use of solvent.In addition, in both cases, reaction dissolvent is formic acid, it can be to artificial at serious skin burn and eye
Damage.Formic acid also has corrosivity to the structural material (MOC) based on metal, such as stainless steel and nickel alloy, will select substantially
It is limited to glass reactor or container.The required a large amount of formic acid of every a batch are directed to using the shortcomings that this solvent, are hindered
Waste processing.
In CN101723915B, focus is the improvement to azanol reaction.Dimethylformamide (DMF) and other solvent generations
Formic acid is replaced.But according to widely used organic chemistry textbooks, such as the Advanced Organic Chemistry of March, page 1287,
Six editions, M.B.Smith and J.March, ISBN0-471-72091-7, the mechanism of reaction are included in the formation of oxime after azanol effect,
It is further dehydrated with the help of suitable reagent, such as formic acid or acetic anhydride to form nitrile.It is not present in such reagent
When, it is contemplated that reaction will be caused at least not complete, so as to cause low-yield and undesirable impurity level, that is,
Intermediate oxime.The impurity of similar structure that these are generated by the reaction of method and that desired product is presented is generally difficult to using normal
It advises industrial technology to remove, such as crystallizes.
In WO2010142653A1, intermediate Febuxostat ethyl ester is prepared by 4- cyanophenols by five-step approach.Non- cloth
Sotan can as first example by alkaline hydrolysis by it correspondence ethyl ester prepare.
Method uses the application of palladium catalyst in final step, in addition, reaction carries out 48 hours under high temperature (145 DEG C)
It (condition for improving energy expenditure) and is generally difficult to be converted into commercial scale.
Therefore, still need to be suitble to higher yield, show meet country or internal authority standard chemical purity, have
The method of commercial viability, convenient and safe method production Febuxostat compound.
Invention content
Invention provides that there are the formyl basal orientation formula IIIs of Formula Il compound with iodine in ammonia and oxygen and metallic catalyst or ammonia
The method of the conversion of the cyano of compound, wherein R1It is hydrogen atom, alkyl, alkenyl or alkynyl group and R2Be alkyl, alkenyl or
Alkynyl group.
This invention another target be to provide the novel method for preparing Febuxostat, which show the yield of raising,
The reagent of safety and industrial applicable technology.
The further object of invention is the method for producing Febuxostat comprising following steps：
A) alkylation of the compound of Formula II a, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably
Ground is ethyl group, to form the compound of Formula II b, wherein R1It is isobutyl group and R2It is alkyl, alkenyl or alkynyl group, it is excellent
Selection of land is ethyl group；
B) in i) ammonia, oxygen and metallic catalyst or ii) in the presence of ammonia and iodine, the formyl basal orientation cyano of Formula II b compounds
Conversion, to produce the compound of formula III b；
C) hydrolysis of the ester group of the compound of formula III b, to produce Febuxostat or its salt；
We have found that above-mentioned route can also carry out when as step a) and b) overturning.Therefore, another mesh of the invention
Mark is to provide the alternative route of production Febuxostat comprising：
A) in i) ammonia, oxygen and metallic catalyst or ii) in the presence of ammonia and iodine, the formyl basal orientation cyanogen of the compound of Formula II a
The conversion of base, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably ethyl group, to produce formula
The compound of IIIa, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably ethyl group；
B) compound of formula III a, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably second
Base group, the alkylation to the compound of formula III b, wherein R1It is isobutyl group and R2It is alkyl, alkenyl or alkynyl group, preferably
Ground is ethyl group；
C) hydrolysis of the ester group of the compound of formula III b is to produce Febuxostat or its salt.
According to a preferred embodiment of the invention, in any one of the above method, formyl in the compound of Formula II
The conversion of basal orientation cyano is in i) ammonia, oxygen and metallic catalyst or ii) ammonia and iodine in the presence of carry out.
Another target of the present invention is the method for preparing Febuxostat, is included in i) ammonia, oxygen and metallic catalyst or ii)
In the presence of ammonia and iodine, the conversion of the cyano of the compound of the formyl basal orientation formula III of compounds of formula II and subsequent general formula
Conversion of the compound of III to Febuxostat.Wherein R2By removing alkyl, alkenyl or alkynyl group and wherein when not being hydrogen
R1When not being isobutyl group, by R1It is changed into isobutyl group, conversion of the compounds of formula III to Febuxostat is easy to implement.
Specific implementation mode
In the present invention, it was demonstrated that in the first of ammonia and oxygen and metallic catalyst or ammonia and the compound of Formula II in the presence of iodine
Acyl group is to the novel way of the conversion of the cyano of the compound of formula III, wherein R1It is hydrogen atom, alkyl, alkenyl or alkynyl group
And R2It is alkyl, alkenyl or alkynyl group, preferably ethyl group.
The present invention also include novel conversion in the method being included in following scheme by this prepare Febuxostat or
Its salt.Due to the feature of its high reaction yield, compound is caused to there is the chemical purity suitable for pharmaceutical use, using safer
Reagent and have the characteristics that be suitable for it is industrialized the fact, the method is more more superior than art methods.
The special purpose of invention is to provide the method for preparing Febuxostat comprising following step：
A) compound of Formula II a, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably ethyl
Group, the alkylation to the compound of Formula II b, wherein R1It is isobutyl groups and R2It is alkyl, alkenyl or alkynyl group, it is excellent
Selection of land is ethyl group；
B) in i) ammonia, oxygen or metallic catalyst or ii) ammonia and in the presence of iodine, the formyl basal orientation cyanogen of the compound of Formula II b
The conversion of base, with the compound of production IIIb；
C) hydrolysis of the ester group of the compound of formula III b is to generate Febuxostat or its salt.
The suitable ester group for being used to prepare Febuxostat is methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary fourth
Base, preferably ethyl ester group.
In step a, isobutyl halides, preferably isobutyl bromide is used to carry out etherification reaction in the presence of a base.It is described
Alkali can be inorganic base.Preferred inorganic base is metal hydroxides and carbonate.Preferred inorganic base is potassium carbonate, carbonic acid
Sodium and lithium carbonate.The alkali is alternatively organic base.Preferred organic base is amine.Preferred organic base is trimethylamine, three second
Amine, diisopropylamine, diisopropylethylamine, N, N- dimethyl aminopyridines.Reaction at a temperature of between 25-100 DEG C of range into
Row.Preferred temperature is 50-80 DEG C.It is polar non-solute to be suitble to the solvent of reaction.Preferably polar non-solute is
Dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide, N-Methyl pyrrolidone, tetrahydrofuran, acetonitrile, acetone, tertiary butyl
Methyl ether.
In stepb, the conversion of formyl basal orientation cyano is carried out using ammonia, oxygen source and metallic catalyst.As metal catalytic
Agent, various metals compound can be used.The non-limiting examples of metal be copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt,
Nickel, manganese, molybdenum, vanadium and rhenium.Preferred metal is copper, iron, ruthenium, palladium, iridium and silver.Preferred metal is copper, iron and ruthenium.Metal is urged
The non-limiting examples of agent are oxide, hydroxide, carry strong acid, such as hydrohalide, sulfuric acid, nitric acid or organic acid, such as
The metal salt of the conjugate base of trifluoromethanesulfonic acid and acetic acid.
The amount of the ammonia used in the reaction can be according to the scale of reaction and sufficient condition variation used by it.In general,
Including in the reaction of such volatilization reagent, the latter is largely used.Moreover, the measurement of the ammonia used in the reaction
Certainly in the available form of wherein reagent.Unrestricted example is the aqueous solution and gaseous ammonia of ammonia.Solvent can be typical case
Organic solvent.Preferred organic solvent is polar non-solute.Preferred polar non-solute is dimethyl sulfoxide (DMSO), two
Methylformamide, dimethylacetylamide, N-Methyl pyrrolidone, tetrahydrofuran, acetonitrile, acetone, t-butyl methyl ether.It carries out anti-
The temperature answered can be changed from room temperature to the boiling point of corresponding solvent.
Optionally, step b is carried out using ammonia and molecular iodine.For the process of reaction, typical organic solvent can be made
With, preferred polar non-solute, as described above.Furthermore the amount of ammonia is the property according to reagent, as described above.It carries out
The temperature of reaction can be changed from 0 DEG C to the boiling point of corresponding solvent.
In step c, ester hydrolysis can carry out under alkaline condition.Such condition includes strong inorganic base.Preferred alkali
For metal oxide, hydroxide and carbonate.Preferred alkali is alkali and alkaline earth metal ions oxide, hydroxide and carbon
Hydrochlorate.Preferred alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, barium monoxide, sodium carbonate, potassium carbonate and carbon
Sour lithium.Reaction can carry out in various solvents, depend primarily on the property of wherein used alkali.It is suitable for this reaction
Typical organic solvents are polar protic and aprotic solvent and the mixture of they and water.Preferred polar non-solute is four
Hydrogen furans, acetone, t-butyl methyl ether, ethyl acetate.Preferred polar aprotic solvent is lower alcohol.Preferred solvent is first
Alcohol, ethyl alcohol, normal propyl alcohol and isopropanol.Reaction can carry out under room temperature to the boiling point of the solvent used.Preferred temperature range
It is from 20 to 80 DEG C.
We have found that when step a) and while b) being carried out with reverse order above route can also be carried out.Condition and preferred
Condition is coequally applied.Therefore, another purpose of invention is to provide the alternative for preparing Febuxostat comprising following step
Suddenly：
A) in i) ammonia, oxygen and metallic catalyst or ii) in the presence of ammonia and iodine, the formyl basal orientation cyanogen of the compound of Formula II a
The conversion of base, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably ethyl group, to produce formula
The compound of IIIa, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably ethyl group；
B) compound of formula III a, wherein R1It is hydrogen atom and R2It is alkyl, alkenyl or alkynyl group, preferably second
Base group, the alkylation to the compound of formula III b, wherein R1It is isobutyl group and R2It is alkyl, alkenyl or alkynyl group, preferably
Ground is ethyl group；
C) hydrolysis of the ester group of the compound of formula III b is to produce Febuxostat or its salt.
The preferred condition of the separate step of method has been described above.
In yet another embodiment of the present invention, the metallic catalyst used in step b is copper catalyst, iron catalyst
Or ruthenium catalyst.
In the another embodiment of invention, metallic catalyst is copper catalyst.Copper catalyst can be selected from (I) or (II)
The inorganic compound and salt of the copper of valence oxidation state.Preferred compound and salt are copper halide, copper nitrate, copper acetate, copper sulphate, three
Fluorine copper methane sulfonate, copper oxide and their hydrate.
In the preferred embodiments of the present invention, the first of Formula II is carried out in the presence of ammonia, oxygen source and metallic catalyst
Conversion of the acyl group to the cyano of formula III.
In another preferred embodiment of the present invention, above-mentioned conversion carries out in polar non-solute.It is preferred that
Aprotic solvent be dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide, N-Methyl pyrrolidone and tetrahydrofuran.
In another preferred embodiment of the present invention, the cyano of the formyl basal orientation formula III of above-mentioned Formula II turns
It carries out at a temperature of changing in the range of 20 DEG C to solvent boiling point, is carried out wherein reacting.Preferred temperature range is 50-140
℃.Preferred temperature range is 60-120 DEG C.More preferred temperature range is 70-110 DEG C.
In the another embodiment of invention, the conversion of the cyano of the formyl basal orientation formula III of the Formula II is in oxygen atmosphere
Lower progress.The percentage for the oxygen being present under reaction atmosphere can change from 1% to 100%.Preferred ranging from 5% to 100%.
Preferred ranging from 20% to 100%.
Known in those skilled in the art to be, when the atmosphere of reaction is less than 100%, remaining percentage is represented by
Other gases.Non-limiting examples are nitrogen, rare gas, methane, hydrogen and carbon dioxide.Therefore, this definition can be considered
Also include the composition of air.
Those skilled in the art are further well known that the reaction time can supply according to the air used in reaction is present in
The percentage of oxygen in giving and change.Reaction time can also change according to the pressure for forming or being applied to reaction.
In yet another embodiment of the present invention, the conversion of the cyano of the formyl basal orientation formula III of Formula II also can use ammonia and
Iodine is realized.
In the preferred embodiments of the present invention, the conversion carries out in polar non-solute.Preferred non-matter
Sub- solvent is dimethyl sulfoxide (DMSO), dimethylformamide, dimethylacetylamide, N-Methyl pyrrolidone, acetonitrile and tetrahydrofuran.
In another preferred embodiment of the present invention, the cyano of the formyl basal orientation formula III of above mentioned Formula II
Conversion carried out at a temperature in the range of 0 DEG C to solvent boiling point, carried out wherein reacting.Preferred temperature range is 0-100
℃.Preferred temperature range is 10-60 DEG C.More preferred temperature range is 10-40 DEG C.
In the another embodiment of invention, the conversion of the cyano of the formyl basal orientation formula III of above mentioned Formula II exists
It is carried out under ordinary atmospheric conditions.It is known in those skilled in the art to be, range of this feature without limitation on invention.
Another target of the present invention is the method for preparing Febuxostat, as described above comprising the compound of Formula II
The conversion of the cyano (nitrile group) of the compound of formyl basal orientation formula III, including：I) ammonia, oxygen and metallic catalyst, or
Ii) ammonia and iodine, and then convert the compound of formula III to Febuxostat.
Experiment
Embodiment 1：The preparation of the compound of Formula II b
At ambient temperature by 14.14g 2- (3- formoxyl -4- hydroxy phenyls) -4- methylthiazole-5-carboxylate (formulas
III it) is dissolved in 55mL dimethylformamides.40g potassium carbonate is added together with 15.9mL isobutyl bromides.Reaction is heated to
75-80 DEG C and stir 4 hours.It is cooled to 25-30 DEG C, while 165mL process waters are added.And then be cooled to 0-5 DEG C and
It stirs 30 minutes at this temperature.Filtering precipitation solid simultaneously washs filter cake with 55mL process waters.Wet cake is done under 40 DEG C of vacuum
Dry 7 hours, to obtain 16.43g 2- (3- formoxyl -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates (Formula II b)
Embodiment 2：The preparation of the compound of formula III b
1.0g under being stirred at 25-30 DEG C into 25mL round-bottomed flasks in loading 3.0mL dimethylformamides
(2.88mmol) 2- (3- formoxyl -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates.Add under being stirred at 25-30 DEG C
Enter 34mg (0.19mmol) copper acetate.With oxygen (O2) rinse and be added the ammonium hydroxide of 0.66mL (34.92mmol) 25%.Use O2Again
It rinses.Reaction mixture is heated to 80-82 DEG C, overnight.By TLC (hexamethylene: ethyl acetate 3: 1) examine reaction into
Degree.Reaction mass is cooled to 25-30 DEG C.25mL ethyl acetate and 25mL brine are added in reaction mass, separation is organic
Layer and with 25mL ethyl acetate aqueous layer extracted twice.Merge organic layer, is dried over anhydrous sodium sulfate, is filtered and concentrated to drying.
Residue is purified by column chromatography (hexamethylene: ethyl acetate 9: 1).Obtain 2- (the 3- cyano-4-isobutoxy benzene of 0.754g
Base) -4- methylthiazole-5-carboxylates (formula III b).Yield：75.4%.
Embodiment 3：The preparation of the compound of formula III b
0.17g (0.49mmol) 2- under being stirred at 25-30 DEG C into 25mL round-bottomed flasks in loading 2.5mL tetrahydrofurans
(3- formoxyl -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates.It is added with stirring 2.9mL at 25-30 DEG C
The ammonium hydroxide of (153.43mmol) 25%.137mg (0.54mmol) iodine (I2) is added into reaction mass, is stirred at 25-30 DEG C
Reaction mixture 15-30 minutes.The progress of reaction is examined by TLC (hexamethylene: ethyl acetate 3: 1).Starting material is consumed.
By 2.5mL 5%w/v sodium thiosulfate Na2S2O3Aqueous solution and 15mL ethyl acetate are added in reaction mass, detach organic layer
15mL ethyl acetate aqueous layer extracted is used in combination twice.Merge organic layer, is dried over anhydrous sodium sulfate, is filtered and concentrated to drying.It receives
Collection obtains 2- (3- cyano-4-isobutoxy phenyls) -4- methylthiazole-5-carboxylates (the formula III b) of 0.158g.
Embodiment 4：The preparation of Febuxostat
2.407g 2- (3- under being stirred at 25-35 DEG C into two neck round-bottom flasks of 100mL in loading 20mL tetrahydrofurans
Cyano-4-isobutoxy phenyl) -4- methylthiazols-Ethyl formate, 0.748g sodium hydroxides and reaction mass is heated to 60-65
DEG C about 8 hours.The progress of reaction is examined by TLC (hexamethylene: ethyl acetate 3: 1).Reaction mass is cooled to 0-5 DEG C and is added
Enter 50mL process waters, maintains the temperature in 0-5 DEG C.With 4.5mL 6N salt acid for adjusting pH to 1-2, maintain the temperature in 0-5 DEG C.
Warm reaction mass is stirred to react to 25-30 DEG C and at the temperature disclosed above material 15 minutes.It is heavy to be filtered under diminished pressure by Buchner funnel
Shallow lake solid with the jet cleaning of 2mL process waters and blots 20-30 minutes.Crude solid is transferred to 50mL round-bottomed flasks,
12mL process waters and 12mL acetone are loaded at 25-30 DEG C.Reaction mass is heated to 50-60 DEG C 60 minutes.By reaction mass
It is cooled to 0-5 DEG C and stirs 60 minutes at the temperature disclosed above.Be filtered under diminished pressure precipitation solid by Buchner funnel, with 2mL acetone and
1: 1 mixture jet cleaning of process water is simultaneously blotted 30-45 minutes.It is dry under 60 DEG C of vacuum.It is collected into 1.821g (chemical combination
Object I) Febuxostat, purity：82.6%, yield：0.62w/w.
Embodiment 5：The preparation of the compound of formula III a
0.5g (1.72mmol) 2- (3- first under being stirred at 25-30 DEG C into 50mL round-bottomed flasks in loading 8.6mL THF
Acyl group -4- hydroxy phenyls) -4- methylthiazole-5-carboxylates.10.3mL (544.94mmol) is added with stirring at 25-30 DEG C
25% ammonium hydroxide.By 480mg (1.89mmol) iodine (I2) be added in reaction mass, mixture 15- is stirred to react at 25-30 DEG C
30 minutes.The progress of reaction is examined by TLC (hexamethylene: ethyl acetate 1: 1).Starting material is consumed.By 8.6mL 5%w/
V aqueous thiosulfates and 40mL ethyl acetate are added in reaction mass, are detached organic layer and are extracted with 40mL ethyl acetate
Layer fetch water twice.Merge organic layer, is dried over anhydrous sodium sulfate, filters and be concentrated and dried.Through column chromatography (hexamethylene: acetic acid second
Ester 3: 1) purification residues obtain 0.213g2- (3- cyano -4- hydroxy phenyls) -4- methylthiazole-5-carboxylate (formulas
IIIa).Yield：42.6%.
Embodiment 6：The preparation of compound IIIb
2.2g2- (3- cyano -4- hydroxy phenyls) -4- methylthiazole-5-carboxylates (Formula IV) are dissolved in 7mL diformazans
Simultaneously 6.6g potassium carbonate and 3.14g isobutyl bromides is added to this mixture in base formamide.15 hours are stirred to react at 75 DEG C simultaneously
It is then cooled to 40 DEG C.15mL process waters are added and are cooled to 0-5 DEG C.It is filtered to remove precipitation solid and with 15mL process waters
Washing, obtains 2.28g2- (3- cyano-4-isobutoxy phenyls) -4- methylthiazole-5-carboxylate (formulas after being dried
IIIb)。
Embodiment 7：The preparation of compound I (Febuxostat)
2.131g2- (3- cyano-4-isobutoxy benzene is loaded under being stirred at 25-35 DEG C into two neck round-bottom flasks of 100mL
Base) -4- methylthiazols-Ethyl formate, 64mL methanol and 2.5mL process waters.1.718g potassium carbonate is added and by reaction mass
It is heated to reflux about 2-3 hours.The progress of reaction is examined by TLC (hexamethylene: ethyl acetate 3: 1).Reaction mass is cooled down
To 20-25 DEG C.In 40 DEG C or less concentrated solvents.43mL process waters, 21mL ethyl acetate and in 25-35 are added into residue
It is stirred 30 minutes at DEG C.Water layer is simultaneously transferred in 100mL round-bottomed flasks by separating layer.25mL 1N hydrochloric acid tune is used at 25-35 DEG C
Save pH to 2.3-2.7.Reaction mass is warmed to 40 DEG C and is stirred to react material at this temperature 60-90 minutes.By reactant
Material is cooled to 25-35 DEG C.It is filtered under diminished pressure precipitation solid by Buchner funnel, with the jet cleaning of 5mL process waters and blots 30-45
Minute.It is dry under 60 DEG C of vacuum.It is collected into 1.708g (compound I) Febuxostat, purity：86.7%, yield：0.69w/w.
Embodiment 8：The preparation of Febuxostat crystal form III
Under being stirred at 25-30 DEG C the thick 2- of the 10g (3- cyano -4- in 200mL ethyl acetate are loaded to 250mL round-bottomed flasks
Isobutoxy phenyl) -4- methylthiazol-5-formic acids (Febuxostat).Reaction mass is heated to flowing back and stirring 30 minutes.It will
Reaction mass is cooled to 25-30 DEG C.Reaction mass is set to warm and be depressurized in the middle part of reaction mass at a temperature of less than 40 DEG C again
Divide ground distilling off solvent.Reaction mass is cooled to 25-30 DEG C.It is filtered under diminished pressure precipitation solid by Buchner funnel and with 10mL second
Acetoacetic ester jet cleaning.It is dry under 60 DEG C of vacuum.It is collected into 8.5g Febuxostats.Yield：85%w/w.Crystalline compounds
XRPD with reported in Chinese patent CN101412700B it is consistent.
Claims (11)
1. method comprising in the presence of ammonia, oxygen and metallic catalyst, the formyl basal orientation cyano of the compound of Formula II turns
Change, with the compound of production III, wherein the metal be selected from copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese,
Molybdenum, vanadium and rhenium；
Wherein R1Hydrogen atom, alkyl, alkenyl or alkynyl group, wherein chain group be straight chain type with 1 to 15 carbon atoms or
The two of branched chain type is one of arbitrary, and R2It is alkyl, alkenyl or alkynyl group, wherein chain group is with 1 to 15 carbon originals
One of the straight chain type of son or the two of branched chain type are arbitrary.
2. the method for producing Febuxostat comprising following steps：
A) in the presence of ammonia, oxygen and metallic catalyst, the conversion of the formyl basal orientation cyano of the compound of Formula II b, with production
The compound of IIIb, wherein R2As defined in claim 1, wherein the metal be selected from copper, iron, zinc, tin, ruthenium, palladium,
Rhodium, iridium, silver, cobalt, nickel, manganese, molybdenum, vanadium and rhenium；
B) hydrolysis of the ester group of the compound of formula III b is to generate Febuxostat or its salt
3. the method for producing Febuxostat comprising following steps：
A) in the presence of ammonia, oxygen and metallic catalyst, the conversion of the formyl basal orientation cyano of the compound of Formula II a, with production
The compound of IIIa, wherein R2As defined in claim 1, wherein the metal be selected from copper, iron, zinc, tin, ruthenium, palladium,
Rhodium, iridium, silver, cobalt, nickel, manganese, molybdenum, vanadium and rhenium；
B) alkylation of the compound of formula III a to the compound of formula III b, wherein R2As defined in claim 1；
C) hydrolysis of the ester group of the compound of formula III b is to generate Febuxostat or its salt
4. according to the method in claim 2 or 3, wherein R2It is ethyl group.
5. method according to claim 1,2 or 3, wherein the metallic catalyst is copper, iron or ruthenium catalyst.
6. according to the method described in claim 5, the wherein described metallic catalyst is copper catalyst.
7. according to the method described in claim 6, the wherein described copper catalyst be copper halide (I) or (II), copper nitrate (I) or
(II), copper acetate (I) or (II), copper sulphate (I) or (II), copper trifluoromethanesulfcomposite (I) or (II), copper oxide (I) or (II) or
Their hydrate.
8. method according to claim 1,2 or 3, wherein the reaction carries out in polar non-solute.
9. according to the method described in claim 8, the wherein described polar non-solute is acetonitrile, dimethyl sulfoxide (DMSO), dimethyl
Formamide, dimethylacetylamide, N-Methyl pyrrolidone or tetrahydrofuran.
10. method according to claim 1,2 or 3, wherein the reaction is with including the oxygen within the scope of 1-100%
It is carried out under the atmosphere of composition, under 1atm to 200atm pressure.
11. according to the method described in claim 10, the wherein described reaction carries out under normal atmosphere composition and pressure.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP2013002361 | 2013-08-07 | ||
| EPPCT/EP2013/002361 | 2013-08-07 | ||
| PCT/EP2014/002079 WO2015018507A2 (en) | 2013-08-07 | 2014-07-30 | A novel process for the preparation of febuxostat |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105452228A CN105452228A (en) | 2016-03-30 |
| CN105452228B true CN105452228B (en) | 2018-10-09 |
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| CN201480044498.XA Active CN105452228B (en) | 2013-08-07 | 2014-07-30 | Prepare the novel method of Febuxostat |
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| JP (2) | JP6585044B2 (en) |
| CN (1) | CN105452228B (en) |
| ES (1) | ES2772131T3 (en) |
| WO (1) | WO2015018507A2 (en) |
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| 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 |
| CN109503512B (en) * | 2018-12-28 | 2021-05-07 | 大连理工大学 | Synthesis method of febuxostat and intermediate thereof |
| CN109503513B (en) * | 2018-12-29 | 2020-09-25 | 嘉实（湖南）医药科技有限公司 | One-pot synthesis method of febuxostat intermediate |
| CN113072519A (en) * | 2021-04-01 | 2021-07-06 | 福建海西新药创制有限公司 | Method for continuously producing febuxostat by using micro-reaction device |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP6585044B2 (en) | 2019-10-02 |
| CN105452228A (en) | 2016-03-30 |
| ES2772131T3 (en) | 2020-07-07 |
| JP2019194203A (en) | 2019-11-07 |
| JP2017509581A (en) | 2017-04-06 |
| WO2015018507A3 (en) | 2015-10-22 |
| WO2015018507A2 (en) | 2015-02-12 |
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