CN117069675A - Preparation method of febuxostat - Google Patents
Preparation method of febuxostat Download PDFInfo
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- CN117069675A CN117069675A CN202311005998.XA CN202311005998A CN117069675A CN 117069675 A CN117069675 A CN 117069675A CN 202311005998 A CN202311005998 A CN 202311005998A CN 117069675 A CN117069675 A CN 117069675A
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- thiazole
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- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000012535 impurity Substances 0.000 claims abstract description 86
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 56
- 238000001953 recrystallisation Methods 0.000 claims abstract description 48
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 44
- NJRGQNNSIAFIJC-UHFFFAOYSA-N ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=C(C=O)C(O)=CC=2)=N1 NJRGQNNSIAFIJC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 239000000047 product Substances 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000003960 organic solvent Substances 0.000 claims description 35
- -1 3-cyano-4-isobutoxyphenyl Chemical group 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 150000002923 oximes Chemical class 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 8
- 239000004280 Sodium formate Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 8
- 235000019254 sodium formate Nutrition 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- CGZDWVZMOMDGBN-UHFFFAOYSA-N 2-Ethylthiazole Chemical compound CCC1=NC=CS1 CGZDWVZMOMDGBN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 description 15
- 238000011282 treatment Methods 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229910017053 inorganic salt Inorganic materials 0.000 description 4
- 238000012797 qualification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000010009 beating Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- 102100033220 Xanthine oxidase Human genes 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 238000006146 oximation reaction Methods 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- MDMGIABSBHFMNF-UHFFFAOYSA-N 2-[3-(hydroxyiminomethyl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound C1=C(C=NO)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 MDMGIABSBHFMNF-UHFFFAOYSA-N 0.000 description 1
- OHIQHHXCAMMCPH-UHFFFAOYSA-N 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound C1=C(C=O)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 OHIQHHXCAMMCPH-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000010981 drying operation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- 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
Abstract
The invention provides a preparation method of febuxostat, and belongs to the technical field of medicine synthesis. According to the invention, 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester is used as a starting material, and is subjected to isobutylating reaction, cyanation reaction, recrystallization and hydrolysis reaction to synthesize febuxostat. The invention has simple synthetic route, and the cyanation product intermediate 5 can enter the next working procedure without being dried, thereby saving the steam cost. And the purity of the synthesized febuxostat is extremely high by controlling the impurity content in the intermediate 5, the quality requirement can be met without further recrystallization, and the yield is greatly improved. The production method is simple and easy to operate, low in energy consumption and suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of febuxostat.
Background
The main component of febuxostat is febuxostat, the chemical name of the febuxostat is 2- [ (3-cyano-4-isobutoxy) phenyl ] -4-methyl-5-thiazole carboxylic acid, and the febuxostat is a Xanthine Oxidase (XO) inhibitor and is suitable for long-term treatment of hyperuricemia with gout symptoms.
The febuxostat has the main synthesis route as follows: 2- (3-aldehyde-4-hydroxy phenyl) -4-methyl-5-ethyl formate thiazole is taken as a starting material, and is subjected to isobutyl, cyaniding and hydrolysis to obtain febuxostat. However, the febuxostat obtained by the synthetic route can obtain a qualified febuxostat finished product through repeated recrystallization, so that the process yield is low, the operation is complex, and the febuxostat is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of febuxostat, which avoids the technical problems of repeated recrystallization, low yield and complicated operation required for obtaining a qualified febuxostat finished product.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method takes 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester as a starting material, and the finished product of febuxostat is synthesized at one time through isobutylating reaction, cyanating reaction, recrystallization and hydrolysis reaction.
Further, in the isobutylating reaction, crystal precipitation by adding water, filtration and drying are carried out, thus obtaining the 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole.
Further, in the isobutylating reaction, the mass ratio of the ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylate to water is 1: 15-20;
and/or, in the isobutylating reaction, 1-bromoisobutane is used as a raw material of the isobutylating reaction, potassium carbonate is used as an acid binding agent, and N, N-dimethylformamide is used as a solvent for reaction, wherein the mol ratio of the 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to the 1-bromoisobutane to the potassium carbonate is 1: 2-3: 0.5 to 1.5; the mass ratio of the 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to the N, N-dimethylformamide is 1:5 to 8.
Further, in the cyanation reaction, the isobutyl product, namely, 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl thiazole, is controlled so that the content of both intermediate 4 and oxime thereof is less than 0.1%, and then the 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl thiazole is obtained.
Further, in the cyanation reaction, an intermediate 4, hydroxylamine hydrochloride, formic acid and sodium formate are used as raw materials for the cyanation reaction, wherein the mol ratio of the intermediate 4 to the hydroxylamine hydrochloride is 1:1.7-2.0; the mass ratio of the intermediate 4 to the formic acid to the sodium formate is 1:10 to 15:0.2 to 0.4.
Further, in the recrystallization, the cyanation product 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole, namely, the intermediate 5, is mixed with a first organic solvent, the intermediate 5 and impurities thereof are completely dissolved by heating, then the intermediate 5 is supersaturated and separated out by cooling, and the impurities are still dissolved in the first organic solvent, so that the fine intermediate 5 is obtained by separation.
Further, in the recrystallization, the mass ratio of the intermediate 5 to the first organic solvent is 1:10 to 15 percent;
and/or the first organic solvent is selected from one or more of methanol, ethanol and isopropanol;
and/or, the final temperature of the temperature rise is 70-85 ℃;
and/or the final temperature of the cooling is 20-25 ℃.
In the hydrolysis reaction, the refined product of the cyano-modified product 2- (3-cyano-4-isobutoxy phenyl) -4-methyl-5-ethyl formate thiazole, namely the refined product of the intermediate 5, is subjected to alkaline hydrolysis reaction, then water is added for crystallization, pH is adjusted by acid, and the product of febuxostat is obtained by filtering and drying once.
In the hydrolysis reaction, the fine intermediate 5 is mixed with a second organic solvent and heated to 50-60 ℃, sodium hydroxide solution is added for hydrolysis reaction, then the temperature is reduced to 20-25 ℃, water is added for mixing for a certain time, hydrochloric acid solution is used for regulating the pH to 2-3, solid is separated out, and the finished febuxostat is obtained after filtration and drying.
Further, the molar ratio of the fine intermediate 5 to sodium hydroxide is 1:1.15 to 1.3;
and/or, the mass ratio of the intermediate 5 refined product to the second organic solvent is 1:10 to 15 percent;
and/or the second organic solvent is selected from one or more of methanol, ethanol, isopropanol and ethyl acetate;
the second organic solvent is the same or different, preferably the same as the first organic solvent;
and/or, the mass ratio of the fine product of the intermediate 5 to water is 1:3 to 5.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the preparation method, the cyanation product 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole (intermediate 5) is subjected to recrystallization treatment before hydrolysis reaction, so that the content of the isobutylated product 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole (intermediate 4) and oximate thereof is greatly reduced, the purity of the intermediate 5 is improved, a large amount of hydrolytic impurities are prevented from being generated by hydrolysis of the intermediate 4 and oximate thereof along with the hydrolysis reaction of the intermediate 5, and further, repeated recrystallization removal treatment of the hydrolytic impurities which are not easy to dissolve in water and organic solvents is avoided, so that a qualified febuxostat finished product is synthesized once, repeated recrystallization is not needed, the yield is improved, and the cost is reduced.
2. According to the preparation method, in the cyanation reaction, the HPLC liquid phase content (namely the content of the intermediate 4 and the oxime compound thereof) is controlled to be less than or equal to 0.1%, so that the intermediate 4 and the oxime compound thereof are completely converted in the cyanation reaction, and the intermediate 5 is used for carrying out recrystallization treatment, so that the content of the intermediate 4 and the oxime compound thereof is less than or equal to 0.05%, the hydrolysis reaction in the next step is facilitated, the purity of the febuxostat obtained by the hydrolysis reaction is extremely high, and the quality standard can be met without carrying out recrystallization treatment.
3. According to the preparation method, the purification and drying operation of the product after each reaction are not needed, and only the intermediate 4 is required to be dried, so that the influence of moisture contained in the intermediate on the reaction progress of the next cyanation reaction is avoided. The intermediate 5 is only required to be recrystallized and purified, and the intermediate 5 does not need to be dried before and after recrystallization, and particularly can directly enter the next hydrolysis reaction after recrystallization, so that the steam is saved, and the energy consumption is reduced.
4. In the preparation method, in the isobutyl reaction, a proper amount of water is further added to improve the yield of the intermediate 4, and meanwhile, the inorganic salt generated in the reaction and unreacted inorganic salt can be dissolved in water and discharged out of the system along with mother liquor so as to prevent the intermediate 4 and oxime thereof from being subjected to incomplete reaction and further generate impurities requiring repeated recrystallization along with the hydrolysis of the intermediate 5.
5. According to the preparation method, in the hydrolysis reaction, the quality and the yield of the febuxostat are further controlled by adding a proper amount of water, and particularly, sodium chloride generated by the reaction of hydrochloric acid and sodium hydroxide is dissolved in water and discharged out of a reaction system, so that the qualification of chloride ions in a febuxostat finished product is ensured; and simultaneously, the yield of febuxostat is improved.
Drawings
FIG. 1 is a HPLC chromatogram of febuxostat as a final product obtained in example 1 of the present invention;
FIG. 2 is a HPLC chart of example 1 of the present invention after intermediate 5 is recrystallized (intermediate 5 top quality);
FIG. 3 is a HPLC chart of example 1 of the present invention before intermediate 5 is recrystallized (crude intermediate 5);
FIG. 4 is a HPLC chromatogram of intermediate 4 in example 1 of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. The embodiments of the present invention are implemented on the premise of the technical solution of the present invention, and detailed implementation manners and processes are given, and it should be apparent to those skilled in the art that the embodiments are merely for aiding in understanding the present invention and should not be taken as specific limitations of the present invention, and the scope of protection of the present invention is not limited to the following embodiments, based on which all other embodiments obtained by a person of ordinary skill in the art without making inventive efforts fall within the scope of protection of the present invention.
The process parameters for which specific conditions are not noted in the examples of the present invention are generally carried out according to conventional conditions. All numbers referring to amounts of components are "molar or mass values or ratios" throughout unless specified and/or stated otherwise. Unless otherwise specified, the raw materials used in the present invention can be obtained from commercial products.
In the present invention, endpoints of the disclosed ranges and any values are not limited to the precise range or value, and such range or value should be understood to include values close to the range or value. For numerical ranges, one or more new numerical ranges may be obtained in combination with each other between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point values, and are to be considered as specifically disclosed in the present invention.
The present invention has the following definitions:
intermediate 3: the isobutylating reaction raw material, namely the starting raw material, namely: 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester;
intermediate 4: the isobutyl reaction product, also a cyanation reaction feed, is: 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl ester thiazole;
intermediate 5: cyanation reaction product, namely: 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl ester thiazole;
intermediate 5 top quality: the recrystallized 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-formic ether thiazole is also a hydrolysis reaction raw material;
qualified febuxostat purity requirement: the maximum mono-impurity content (mono-impurity) is less than or equal to 0.1%; the total impurity content (total impurities) is less than or equal to 0.5 percent.
In addition, febuxostat has the following structural formula:the impurities may be remained or not removed by insufficient reaction except for the required final product febuxostat in the preparation process, and the specific steps are as follows:
in the preparation method of the invention, the reaction equation involved is as follows:
(1) Isobutyl reaction
(2) Cyanation reaction
(3) Hydrolysis reaction
The invention provides the following specific embodiments:
the preparation method takes 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester (intermediate 3) as a starting raw material, and the finished product of febuxostat is synthesized at one time through isobutylating reaction, cyanating reaction, recrystallization and hydrolysis reaction.
In the research process of the preparation method, the inventor finds that the intermediate 4, hydroxylamine hydrochloride oximation hydrolysis impurities (namely intermediate 4 oximation hydrolysis product, impurity 9) and intermediate 4 hydrolysis product (impurity 7) are often detected in the febuxostat crude product synthesis, and the two impurities, namely the impurity 9 and the impurity 7, have extremely low solubility in organic solvents such as ethanol and are not easy to remove, so that the febuxostat obtained after hydrolysis can meet the requirement of qualified purity through repeated recrystallization. Therefore, the purity of the febuxostat is improved by directly avoiding the generation of the two hydrolysis impurities in the preparation method, so that the febuxostat obtained after hydrolysis is prevented from being recrystallized and purified for multiple times. The invention particularly reduces the content of the intermediate 4 (impurity 6) and the oxime compound (impurity 8) in the intermediate 5 by recrystallizing the cyanation product intermediate 5, avoids being carried into the next hydrolysis reaction, hydrolyzes to generate the impurities (impurity 7 and impurity 9) which are difficult to remove, realizes the one-time synthesis of the febuxostat finished product, does not need to carry out repeated recrystallization, improves the yield and reduces the cost.
As an alternative embodiment of the invention, the isobutylating reaction comprises crystallization by adding water, filtering and drying to obtain the 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-formic ether thiazole as the intermediate 4.
In the above technical scheme, the purpose of adding water is two: firstly, the intermediate 4 is insoluble in water, and water is added to enable the intermediate 4 to be more separated out, so that the yield is improved. Secondly, inorganic salts generated and unreacted in the isobutyl reaction can be dissolved in water and discharged out of the system along with mother liquor so as not to influence the next cyanation reaction, as the inorganic salts can influence the buffer solution system of formic acid and sodium formate in the cyanation reaction, and the intermediate 4 and oxime thereof have incomplete reaction. Wherein the unreacted inorganic salt such as potassium carbonate, etc., the inorganic salt such as potassium bicarbonate, potassium bromide, etc. is produced. In addition, intermediate 4 needs to be dried because the next step is cyanation reaction, the byproduct is water, and moisture in intermediate 4 will affect the progress of the reaction.
As an alternative embodiment of the present invention, in the isobutylating reaction, the mass ratio of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylate to water is 1: 15-20 (specifically 1:15.5, 1:16, 1:16.5, 1:17, 1:17.5, 1:18, 1:18.5, 1:19, 1:19.5).
As an alternative embodiment of the present invention, in the isobutylating reaction, 1-bromoisobutane is used as a raw material for the isobutylating reaction, potassium carbonate (K) 2 CO 3 ) As an acid binding agent, N-Dimethylformamide (DMF) is taken as a solvent for reaction, wherein the mol ratio of the 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester, the 1-bromoisobutane to the potassium carbonate is 1: 2-3: 0.5 to 1.5 (specifically, 1:2.2:1.5, 1:2.4:1.3, 1:2.6:1.1, 1:2.8:0.9, 1:3:0.7); the mass ratio of the 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to the solvent DMF is 1:5 to 8 (specifically, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8).
In the technical scheme, the proportion of the 1-bromoisobutane is properly increased, so that the time of the isobutylating reaction can be shortened to 3-4 h (such as 3.2h, 3.4h, 3.6h and 3.8 h).
As an alternative embodiment of the present invention, in the cyanation reaction, after controlling the content of both intermediate 4 and its oxime compound to be less than 0.1% (specifically, for example, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%), 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl thiazole is obtained as intermediate 5.
The inventors have further studied and found that the cyanation of the aldehyde group in intermediate 4 is essentially a two-step reaction, in which the aldehyde group (formyl group) is reacted first with hydroxylamine hydrochloride to give an oxime (-ch=n—oh), followed by dehydration of the oxime under high temperature conditions to form a nitrile (-c≡n). If intermediate 4 is not completely converted, then the subsequent hydrolysis of intermediate 5 proceeds to form impurity 7, 2- [ 3-formyl-4-isobutoxyphenyl ] -4-methyl-5-thiazolecarboxylic acid, according to the following reaction equation:
if the oxime is not completely converted at high temperature, it is hydrolyzed with the subsequent hydrolysis of intermediate 5 to form impurity 9, 2- [3- (hydroxyimino) methyl-4-isobutoxyphenyl ] -4-methyl-5-thiazolecarboxylic acid, according to the following reaction scheme:
therefore, the cyanation reaction ensures that the intermediate 4 and the oxime compound thereof are reacted as completely as possible, and if the residual quantity is large, new impurities are generated by hydrolysis in the hydrolysis reaction process, and the impurities can be removed only by repeated recrystallization, so that the operation is complicated, and the yield is influenced. In the preparation process of the invention, the content of the intermediate 4 and the oxime compound thereof is detected by HPLC (high performance liquid chromatography) to control the content thereof to be less than 0.1 percent. The HPLC has extremely high accuracy and sensitivity, and can be used for qualitative and quantitative detection under the condition of extremely low substance concentration.
As an alternative embodiment of the present invention, in the cyanation reaction, intermediate 4, hydroxylamine hydrochloride, formic acid and sodium formate are reacted as raw materials for the cyanation reaction, wherein the molar ratio of the intermediate 4 to the hydroxylamine hydrochloride is 1:1.7 to 2.0 (specifically, 1:1.75, 1:1.8, 1:1.85, 1:1.9, 1:1.95); the mass ratio of the intermediate 4 to the formic acid to the sodium formate is 1:10 to 15:0.2 to 0.4 (specifically, 1:10:0.4, 1:11:0.35, 1:12:0.3, 1:13:0.25, 1:14:0.2).
As an alternative embodiment of the present invention, in the cyanation reaction, the reaction temperature is 120-126 ℃ (specifically, such as 121 ℃, 122 ℃, 123 ℃, 124 ℃, 125 ℃).
According to the technical scheme, the cyanidation reaction condition is further optimized to reduce the content of the intermediate 4 and the oxime compound thereof in the intermediate 5, so that the intermediate is prevented from being brought into the next hydrolysis reaction to generate impurities which are difficult to remove, the febuxostat finished product is synthesized once, repeated recrystallization is not needed, the yield is improved, and the cost is reduced. Specifically, the molar ratio of the intermediate 4 to hydroxylamine hydrochloride is controlled to be 1:1.7 to 2.0, so that the auxiliary material hydroxylamine hydrochloride is excessive, the cyanidation reaction is fast, and the intermediate 4 is completely reacted. In addition, the cyanide reaction mechanism shows that the high temperature is favorable for further dehydration of oxime to form cyano, so that the reaction temperature is increased to 120-126 ℃, the equilibrium shift is promoted by the formation of nitrile (-C.ident.N) and the consumption of oxime (-CH=N-OH), and the complete reaction of the intermediate 4 and the oxime compound thereof is ensured.
As an alternative embodiment of the present invention, in the recrystallization, the intermediate 5 is mixed with the first organic solvent, the intermediate 5 and the impurities thereof are completely dissolved by heating, then the intermediate 5 is supersaturated and separated out by cooling, and the impurities are still dissolved in the first organic solvent, thereby separating to obtain the fine intermediate 5.
In the above technical solution, the first organic solvent may be any liquid capable of dissolving the intermediate 5 and impurities thereof, and typically includes, but is not limited to, one or more of methanol, ethanol and isopropanol. For example, when the intermediate 5 is mixed with ethanol, the temperature is raised to enable the intermediate 5 and impurities wrapped in the intermediate 5 to be in a complete dissolution state, then the temperature is lowered to enable the intermediate 5 to reach a supersaturation state and separate out, and the impurities are still dissolved in the ethanol, so that the separation of the intermediate 5 and the impurities is realized, and a fine product of the intermediate 5 is obtained through suction filtration.
Through carrying out recrystallization to intermediate 5 with first organic solvent, can remove impurity, improve intermediate 5's purity, can also remove the drying to the crude filter cake of acid intermediate 5, avoid the acid resistance requirement of drying equipment, practice thrift the energy consumption when reducing equipment cost etc.. In addition, even if the recrystallized intermediate 5 fine filter cake contains a small amount of the first organic solvent, the next hydrolysis reaction is not affected, and the solvent used in the next hydrolysis reaction can be the same as the first organic solvent, and the same substance is not introduced into the solvent, so that the drying and impurity removal are not needed.
As an alternative embodiment of the present invention, in the recrystallization, the mass ratio of the intermediate 5 to the first organic solvent is 1:10 to 15 (specifically, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, 1:13.5, 1:14, 1:14.5).
As an alternative embodiment of the present invention, in the recrystallization, the final temperature of the elevated temperature is 70 to 85 ℃ (specifically, 71 ℃, 73 ℃, 75 ℃, 77 ℃, 79 ℃, 81 ℃, 83 ℃).
In the above-described embodiments, the temperature of the heating may be determined comprehensively according to the dissolution temperature of the intermediate 5, the dissolution temperature of the impurity, and the boiling point of the solvent, for example, when the first organic solvent is ethanol, the boiling point is about 78 ℃, and thus the maximum temperature of the heating may be controlled to about 78 ℃.
As an alternative embodiment of the present invention, in the recrystallization, the final temperature of the cooling is 20 to 25 ℃ (specifically, 20.5 ℃, 21 ℃, 21.5 ℃, 22 ℃, 22.5 ℃, 23 ℃, 23.5 ℃, 24 ℃, 24.5 ℃).
In the above technical solution, the temperature of the cooling may be comprehensively determined according to the precipitation temperature of the intermediate 5 and the precipitation temperature of the impurity, so that the intermediate 5 is precipitated as much as possible while the impurity is not precipitated.
In the hydrolysis reaction, the refined intermediate 5 is subjected to alkaline hydrolysis reaction, then water is added for crystallization, the pH is adjusted by acid, and the final product febuxostat is obtained through filtration and drying.
In the hydrolysis reaction, the intermediate 5 is mixed with a second organic solvent and heated to 50-60 ℃ (specifically, for example, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃) and then added with sodium hydroxide solution to carry out the hydrolysis reaction, the temperature is reduced to 20-25 ℃ (specifically, for example, 20.5 ℃, 21 ℃, 21.5 ℃, 22 ℃, 22.5 ℃, 23 ℃, 23.5 ℃, 24 ℃, 24.5 ℃) and then added with water to mix for a certain time, and then the pH is adjusted to 2-3 (specifically, for example, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9) by hydrochloric acid solution, solid is precipitated, and the finished febuxostat is obtained after filtration and drying.
In the technical scheme, the purposes of adding water are two, namely, firstly, the hydrochloric acid reacts with sodium hydroxide to generate sodium chloride, the sodium chloride is required to be dissolved in the water and discharged out of a reaction system, so that the qualification of chloride ions in the febuxostat finished product is ensured; secondly, the yield of febuxostat is improved. The second organic solvent may be any solvent capable of dissolving the raw materials such as the intermediate 5, and typically includes, but is not limited to, one or more of methanol, ethanol, isopropanol, and ethyl acetate. Preferably, the second organic solvent is the same as the first organic solvent to avoid introducing more material and to increase the removal operation.
As an alternative embodiment of the present invention, in the hydrolysis reaction, the molar ratio of the fine product of intermediate 5 to sodium hydroxide is 1:1.15 to 1.3 (specifically, 1:1.16, 1:1.18, 1:1.2, 1:1.22, 1:1.24, 1:1.26, 1:1.28).
As an alternative embodiment of the present invention, in the hydrolysis reaction, the mass ratio of the fine product of intermediate 5 to the second organic solvent is 1:10 to 15 (specifically, 1:10.5, 1:11, 1:11.5, 1:12, 1:12.5, 1:13, 1:13.5, 1:14, 1:14.5).
As an alternative embodiment of the present invention, in the hydrolysis reaction, the mass ratio of the fine product of the intermediate 5 to water is 1:3 to 5 (specifically, 1:3.3, 1:3.5, 1:3.7, 1:4, 1:4.3, 1:4.5, 1:4.7).
The present invention will be described in further detail with reference to specific examples.
Example 1
The preparation method of febuxostat specifically comprises the following reaction processes:
first step isobutyl reaction: 100g of 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester (intermediate 3), 141g of 1-bromoisobutane, K 2 CO 3 52.2g and 600g DMF are added into a four-mouth bottle, stirring and heating are started, the temperature is raised to 90 ℃ for starting timing, the reaction is carried out for 4 hours, and the reaction is stoppedStopping the reaction, cooling to 20 ℃, adding 1500g of water, stirring and crystallizing for 40min, filtering, and drying the filter cake by blowing at 100 ℃ to obtain 118.1g of light yellow solid 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole (intermediate 4) with the yield of 99 percent.
Second step cyanation reaction
118.1g of intermediate 4 dry product, 40g of hydroxylamine hydrochloride, 1181g of formic acid and 35.4g of sodium formate are added into a four-necked flask, stirring and heating are started, reflux reaction is carried out for 4 hours at 120 ℃, stirring and cooling are carried out, solid precipitation is carried out, cooling is carried out, the temperature is reduced to 20 ℃, and suction filtration is carried out, thus obtaining 123.5g (dried 111.1 g) of 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole (intermediate 5) as a pale yellow wet product, and the yield is 95%.
Intermediate 5 recrystallization
123.5g of intermediate 5 wet product is added into 1235g of ethanol, the temperature is raised to 80 ℃, the intermediate 5 and impurities coated on the inner part and the surface of the intermediate 5 are in a complete dissolution state, then the temperature is slowly reduced to 20 ℃, and suction filtration is carried out, so that 107.5g of intermediate 5 wet product (dried 99.99 g) is obtained, and the yield is 90%.
Third step hydrolysis reaction
Adding 107.5g of ethanol recrystallized intermediate 5 wet product and 1075g of absolute ethanol into a reaction kettle, heating to 60 ℃, adding 13.9g of sodium hydroxide (namely 139g of 10% sodium hydroxide solution), reacting for 1h, stirring and cooling, cooling to 20 ℃, adding 300g of water, stirring for 30min, adjusting the pH to about 2-3 by using 10% hydrochloric acid solution, separating out solids, stirring for 40min, filtering, and drying at 60 ℃ to obtain 84.5g of febuxostat with a yield of 92%.
Example 2
The preparation method of febuxostat is different from example 1 only in that in the first isobutyl reaction, the mass ratio of 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to water is 1:5.
example 3
The preparation method of febuxostat is different from example 1 only in that in the first isobutyl reaction, the mass ratio of 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to water is 1:20.
example 4
The preparation method of febuxostat is different from example 1 only in that in the first isobutyl reaction, the mass ratio of 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to water is 1:25.
example 5
A process for the preparation of febuxostat was different from example 1 only in that in the second cyanation reaction, reflux reaction was carried out at 115℃for 4 hours, and the rest of the arrangement was the same as in example 1.
Example 6
A process for the preparation of febuxostat was different from example 1 only in that in the second cyanation reaction, reflux reaction was carried out at 125℃for 4 hours, and the rest of the arrangement was the same as in example 1.
Example 7
A process for the preparation of febuxostat was different from example 1 only in that in the second cyanation reaction, reflux reaction was carried out at 128℃for 4 hours, the rest of the arrangement was the same as in example 1.
Example 8
The only difference between the febuxostat preparation method and the example 1 is that in the second cyanation reaction, the molar ratio of the intermediate 4 to hydroxylamine hydrochloride is 1:1.5, the rest of the settings are the same as in example 1.
Example 9
The only difference between the febuxostat preparation method and the example 1 is that in the second cyanation reaction, the molar ratio of the intermediate 4 to hydroxylamine hydrochloride is 1:2.0, the rest of the settings are the same as in example 1.
Example 10
The only difference between the febuxostat preparation method and the example 1 is that in the second cyanation reaction, the molar ratio of the intermediate 4 to hydroxylamine hydrochloride is 1:2.5, the rest of the settings are the same as in example 1.
Example 11
The preparation method of febuxostat is different from example 1 only in that in the recrystallization of intermediate 5, the mass ratio of intermediate 5 to absolute ethyl alcohol is 1:8, the rest of the settings are the same as in example 1.
Example 12
The preparation method of febuxostat is different from example 1 only in that in the recrystallization of intermediate 5, the mass ratio of intermediate 5 to absolute ethyl alcohol is 1:15, and the rest are the same as in example 1.
Example 13
The preparation method of febuxostat is different from example 1 only in that in the recrystallization of intermediate 5, the mass ratio of intermediate 5 to absolute ethyl alcohol is 1:17, the rest of the settings are the same as in example 1.
Example 14
The preparation method of febuxostat is different from example 1 only in that in the recrystallization of intermediate 5, the final temperature of the cooling is 15 ℃, and the rest settings are the same as those of example 1.
Example 15
The preparation method of febuxostat is different from example 1 only in that in the third hydrolysis reaction, the mass ratio of the fine product of the intermediate 5 to water is 1:0, and the rest are the same as in example 1.
Example 16
The preparation method of febuxostat is different from example 1 only in that in the third hydrolysis reaction, the mass ratio of the fine product of the intermediate 5 to water is 1:7, the rest of the settings are the same as in example 1.
Comparative example 1
A process for the preparation of febuxostat was distinguished from example 1 only in that there was no recrystallization of intermediate 5 after the second cyanation reaction and before the third hydrolysis reaction, and the rest of the arrangement was the same as in example 1.
Comparative example 2
The preparation method of febuxostat was different from example 1 only in that a beating treatment was used instead of the intermediate 5 recrystallization treatment after the second cyanation reaction and before the third hydrolysis reaction, and the rest of the arrangement was the same as in example 1. The pulping process is as follows:
and mixing and pulping the intermediate 5 with the first organic solvent, wherein the pulping time is the same as the recrystallization treatment time, and finally, carrying out suction filtration to obtain a fine intermediate 5 product.
Testing and results
1. HPLC detection
HPLC detection is carried out according to 0512 high performance liquid chromatography of the four-part rule of the 2020 edition of Chinese pharmacopoeia.
2. Analysis of results
The content of each reaction or treatment stage product in examples 1-16 and comparative examples 1-2 was tested using the HPLC detection method described above, wherein the specific test patterns of example 1 are shown in FIGS. 1-4, and the content data obtained from the patterns are shown in Table 1:
TABLE 1 Table of the contents of the products of the individual reaction or treatment phases in example 1
From the data in table 1, it was found that the impurity content was significantly reduced after recrystallization of intermediate 5, with intermediate 4 (impurity 6) from 0.099% to 0.037% and intermediate 4 having an oxime (impurity 8) content as low as undetectable. Therefore, the hydrolysis of the intermediate 4 and the oxime compound thereof during the hydrolysis reaction is avoided to generate a large amount of intermediate 4 hydrolysates (impurity 7) and intermediate 4 oxime compound hydrolysates (impurity 9) which are both difficultly soluble in water and organic solvents, and repeated recrystallization purification treatment of febuxostat after the hydrolysis reaction is avoided. The febuxostat obtained in the example 1 is finished febuxostat, the purity of the febuxostat reaches 99.852%, the maximum single impurity is 0.066%, the total impurity is 0.148%, the purity requirement of the finished febuxostat is met (the maximum single impurity is not more than 0.1%, and the total impurity is not more than 0.5%), and the yield of the febuxostat reaches 92%.
In addition, as can be seen from the data in table 1, although the content of intermediate 5 after cyanation reaction has reached 98.695%, intermediate 4 and impurity 8 are still present and both are less than 0.1%, the content of intermediate 5 after recrystallization treatment is increased to 99.369%, both the content of intermediate 4 and impurity 8 are less than 0.05%, and the finished febuxostat with 92% yield and 99.852% purity is directly obtained after hydrolysis reaction, therefore, the content of intermediate 4 and oxime compound (impurity 8) thereof should be strictly controlled to ensure that febuxostat can reach quality standard without recrystallization, and is qualified once.
The results of the contents of intermediate 4 obtained after the isobutylation reaction, intermediate 5 obtained after the cyanation reaction and intermediate 4 (impurity 6) and impurity 8 obtained after the recrystallization of intermediate 5, intermediate 5 and intermediate 4 (impurity 6) and impurity 8 in examples 1 to 16 and comparative examples 1 to 2 are shown in Table 2, and the corresponding yields calculated from the corresponding contents are also shown in Table 2,
the corresponding yields were calculated according to the following formula:
(1)/>
(2)
(3)
table 2 shows the following:
TABLE 2 purity/content and yield of the products of the respective reaction or treatment stages in examples 1 to 16 and comparative examples 1 to 2
From the data in Table 2, it can be seen that, in the isobutylating reaction, when the amount of water added is small at the time of crystal precipitation, the yield of intermediate 4 obtained in example 2 is significantly lower than that of examples 1, 3 and 4, and the content (purity) is also lower than that of examples 1 and 3, but rather the content thereof as impurity 6 is higher after the cyanating reaction; on the other hand, when the amount of water added was large, the content of intermediate 4 obtained in example 4 was not increased but decreased as compared with examples 1 to 3. From this, a proper amount of water was added in an amount of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylate and a mass ratio of water of 1:15 to 20, the yield and purity of the intermediate 4 can be ensured at the same time, and the influence on the subsequent reaction is reduced.
As can be seen from comparison of examples 1, 5, 6 and 7, in cyanation reaction, when the reaction temperature is lower, the yield and content (purity) of intermediate 5 obtained in example 5 are lower than those in examples 1, 6 and 7, and the contents of impurity 6 and impurity 8 are higher; on the other hand, when the reaction temperature was high, the content and purity of intermediate 5 obtained in example 7 were not increased but decreased as compared with those in examples 1 and 6. Therefore, when the temperature is controlled to be 120-126 ℃, the conversion of the intermediate 4 and the impurity 8 can be promoted along with the increase of the temperature, the yield and the purity of the intermediate 5 are ensured, and the content of the impurity 6 (the intermediate 4) and the impurity 8 (the oxime compound of the intermediate 4) is less than 0.1 percent.
As can be seen from comparison of examples 1, 8, 9 and 10, in cyanation reaction, when the hydroxylamine hydrochloride content is low, the yield and content (purity) of intermediate 5 obtained in example 8 are lower than those in examples 1, 9 and 10, and the content of impurity 6 and impurity 8 are extremely high; on the other hand, when the hydroxylamine hydrochloride content was high, the content and purity of intermediate 5 obtained in example 10 were not increased but decreased as compared with examples 1 and 9. It follows that the appropriate amount of hydroxylamine hydrochloride is controlled and controlled to give a molar ratio of intermediate 4 to hydroxylamine hydrochloride of 1:1.7 to 2.0, the conversion of the intermediate 4 and the impurity 8 can be promoted along with the increase of the content of hydroxylamine hydrochloride, the yield and the purity of the intermediate 5 are ensured, and the content of the impurity 6 (the intermediate 4) and the content of the impurity 8 (the oxime compound of the intermediate 4) are both less than 0.1 percent.
As can be seen from comparison of examples 1, 11, 12, 13, in recrystallization of intermediate 5, when the amount of absolute ethanol used is low, the content (purity) of intermediate 5 obtained in example 11 is lower than that in examples 1, 12, 13, and the contents of impurity 6 and impurity 8 are higher; on the other hand, when the amount of absolute ethanol used was high, the yield of intermediate 5 obtained in example 13 was not increased as compared with examples 1, 11 and 12, but rather was significantly decreased. From this, a proper amount of absolute ethyl alcohol is used, and the mass ratio of the fine intermediate 5 to the absolute ethyl alcohol is 1:10 to 15, the yield and purity of intermediate 5 can be ensured at the same time, and the contents of impurity 6 (intermediate 4) and impurity 8 (oxime compound of intermediate 4) are both made smaller than 0.05%.
As is clear from a comparison between example 1 and example 14, when intermediate 5 is recrystallized, the temperature is lowered too low to precipitate impurities easily during the cooling crystallization, resulting in insignificant decrease in the content of impurities 6 and 8, which is still 0.055% or more.
As can be seen from a comparison of example 1 and comparative example 2, the impurity 6 and impurity 8 levels were not significantly reduced and were still above 0.075% after the intermediate 5 was slurried.
The results of the febuxostat case measurements obtained in examples 1-16 and comparative examples 1-2 are listed in table 3, wherein febuxostat yields were calculated according to the following formula:
table 3 shows the following:
TABLE 3 results of febuxostat status detection obtained in examples 1-16 and comparative examples 1-2
| Project | Febuxostat purity (%) | Febuxostat yield (%) | Single impurity content (%) | Total impurity content (%) |
| Example 1 | 99.852 | 92 | 0.066 | 0.148 |
| Example 2 | 99.652 | 91.4 | 0.136 | 0.348 |
| Example 3 | 99.874 | 92.1 | 0.052 | 0.126 |
| Example 4 | 99.587 | 91.2 | 0.125 | 0.413 |
| Example 5 | 99.148 | 91.8 | 0.214 | 0.852 |
| Example 6 | 99.861 | 92.2 | 0.036 | 0.139 |
| Example 7 | 99.637 | 91.6 | 0.138 | 0.363 |
| Example 8 | 97.013 | 90.2 | 1.356 | 2.987 |
| Example 9 | 99.856 | 92.3 | 0.058 | 0.144 |
| Example 10 | 99.547 | 91.5 | 0.119 | 0.453 |
| Example 11 | 99.712 | 91.6 | 0.108 | 0.288 |
| Example 12 | 99.869 | 92.3 | 0.047 | 0.131 |
| Example 13 | 99.872 | 90.5 | 0.041 | 0.128 |
| Example 14 | 99.715 | 91.5 | 0.108 | 0.285 |
| Example 15 | 99.862 | 88 | 0.109 | 0.295 |
| Example 16 | 99.217 | 92.6 | 0.105 | 0.783 |
| Comparative example 1 | 99.458 | 91.5 | 0.156 | 0.542 |
| Comparative example 2 | 99.589 | 91.9 | 0.116 | 0.411 |
From the data in table 3, it can be seen that the comparison between example 1 and comparative example 1 shows that the qualified febuxostat finished product can be synthesized once by only recrystallizing intermediate 5 before the hydrolysis reaction, which meets the requirements that the maximum single impurity content (in the table, the single impurity content) is less than or equal to 0.1% and the total impurity content is less than or equal to 0.5%, and the hydrolysis is not required to be repeated for recrystallization, so that the yield is improved and the cost is reduced.
As can be seen from a comparison of example 1 with comparative example 2, even if intermediate 5 was subjected to beating treatment before hydrolysis, the finally obtained febuxostat was not acceptable, and the maximum single impurity content exceeded the requirement of 0.1%, and it was found that the beating impurity removal effect on intermediate 5 before hydrolysis reaction was inferior to the recrystallization effect.
In addition, through the optimization and adjustment of technological parameters, in the cyanation reaction, the conversion of the intermediate 4 and the oxime compounds thereof in the cyanation reaction can be ensured to be complete by controlling the liquid phase content (namely the content of the intermediate 4 and the oxime compounds thereof) to be less than or equal to 0.1 percent, the intermediate 5 is used for recrystallization treatment, so that the intermediate 4 and the oxime compounds thereof are less than or equal to 0.05 percent, the febuxostat obtained by the hydrolysis reaction is extremely high in purity, and the quality standard can be met without recrystallization treatment, and the febuxostat obtained in examples 1, 3, 6, 9 and 12 is qualified and meets the requirements that the maximum single impurity content is less than or equal to 0.1 percent and the total impurity content is less than or equal to 0.5 percent.
Specifically, the test results of febuxostat obtained in examples 1-4 show that the febuxostat can be qualified by one-time synthesis by adding a proper amount of water when crystals are precipitated in the isobutyl reaction.
The test results of febuxostat obtained in examples 1, 5, 6 and 7 show that the febuxostat can be qualified by one-time synthesis by properly increasing the reaction temperature in the cyanation reaction.
The test results of febuxostat obtained in examples 1, 8, 9 and 10 show that the proper increase of the hydroxylamine hydrochloride content in the cyanation reaction can promote the one-time synthesis qualification of febuxostat.
The test results of febuxostat obtained in examples 1, 11, 12 and 13 show that the one-time synthesis of febuxostat can be qualified by properly increasing the amount of the absolute ethyl alcohol solvent in the recrystallization of the intermediate 5. However, if the amount is too large, the yield of the final febuxostat is lowered.
The results of the tests of febuxostat obtained in examples 1, 15 and 16 show that the proper addition of water in the hydrolysis reaction can promote the one-time synthesis qualification of febuxostat.
The applicant declares that the above is only the preferred embodiments of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention, such as equivalent substitution of raw materials for the product, addition of auxiliary components, selection of specific modes, etc. fall within the scope and disclosure of the present invention.
Claims (10)
1. The preparation method is characterized in that 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester is used as a starting material, and the finished product of febuxostat is synthesized at one time through isobutylating reaction, cyanating reaction, recrystallization and hydrolysis reaction.
2. The process according to claim 1, wherein the isobutylating reaction comprises crystallization by adding water, filtration and drying to obtain 2- (3-aldehyde-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl ester thiazole.
3. The production method according to claim 2, wherein in the isobutylating reaction, the mass ratio of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylate to water is 1: 15-20;
and/or, in the isobutylating reaction, 1-bromoisobutane is used as a raw material of the isobutylating reaction, potassium carbonate is used as an acid binding agent, and N, N-dimethylformamide is used as a solvent for reaction, wherein the mol ratio of the 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to the 1-bromoisobutane to the potassium carbonate is 1: 2-3: 0.5 to 1.5; the mass ratio of the 2- (3-formyl-4-hydroxyphenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester to the N, N-dimethylformamide is 1:5 to 8.
4. The process according to claim 1, wherein the cyanation reaction gives 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethylthiazole having a content of less than 0.1% of both the intermediate 4 and the oxime thereof as the isobutyl product.
5. The process according to claim 4, wherein in the cyanation reaction, intermediate 4, hydroxylamine hydrochloride, formic acid and sodium formate are reacted as raw materials for the cyanation reaction, wherein the molar ratio of intermediate 4 to hydroxylamine hydrochloride is 1:1.7 to 2.0; the mass ratio of the intermediate 4 to the formic acid to the sodium formate is 1:10 to 15:0.2 to 0.4;
and/or, in the cyanation reaction, the reaction temperature is 120-126 ℃.
6. The process according to claim 1, wherein in the recrystallization, the cyanated product 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-carboxylic acid ethyl ester thiazole, namely, intermediate 5, is mixed with the first organic solvent, the intermediate 5 and impurities thereof are completely dissolved by heating, and then the intermediate 5 is supersaturated and separated out by cooling, while the impurities remain dissolved in the first organic solvent, thereby separating to obtain a fine product of intermediate 5.
7. The process according to claim 6, wherein in the recrystallization, the mass ratio of the intermediate 5 to the first organic solvent is 1:10 to 15 percent;
and/or the first organic solvent is selected from one or more of methanol, ethanol and isopropanol;
and/or, the final temperature of the temperature rise is 70-85 ℃;
and/or the final temperature of the cooling is 20-25 ℃.
8. The process according to any one of claims 1 to 7, wherein in the hydrolysis reaction, the refined product of 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-ethyl formate thiazole, intermediate 5, obtained by recrystallization is subjected to alkaline hydrolysis reaction, and then water is added for crystallization, pH is adjusted by acid, and the mixture is filtered and dried to obtain febuxostat as a finished product at one time.
9. The preparation method of claim 8, wherein in the hydrolysis reaction, the refined intermediate 5 is mixed with the second organic solvent and heated to 50-60 ℃, sodium hydroxide solution is added for hydrolysis reaction, then the temperature is reduced to 20-25 ℃, water is added for mixing for a certain time, hydrochloric acid solution is used for adjusting the pH to 2-3, solid is separated out, and the finished febuxostat is obtained after filtration and drying.
10. The process of claim 9 wherein said intermediate 5 is present in a molar ratio of 1:1.15 to 1.3;
and/or, the mass ratio of the intermediate 5 refined product to the second organic solvent is 1:10 to 15 percent;
and/or the second organic solvent is selected from one or more of methanol, ethanol, isopropanol and ethyl acetate;
the second organic solvent is the same or different, preferably the same as the first organic solvent;
and/or, the mass ratio of the fine product of the intermediate 5 to water is 1:3 to 5.
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