CN107674040B - Method for converting febuxostat impurities into febuxostat - Google Patents
Method for converting febuxostat impurities into febuxostat Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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Abstract
The invention relates to a synthetic method for converting febuxostat impurities into febuxostat, which mainly comprises the steps of adding a dehydration reagent of Piv-Cl/Py, Piv-Cl/DIPEA or Piv-Cl/NEt3Under the action of the (3-amidofebuxostat) or the 3-hydroxamic acid febuxostat is subjected to amide or hydroxamic acid to cyano conversion in an organic solvent, and finally febuxostat is obtained. The invention discloses a method for synthesizing febuxostat by using main impurities of febuxostat as initial raw materials through functional group conversion for the first time. The synthesis method has the characteristics of simple synthesis process, convenient operation, high yield and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a synthetic method for converting pharmaceutical impurities into finished pharmaceutical products, in particular to a method for converting febuxostat impurities into febuxostat, which comprises the following steps: 3-amidofebuxostat or 3-hydroxamic acid febuxostat is converted into febuxostat.
Background
The chemical name of Febuxostat (Febuxostat) is 2- (3-cyano-4-isobutoxy) -4-methyl-5-thiazolecarboxylic acid, and the chemical structural formula is as follows:
febuxostat, a new generation of anti-gout drugs synthesized by Teijin, is first marketed in japan in 2004 and then marketed in europe and the united states, respectively, is a novel non-purine Xanthine Oxidoreductase (XOR) inhibitor, has high selectivity for XOR, has a significant inhibitory effect on both oxidized and reduced XORs, and is clinically used for treating hyperuricemia (gout).
The existing synthetic routes of febuxostat mainly comprise the following 4 types: 1) EP 0513379, JP 1993500083, US 5614520 and WO 9209279 describe that 3-nitro-4-hydroxybenzaldehyde is used as a raw material, and is subjected to oxime formation with hydroxylamine, then dehydration is carried out to prepare 3-nitro-4-hydroxybenzonitrile, and the 3-nitro-4-hydroxybenzonitrile is reacted with thioacetamide to generate an important intermediate 3-nitro-4-hydroxyphenyl thiocarbamide, and then the intermediate is cyclized with 2-chloroacetoacetic acid ethyl ester, bromo-isobutane is alkylated, catalytic hydrogenation, diazotization, cyanation and hydrolysis to finally obtain febuxostat. The reaction steps of the route are long, the diazotization reaction is not easy to control, and the measured cuprous cyanide required by the cyanidation reaction is easy to cause environmental pollution; 2) JP 1994329647 discloses a method for preparing febuxostat as a target compound by using 4-hydroxyphenyl thiocarboxamide as a raw material, carrying out cyclization reaction on the 4-hydroxyphenyl thiocarboxamide and 2-bromoacetoacetic ester to generate 2- (4-hydroxyphenyl) -4-methyl-5-thiazole ethyl formate, and carrying out formylation, alkylation, hydroxylamine oxime formation, dehydration and hydrolysis on the 2- (4-hydroxyphenyl) -4-methyl-5-thiazole ethyl formate. 3) JP 1998045733 discloses that 4-hydroxyphenyl thiocarboxamide is used as a raw material to perform cyclization reaction with 2-bromoacetoacetic ester to generate 2- (4-hydroxyphenyl) -4-methyl-5-thiazole ethyl formate, and the target compound febuxostat 4 is prepared by formylation, hydroxylamine oxime formation, dehydration to nitrile, alkylation and hydrolysis.A JP 6345724 discloses that 4-nitrobenzonitrile is used as a starting material to firstly form a dinitrile compound under the action of potassium cyanide, react with isobutyl bromide to obtain 4-isopropoxy-1, 3-benzenedinitrile, and then react with thioacetamide to prepare 3-cyano-4-isopropoxyphenylthioacetamide; cyclizing with 2-chloroacetoacetic acid ethyl acetate to obtain 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-thiazole acetic acid ethyl acetate, and finally hydrolyzing to obtain the non-butadine.
The document K Ishihara, Y Furuya, H Yamamoto,Angew. Chem. Int. Ed2002, 41, 2983-2986 report a method for synthesizing a cyano group by using amide and oxime as starting materials, rhenium oxide as a catalyst and toluene as a solvent; A.V. Narsaiah, K. Nagaiah, Adv. Synth. Catal,.2004, 346, 1271-1274 reports a method for synthesizing a cyano group by taking amide and oxime as starting materials and taking Piv-Cl/Py as a dehydration reagent, and WO 2011/141933 discloses a method for synthesizing 3-amidofebuxostat and 3-hydroxamic acid febuxostat. The synthesis methods of the two impurities are also reported in the literature, and no research report for converting the two impurities into febuxostat exists so far.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings in the prior art, and develops a synthetic method for converting febuxostat impurities into febuxostat, which takes 3-amidofebuxostat or 3-hydroximic acid febuxostat serving as main impurities of febuxostat as starting raw materials to prepare febuxostat through functional group conversion.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthetic method for converting febuxostat impurities into febuxostat is characterized by comprising the following steps:
reacting a compound I (3-amidofebuxostat) or a compound II (3-hydroxamic acid febuxostat) in an organic solvent for 6-12 hours at 40-75 ℃ under the action of a dehydration reagent, detecting by TLC, washing a reaction solution by using dilute hydrochloric acid after the reaction is finished, washing by using water, concentrating, recrystallizing by using ethanol, and filtering to obtain a compound III (febuxostat).
In the synthetic method, the dehydration reagent combination is Piv-Cl/Py, Piv-Cl/DIPEA or Piv-Cl/NEt3。
In the synthesis method, the organic solvent for the reaction of the compound I (3-amidofebuxostat) or the compound II (3-hydroxamic acid febuxostat) and the dehydration reagent is toluene, acetonitrile or toluene: acetonitrile is mixed solution with the volume ratio of 1:1.
The reaction time of the compound I (3-amidofebuxostat) or the compound II (3-hydroxamic acid febuxostat) is 6-12 hours, and the reaction temperature is 40-75 ℃.
For better experimental results, the dehydration reagent combination is Piv-Cl/Py, Piv-Cl/DIPEA, and the selection is Piv-Cl/DIPEA.
The organic solvent for the reaction of the compound I (3-amidofebuxostat) or the compound II (3-hydroxamic acid febuxostat) and the dehydration reagent is toluene and acetonitrile.
In the synthesis method, the ratio of Piv-Cl: the molar ratio of DIPEA was: 1: 1-2
Compound I or compound II: Piv-Cl: the molar ratio of DIPEA was: 1:1 to 2
The reaction time of the compound I (3-amidofebuxostat) or the compound II (3-hydroxamic acid febuxostat) is 7-10 hours, and the reaction temperature is 55-70 ℃.
The organic solvent for the reaction of the compound I (3-amidofebuxostat) or the compound II (3-hydroxamic acid febuxostat) and the dehydration reagent is toluene; Piv-Cl: the molar ratio of DIPEA was: 1: 1.09; compound I or compound II: Piv-Cl: the molar ratio of DIPEA was: 1:1.1:1.2
The reaction time of the compound I (3-amidofebuxostat) or the compound II (3-hydroxamic acid febuxostat) is 8 hours, and the reaction temperature is 65 ℃.
The reaction process of the invention is as follows:
compared with the content disclosed by the prior art, the synthetic method for converting febuxostat impurities into febuxostat has the advantages and characteristics that:
the invention discloses a method for synthesizing febuxostat by using main impurities of febuxostat, namely 3-amidofebuxostat or 3-hydroxamic acid febuxostat, as starting raw materials through functional group conversion. The synthesis method has the advantages of simple synthesis process, convenient operation, high yield and the like.
Detailed Description
For the sake of simplicity and clarity, descriptions of well-known techniques are omitted appropriately below to avoid unnecessary detail affecting the description of the present solution. The synthesis of febuxostat as an impurity for converting febuxostat to febuxostat according to the present invention is further illustrated below with reference to preferred examples, and 3-amidofebuxostat, 3-hydroxamic acid febuxostat, is specifically illustrated and can be synthesized by the method provided in WO 2011/141933 or commercially available.
Example 1
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-necked bottle provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 1.58 g (0.02 mol) of pyridine, heating to 65 ℃, carrying out heat preservation reaction for 12 hours, monitoring the completion of the reaction by TLC, washing the reaction solution with dilute hydrochloric acid, washing with water, evaporating to remove the toluene in the reaction solution, and recrystallizing with ethanol to obtain 2.56 g of febuxostat with the yield of 81% and the content of 96.9%.
Example 2
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-necked bottle provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 8 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove the toluene in the reaction solution, and recrystallizing by using ethanol to obtain 3.01 g of febuxostat with the yield of 95% and the content of 98.3%.
Example 3
To a 250 ml three-necked flask equipped with a thermometer, mechanical stirrer, reflux condenser, 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of toluene were added, respectively, and 2.02 g (0.02 mol) of NEt was slowly added3Heating to 65 ℃, keeping the temperature for reaction for 10 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.67 g of febuxostat, wherein the yield is 85%, and the content is 98.0%.
Example 4
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of acetonitrile into a 250 ml three-necked bottle provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 6 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.78 g of febuxostat with the yield of 88% and the content of 97.5%.
Example 5
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of mixed solution (the volume ratio is 1: 1) of toluene acetonitrile into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 7 hours, carrying out TLC monitoring reaction, washing reaction liquid with dilute hydrochloric acid, washing with water, evaporating toluene in the reaction liquid, and recrystallizing with ethanol to obtain 2.72 g of febuxostat, wherein the yield is 86%, and the content is 97.8%.
Example 6
Respectively adding 3.34 g (0.01 mol) of 3-formamido febuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of mixed solution (the volume ratio is 1: 1) of toluene acetonitrile into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 40 ℃, carrying out heat preservation reaction for 12 hours, carrying out TLC monitoring reaction, washing reaction liquid with dilute hydrochloric acid, washing with water, evaporating toluene in the reaction liquid, and recrystallizing with ethanol to obtain 2.62 g of febuxostat, wherein the yield is 83%, and the content is 96.9%.
Example 7
Respectively adding 3.34 g (0.01 mol) of 3-formamido febuxostat, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of mixed solution of toluene acetonitrile into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 75 ℃, carrying out heat preservation reaction for 6 hours, carrying out TLC monitoring reaction, washing the reaction solution with dilute hydrochloric acid, washing with water, evaporating to remove toluene in the reaction solution, and recrystallizing with ethanol to obtain 2.92 g of febuxostat, wherein the yield is 92%, and the content is 98.6%.
Example 8
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-necked flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 1.29 g (0.01 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 11 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove the toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.58 g of febuxostat, wherein the yield is 82%, and the content is 96.7%.
Example 9
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 2.41 g (0.02 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 7 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove the toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.84 g of febuxostat, wherein the yield is 90%, and the content is 97.5%.
Example 10
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-necked flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 9 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove the toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.91 g of febuxostat, wherein the yield is 92%, and the content is 98.1%.
Example 11
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-necked flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 55 ℃, carrying out heat preservation reaction for 9 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove the toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.84 g of febuxostat, wherein the yield is 90%, and the content is 98.0%.
Example 12
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-necked flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 70 ℃, carrying out heat preservation reaction for 7.5 hours, monitoring the reaction by TLC, washing the reaction solution by dilute hydrochloric acid, washing by water, evaporating to remove the toluene in the reaction solution, and recrystallizing by ethanol to obtain 2.94 g of febuxostat with the yield of 93% and the content of 98.2%.
Example 13
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.33 g (0.011 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 1.558 g (0.012 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 8 hours, monitoring the reaction completion by TLC, washing the reaction solution by dilute hydrochloric acid, washing by water, evaporating to remove the toluene in the reaction solution, and recrystallizing by ethanol to obtain 3.03 g of febuxostat with the yield of 96 percent and the content of 98.9 percent.
Example 14
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, 1.58 g (0.02 mol) of pyridine is slowly added, the temperature is increased to 65 ℃, the heat preservation reaction is carried out for 12 hours, the TLC is used for monitoring the completion of the reaction, the reaction solution is washed by dilute hydrochloric acid, washed by water, the toluene in the reaction solution is evaporated, and ethanol is used for recrystallization to obtain 2.48 g of febuxostat, the yield is 78%, and the content is 96.2%.
Example 15
Respectively adding 3.34 g (0.01 mol) of 3-febuxostat hydroxamate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 8 hours, monitoring the reaction completion by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove the toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.91 g of febuxostat with the yield of 92% and the content of 97.9%.
Example 16
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-necked flask equipped with a thermometer, a mechanical stirrer and a reflux condenser, and 2.02 g (0.02 mol) of NEt is slowly added3Heating to 65 ℃, keeping the temperature for reaction for 10 hours, monitoring the reaction by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by water, evaporating to remove toluene in the reaction solution, recrystallizing by using ethanol to obtain 2.59 g of febuxostat with the yield of 82 percent97.6%。
Example 17
Respectively adding 3.34 g (0.01 mol) of 3-febuxostat hydroxamate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of acetonitrile into a 250 ml three-necked bottle provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 6 hours, monitoring the reaction completion by TLC, washing the reaction solution by using dilute hydrochloric acid, washing by using water, evaporating to remove toluene in the reaction solution, and recrystallizing by using ethanol to obtain 2.68 g of febuxostat, wherein the yield is 85%, and the content is 97.1%.
Example 18
Respectively adding 3.34 g (0.01 mol) of 3-febuxostat hydroxamate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of mixed solution of toluene acetonitrile into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 65 ℃, carrying out heat preservation reaction for 7 hours, carrying out TLC monitoring reaction, washing the reaction solution with dilute hydrochloric acid, washing with water, evaporating to remove toluene in the reaction solution, and recrystallizing with ethanol to obtain 2.62 g of febuxostat with the yield of 83% and the content of 97.4%.
Example 19
Respectively adding 3.34 g (0.01 mol) of 3-febuxostat hydroxamate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of mixed solution of toluene acetonitrile into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 40 ℃, carrying out heat preservation reaction for 12 hours, carrying out TLC monitoring reaction, washing the reaction solution with dilute hydrochloric acid, washing with water, evaporating to remove toluene in the reaction solution, and recrystallizing with ethanol to obtain 2.53 g of febuxostat with the yield of 80% and the content of 96.5%.
Example 20
Respectively adding 3.34 g (0.01 mol) of 3-febuxostat hydroxamate, 1.81 g (0.015 mol) of Piv-Cl and 100 ml of mixed solution of toluene acetonitrile into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 75 ℃, carrying out heat preservation reaction for 6 hours, carrying out TLC monitoring reaction, washing the reaction solution with dilute hydrochloric acid, washing with water, evaporating to remove toluene in the reaction solution, and recrystallizing with ethanol to obtain 2.72 g of febuxostat with the yield of 89% and the content of 98.2%.
Example 21
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, 1.29 g (0.01 mol) of DIPEA is slowly added, the temperature is increased to 65 ℃, the heat preservation reaction is carried out for 11 hours, the TLC monitors that the reaction is finished, the reaction solution is washed by dilute hydrochloric acid, washed by water, the toluene in the reaction solution is evaporated, and the ethanol is used for recrystallization to obtain 2.50 g of febuxostat, the yield is 79%, and the content is 96.3%.
Example 22
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 2.41 g (0.02 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, 2.58 g (0.02 mol) of DIPEA is slowly added, the temperature is increased to 65 ℃, the heat preservation reaction is carried out for 7 hours, the TLC monitors that the reaction is finished, the reaction solution is washed by dilute hydrochloric acid, washed by water, the toluene in the reaction solution is evaporated, and the ethanol is used for recrystallization to obtain 2.75 g of febuxostat, wherein the yield is 87%, and the content is 97.1%.
Example 23
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, 2.58 g (0.02 mol) of DIPEA is slowly added, the temperature is raised to 65 ℃, the heat preservation reaction is carried out for 9 hours, the TLC monitors that the reaction is finished, the reaction solution is washed by dilute hydrochloric acid, washed by water, the toluene in the reaction solution is evaporated, and the ethanol is used for recrystallization to obtain 2.81 g of febuxostat, wherein the yield is 89%, and the content is 97.7%.
Example 24
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, 2.58 g (0.02 mol) of DIPEA is slowly added, the temperature is raised to 55 ℃, the heat preservation reaction is carried out for 9 hours, the TLC monitors that the reaction is finished, the reaction solution is washed by dilute hydrochloric acid, washed by water, the toluene in the reaction solution is evaporated, and the ethanol is used for recrystallization to obtain 2.75 g of febuxostat, wherein the yield is 87%, and the content is 97.6%.
Example 25
Respectively adding 3.34 g (0.01 mol) of 3-formamidofebuxostat, 1.21 g (0.01 mol) of Piv-Cl and 100 ml of toluene into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, slowly adding 2.58 g (0.02 mol) of DIPEA, heating to 70 ℃, carrying out heat preservation reaction for 7.5 hours, monitoring the reaction by TLC, washing the reaction solution by dilute hydrochloric acid, washing by water, evaporating to remove the toluene in the reaction solution, and recrystallizing by ethanol to obtain 2.84 g of febuxostat, wherein the yield is 90%, and the content is 97.8%.
Example 26
3.34 g (0.01 mol) of febuxostat 3-hydroximate, 1.33 g (0.011 mol) of Piv-Cl and 100 ml of toluene are respectively added into a 250 ml three-neck flask provided with a thermometer, a mechanical stirrer and a reflux condenser, 1.558 g (0.012 mol) of DIPEA is slowly added, the temperature is increased to 65 ℃, the heat preservation reaction is carried out for 8 hours, the TLC monitors the reaction to be finished, the reaction solution is washed by dilute hydrochloric acid, washed by water, the toluene in the reaction solution is evaporated, and the ethanol is used for recrystallization to obtain 2.97 g of febuxostat, the yield is 94%, and the content is 98.6%.
The measurement data of febuxostat (example 13) prepared by the invention are as follows:
melting point: 207 ℃ C. 209 ℃ C
IR（KBr）（cm-1）: 3429, 2962, 2876, 2229, 1680, 1606, 1515, 1431, 1385, 1370, 1323, 1294, 1121, 962.
1H NMR( 600 MHz, DMSO-d 6) δ: 13.42( s, 1H) ,8.26(d, J=2.3 Hz, 1H) , 8.21(dd, J=2.3 Hz，J=9.0 Hz, 1H) , 7.38(d, J=9.0 Hz, 1H) , 3.99(d, J=6.5 Hz, 2H) , 2.75(s, 3H) , 2.11 - 2.15(m, 1H) , 1.13(d, J=6.7 Hz, 6H).
1C NMR( 150 MHz, DMSO-d 6) δ: 166, 163, 162, 160, 133, 132, 125, 123, 115, 114, 102, 75, 28, 19, 17.
ESI-MS(m/z) : 315 [M-H]- .
The results show that: the above spectral data prove that the product prepared by the invention is febuxostat.
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the spirit and scope of the invention, and it is intended that all such changes and modifications as fall within the true spirit and scope of the invention be interpreted in accordance with the principles of the invention. And the invention is not limited to the example embodiments set forth in the description.
Claims (1)
1. A method for converting febuxostat impurities into febuxostat is characterized by comprising the following steps: carrying out dehydration reaction on the 3-amidofebuxostat compound I or the 3-hydroxamic acid febuxostat compound II in an organic solvent, wherein the reaction time is 7-10 hours, the reaction temperature is 55-70 ℃, and the amidocyanogen or the hydroxamic acid is converted into a cyano group to finally obtain a febuxostat compound III;
the dehydration reagent for the dehydration reaction is Piv-Cl/DIPEA;
the compound I or the compound II: Piv-Cl: the molar ratio of DIPEA was: 1: 1-2; the organic solvent is toluene, acetonitrile or a mixed solution of toluene and acetonitrile; the Piv-Cl: the molar ratio of DIPEA was: 1: 1-2; the mixed liquid refers to toluene: and (3) a mixed solution of acetonitrile in a volume ratio of 1:1.
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|---|---|---|---|---|
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
| CN103788010A (en) * | 2012-11-01 | 2014-05-14 | 北大方正集团有限公司 | Febuxostat intermediate and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011141933A2 (en) * | 2010-05-12 | 2011-11-17 | Msn Laboratories Limited | Process for preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid and its pharmaceutically acceptable salts |
| CN103788010A (en) * | 2012-11-01 | 2014-05-14 | 北大方正集团有限公司 | Febuxostat intermediate and preparation method thereof |
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| An Efficient and Improved Method for the Preparation of Nitriles from Primary Amides and Aldoximes;A. Venkat Narsaiah等;《Adv. Synth. Catal.》;20041231;第346卷;第1271-1274页 * |
| 非布司他副反应及降解杂质的分离和鉴定;吴强等;《药物分析杂志》;20151231;第35卷(第3期);第440-446页 * |
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