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A method for synthesizing intermediate impurities of antigout drug febuxostat and applications of the synthesized impurities

A technology for febuxostat and an anti-gout drug, applied in the field of medicine, can solve problems such as impurities that cannot meet identification standards, and achieve the effects of simple synthesis method and high purity

Inactive Publication Date: 2018-05-15
QINGDAO HUANGHAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] There are impurities produced in the above-mentioned preparation process of febuxostat, but the obtained impurities can not reach the identification standard, and there is an urgent need to obtain pure impurities in the preparation process of febuxostat that can be controlled.

Method used

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  • A method for synthesizing intermediate impurities of antigout drug febuxostat and applications of the synthesized impurities
  • A method for synthesizing intermediate impurities of antigout drug febuxostat and applications of the synthesized impurities
  • A method for synthesizing intermediate impurities of antigout drug febuxostat and applications of the synthesized impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of Impurity A

[0037] In a 50mL three-necked flask equipped with a magnetic stirrer, a condenser and a thermometer, add 5.00 g (32.63 mmol) of 4-hydroxythiobenzamide, 40 g of absolute ethanol, and 3.60 g (39.16 mmol) of chloroacetone at 75 ° C The reaction was stirred for 2 hours (monitored by TLC). After the reaction stopped, the temperature was lowered to 20-25° C., filtered, and the filter cake was washed with absolute ethanol to obtain 6.18 g of intermediate 1 as a white solid, HPLC: 98.25%, yield: 99.03%;

[0038] In a 100mL three-necked flask equipped with a magnetic stirrer, a condenser and a thermometer, add 10.00g (52.28mmol) of intermediate 1 and 60g of TFA and stir and mix. ℃, react at the same temperature for 5 hours, after the reaction stops, cool down to 20-25℃, add 100g of purified water, 100g of dichloromethane for extraction, after separation, the organic phase is sequentially washed with saturated NaHCO 3 Solution washing, saturated brine w...

Embodiment 2

[0045] Synthesis of Impurity A

[0046] In a 50mL three-necked flask equipped with a magnetic stirrer, a condenser and a thermometer, add 10.00 g (65.26 mmol) of 4-hydroxythiobenzamide, 80 g of absolute ethanol, and 7.20 g (78.32 mmol) of chloroacetone at 78 ° C The reaction was stirred for 3 hours (monitored by TLC). After the reaction stopped, the temperature was lowered to room temperature, filtered, and the filter cake was washed with absolute ethanol to obtain 11.18 g of intermediate 1 as a white solid, yield: 89.58%;

[0047] In a 100mL three-necked flask equipped with a magnetic stirrer, a condenser and a thermometer, add 15.00g (78.43mmol) of Intermediate 1 and 90g of TFA to stir and mix, add 15.83g of HMTA (109.79mmol) after clarification, and heat up to 100°C. React at the same temperature for 6 hours. After the reaction stops, cool down to 25°C, add 100g of purified water, and extract with 100g of dichloromethane. After liquid separation, the organic phase is sequen...

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Abstract

The invention relates to the field of medicines, and particularly relates to a method for synthesizing intermediate impurities of antigout drug febuxostat and applications of the synthesized impurities. The method includes (1) reacting 4-hydroxy thiobenzamide adopted as an initial material with chloroacetone, and subjecting an obtained reaction product, trifluoroacetic acid and hexamethylenetetramine to a Duff reaction to generate the impurity A; (2) reacting 4-hydroxy thiobenzamide adopted as an initial material with ethyl 2-chloro-3-oxopropanoate, and subjecting an obtained reaction product,trifluoroacetic acid and hexamethylenetetramine to a Duff reaction to generate the impurity B; and (3) determining structures of the impurity A and the impurity B through nuclear magnetic resonance.The method is simple, raw materials are easily available, and purity of the obtained impurity A and purity of the impurity B are high and are 99.55% and 98.13% respectively.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing an intermediate impurity of the anti-gout drug febuxostat and the application of the impurity synthesis. Background technique [0002] Febuxostat, chemical name: 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, is a product developed by Japan Teijin (Teijin Corporation) A xanthine oxidase inhibitor, which was launched in Europe in 2008. Compared with other drugs for the treatment of gout, it has higher selectivity and higher activity for the inhibition of xanthine oxidase, and can rapidly reduce blood uric acid It has a significant effect on the treatment of gout, and has great application prospects in the treatment of hyperuricemia and gout. [0003] At present, febuxostat is gradually replacing the original gout drug, and it is gradually being used in large quantities. There are many patent documents about the preparation of febuxostat, and t...

Claims

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Application Information

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IPC IPC(8): C07D277/24C07D277/56G01N30/06
CPCC07D277/24C07D277/56G01N30/06
Inventor 刘传飞李延顺陈晓涛辛海强李飞飞冷晓杨克宝刘宁宁
Owner QINGDAO HUANGHAI PHARM CO LTD
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