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Method for synthesizing febuxostat and intermediate thereof

A reaction mixture, methyl technology, applied in the field of medicine, can solve the problem of low yield

Pending Publication Date: 2020-04-21
HANGZHOU ZHUYANGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, in the synthetic route 3 of the above-mentioned literature review, there is a literature (CN103058950A) that describes from the intermediate 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl carboxylate to the intermediate The yield in the synthetic process of 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester is low, so improving the yield of this synthetic step is also is eagerly awaited by those skilled in the art

Method used

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  • Method for synthesizing febuxostat and intermediate thereof
  • Method for synthesizing febuxostat and intermediate thereof
  • Method for synthesizing febuxostat and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0110] (1) Add 1 molar portion of the reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester (actual dosage 80g) to (in a 1L reaction bottle) and preheat to 80 In a homogeneous mixture composed of 1.75 molar parts of polyphosphoric acid and 2.5 molar parts of methanesulfonic acid at ℃, stir evenly;

[0111] (2) Add 1.4 molar parts of Duff reaction reagent hexamethylenetetramine to the above reaction mixture under stirring, continue to react at a temperature of 80° C. for 6 hours, and cool the reaction mixture to 40° C. after the reaction is completed;

[0112] (3) Slowly add saturated ice brine (to about 80% of the total capacity of the reaction flask) into the cooled reaction mixture, filter after the solid is precipitated, wash the solid with water to neutrality, and dry to obtain a light yellow solid as 2- (3-formyl-4-hydroxyphenyl)-4-methyl-5-th...

Embodiment 2

[0113] Example 2: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0114] (1) Add 1 molar portion of reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazole formic acid ethyl ester (actual feeding amount 80g) to (in 1L reaction bottle) and preheat to 70 In a homogeneous mixture composed of 3 molar parts of polyphosphoric acid and 2 molar parts of methanesulfonic acid at ℃, stir evenly;

[0115] (2) Add 1.5 molar parts of Duff reaction reagent hexamethylenetetramine to the above reaction mixture under stirring, continue to react at a temperature of 70° C. for 8 hours, and cool the reaction mixture to 37° C. after the reaction is completed;

[0116] (3) Slowly add saturated ice brine (to about 80% of the total capacity of the reaction flask) into the cooled reaction mixture, filter after the solid is precipitated, wash the solid with water to neutrality, and dry to obtain a light yellow solid as 2- Ethyl (3-formaldehyde-4-hydroxyphenyl)-4-meth...

Embodiment 3

[0117] Example 3: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate

[0118] (1) Add 1 molar portion of the reactant 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester (actual dosage 80g) to (in a 1L reaction bottle) and preheat to 100 In a homogeneous mixture composed of 1.5 molar parts of polyphosphoric acid and 2 molar parts of methanesulfonic acid at ℃, stir evenly;

[0119] (2) Add 1.2 molar parts of Duff reaction reagent hexamethylenetetramine to the above reaction mixture under stirring, continue to react for 7 hours at a temperature of 75°C, and cool the reaction mixture to 38°C after the reaction is completed;

[0120] (3) Slowly add saturated ice brine (to about 80% of the total capacity of the reaction flask) into the cooled reaction mixture, filter after the solid is precipitated, wash the solid with water to neutrality, and dry to obtain a light yellow solid as 2- Ethyl (3-formaldehyde-4-hydroxyphenyl)-4-meth...

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Abstract

The invention relates to a method for synthesizing febuxostat and an intermediate thereof, specifically a method for synthesizing 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. The method comprises the following steps: preparing 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate; enabling the product obtained in the step (a) to react in DMF (Dimethyl Formamide) in the presence of potassium carbonate and bromo-isobutane, adding water and ethyl acetate for extraction, concentrating to obtain an organic layer, and recrystallizing with DMF to obtain 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. The invention also relates to 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester and 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazoleethyl formate and application thereof to the preparation of febuxostat. The method of the invention has excellent performance.

Description

technical field [0001] The present invention relates to the field of medical technology, relates to a xanthine oxidase inhibitor, especially the pharmaceutical compound febuxostat for gout, and also relates to an intermediate for preparing the febuxostat, for example, relates to the preparation of intermediate 2 -(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester and intermediate 2-(3-formyl-4-isobutoxy-phenyl)-4-methanol Ethyl-thiazole-5-carboxylate. The preparation method of febuxostat and its intermediate of the present invention has excellent performance. Background technique [0002] Hyperuricemia is caused by increased uric acid production and / or decreased renal uric acid secretion, and is the most risky factor for inducing gout. The use of drugs to reduce blood uric acid concentration is one of the common methods to prevent gout, such drugs include uricosuric drugs and xanthine oxidase / xanthine dehydrogenase inhibitors that can block the absor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 唐建飞马雯霞何海珍郭艳超赵福斌张群
Owner HANGZHOU ZHUYANGXIN PHARMA
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