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Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate

A technology of ethyl thiazole formate and hydroxyphenyl is applied in the field of preparation of ethyl 2--4-methyl-5-thiazole formate, and can solve the problems of cumbersome post-processing, poor PPA fluidity, difficulty in mass production, and the like, Achieve the effect of increasing yield, reducing production costs and reducing emissions

Inactive Publication Date: 2009-04-22
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In document JP1045733, PPA is used as solvent, and the yield is acceptable (70%), but the aftertreatment is loaded down with trivial details, and the amount of three wastes is large, and PPA has poor fluidity, and mass production is more difficult

Method used

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  • Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate
  • Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate
  • Preparation of 2-(3-carboxaldehyde-4-hydroxy phenyl)-4-methyl-5-thiazole ethyl formate

Examples

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Embodiment 1

[0030] Embodiment 1: the preparation of 4-hydroxyl thiobenzamide (3)

[0031] In a 5L reaction flask, 400g of p-cyanophenol and 584g of thioacetamide were added to 4000ml of saturated HCl / DMF solution. Reacted at 40°C for 48 hours, TLC showed that the reaction was almost complete, concentrated to dryness, added saturated Na 2 CO 3 The solution was 1350ml, stirred for 2 hours, filtered, and dried to obtain 465.8g of brown solid (3). Yield 87.6%.

Embodiment 2

[0032] Embodiment 2: Preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (2)

[0033] Add 465.8g of 4-hydroxythiobenzamide (3) and 2.8L of absolute ethanol into a 5L reaction flask, heat to 60°C, add 560g of ethyl 2-chloroacetoacetate dropwise, and then reflux for 2 hours. Then it was cooled to 10°C under stirring, filtered, washed with ethanol, and dried to obtain 721.1 g of yellow solid (2), with a yield of 80.6%.

Embodiment 3

[0034] Example 3: Preparation of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (1)

[0035] Add 120g of (2), 63.8g of urotropine and 660ml of trifluoroacetic acid into a 3L reaction flask, heat to 100°C for 24 hours, then concentrate the reaction solution to dryness, add 2L of water and stir for 5 hours, filter and dry to obtain 126.5 g of yellow solid (1), yield 95.3%.

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Abstract

The invention provides a method for preparing 2-(3-formaldehyde base-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate. The method uses para-cyano-phenol and thioacetamide as raw materials which are reacted with each other to obtain 4-hydroxy-thiobenzamide, and the obtained product is reacted with 2-chloro acetylacetic ether to obtain 2-(4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate, and then is reacted with urotropine to obtain the 2-(3-formaldehyde base-4-hydroxyphenyl)-4-methyl-5-thiazole ethyl formate.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate. Background technique [0002] Ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate is an important intermediate in the synthesis of the antihyperuricemia drug Febuxostat. Its structure It is shown in the following formula (1). [0003] [0004] JP1045733 and JP11060552 report the synthetic method of formula I compound, take p-cyanophenol and thioacetamide as raw material, carry out Hantzch reaction with ethyl 2-chloroacetoacetate in polyphosphoric acid to obtain 2-(4-hydroxyphenyl )-4-methyl-5-thiazolecarboxylic acid ethyl ester, reacted at 85°C, as shown in the following formula II. Then the compound of formula II and hexatropine are subjected to Duff-Bills reaction in polyphosphoric acid at 80° C. to obtain the compound of formula I after treatment. [000...

Claims

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Application Information

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IPC IPC(8): C07D277/56
Inventor 隋强王小妹王哲烽时惠麟王小梅孙玮鸿
Owner SHANGHAI INST OF PHARMA IND
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