Preparation method of important intermediate of novel febuxostat

A technology of ethyl methyl and thiazole carboxylate, which is applied in the chemical and pharmaceutical fields, and can solve problems such as high cost, great environmental hazards, and low reaction yield

Inactive Publication Date: 2010-06-30
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The object of the present invention is to provide a kind of preparation method of new 2-[3-cyano group-(2-isobutyloxy) phenyl]-4-methyl-5-thiazole carboxylic acid ethyl ester, overcome existing In the technology, the reaction yield is low, the cost is high, and the defects of great environmental hazards, but the raw materials used in the present invention have a wide range of sources, are easy to prepare, and the reaction conditions are mild, easy to operate, and the production cost is low, which is suitable for industrial production.

Method used

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  • Preparation method of important intermediate of novel febuxostat
  • Preparation method of important intermediate of novel febuxostat
  • Preparation method of important intermediate of novel febuxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The preparation method of p-nitrophenylsulfamide:

[0036] Put p-nitrobenzonitrile (10g) and thioacetamide (12.7g) into 85mL DMF (10% HCl) at room temperature, stir for 5mins and then raise the temperature to 100°C, keep warm until TLC traces no raw materials (about 3h), Cool, pour into 30g of ice, filter, wash the filter residue with water (20×3), and dry to obtain 10g of light yellow solid with a yield of 81%.

Embodiment 2

[0038] The preparation method of 2-(4-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester:

[0039] Take p-nitrophenylsulfamide (10g) and add it to 50mL of ethanol, add 2-chloro-ethyl acetoacetate (11.5g), heat up to reflux under stirring, cool down after TLC tracking until there is no raw material, filter to obtain 13g of white solid , yield 80%.

Embodiment 3

[0041] The preparation method of 2-[3-cyano-(2-isobutyloxy)phenyl]-4-methyl-5-thiazolecarboxylic acid ethyl ester:

[0042] Take ethyl 2-(4-nitrophenyl)-4-methyl-5-thiazolecarboxylate (14.8g) and potassium cyanide (4.9g) into 150mL DMSO at room temperature, stir, and heat to 102°C. Insulate the reaction until TLC traces no raw materials (about 2 ~ 3h), cool, add K 2 CO 3 (3.8g), bromoisobutane (16g), be warming up to 80 ℃ under stirring, insulation reaction is followed to TLC reaction completely (about 7

[0043] h), cooled, poured into ice, extracted with ethyl acetate, washed the organic layer with water, dried, and spin-dried to obtain a yellow solid, which was recrystallized from ethyl acetate to obtain 15 g of off-white solid with a yield of 85%.

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Abstract

The invention relates to a preparation method of important intermediate 2-[3-cyan-(2-isobutoxy) phenyl]-4-methyl-5-thiazolecarboxylate of febuxostat which is a new generation of xanthine oxidase inhibitor. The method takes 2-(4-nitrobenzophenone)-4-methyl-5-thiazolecarboxylate as material to have cyanation reaction and isobutylation reaction under the existence of dimethyl sulfoxide to produce 2-[3-cyan-(2-methylpropoxy) phenyl]-4-methyl-5-thiazolecarboxylate. The material source is wide, the intermediate is easy to prepare, the reaction condition is mild, the operation is easy and the production cost is low, therefore, the preparation method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a new preparation method of febuxostat important intermediate 2-[3-cyano-(2-isobutyloxy)phenyl]-4-methyl-5-thiazole ethyl carboxylate, It belongs to the chemical and pharmaceutical field. Background technique [0002] Ethyl 2-[3-cyano-(2-isobutyloxy)phenyl]-4-methyl-5-thiazolecarboxylate is a compound in the synthesis of antihyperuricemia drug Febuxostat Important intermediate, its structural formula is as shown in formula (4): [0003] [0004] Formula (4) [0005] JP11060552 reports 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 - Ethyl-methyl-5-thiazolecarboxylate, then reacted with urotropine in polyphosphoric acid to give ethyl 2-(3-formaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate , After condensation with bromoisobutane, the aldehyde...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 沈巍巍蹇锋
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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