Preparation method of febuxostat intermediate

A febuxostat and intermediate technology, applied in the field of medicine, can solve the problems of harsh reaction conditions, strong corrosion, and highly toxic reaction raw materials, and achieve the effect of mild reaction conditions, low toxicity, and low corrosion

Inactive Publication Date: 2015-03-18
上海龙翔生物医药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The technical problem to be solved by the present invention is that in order to overcome the harsh reaction conditions of the preparation method of febuxostat intermediates

Method used

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  • Preparation method of febuxostat intermediate

Examples

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Effect test

Embodiment 1

[0033] The synthesis of embodiment 1 p-hydroxyl thiobenzamide

[0034] Add 1.5g of p-cyanophenol and 15mL of DMF into a 250mL three-necked flask, stir, then add 2.02g of 70% sodium hydrosulfide and 3.84g of magnesium chloride hexahydrate, and react the reaction mixture at 25 degrees for 24 hours, TLC detection (dichloromethane: Methanol=30:1, volume ratio) The raw materials basically reacted completely. Cool, filter with suction, pour into stirred ice water (100mL), extract the aqueous phase with ethyl acetate (3×30mL), combine the organic phases and dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure to obtain 1.5g of a brown solid, yield 90%.

Embodiment 22

[0035] Synthesis of Example 22-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0036] Add 0.7g of p-hydroxythiobenzamide, 2.8mL of ethanol and 0.9g of ethyl 2-chloroacetoacetate into a 50mL three-necked flask, heat the reaction mixture under reflux for 2 hours, and detect it by TLC (dichloromethane:methanol=30:1 , volume ratio) the raw materials basically reacted completely. Cool, filter with suction, rinse the filter cake with ethanol, and dry the filter cake in vacuum at 50°C to obtain 1.0 g of a yellow solid with a yield of 84%.

Embodiment 3

[0037] Synthesis of Example 32-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0038] Add 2.0g (0.0076mol) of ethyl 2-(4-hydroxyphenyl)-4-methyl-thiazole-5carboxylate and 20mL glacial acetic acid into a 50mL three-necked flask, heat up to 80-90°C, and then add 2.1 g (0.015mol) urotropine, 1.0g (0.0027mol) cerium trichloride, the reaction mixture was heated to 118°C for 4 hours, TLC detection (petroleum ether: ethyl acetate = 3:1, volume ratio) raw materials The basic response is complete. Cool to room temperature, add 0.05mL of concentrated sulfuric acid dropwise, add 20mL of water after 5 minutes, shake fully, a large amount of solid precipitates, extract with ethyl acetate (3×30mL), combine the organic phases and wash with saturated brine until neutral, the organic phase is free of Water was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of a yellow solid with a yield of 50% and a HPLC purity ...

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Abstract

The invention relates to a preparation method of a febuxostat intermediate. The preparation method comprises the following steps of in the presence of cerium trichloride, performing formylation reaction on 2-(4-hydroxyphenyl)-4-methyl-thiazole-5carboxylic ethyl ester and urotropine by taking acetic acid as a solvent. The preparation method disclosed by the invention is small in raw material corrosion, small in toxicity, gentle in reaction condition and more suitable for the industrial production needs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of febuxostat intermediate 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester. Background technique [0002] Febuxostat is a new type of non-purine xanthine oxidase inhibitor, clinically used for the prevention and treatment of hyperuricemia and gout caused by it, with good curative effect and safety. Japan's Teijin Corporation applied for listing in Japan in early 2004, and in the United States at the end of the same year. The European Union approved its listing in May 2008, and the FDA approved it for listing in February 2009. Febuxostat is a new non-purine highly efficient selective xanthine oxidase inhibitor, an effective substitute for allopurinol allergic or intolerant gout patients, especially for gout patients with renal insufficiency. It has a high dissolution rate for tophi, and fatal allergic syndrome rarely occurs. [...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 崔英杰冯虓
Owner 上海龙翔生物医药开发有限公司
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