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New preparation method of febuxostat

A technology of febuxostat and intermediates, which is applied in the field of pharmaceutical synthesis, can solve the problems of unfavorable recovery, etc., and achieve the effects of convenient large-scale production, high yield, and small genotoxic impurities

Active Publication Date: 2019-09-13
福安药业集团重庆博圣制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ethyl acetate is used in the preparation process of compound IV. Under the condition of alkaline acid-binding agent, ethyl acetate will be hydrolyzed, which is not conducive to recovery.

Method used

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  • New preparation method of febuxostat
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  • New preparation method of febuxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The preparation of embodiment 1 febuxostat product

[0067] 1. Preparation of crude febuxostat

[0068] Add 400kg DMF, 100kg 2-(3-formyl-4-hydroxyl phenyl)-4-methylthiazole-5-carboxylate ethyl ester, 50kg bromoisobutane, 35kg triethylamine in reaction tank, heat up Reaction at 70°C for 15h. Then cool down and add 25kg of hydroxylamine hydrochloride, and react at 70°C for 3h. Then 30kg of acetyl chloride was added dropwise and reacted at 75°C for 7h. After the reaction is complete, cool down to 20-30°C, add water, add 20kg of sodium hydroxide, and hydrolyze at 40°C for 6 hours. Then hydrochloric acid was added dropwise to adjust the pH to 6.0-7.0. Lower the temperature by 0-5°C, then add water, and crystallize for 2 hours. Centrifuge to obtain a white solid powder, and obtain the febuxostat crude product with a wet weight of 122kg.

[0069] 2. Preparation of febuxostat

[0070] The crude product of febuxostat is dissolved in 90% methanol, decolorized by activated ...

Embodiment 2

[0071] The preparation of embodiment 2 febuxostat products

[0072] 1. Preparation of crude febuxostat

[0073] Add 400kg DMAC, 100kg 2-(3-formyl-4-hydroxyl phenyl)-4-methylthiazole-5-carboxylate ethyl ester, 50kg bromoisobutane, 35kg triethylamine in reaction tank, heat up Reaction at 75°C for 15h. Then cool down and add 25kg of hydroxylamine hydrochloride, and react at 75°C for 3h. Then 30kg of acetyl chloride was added dropwise, and reacted at 80°C for 7h. After the reaction is complete, cool down to 20-30°C, add water, add 20kg of sodium hydroxide, and hydrolyze at 45°C for 6 hours. Then hydrochloric acid was added dropwise to adjust the pH to 6.0-7.0. Lower the temperature by 0-5°C, then add water, and crystallize for 2 hours. Centrifuge to obtain a white solid powder, and obtain the febuxostat crude product with a wet weight of 128kg.

[0074] 2. Preparation of febuxostat

[0075] Dissolve the crude product of febuxostat in 90% methanol, decolorize it with activat...

Embodiment 3

[0076] The preparation of embodiment 3 febuxostat products

[0077] 1. Preparation of crude febuxostat

[0078] Add 400kgDMF, 100kg 2-(3-formyl-4-hydroxyl phenyl)-4-methylthiazole-5-carboxylate ethyl ester, 50kg bromoisobutane, 35kg triethylamine in reaction tank, be warming up to Reaction at 80°C for 16h. Then cool down and add 25kg of hydroxylamine hydrochloride, and react at 80°C for 4h. Then 30kg of acetyl chloride was added dropwise and reacted at 85°C for 8h. After the reaction is complete, cool down to 20-30°C, add water, add 20kg of sodium hydroxide, and hydrolyze at 50°C for 8 hours. Then hydrochloric acid was added dropwise to adjust the pH to 6.0-7.0. Lower the temperature by 0-5°C, then add water, and crystallize for 2 hours. After centrifugation, a white solid powder was obtained, and the powder was extracted to obtain a crude febuxostat product with a wet weight of 132kg.

[0079] 2. Preparation of febuxostat

[0080] Dissolve the crude product of febuxost...

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Abstract

Belonging to the technical field of pharmaceutical synthesis, the invention in particular relates to a preparation method of a febuxostat intermediate I, a preparation method of a febuxostat intermediate II and application thereof, as well as a preparation method of a febuxostat product. The preparation method of the febuxostat product includes: preparing the febuxostat intermediate I and the febuxostat intermediate II, directly adding water and organic alkali into a solution of the febuxostat intermediate II, and carrying out hydrolysis reaction; at the end of the reaction, adjusting the pH to 6.0-7.0 with hydrochloric acid, adding water for crystallization, performing cooling and centrifugation to obtain a febuxostat crude product, and then performing further preparation to obtain the febuxostat product. The febuxostat finished product has high purity, the preparation method has high yield and is low in cost, solid-liquid separation is easy to realize, the residual solvent is easilyremoved in the finished product preparation step, and the method is convenient for "consistency evaluation" by a preparation manufacturer, has great market competition advantage, and is green and environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of a febuxostat intermediate I, a preparation method and application of a febuxostat intermediate II, and a preparation method of a febuxostat product. Background technique [0002] Febuxostat is a novel xanthine oxidase (XO) inhibitor and the first non-purine XO inhibitor. Its chemical name is: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, and its molecular formula is C 16 h 16 N 2 o 3 S, the structural formula is as shown in formula I: [0003] [0004] Febuxostat is the latest generation of drugs that inhibit the synthesis of uric acid, which was first developed by Japan's Teijin (TAP) Pharmaceutical Company. It is suitable for the long-term treatment of hyperuricemia in patients with gout. [0005] It was approved for marketing in the European Union in May 2008 and in the United States in F...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 章永强洪荣川袁明华丁东张雄车瑶罗浩
Owner 福安药业集团重庆博圣制药有限公司
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