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Preparation method for febuxostat

A febuxostat and reaction technology, applied in the field of preparation of febuxostat, can solve the problems of increasing the difficulty of post-processing operations, low total yield of febuxostat, unfavorable environment, etc. Conducive to industrial scale-up production and the effect of safe reaction conditions

Inactive Publication Date: 2013-09-18
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The total yields of the synthetic methods of febuxostat reported above are all low, generally 20% to 40%.
In addition to the low yield, highly toxic substances such as cuprous cyanide and potassium cyanide are often used in the introduction of nitrile groups in the reaction process, and the introduction of aldehyde groups and thioamides is also often carried out in polyphosphoric acid, which increases the aftermath. Operationally difficult to handle and not good for the environment

Method used

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  • Preparation method for febuxostat

Examples

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Embodiment 1

[0043] A preparation method of febuxostat, the specific steps are as follows:

[0044] (1) Add 200mL of concentrated hydrochloric acid (concentration: 12mol / L) into the flask, add 13.0g of thioacetamide under mechanical stirring, add 10.0g of 4-hydroxybenzonitrile after complete dissolution, stir at 50°C for 4 hours, cool down, A large amount of solids precipitated, filtered, washed with a small amount of water until neutral, and dried to obtain 12.3 g of intermediate (III), with a yield of 95.8%.

[0045] (2) Dissolve 12.3g of intermediate III in 60mL of absolute ethanol, heat to reflux, slowly add 14.2g of ethyl 2-chloroacetoacetate dropwise, and continue to reflux for 5 hours. After the reaction is complete, add it to an ice-water bath to cool. A large amount of solids were precipitated, filtered and dried to obtain 20.4 g of intermediate IV as a yellow solid, with a yield of 96.0%.

[0046] (3) Dissolve 20.4g of intermediate IV in a mixture of 90mL of methanesulfonic acid a...

Embodiment 2

[0050] The difference between this embodiment and embodiment 1 is:

[0051] Add 200mL of dilute hydrochloric acid (concentration: 3mol / L) into the flask, add 13.0g of thioacetamide under mechanical stirring, add 10.0g of 4-hydroxybenzonitrile after complete dissolution, stir at 50°C for 4 hours, cool, and there are a lot of solids Precipitate, filter, wash with a small amount of water until neutral, and dry to obtain 9.8g. The yield of 4-hydroxythiobenzamide is 76.6%.

Embodiment 3

[0053] The difference between this embodiment and embodiment 1 is:

[0054] Dissolve 20.4g of intermediate IV in 110mL of methanesulfonic acid and 10mL of trifluoroacetic acid, heat to 90°C, add 27.9g of hexamethylenetetramine three times under mechanical stirring (half an hour apart), and continue the reaction for 8 hours. Add 300mL ice-cold salt water, stir for 1 hour, a large amount of yellow solid precipitates, filter, wash with water until neutral, dry to obtain 16.7g, 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5 - The yield of ethyl carboxylate is 74.9%.

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Abstract

The invention discloses a preparation method for febuxostat. The preparation method for febuxostat comprises the following steps of: by using 4-hydroxybenzonitrile and thioacetamide as raw materials, and reacting in hydrochloric acid solution to prepare 4-hydroxythiobenzamide; carrying out a reaction on 4-hydroxythiobenzamide and 2-chloroacetoacetic acid ethyl ester to prepare 2-(4-hydroxylphenyl)-4-methylthiazol-5-carboxylic acid ethyl ester; carrying out a reaction on the obtained compound and hexamine in the mixed acid system of methanesulfonic acid and trifluoroacetic acid to prepare 2-(3-formyl-4-hydroxylphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester; synthesising 2-(3-nitrile-4-isobutoxylphenyl) -4-methylthiazole-5-carboxylic acid ethyl ester from the compound, hydroxylamine hydrochloride, potassium carbonate, iso-butyl bromide and the like in a polar protonic solvent via a one-pot method; and finally hydrolyzing in an alkaline condition to obtain the target product, namely, febuxostat. The total yield of the preparation method for febuxostat disclosed by the invention is increased to 66%, the separation steps are reduced, any extremely toxic substance is not involved, and the environmental pollution is less.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and in particular relates to a preparation method of febuxostat. Background technique [0002] Febuxostat (English name: Febuxostat, chemical name: 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid) is a kind of Selective xanthine oxidase inhibitor, showing good inhibitory activity on xanthine oxidoreductase (XOR), but at the same time it will not act on other related enzymes in the metabolic pathway of purine and pyrimidine, and will not affect the metabolism of purine and pyrimidine Normal metabolism. Compared with other gout drugs, febuxostat has fewer side effects. Therefore, febuxostat, as the third-generation anti-gout drug after allopurinol and probenecid, has attracted widespread attention. [0003] There have been many literature and patent reports on the synthesis process of febuxostat: [0004] Patent EP 0513379 has reported that 4-chloro-3-nitrobenzonitr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
Inventor 张雷任月娇李晶
Owner SOUTH CHINA UNIV OF TECH
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