Preparation method of febuxostat intermediate

A technology of hydroxyphenyl and methyl group, applied in the field of medicinal chemistry, can solve the problems such as the large corrosion of trifluoroacetic acid equipment, which is difficult for industrialization, the environmental pollution of hydrogen sulfide, which is unsuitable for industrialization, and the preciousness of hydroxybenzene thiocarboxamide, so as to overcome the equipment corrosion. Powerful, easy to industrialize production, low price effect

Active Publication Date: 2010-03-10
CHINA PHARM UNIV +1
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This technique is an industrial preferred route. The problem of this technique is that the starting material p-hydroxybenzenethiocarboxamide is more expensive and difficult to prepare, and the preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole -Ethyl 5-carboxylate uses trifluoroacetic acid, which is more corrosive to equipment and difficult to industrialize
[0009] 3 febuxostat synthesis patent Japanese patent JP1998045733 uses polyphosphoric acid as a solvent in the preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, due to polyphosphoric acid Polyphosphoric acid is too viscous and unsuitable for industrialization
Due to the strong odor of hydrogen sulfide and the large environmental pollution, it is not suitable for industrialization

Method used

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  • Preparation method of febuxostat intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Synthesis of p-Hydroxythiobenzamide

[0024] Add 30 g of p-cyanophenol and 500 ml of DMF into a 1 L three-necked flask, stir, add 40 g of 70% sodium hydrosulfide, and react at room temperature for 50 g of magnesium chloride hexahydrate for 24 hours. TLC detection (petroleum ether: ethyl acetate=2: 1) confirms the reaction It was nearly complete, poured into 2L of water under stirring, cooled to 8°C with ice water, extracted with ethyl acetate, spin-dried the solvent and dried to obtain 36.6 g of brown solid, yield 95%, mp.201-202°C.

Embodiment 2

[0026] Synthesis of ethyl 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylate

[0027] Add 113g of 4-hydroxythiobenzamide and ethanol into a 2L four-necked flask, stir and heat to 60°C, stop heating, add 2-ethyl chloroacetoacetate dropwise, continue to reflux for 4 hours after dropping, TLC detection ( Petroleum ether: ethyl acetate = 2:1) to confirm that the reaction was complete, after cooling, it was filtered with suction, washed with 150 mL of ethanol, and dried at 60°C to obtain 155.7 g of a light yellow solid with a yield of 80%. mp.210~211℃.

Embodiment 3

[0029] Synthesis of 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester

[0030] Add 155.7g of ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate and an appropriate amount of acetonitrile into a 2L four-necked flask, stir, add 93g of anhydrous magnesium chloride, and add 124g of paraformaldehyde in batches, Add 310mL of triethylamine dropwise, heat to reflux for 6 hours, TLC detection (petroleum ether: ethyl acetate = 2: 1) confirms that the reaction is nearly complete, after cooling slightly, pour an appropriate amount of water to quench the reaction, dilute hydrochloric acid Adjust the pH to 5-6, add a large amount of water, cool and precipitate the product, filter to obtain a yellow solid, and obtain 163.6 g after drying, with a yield of 95%.

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 2-(3-formoxyl-4-hydroxy phenyl)-4-methyl-thiazole-5-carboxylate as an intermediate of pharmaceutical febuxostat for treating gout; the invention is characterized in that the intermediate is prepared through the reaction of 2-(4-hydroxy phenyl)-4-methyl-thiazole-5-carboxylate and paraformaldehyde under the catalysis of tin tetrachloride. The preparation method avoids the use of trifluoroacetic acid and methenamine as corrosive reagents, the yield of a formylation reaction of the febuxostat and low toxicity paraformaldehyde in acetonitrile can reach more than 95 percent, and the preparation method is easy for industrialization.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the preparation of an important intermediate 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester of febuxostat for the treatment of gout method. Background technique [0002] Febuxostat was developed by Teijin Corporation of Japan. On May 5, 2008, Ipsen Company was approved by the European Union to be listed in France. It is a new type of non-purine xanthine oxidase inhibitor, which is clinically used to treat hyperuricemia (gout) . The main related synthetic methods at home and abroad: [0003] 1 The synthesis process of U.S. Patent US5614520 Febuxostat is as follows: [0004] [0005] This process requires the use of highly toxic potassium cyanide and cuprous cyanide, and the reaction conditions are harsh and difficult to industrialize. Therefore, this route is rarely used in industry and is mostly a small amount of laboratory method. [0006]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56C07C327/48
Inventor 朱雄蒋晓萌张印广殷之武刘嵘周明建施存元
Owner CHINA PHARM UNIV
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