Z. Bin
2012
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Journal
Chinese Journal of Medicinal Chemistry
Abstract
Febuxostat,an inhibitor of xanthine oxidase,is indicated for use in the treatment of hyperuricemia and gout.A new method was investigated to synthesize the target structure in this paper.Total six steps including cyclization,formylation,dehydration,condensation,hydrolysis and acidification were used to obtain febuxostat.4-Hydroxybenzothioamide was treated with ethyl 2-chloroacetoacetate to give ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate,which was subjected to Duff-Bills reaction to afford ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate(13),followed by dehydration with hydroxylamine hydrochloride to afford ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate(14),which was treated with isobutyl bromide to prepare ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate(7).7 was hydrolyzed and acidified to afford febuxostat with an overall yield of 23%.The above reaction conditions were mild,simple and suitable for scale-up production.