2-（3-氰基－4-羟基）苯基－4-甲基－5-噻唑甲酸乙酯的合成

Objective To optimize the synthetic method of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate(4), a key intermediate for the synthesis of febuxostat. Methods 4-Hydroxy-benzonitrile was treated with sodium hydrogen sulfide and anhydrous magnesium chloride in dimethylformamide to give thioamide, which was then directly cyclized with ethyl 2-chloroacetoacetate without separation to give ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate(2) in one-pot;then 2 was formylated with Duff reaction adopting hexamethylenetetramine in trifluoroacetic acid to give ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (3); finally, the target compound was obtained by the treatment of 3 with hydroxylamine hydrochloride and sodium formate in formic acid. Results The key intermediate 4 for the synthesis of febuxostat was synthesized via a four-step procedure in a total yield of 22.6% and its structure was confirmed by 1H-NMR and ESI-MS. Conclusions The improved process does not need column chromatography to purify and the end product is very suitable for industrial preparation.