2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯的合成

Synthesis of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate

目的优化非布司他关键中间体2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(4)的合成方法。方法采用"一勺烩"方法,以4-羟基苯甲腈为起始原料,首先与硫氢化钠和无水氯化镁在N,N-二甲基甲酰胺中反应,所得中间体不经分离,直接加入2-氯乙酰乙酸乙酯进行环合反应,得到2-(4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(2);然后通过六亚甲基四胺/三氟乙酸进行Duff反应,得到2-(3-甲酰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(3);再经盐酸羟胺/甲酸/甲酸钠体系脱水得到目标化合物。结果经四步反应合成非布司他关键中间体4,总收率为22.6%,其结构经核磁共振氢谱、质谱确证。结论改进后的工艺终产品无需柱色谱纯化,适合工业化生产。

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.