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目的研究非布索坦的合成工艺。方法 4-羟基硫代苯甲酰胺与2-氯乙酰乙酸乙酯经环合制得2-(4-羟基苯基)-4-甲基-5-噻唑甲酸乙酯(12),12经Duff-Bills反应得到2-(4-羟基-3-甲酰基苯基)-4-甲基-5-噻唑甲酸乙酯(13),13与盐酸羟胺经高温脱水得到2-(3-氰基-4-羟基苯基)-4-甲基-5-噻唑甲酸乙酯(14),14与溴代异丁烷缩合制得2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸乙酯(7),最后经碱水解、酸中和制得非布索坦(1)。结果与结论目标化合物的结构经1H-NMR、MS谱等确证,总收率为23%(以4-羟基硫代苯甲酰胺计)。改进后的成本约为每千克2.5万元,反应操作简单,更适合于工业化生产。
Objective To study the synthesis of febuxostat. Methods Ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate (12) was prepared by cyclization of 4-hydroxythiobenzamide and ethyl 2-chloroacetoacetate. -Bills to give ethyl 2- (4-hydroxy-3-formylphenyl) -4-methyl-5-thiazolecarboxylate (13), dehydration of 13 with hydroxylamine hydrochloride at elevated temperature gives 2- (3- (14), 14 is condensed with bromoisobutane to give 2- (3-cyano-4-isobutyloxyphenyl) - 4-hydroxyphenyl) Methyl 4-methyl-5-thiazolecarboxylate (7), and finally alkali hydrolysis, acid neutralization febuxostat (1). Results and Conclusions The structure of the target compound was confirmed by 1H-NMR and MS spectra. The overall yield was 23% (based on 4-hydroxythiobenzamide). The improved cost is about 25,000 yuan per kilogram, the reaction is simple, more suitable for industrial production.