抗痛风药非布索坦的合成工艺研究  

Improved synthesis of antipodagri febuxostat

作　　者：解鹏[1] 张瑾[1] 金华[1] 李建其[1] 周斌[1] 

机构地区：[1]上海医药工业研究院,上海药物合成工艺过程工程技术研究中心,上海200437

出　　处：《中国药物化学杂志》2012年第5期369-372,共4页Chinese Journal of Medicinal Chemistry

摘　　要：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。Febuxostat, an inhibitor of xanthine oxidase, is indicated for use in the treatment of hyperuricernia and gout. A new method was investigated to synthesize the target structure in this paper. Total six steps in- cluding 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 hydroxyla- mine 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-thia- zolecarboxylate （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.

关 键 词：非布索坦 抗痛风药物 黄嘌呤氧化酶抑制剂 合成 

分 类 号：R914[医药卫生—药物化学]