抗痛风药非布索坦的合成

Synthesis of Antipodagra Febuxostat

摘要:

以4-羟基苯甲腈为原料，经烷基化、溴代、硫代甲酰化、环合、氰基化反应、水解制得抗痛风药非布索坦（1）。改进后的工艺采用氯化锂促进的硫代甲酰化反应，条件温和、反应时间较短，并且避免强酸的使用。氰基化反应采用痕量的醋酸钯为催化剂，无需无水无氧操作，且利用无毒的亚铁氰化钾作为氰基来源，避免了剧毒氰化物的使用。路线总收率达到64.3 %。目标化合物及中间体的结构经熔点、1H NMR、13C NMR 和ESI-MS 确认。

Abstract:

Febuxostat was synthesized from 4-hydroxybenzonitrile via alkylation，bromination，thioformylation，cyclization，cyanation，and hydrolysis. In the improved process，a LiCl-promoted thioformylation needed less time as well as avoided the use of strong acidic conditions. With the catalysis of trace Pd(OAc)2，a cyano group was smoothly installed in the presence of K4[Fe(CN)6] without anhydrous anaerobic operation. Non-toxic K4[Fe(CN)6] was used advantageously compared to toxic cyanide sources. The total yield was as high as 64.3 %．The structure was confirmed by melting point，1H NMR，13C NMR and ESI-MS.