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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(Ⅰ)。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、1HNMR、13CNMR和ESI-MS确认。
Using 4 - hydroxybenzonitrile as raw material, we obtained the antifoam drug (Ⅰ) by alkylation, bromination, thioformylation, cyclization, cyanation and hydrolysis. The improved process uses lithium chloride promoted thioformylation reaction, mild conditions, shorter reaction time, and to avoid the use of strong acids. Cyanation reactions using traces of palladium acetate as a catalyst, without the need for anhydrous and anaerobic operation, and the use of non-toxic potassium ferrocyanide as a source of cyanogens to avoid the use of highly toxic cyanide. Route total yield reached 64.3%. The structures of the target compounds and intermediates were confirmed by melting point, 1 HNMR, 13CNMR and ESI-MS.