目的 对安立生坦合成工艺的改进进行研究。方法 以二苯甲酮为起始原料,经过缩合、醇解、水解、拆分和取代反应合成安立生坦。醇解采用盐酸进行反应,采用拆分剂盐酸盐和碱试剂通过“一锅法”进行拆分。结果 优化了醇解和拆分反应,避免了高毒性物质的产生;优化后,安立生坦的质量分数为99.7%,光学纯度达99.8%,工艺的总收率为30.0%。结论 安立生坦的合成工艺改进后操作性好,条件温和,避免产生基因毒性和其他高毒性物质,成本较低,更适于药品的工业化生产。

Objective To study the improved method for synthesis of ambrisentan. Methods Benzophenone was used as starting material to synthesize the target compound by condensation, alcoholysis, hydrolysis, resolution, and substitution reactions. Hydrochloric acid was used in alcoholysis reaction, and resolving agents hydrochloride and alkali were used in resolution reaction by “one pot” method. Results Alcoholysis and resolution reactions were optimized, avoiding the production of highly toxic substances. After optimization, the purity was 99.7%, and the optical purity was 99.8%. The total recovery of the synthetic route was 30.0%. Conclusion After optimization, the synthetic process of ambrisentan has the advantage of simple operation, mild condition, avoiding gene toxic reagent and other toxic reagent, with low cost, and is suitable for industrial production of drugs.