摘要
本文在醋酸乌利司他现有合成路线的基础上,选择以双缩酮(22)为起始物料,通过环氧化、格氏反应、水解和乙酰化反应合成醋酸乌利司他(1)。鉴于路线工艺控制相关文献报道较为有限,本研究通过精确控制反应温度提高环氧化选择性,优化格氏反应温度和确定磷酸氢二钾为最佳水解反应试剂,从而有效提高产品纯度。最终建立了有效质量控制策略,成品液相单杂纯度小于0.10%,液相纯度达到99%以上,符合原料药质量标准。该工艺操作简单、稳定性高,已完成中试生产,为工业化应用提供技术支持。
This article systematically reviews the existing synthetic routes of ulipristal acetate and selects diketone as the starting material to prepare ulipristal acetate through epoxidation,Grignard reaction,hydrolysis,and acetylation.Given the limited literature reports on process control related to this route,this study significantly improved product quality by optimizing reaction conditions.Specifically,the selectivity of epoxidation was enhanced by precisely controlling the reaction temperature,and the purity of the product was effectively increased by optimizing the temperature of the Grignard reaction and identifying potassium hydrogen phosphate as the optimal hydrolysis conditions.A comprehensive quality control strategy was ultimately established,with the final product exhibiting a single impurity of less than 0.10%in liquid chromatography and a purity of over 99%,fully meeting the quality standards for active pharmaceutical ingredients.The optimized process is simple to operate,highly stable,and has been successfully scaled up to pilot production,providing reliable technical support for industrial applications.
作者
夏志强
汪玉琳
李岩
罗剑
姚倩
邹辉
杜乐
XIA Zhiqiang;WANG Yulin;LI Yan;LUO Jian;YAO Qian;ZOU Hui;DU Le(College of Pharmacy,Hunan Normal University,Changsha 410000,China;Changsha Jingyi Medical Technology Co.,Ltd.,Changsha 410000,China;School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Benxi 117004,China;Ordos Central Hospital,Ordos 017000,China)
出处
《合成化学》
2026年第2期121-130,共10页
Chinese Journal of Synthetic Chemistry
关键词
醋酸乌利司他
紧急避孕药
环氧化反应
格氏反应
杂质研究
ulipristal acetate
emergency contraceptive pill
epoxidation reaction
grignard reaction
impurity research
