来瑞特韦关键原料SMA-1的手性异构体的制备与结构鉴定  

Preparation and structural identification of the chiral isomers of SMA-1,the key starting material of leritrelvir

作　　者：李波 刘呈武 黎志豪 王李 姜文浩 LI Bo;LIU Cheng-wu;LI Zhi-hao;WANG Li;JIANG Wen-hao(Technology Development Department,Guangdong Zhongsheng Raynovent Biotechnology Co.,Ltd.,Guangzhou 510700,China)

机构地区：[1]广东众生睿创生物科技有限公司工艺开发部,广东广州510700

出　　处：《中国药物化学杂志》2023年第12期904-909,共6页Chinese Journal of Medicinal Chemistry

摘　　要：目的对来瑞特韦关键原料SMA-1的手性异构体杂质进行研究。方法以环戊烯(1)为起始原料,经加成、消除、环合、取代、氢化加成、消除、手性拆分、成盐反应得到SMA-1-A和SMA-1-B。以3-氮杂双环[3.3.0]辛烷盐酸盐(10)为起始原料,经氧化、加成、水解、手性拆分、成盐反应得到SMA-1-C。结果3个手性异构体杂质的结构均经1H-NMR、13C-NMR、ESI-MS、XRD、DSC谱确证。结论3个手性异构体杂质的纯度均达到95%(HPLC)以上,可用作来瑞特韦原料药和制剂质量控制的杂质对照品,通过从源头控制SMA-1异构体杂质的含量,可进一步确保来瑞特韦原料药工艺的合理性。For the quality control of the active pharmaceutical ingredient and drug production of leritrelvir,three chiral isomers of the key starting material SMA-1 were synthesized.With 1,3-cyclopentadiene as the starting material,the impurities SMA-1-A and SMA-1-B were obtained by addition,elimination,ring closing,substitution,hydrogenation addition,elimination,chiral resolution,salt formation reaction.With 3-azabicyclo[3.3.0]octane hydrochloride as the starting material,the target impurity SMA-1-C was prepared through oxidation,addition,hydrolysis,chiral resolution,salt formation reaction.The structures of target chiral isomers were confirmed by 1H-NMR,13C-NMR,ESI-MS,XRD and DSC detections.The purities of the chiral isomers were up to 95%(HPLC)and they can be used as the impurity reference for the quality control of leritrelvir drug impurities and drug product.

关 键 词：来瑞特韦 SMA-1 手性异构体杂质 手性拆分 

分 类 号：R914[医药卫生—药物化学]