依折麦布及其差向顺式异构体杂质的合成工艺研究  

Study on the synthetic process of ezetimibe and its epimer impurities

作　　者：杨勇 宋志刚 何雷 徐婷 刘学良 吴成军 孙铁民[1] YANG Yong;SONG Zhigang;HE Lei;XU Ting;LIU Xueliang;WU Chengjun;SUN Tiemin(School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China;Jiangsu Hansoh Pharmaceutical Group Co.,Ltd.,Lianyungang 222069,China)

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]江苏豪森药业集团有限公司,江苏连云港222069

出　　处：《中国药物化学杂志》2024年第5期388-397,420,共11页Chinese Journal of Medicinal Chemistry

摘　　要：目的优化依折麦布合成工艺,有利于放大生产;合成依折麦布差向顺式异构体杂质,用于开展质量研究。方法以4-(4-氟苯甲酰基)丁酸为起始原料,经缩合、不对称还原反应得到(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基戊酰基]-4-苯基-1,3-氧氮杂环戊烷-2-酮(14),14与4-苄氧基苯亚甲基-4-氟苯胺(5)发生Mannich反应得到关键中间体3-[(2R)-[(S)-(4-苄氧苯基)-(4-氟苯氨基)-甲基]-5-(4-氟苯基)-(5S)-羟戊酰基]-(4S)-苯基-2-噁唑烷酮(24)及其差向顺式异构体杂质,上述中间体及其差向顺式异构体杂质分别在N,O-双三甲硅基乙酰胺和三水合四丁基氟化铵作用下发生环合反应,依次脱除三甲基硅基和苄基得到依折麦布(1)及其差向顺式异构体杂质。结果与结论所得目标化合物的结构均经MS、^(1)H-NMR和^(13)C-NMR谱确证。优化后的依折麦布工艺已完成3批公斤级放大验证,化学纯度大于99.7%,光学纯度大于99.8%(HPLC法),工艺稳定,适合工业化生产;完成差向顺式异构体杂质的制备,便于定量分析依折麦布异构体含量。The synthetic process of ezetimibe was optimized to make it suitable for large-scale production and the synthesis of cis isomeric impurities were provided for quality research.Starting from 4-(4-fluorobenzoyl)butyric acid,the key intermediate 24 and its cis isomer impurities were synthesized through condensation and asymmetric reduction.The above intermediates underwent cyclization reaction under the action of BSA and TBAF,removing trimethylsilyl and benzyl groups to obtain ezetimibe(1)and its cis isomer impurities.The structures of the target compounds obtained were confirmed by MS,^1H-NMR and ^(13)C-NMR spectra.Ezetimibe has successfully completed three validation batches,three process stability batches,and kilogram scale amplification validation in the cGMP workshop,proving that the process used is stable,with a chemical purity more than 99.7%and an optical purity greater than 99.8%.

关 键 词：依折麦布 MANNICH反应 环合反应 差向顺式异构体 合成 

分 类 号：R914[医药卫生—药物化学]