克唑替尼关键中间体(S)-1-(2,6-二氯-3-氟苯基)乙醇的不对称合成  

Synthesis of Crizotinib Key Intermediate (S)-1-(2,6-Dichloro-3-fluorophenyl) ethanol

作　　者：张杰[1] 李国贤[1] 乔萍[1] 罗宏军 梁文[1] 薛涛[1] 

机构地区：[1]扬子江药业集团有限公司,江苏泰州225300

出　　处：《合成化学》2017年第9期779-783,788,共6页Chinese Journal of Synthetic Chemistry

摘　　要：(S)-1-(2,6-二氯-3-氟苯基)乙醇(2)是合成抗癌药物克唑替尼的关键手性前体。本文以1-(2,6-二氯-3-氟苯基)乙酮为起始原料,利用二异松莰基氯化硼[(-)-Ipc_2BCl]不对称还原制得光学纯的2;并将中间体2经Mitsunobu反应、还原、溴代、Suzuki偶联及脱除Boc保护合成克唑替尼,其结构~1H NMR,^(13)C NMR和HR-MS(ESI)确证。对关键中间体2的合成条件进行了优化,并其对反应机理进行了推测。Using （ - ）-Ipc2 BCl as the chair reduction agent, corresponding chiral precursor of Crizo- tinib. （S） -1 - （2,6-diehloro-3-fluorophenyl） ethanol （2） was yielded by asymmetric reduction from 2, 6-dichloro-3-fluro acetophenone. Based on key intermediate 2, Crizotinib was synthesized. The process included Mitsunobu reaction, reduction of an arylnitro group, bromination reaction, Suzuki coupling and Boc deproteetion. The strueture of target eompound was confirmed by ^1H NMR, 13C NMR and HR-MS（ESI）. The synthetic process of key intermediate 2 was optimized and the possible reaction mechanism was proposed.

关 键 词：2 6-二氯-3-氟苯乙酮 (S)-1-(2 6-二氯-3-氟苯基)乙醇 克唑替尼 二异松莰基氯化硼 不对称 还原 药物合成 

分 类 号：R914.5[医药卫生—药物化学] O621.3[医药卫生—药学]