摘要
拉罗替尼为第一代神经营养因子酪氨酸激酶受体(TRK)抑制剂,具有广谱抗癌效果,但其用药价格非常昂贵,根本原因之一在于其关键手性片段(R)-2-(2,5-二氟苯基)吡咯烷的生产成本极高,通过研究新的工艺路线达到降低其生产成本为该药物研发的重要课题。为此,本论文设计了(R)-2-(2,5-二氟苯基)吡咯烷的全新合成路线,即以廉价的2,5-二氟甲苯为起始原料,经氧化得到中间体1,经酯化生成中间体2,后经亲核取代、酸解、脱羧和环合一步法得到中间体3,经还原得到消旋化物中间体4,再经化学拆分得到手性胺目标物,总收率为23%,该工艺路线避免了使用昂贵的原材料和试剂如手性诱导试剂、低温和无水无氧环境,更适合(R)-2-(2,5-二氟苯基)吡咯烷的产业化。
Larotrectinib,which is the first generation of TRK inhibitor,shows broad and excellent anticancer activity.But the cost for using Larotrectinib in clinic is very expensive.One of the main reason is that the production cost for the key chiral intermediate,([WT5"BX]R)-2-(2,5-difluorophenyl)pyrrolidine,is very high.Therefore,it is an important theme to explore new synthetic route to reduce its cost of production.In this paper,we reported a new synthetic process to prepare([WT5"BX]R)-2-(2,5-difluorophenyl)pyrrolidine.2,5-Difluorotoluene as starting material was oxidized to produce intermediate 1.Following by esterification of intermediate 1 to yield intermediate 2.The intermediate 3 was obtained by one pot reaction including nucleophilic substitution,acidolysis,and decarboxylation.Chiral amines were obtained by chemical resolution of the reduction product of intermediate 3.The total yield of this synthetic route is 23%.This synthetic route,which avoids expensive raw materials,low temperature,anhydrous and oxygen-free environment,is more suitable for the production of([WT5"BX]R)-2-(2,5-difluorophenyl)pyrrolidine.
作者
裴超
陈玉琴
吴筱斐
柴文静
杨爱青
王磊磊
刘团伟
魏金建
孙洪宜
张志德
Pei Chao;Chen Yuqin;Wu Xiaofei;Chai Wenjing;Yang Aiqing;Wang Leilei;Liu Tuanwei;Wei Jinjian;Sun Hongyi;Zhang Zhide(Zhonghan(Qihe County)Bio-Pharmaceutical Technology Co.,Ltd.,Dezhou 251114,China;College of Chemistry,Chemical Engineering and Materials Science,Shandong Normal University,Jinan 250014,China;Ecology Institute of Shandong Academy of Sciences,Shandong Province Key Laboratory of Applied Microbiology,Qilu University of Technology(Shandong Academy of Sciences),Jinan 250014,China)
出处
《山东化工》
CAS
2023年第22期22-25,共4页
Shandong Chemical Industry
基金
山东省科技型中小企业创新能力提升工程项目(No.2021TSGC1293)
山东省教育厅科技计划项目(No.J02C01)
大学生创新创业训练计划(No.2022150204)资助。
关键词
TRK抑制剂
拉罗替尼
手性胺
医药中间体
合成工艺
TRK inhibitor
larotrectinib
chiral amine
chemical intermediate
synthetic process
