Multistep continuous flow synthesis of Erlotinib

作     者：Hui Jin Qin Cai Peiwen Liu Yan Chen Derong Wang Weiping Zhu Yufang Xu Xuhong Qian Hui Jin;Qin Cai;Peiwen Liu;Yan Chen;Derong Wang;Weiping Zhu;Yufang Xu;Xuhong Qian

作者机构：State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Chemical BiologySchool of PharmacyEast China University of Science and TechnologyShanghai 200237China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2024年第35卷第4期

页      面：371-375页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 

基　　金：the National Natural Science Foundation of China(Nos.21878088, 21476077) Key Projects of Shanghai Science and Technology Commission (No.18DZ1112703) for financial support 

主　　题：Erlotinib Continuous flow synthesis Microchannel flow reactor Process optimization Continuous nitration Continuous hydrogenation 

摘      要：Erlotinib is an orally administered, highly effective, specific epidermal growth factor receptor tyrosine kinase inhibitor, used to treat non-small cell lung cancer and pancreatic cancer. The traditional synthetic methods for Erlotinib exhibit long reaction time and safety concern. Herein, we describe a novel five-step route for the synthesis of Erlotinib in flow. These five steps comprise etherification, nitration, reduction,addition and cyclization reactions. All steps were optimized and converted to continuous flow process,which drastically reduces the reaction time and considerably improves the process safety as well as the total yield. Enabled by five continuous flow units, Erlotinib is efficiently afforded with an E-factor of 38,an overall yield of 83%, and a total residence time of 25.1 min. Majority steps in this process have been optimized for quantitative conversion, which offers the possibility of telescoping the entire process.