第四代表皮生长因子抑制剂TQB3804合成工艺研究  

Synthesis Process Research of the Forth-Generation EGFR-TKIs TQB3804

作　　者：桂豫乐 王杰 唐春雷 GUI Yule;WANG Jie;TANG Chunlei(School of Life Science and Health Engineering,Jiangnan University,Wuxi 214112,China)

机构地区：[1]江南大学生命科学与健康工程学院,无锡214122

出　　处：《化工时刊》2024年第5期15-20,113,共7页Chemical Industry Times

摘　　要：本研究在现有专利和文献的基础上对第四代表皮生长因子抑制剂TQB3804(1)的合成工艺进行了优化。以价廉易得的2-甲硫基-4-氯-5-溴嘧啶(17)、6-氨基喹喔啉(6)和3-氟4-甲基苯酚(19)为起始原料,经氧化、碘代、亲核取代、催化还原、C-N偶联等反应得到目标产物TQB3804(1)。经工艺优化后,TQB3804的总收率为41.1%(以化合物19计),HPLC纯度为99.4%(面积归一化法)。目标物的结构经HRMS、1H-NMR确证。此路线缩短了原研专利路线的合成步骤,提高了反应选择性,后处理操作更简单,反应条件更温和,经济和环境效益更高。本研究可为TQB3804(1)及其衍生物的合成提供理论参考。In this study,the synthesis process of TQB3804(1)was optimized on the basis of existing patents and literature.The target TQB3804(1)products were obtained by oxidation,iodine,nucleophilic substitution,catalytic reduction,C-N coupling and other reactions with 2-methylthio-4-chloro-5-bromopyrimidine(17),6-aminoquinoxaline(6)and 3-fluoro-4-methylphenol(19)as starting materials.After process optimization,the total yield of the TQB3804 was 41.1%(calculated based on compound 19)and the HPLC purity was 99.4%(area normalized method).The structure of the target products was confirmed by HRMS and 1H-NMR.This route shortens the synthesis step of the original patented route,improves the regioselectivity of the reaction,makes the post-processing operation simpler,the reaction conditions are milder,and the economic and environmental benefits are higher.This study can provide a theoretical reference for the synthesis of TQB3804(1)and its derivatives.

关 键 词：TQB3804 合成工艺优化 第四代 EGFR-TKIS 非小细胞肺癌 C797S 突变 

分 类 号：TQ463[化学工程—制药化工]