AZD0914关键中间体(2R,6R)-2,6-二甲基吗啉的合成工艺研究  

Study on The Synthesis Process of AZD0914 Key Intermediate(2 R,6 R)-2,6-Dimethylmorpholine

作　　者：雷响 张银勇 张丹 赵文豪 孟昕 杨玉社 LEI Xiang;ZHANG Yinyong;ZHANG Dan;ZHAO Wenhao;MENG Xin;YANG Yushe(School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China)

机构地区：[1]南京中医药大学新中药学院,江苏南京210023 [2]中国科学院上海药物研究所,上海201203

出　　处：《合成化学》2022年第12期937-944,共8页Chinese Journal of Synthetic Chemistry

基　　金：国家科技重大专项项目(2018ZX09711002-006-010)。

摘　　要：(2 R,6 R)-2,6-二甲基吗啉(1)为合成新型细菌II型拓扑异构酶抑制剂AZD0194(Zoliflodacin)的关键中间体。本文以(S)-2-羟基丙酸乙酯(12)为原料,经三氟甲磺酰化、S_(N)2反应、硼氢化钠还原、对甲苯磺酰化、环合、成盐、催化氢解、游离和蒸馏提纯等步骤,成功合成了化合物1。经过对合成路线中反应条件及提纯方法的优化,以6步反应且总收率为32%获得化合物1。(2 R,6 R)-2,6-Dimethylmorpholine(1)is a key intermediate for the synthesis of a novel bacterial type II topoisomerase that inhibits AZD0194(Zoliflodacin).Employing(S)-2-hyd-roxypropionic acid ethyl ester(12)as the starting material,the key intermediate 1 was obtained through the sequential operations of triflation,S_(N)2 reaction,reduction by sodium borohydride,tosylation,cyclization,catalytic hydrogenolysis,release of amine,and distillation.The reaction conditions and purification methods in the synthetic route were optimized,and the total yield was 32%.

关 键 词：拓扑异构酶抑制 AZD0914 关键中间体 (2R 6R)-2 6-二甲基吗啉 工艺改进 合成 

分 类 号：O62[理学—有机化学] R914.5[理学—化学]