奈玛特韦手性中间体的合成工艺改进  

Improved Synthetic Process of the Chrial Intermediate of Nirmatrelvir

作　　者：董明明 汤佳伟 陈少欣[2] 张福利[2] 王建博 余俊 DONG Mingming;TANG Jiawei;CHEN Shaoxin;ZHANG Fuli;WANG Jianbo;YU Jun(School of Chemistry and Chemical Engineering,Shanghai University of Engineering Science,Shanghai 201620;Shanghai Institute of Pharmaceutical Industry Co.,Ltd.,China State Institute of Pharmaceutical Industry,Shanghai 201203;Sinopharm Group Co.,Ltd.,Beijing100077)

机构地区：[1]上海工程技术大学化学化工学院,上海201620 [2]中国医药工业研究总院上海医药工业研究院有限公司,上海201203 [3]国药控股有限公司,北京100077

出　　处：《中国医药工业杂志》2023年第8期1187-1192,共6页Chinese Journal of Pharmaceuticals

基　　金：科技部国家重点研发计划“绿色生物制造”项目(2021YFC2102100)。

摘　　要：文章对合成奈玛特韦的手性中间体(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯(1)盐酸盐的合成工艺进行了改进。以6,6-二甲基-3-氧杂双环[3.1.0]己烷-2,4-二酮(2)为起始原料,与脲发生氨化反应生成6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮(9)。9经过还原反应制得6,6-二甲基-3-氮杂双环[3.1.0]己烷(5),5经过含有单胺氧化酶AtMAON-M12的工程菌催化氧化,立体选择性地生成(1R,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烯(6),6再经加成、氰化、Pinner反应后成盐制得1盐酸盐,纯度99.9%,ee值大于99.9%,总收率达60.5%。利用单胺氧化酶AtMAON-M12合成单一构型的化合物6,不需要拆分,符合绿色化学的原子经济性原则。In this paper,the synthesis process of a key chrial intermediate of nirmatrelvir,named methyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate(1)hydrochloride was improved.Compound 6,6-dimethyl-3-oxobicyclo[3.1.0]hexane-2,4-dione(2)was used as the starting material to synthesize 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione(9)by ammoniation with urea.Compound 6,6-dimethyl-3-azabicyclo[3.1.0]-hexane(5)was synthesized from 9 by reduction.Compound(1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexene(6)was stereoselectively synthesized from 5 via oxidation by the engineered bacteria containing monoamine oxidase AtMAON-M12.Compound 1 hydrochloride was obtained from 6 with purity of 99.9%and enantiomeric excess up to 99.9%by addition,cyanidation,Pinner reaction and salification,while the total yield reached 60.5%.The single enantiomer 6 was obtained by using monoamine oxidase AtMAON-M12 without resolution,which conformed to the green chemistry principle of atom economy.

关 键 词：奈玛特韦 中间体 单胺氧化酶 工艺改进 

分 类 号：R978.7[医药卫生—药品] TQ460.6[医药卫生—药学]