酶法制备克唑替尼关键手性前体及工艺优化  

Enzymatic preparation of key chiral precursor of crizotinib and process optimization

作　　者：方丽研 朱文韬 彭艳 杨宝兴 陆群[1] 赵昱 FANG Liyan;ZHU Wentao;PENG Yan;YANG Baoxing;LU Qun;ZHAO Yu(School of Life Science and Engineering,Southwest Jiaotong University,Chengdu 610031,China;Engineering Laboratory of Development and Utilization of Medicinal Insects and Arachnids Resources in Yunnan Province,Dali 671000,China)

机构地区：[1]西南交通大学生命科学与工程学院,四川成都610031 [2]云南省药用昆虫及蛛形类资源开发利用工程实验室,云南大理671000

出　　处：《发酵科技通讯》2024年第1期21-27,共7页Bulletin of Fermentation Science and Technology

基　　金：国家自然科学基金资助项目(2019G010129);四川省科技支撑计划项目(2015FZ0016)。

摘　　要：利用羰基还原酶NsCRs19不对称催化制备克唑替尼关键手性前体(S)-1-(2,6-二氯-3-氟苯基)乙醇。通过构建羰基还原酶葡萄糖脱氢酶双酶催化体系对2,6-二氯-3-氟苯乙酮进行不对称还原,确定了该催化体系最适反应条件,并对其反应体系进行优化。在温度为(40±2)℃、pH为(7.5±0.5)的条件下,生物酶质量分数约为6%反应24 h即可完全还原质量浓度为165 g/L(约0.8 mol/L)的2,6-二氯-3-氟苯乙酮,转化率>99.2%,收率>93.7%,手性纯度e.e.(s)>99.9%。以生物酶法不对称还原制备克唑替尼关键手性前体,缩短了工艺流程,节约了生产成本,避免了手性拆分,为克唑替尼的化学酶法合成提供了可靠的支持。The key chiral precursor,(S)-1-(2,6-dichloro-3-fluorophenyl)ethan-1-ol,for crizotinib was synthesized asymmetrically using the carbonyl reductase NsCRs19.The asymmetric reduction of 1-(2,6-dichloro-3-fluorophenyl)ethan-1-one by constructing a carbonyl reductase-glucose dehydrogenase dual enzyme catalytic system.The optimum reaction conditions for this catalytic system was determined,and its reaction system was optimized.Under the conditions of(40±2)℃and pH(7.5±0.5),6%biological enzyme reacted for 24 hours completely reducing 165 g/L(about 0.8 mol/L)1-(2,6-dichloro-3-fluorophenyl)ethan-1-one with conversion>99.2%,yield>93.7%and e.e.(s)>99.9%.The use of biocatalysis in the asymmetric reduction process for the synthesis of the key chiral precursor of crizotinib has shortened the manufacturing process,reduced production costs,avoided chiral separation,and provided reliable support for the enzymatic synthesis of crizotinib.

关 键 词：克唑替尼 羰基还原酶 生物催化 工艺优化 

分 类 号：Q554.2[生物学—生物化学]