Corey内酯的酶法拆分与手性诱导加成反应制备重大手性药物关键中间体的机理及其应用研究

抗乙肝病毒药物恩替卡韦和前列腺素类药物是重大临床一线药物，年销售总和超过100亿元，有广泛的临床需求。多手性中心Corey内酯二醇是其关键中间体。本项目研究脂肪酶与底物Corey内酯手性选择性的识别规律和催化反应动力学规律，建立不对称水解动力学拆分的高效反应体系；研究脂肪酶固定床催化反应—逆流萃取分离耦合、副产物异构体资源化利用等新技术；研究Corey内酯的Prins反应手性诱导机理和调控，构建了一种手性诱导反应和重结晶纯化耦合的新策略。本项目拟突破原有工艺中的化学拆分和手性诱导反应的效率不高，异构体杂质分离纯化困难等关键产业化技术瓶颈问题，实现关键手性中间体手性Corey内酯二醇的高效制备，工艺成本有突破性降低。本项目通过反应分离耦合机理研究，为重大药物品种恩替卡韦和前列腺素类药物的化学制药工艺路线创新和重大改进提供技术和理论储备，是“需求牵引、突破瓶颈”的典型案例。

Antihepatitis B drugs entecavir and prostaglandins are major clinical first-line drugs, with an annual total sales more than 10 billion yuan, which have a wide range of clinical needs. Corey lactone diol is the key intermediate and the key source of core pharmacodynamic group fragment. In this project, we would study the recognition rule of chiral selectivity between lipase and substrate Corey lactone and the kinetic rule of catalytic reaction, and would establish an efficient reaction system of asymmetric hydrolysis kinetic resolution.We would establish the coupling of lipase fixed bed catalytic reaction and countercurrent extraction separation, and utilization of by-product isomer.We would study the mechanism and regulation of chiral induction of PRINS reaction of Corey lactone. A new coupling strategy of chiral induction reaction and recrystallization purification would be constructed. This project intends to break through the bottleneck problems of key industrialization technologies, such as the low efficiency of chemical resolution and chiral induced reaction in the original process, and the difficulty of purifying isomeric impurities, so as to realize the efficient preparation of the key chiral intermediate, Corey lactone diol, with a breakthrough reduction in process cost. Through the study of reaction separation coupling mechanism, this project provides technical and theoretical reserves for the innovation and major improvement of process route of major drug entecavir and prostaglandins. there is a typical case of "demand traction and breakthrough bottleneck".