立体选择性酶催化-离心逆流萃取耦合连续拆分对映体过程研究

Large scale preparation of enantiopure compounds is a significant research area in chemical industry, pharmaceuticals industry and other related fields. This project proposes a new technique by combining the stereo-selective enzyme catalysis which possesses the advantages of high selectivity, mild condition, being environment-friendly, and centrifugal counter-current extraction which possess the advantages of strong separation ability, low energy consumption, being easy in scaling-up and continuous production. The technique couples the reaction and separation process and can be applied to continuous resolution of enantiomers. The reaction system with esters and amides as substrate is screened and modified to obtain the reaction system which can produce multiple valuable and enantiopure compounds. Thermodynamics and kinetics are studied for reaction and separation processes, mathematical model is established for simulation and optimization of the reaction and separation processes, and optimized reaction system and separation system is obtained. Based on the above research, the equipment is designed and their parameters are optimized. The reaction-separation coupling process is then established. The whole process is simulated and optimized on the Aspen plus software platform to obtain the optimized technological parameters. Several substrates are resolved by the optimized process. The studied technique can achieve green utilization of the substrates. The reaction can overcome the limitation of reactive thermodynamics by removing the product quickly from the reaction system through the centrifugal counter-current extraction process, which will make the resolution of enantiomers continuous and efficient. The project provides a new technical proposal and the theoretical basis for large scale preparation of enantiopure compounds.

手性纯化合物的规模化制备在化工、制药等领域是一个重要研究方向。本项目利用立体选择性酶催化反应选择性高、条件温和、环境友好以及离心萃取分离能力强、能耗低、易于工业放大和连续化生产等优势，提出一种新的反应-分离耦合对映体连续拆分技术。以外消旋酯类或酰胺类等化合物为底物，通过反应体系的筛选和改进，获得具有多产高值手性纯化合物应用潜力的反应体系；研究反应和分离过程热力学及动力学，并构建数学模型对反应和分离体系进行模拟和优化，获得最佳反应和分离体系；在此基础上研究设备设计和参数优化，构建反应-分离耦合体系，基于Aspen plus软件平台对全过程进行模拟和优化，获得最佳工艺参数，并完成多种底物的拆分。本项目将实现底物的绿色化利用，并利用离心逆流萃取过程使产物迅速移出反应体系，突破反应的热力学限制，实现手性拆分连续化和高效化，为手性纯化合物的规模化制备提供一种新的技术和理论基础。

针对光学纯化合物制备，本项目利用酶催化反应立体选择性高、条件温和、环境友好等优势，构建了酶催化立体选择性水解芳香酸酯，非水溶液立体选择性酯化拆分芳香酸、非水溶液立体选择性酯交换拆分羟基酸等新型动力学拆分体系，完成了一系列芳香酸(含芳香丙酸、丁酸等)、羟基酸等对映体高效手性拆分。针对水解反应体系底物溶解度低，催化活性低等问题，提出了包合增溶法、表面活性剂添加法等，显著提高了催化活性。基于立体选择性酶催化机理的深入研究，构建了水相增溶体系内酶催化水解动力学拆分全过程定量数学模型、多相液滴传质酶催化水解动力学拆分模型、非水溶液体系酶催化酯交换动力学拆分模型等新型数学模型，能准确模拟复杂反应过程。利用MOF材料特殊的结构与性能制备了一系列MOF载体固定化酶，研究了酶表面和载体表面改性，提高了酶的活性，并且强化了酶的稳定性，固定化酶具有较好的循环使用性能，可解决游离酶工业应用中不稳定、难以回收、影响产品纯度等难题。进行了立体选择性酶催化-离心逆流萃取耦合连续拆分对映体新技术研究，构建了过程数学模型，初步验证了技术的可行性。以上研究为酶法动力学拆分过程优化和工业应用提供了理论和技术参考。