基于反应萃取的高速逆流色谱手性分离新技术

Chirality is a hot topic of scientific community and is at the frontier of the scientific field. Researching and developing technology for chiral separation is of much significance in science. High-speed counter-current chromatograph (HSCCC) is a modern chromatographic separation and preparation technology. This project develops a new technology for chiral separation by combining HSCCC with the chiral reactive extraction, which can take the advantage of the high enantioselectivity of the chiral reactive extraction and will be used for resolution of aromatic acid enantiomers. A series of efficient β-cyclodextrin and tartrate chiral selectors will be designed and prepared based on the theory of chiral match between the selectors and the enantiomers. The solvent systems will be screened according to the polar match between enantiomers (selectors) and the solvent. By combining with the mathematical modeling and optimization, high efficient reactive extraction systems will be established. On this basis, methods of HSCCC separation of enantiomers will be built, the factors influencing the separation process will be investigate and mechanism of HSCCC separation of enantiomers will be studied on. Based on the reactive extraction model, taking into account equilibrium relations and mass balance, mathematical model will be established for modeling the process of HSCCC separation of enantiomers. Multiobjective optimization of the process will be performed by programing on the software platform of Matlab. Through the research of this project, a new and efficient technology for chiral separation will be obtained, which will provide technical parameters for separation and preparation of aromatic acids enantiomers and provide theoretical basis for expanding the applied range of HSCCC technology for chiral separation.

手性是当今科学界的前沿和热点之一，研究和开发高效手性分离技术具有重要科学意义。高速逆流色谱(HSCCC)是一种现代色谱分离制备技术。本项目基于手性反应萃取高的立体选择性，提出高速逆流色谱手性分离新技术，对芳香酸对映体进行分离研究。基于手性选择体与对映体的手性匹配原理，设计和制备高效的β-环糊精类和酒石酸酯类手性选择体；依据手性选择体与对映体极性匹配，确定溶剂系统；结合反应萃取数学模型模拟和优化，构建反应萃取体系。在此基础上，建立HSCCC手性分离方法，考察分离过程的影响因素，研究HSCCC手性分离机理。以反应萃取数学模型为基础，结合体系平衡关系和物料衡算，建立HSCCC手性分离数学模型；运用Matlab设计程序，对HSCCC手性分离过程进行多目标优化研究。通过本项目的研究将获得一种新型高效手性分离技术，为分离芳香酸对映体提供技术参数，并为HSCCC手性分离技术进一步拓展应用提供理论基础。

本项目将双相识别手性萃取、β-环糊精包合反应萃取等手性萃取技术的基本原理应用于高速逆流色谱(HSCCC)分离过程，获得了一种基于反应萃取的高速逆流色谱制备性手性分离新技术。基于手性匹配的原理，制备和筛选了一系列基于β-环糊精和酒石酸酯的手性选择剂；建立了对映体在两相体系的分配平衡模型，基于实验和模型研究了分离过程的重要参数如温度、手性选择剂浓度、水相pH值等重要因素对分配性能的影响，通过模拟和优化获得两相体系的最佳条件；在此基础上进行手性药物及其中间体的HSCCC手性分离。研究发现，通过本项目对两相体系优化，提高过程的本质分离推动力，从而显著提高了的HSCCC过程的分离效率。同时，为了实现某些难分离对映体的制备性分离，将闭路循环洗脱模式的应用于HSCCC过程进一步提高了分离能力，拓展了HSCCC技术的应用范围。基于以上理论和实践成果，实现了苯基琥珀酸、2-苯基丁酸、3氯地平、奥昔布宁、非尼拉敏等10余种对映体制备性分离，得到的对映体单体纯度均大于98.5%，单体回收率在90%左右，具备较好的应用潜力。将数学模型应用于高速逆流色谱分离过程，大大减少分离过程的开发时间和实验工作量，同时优化结果更具可靠性。