Fischer吲哚反应工艺优化和过程强化的研究

Fischer indole reaction is one of the most important reactions of indole compounds, and is widely used in the syntheses of antimigraine triptans, major tranquilizers 5-hydroxy- tryptamine, and so on. However, due to severe reactants mass returning and mixing in traditional batchwise reactors, a series of successive side reactions occur resulting in difficult separation and purification, and low yields. These problems can not be effectively solved via adjustment of reaction parameters such as temperature, time, and concentration. This proposal aims at developing novel tubular Fischer reaction process and solving the common problems associated with batchwise reactors, through studying the relationships between main and side reactions, constructing kinetic models, studying the variations and corrections of the kinetic models, guiding optimization of Fischer reaction conditions, and finally guiding the design of the high pressure tubular reactor. In the end, the present study hopes to develop a thereotical system for the research and development of Fischer reaction with optimized conditions and intensified processes.

Fischer吲哚反应是制备吲哚类衍生物的重要反应之一，广泛用于曲坦类抗偏头痛药物、抗精神分裂症药物5-羟色氨等药物的生产中，但传统的釜式反应因为物料返混，引发大量串联式副反应、导致分离纯化困难、产品收率低等问题，仅仅通过调整反应温度，时间，浓度等参数都无法有效解决上述难题。本项目拟通过研究Fischer吲哚主副反应之间的关系，建立动力学模型，通过检查参数变式与校正，指导优化Fischer吲哚反应条件，然后以动力学研究数据指导高压管式反应器设计，开发Fischer吲哚反应新工艺，解决釜式反应器普遍存在的问题。最终形成一种Fischer吲哚反应工艺优化和过程强化的研究开发体系。

吲哚类化合物作为重要的N-杂环化工原料，在合成除草剂，杀真菌剂、染料和防腐剂等方面有着广泛的应用。然而由于吲哚合成过程复杂，条件苛刻（长时间高温），同时副反应多导致产率低下以及提纯过程繁琐。连续流技术为近年新兴的一类可精准控制、安全、连续化过程强化工艺。由于传质速度快，反应物在流动的过程中短时间内即可充分混合，而且，由于连续流反应器的比表面积大，具有很高的热交换效率，可以将释放的反应热及时转移，维持反应温度在安全范围以内。本项目针对Fischer法合成7-乙基吲哚及其衍生物过程中产率低，后处理复杂等问题，通过探究主副反应规律，设计合适连续流反应工艺，显著提高了该类反应的选择性。