管式反应器控制的对称多元体系选择性酰化反应基础研究

Selective acylation of symmetrical multicomponent systems is one of hot and challenge researches in synthetic community. Functional groups in same chemistry environment can easily be acylated. Therefore, how to avoid multi-acylated products is the essential problem. All the literatures that covered this aspect shared same problems: narrow range of substrates’ selection, using large quantity of expensive reagents, having difficulties in isolation and purification of products, long reaction time, and low selectivity. For a typical competitive consecutive reaction, using tubular reactor may enhance the selectivity of acylation in symmetrical multicomponent systems. This project intends to design suitable tubular reactor by studying macro-kinetics of acylation and other relevant aspects; Take the advantage of tubular reactor’s plug flow and continuous flow properties to enhance selectivity of acylation to produce mono-acylated intermediates; Research O-acylation, N-acylation and C-acylation of symmetrical multicomponent systems with acylation reagents of different activities, and apply tubular acylation to industrialized preparation of Active Pharmaceutical ingredient (API) and their intermediates.

对称多元体系选择性酰化反应是合成界研究热点和难点之一，其困难在于官能团的化学环境相同，很容易形成多酰化产物。然而已有文献报道的方法中存在底物适用范围有限、使用大量昂贵试剂、产品分离纯化困难、反应时间长、选择性差等缺点。作为典型竞争性连串反应的对称多元体系选择性酰化反应，管式反应器特别适合于提高其中间产物的选择性。本项目拟在酰化反应的宏观动力学研究等基础上，设计出合适的管式反应器，利用管式反应器平推流特性和连续流动操作的优势，提高单酰化中间产物的选择性；研究不同活性酰化试剂参与的多元对称体系的O-酰化、N-酰化、C-酰化反应，并将管式酰化反应方法应用于药物及中间体的合成中，推进其工业化进程。

对称多元体系选择性酰化反应是合成界研究热点和难点之一，其困难在于官能团的化学环境相同，很容易发生串联副反应，生成多酰化副产物。而已有方法是通过使用昂贵试剂或在极低反应温度下进行，实用性差。本项目利用管式反应器平推流无返回和过程强化等优点，针对多元体系选择性酰化反应，探究主副反应规律，设计合适管式反应工艺，显著提高了反应选择性，并将管式反应技术应用于球痢灵、2-氯磺酰基苯甲酸甲酯、3-(2,4-二氯-5-氟苯甲酰)-2-(甲基氨基)丙烯酸乙酯、脱氧熊果苷等药物及中间体的合成中。