霍夫曼重排反应过程微型化的基础研究

微反应技术在化工过程强化和药物合成中有重要应用，利用微反应技术混合高效、传热传质效率高、过程可控以及本征安全等优点，可以很好地处理药物合成过程中难以避免的危险反应。霍夫曼重排反应作为一种制备伯胺及其衍生物的经典方法，现有传统釜式工艺存在流程复杂、生产成本高以及稳定性差等问题。利用微反应技术实现反应过程强化是制药行业发展的新趋势。然而，现有的微反应研究大多停留于对反应结果的直接描述上，对其中传递与反应过程耦合的共性问题缺乏系统而深入的研究。本课题以微反应器为关键核心技术，以基于水介质的次氯酸钠和氢氧化钠为反应体系，以芳烃酰胺和脂肪族酰胺为底物，研究该反应体系的普适性，探讨酰胺分子结构对于转化性能的影响规律，深入研究非均相霍夫曼重排反应的动力学规律和机理过程，探索产物、反应试剂和溶剂环境的相互作用规律，建立重排反应的数学模型，为发展新一代霍夫曼重排反应新技术和新装备提供基础。

Microreaction technology has important applications in chemical process intensification and drug synthesis. The advantages of microreaction technology, such as high mixing efficiency, high heat and mass transfer efficiency, controllable process and intrinsic safety, can be used to deal with the unavoidable dangerous reactions which appear in drug synthesis. Hofmann rearrangement reaction is a classical method for the preparation of primary amines and their derivatives. The existing traditional batch process has the problems of complex process, high production cost and poor stability. It is a new trend of pharmaceutical industry to realize process intensification by microreaction technology. However, most of the existing works on microreactions are focused on the direct description of the reaction results, and there is a lack of systematic and in-depth research on the common problems of the coupling of transfer and reaction process. In this project, microreactor is the key tool to achieve miniaturization of Hofmann rearrangement reaction. Sodium hypochlorite and sodium hydroxide are used as the main reaction reagents. Aromatic amide and aliphatic amide are used as the substrates, the universality of the reaction system is studied. The influence of amide molecular structure on the conversion performance is discussed, and the kinetics and mechanism of heterogeneous Hofmann rearrangement are deeply studied. The interaction law of products, reagents and solvent environment is explored. And the mathematical model of rearrangement reaction was established to provide the basis theory for the development of new technology and new equipment of Hofmann rearrangement reaction.