Fang Jingjie, Ke Miaolin, Huang Guanxin, Tao Yuan, Cheng Dang, Chen Fen-Er
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, School of Pharmaceutical Sciences, Zhejiang University of Technology 18 Chao Wang Road 310014 Hangzhou PR China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University 220 Handan Road Shanghai 200433 PR China
RSC Adv. 2019 Mar 21;9(16):9270-9280. doi: 10.1039/c9ra01347d. eCollection 2019 Mar 15.
The Chapman rearrangement is of practical significance in pharmaceutical and fine chemical industries. It is a high temperature reaction with an exothermic nature in numerous cases. The conventional batch-wise synthesis is limited by its operational complexities, temperature control difficulties and scale-up hurdles. In this work, a microreactor-based continuous-flow approach was developed to perform the rearrangement in a highly controlled and safer manner. High conversions were obtained within short residence times (≤20 minutes). The detailed kinetics of this reaction, using 2,6-dichloro-phenyl -phenyl benzimidate and 2-carbomethoxy-phenyl -phenyl benzimidate as the representative reactants, was explored at varying temperatures to understand the intensified reaction behavior, and was modelled based on the obtained experimental data. The continuous process was scaled up to a 16-fold larger reactor volume by increasing the diameter of the microreactor while maintaining the residence time without further optimization. A very slight variation was observed in the conversion for the larger-sized flow system. Upscaling the batch reaction to a 10 times larger volume, by contrast, resulted in a dramatic decrease in the conversion. The simplicity of scaling up continuous-flow system was clearly demonstrated. A CFD model coupled with the obtained rearrangement kinetics was developed and well validated against the experimental data, which provided a robust platform for guiding the relevant process design and optimization of the continuous-flow processes. The results presented shed new light on the developments and applications of continuous-flow method for the classical Chapman rearrangement that require harsh high temperatures.
查普曼重排在制药和精细化工行业具有实际意义。在许多情况下，它是一种高温反应，具有放热性质。传统的间歇式合成受到操作复杂性、温度控制困难和放大障碍的限制。在这项工作中，开发了一种基于微反应器的连续流方法，以高度可控和更安全的方式进行重排反应。在短停留时间（≤20分钟）内获得了高转化率。以2,6-二氯苯基-苯基苯并咪唑酯和2-甲氧羰基苯基-苯基苯并咪唑酯作为代表性反应物，在不同温度下探索了该反应的详细动力学，以了解强化反应行为，并根据获得的实验数据进行建模。通过增加微反应器的直径同时保持停留时间，而无需进一步优化，将连续过程放大到16倍大的反应器体积。对于更大尺寸的流动系统，转化率仅观察到非常轻微的变化。相比之下，将间歇反应放大到10倍大的体积会导致转化率急剧下降。这清楚地证明了连续流系统放大的简易性。开发了一个结合所获得的重排动力学的计算流体动力学（CFD）模型，并根据实验数据进行了充分验证，这为指导连续流过程的相关工艺设计和优化提供了一个强大的平台。所呈现的结果为需要苛刻高温的经典查普曼重排的连续流方法的发展和应用提供了新的思路。
