Design and Integrated Optimization of the Combined Process of a Flow Reactor and Simulated Moving Bed Chromatography

Coupling and integration of upstream and downstream are current trends to increase productivity and decrease operating costs. Many modern upstream units (i.e. flow reactors) continuously produce complex chemical products and it is required to remove byproducts efficiently. Due to strict purity requirements in fine chemical or pharmaceutical fields, chromatographic purification methods are becoming important. Continuous chromatography (i.e. simulated moving bed, SMB) offers attractive solutions for difficult separation problems. If the reaction medium can be easily transferred into the separation medium, a continuous flow reactor and a SMB unit can be directly coupled and operated as a single unit. In this work, the reaction mixture produced from a continuous flow reactor was directly fed into a SMB unit. To adjust the solvent composition of reactor outlet to the required mobile phase composition of chromatographic separation, the reactor effluent was mixed with a makeup solvent. The isomeric reaction products from the nucleophilic aromatic substitution (SNAr) reaction of 2, 4-difluoronitrobenzene with morpholine were chosen as the model system. After investigating reaction and separation behaviors separately, we explored the methods of connecting the two processes and demonstrated that a directly coupled system can be operated in a stable manner under cyclic steady-state conditions. Optimization of the reactor and the SMB unit was performed to increase process performances and to improve the operation robustness. This system was experimentally validated to provide continuously an output of the desired compound in excellent purity and with high yield