https://doi.org/10.1021/acs.oprd.9b00416


In recent years, with the advancements in continuous flow technology and the ever-increasing demand for green processes, continuous flow chemistry has become more and more widely adopted in the pharmaceutical industry. In this work, the continuous hydrogenolysis of N-diphenylmethylazetidin-3-ol to 3-azetidinol in micropacked bed reactors was demonstrated. The effects of different catalysts, solvent types, and the additives on the reaction in a micropacked-bed reactor were investigated. The results indicate that the reaction rate per reactor volume is increased by 100 times because of the larger interfacial area and shorter diffusion distance in micropacked reactors. To further study the long-term stability of the reaction system, the flow system was successfully operated for 240 h by adjusting the reaction temperature and liquid flow rate. The reaction kinetics model for the hydrogenation of N-diphenylmethylazetidin-3-ol in methanol was studied after the internal and external diffusion limitations were eliminated. In addition, the type of adsorption of the reactants on the catalyst and the rate-determining step of the reaction were investigated.