Synthesis of a dipeptide by integrating a continuous flow reaction and continuous crystallization

This paper describes a case study on integrating a continuous flow reaction and continuous crystallization. For the synthesis of Fmoc-l-Phe-l-Phe-OMe, we previously reported that this coupling reaction via acid chloride could be completed in approximately 1 min under continuous conditions. However, the crystals of Fmoc-l-Phe-l-Phe-OMe were obtained by batch crystallization. The quenched solution was unstable and rapid transfer to the crystallization step was desirable. Under such circumstances, continuous crystallization was considered to be the most reliable strategy for a robust scalable synthesis methodology. For this, we tested a mixed-suspension mixed-product-removal (MSMPR) crystallizer that allows for rapid crystallization without seeding and clogging. The steady state for the continuous crystallization could be monitored by particle size distribution using in-line monitoring. As a result, the integration of a continuous flow reaction and continuous crystallization worked smoothly for 2 h, which showed the feasibility of manufacturing using this integration system.