Continuous Synthesis of Safinamide Mesylate using Flow Reactions, Inline Extraction, and Crystallization

Safinamide mesylate is a pharmaceutical agent approved in various countries for the treatment of Parkinson’s disease. However, owing to the lack of an efficient flow-compatible synthetic route and the requirement for intermediate purification, a continuous flow method for its synthesis has not yet been reported. In this study, we aimed to develop a fully continuous flow process to synthesize safinamide mesylate. A sequence of flow reactions, inline extraction, and crystallization steps was employed for the continuous flow synthesis of safinamide mesylate. In particular, C–O bond formation was achieved using a plug flow reactor, while reductive amination was performed in a packed-bed flow reactor. Moreover, crystallization was conducted via neutralization with methanesulfonic acid. Safinamide mesylate was obtained in an overall yield of 83% without the isolation or purification of the intermediates. The scale-up of the continuous synthesis process was successfully demonstrated, resulting in a yield and production rate of 97% and 22.0 g h^–1, respectively. Our proposed method for continuous synthesis and purification could contribute to the production of various fine chemicals and pharmaceuticals.