Establishment and Development of Organolithium-Mediated Continuous Flow Process for Intermediate of Canagliflozin

Organolithium species are among the most reactive and useful reagents in organic synthesis, performing a diverse array of valuable chemical transformations, including C–C bond formation in complex compounds. Organolithium-mediated reactions, however, typically require cryogenic conditions to mitigate the generation of impurities arising from unstable lithiated species in the conventional batch mode, leading to yield and quality issues in a commercial manufacturing environment owing to poor heat transfer and prolonged operation time. Flow chemistry, especially using a plug flow reactor (PFR), overcomes many of the limitations associated with batch chemistry owing to its excellent heat removal efficiency and short residence time, resulting in cryogenic conditions not being required. An efficient and robust flow reactor system employing organolithium reagents at a convenient temperature was developed in this study to prepare an intermediate of canagliflozin in good-to-excellent yields. Furthermore, it was demonstrated that this system could be readily scaled up to a throughput of 3.4 kg/h for the desired product without any clogging.