Continuous-inline extraction of polar co-solvent during sequential flow reactions†

The development of multistep flow synthesis methods for fine chemicals and pharmaceuticals is desirable in terms of cost and energy efficiency. Methods for connecting the first and second flow reactions are essential for the development of multistep flow reactions; however, some reactions are incompatible with necessary solvents. Herein, we developed continuous-removal methods for polar co-solvents that negatively affect subsequent reactions. These sequential flow reactions facilitated the production of multicomponent compounds from simple starting materials. Furthermore, scaled-up experiments for the sequential flow reaction using reaction columns approximately 40 times larger than the original were successfully conducted, with a productivity of 16.1 g h⁻¹. We believe that our continuous extraction method holds promise for various sequential flow reactions for the synthesis of fine chemicals and pharmaceuticals.