An Automated Intermittent Flow Approach to Continuous Suzuki Coupling

A fully automated fill/empty reactor system for liquid-liquid biphasic Suzuki couplings is described. The system was capable of charging reactant and catalyst solutions to a heated vessel, heating reagent solutions by flow heat exchanger on the way into the reactor, allowing the reaction to occur, monitoring reaction completion, discharge of the product solution, and initiation of another cycle in a repeating fashion. A unique noncontact colorimetric method was used to monitor reaction completion. The reactor system exhibits many of the characteristics of a fully continuous reactor such as (1) high productivity from a small process footprint, (2) a large number of volume turnovers each day, (3) higher heat transfer area per unit volume compared to batch because the reactor is SOX smaller, and (4) rapid heat up and cool down of process streams enabled by heat exchangers. Downstream unit operations that are intended for eventual integrated end-to-end continuous production included a batch metal removal step and a continuous antisolvent crystallization to isolate the product in high yield and purity.