Proof-of-Concept of a Continuous-Flow Heck Coupling and HBr-Catalyzed Oxidation for Pharmaceutical Lab-Hood Manufacturing

Continuous-flow GMP manufacture of APIs with demand of less than 5 tons is feasible using only equipment and setups of laboratory fume hood scale. The development of a continuous-flow method for the Heck coupling and bromic-acid-catalyzed oxidation steps in an API GMP sequence is presented. This process was designed with the goal of increasing reproducibility, robustness, operational safety, and manufacturing cost. The Heck coupling was demonstrated in flow, with ongoing work towards telescoping it via continuous crystallization to the subsequent step. The oxidation reaction has been modified to provide a homogeneous starting solution while minimizing the number and quantity of solvents/reagents. Performing it in a CSTR followed by a reactive crystallizer maximized reaction yield by increasing the residence time of certain reactive intermediates relative to the starting material. Direct crystallization of the diketone free base was also possible, eliminating one process crystallization step. Overall, significant progress was made towards continuous synthesis of several GMP steps in a laboratory fume hood at manufacturing scales to meet the anticipated 500-kg/year API demand.