Abstract

Multistep Flow Synthesis for API and Flow-Enabled Reaction Kinetics? Probing for Reaction Discovery

Chenguang Liu, Professor, Fuzhou University

Telescoped multistep flow synthesis integrates sequential reactions into a continuous sequence without intermediate isolation and has become an appealing strategy for efficient and safe API manufacturing. Despite its advantages, broader implementation is frequently constrained by interstep incompatibilities arising from mismatched solvents, reagents, pressures, and catalytic systems. Herein, reaction-compatibility challenges in multistep flow systems have been alleviated by both efforts from precise molecular-level reaction modulation and flow-based process intensification to address. Key enabling strategies include the hybridization of micro packed-bed and micro-tubing reactors, solvent-free or solvent-simplified reaction designs, and early incorporation of telescoping logic during reaction development. These concepts have enabled continuous-flow syntheses of pharmaceutically relevant targets, including Cyproflanilide, Broflanilide, and Oxolinic Acid. Leveraging the 'mix-and-react' capability within microreactors, we determined that the Iodine(I)$-induced cyclization of $\alpha$-BCB alcohols/amines into O/N-[2.1.1]BCH occurs on a second-level timescale, which is technically difficult to approach in traditional batch flasks.