Enhancing Reaction Compatibility in Telescoped Multistep Flow Synthesis via Hybridizing Micro Packed-Bed/Micro Tubing Reactors: Application to Cyproflanilide and Broflanilide

Telescoped multistep flow synthesis, which integrates sequential reactions into a seamless sequence without intermediate isolation, serves as a transformative force propelling the advancement of continuous drug manufacturing. However, interstep incompatibility caused by varying reaction conditions hinders its development and application. To address this critical challenge, we present a hybrid flow system combining micro packed bed reactors (μPBRs) and microtubular reactors (μTRs). μPBRs house heterogeneous catalytic processes, improving solvent and reagent compatibility and operational ease, while μTRs enable intensified homogeneous reactions with enhanced kinetics. This hybrid strategy was applied to the telescoped synthesis of N-acyl-N-alkyl anilines─key pharmacophores in pharmaceuticals and agrichemicals─via a four-step continuous process: nitro reduction, reductive amination, amide coupling, and ester hydrolysis. High yields of N-acyl-N-alkyl anilines 5a (87% in 15.5 min) and 5b (84% in 13.8 min) were achieved without intermediate isolation. Furthermore, the complete eight-step continuous synthesis of both insecticides, cyproflanilide and broflanilide, was also realized. Notably, this project leveraged dibenzo-18-crown-6 to modulate intrinsic kinetics and tailored flow configurations to intensify apparent kinetics, thus enabling a scalable, biphasic (water/oil) sulfinato-dehalogenation protocol, producing insecticide intermediates at the kilogram-per-day scale. This hybrid strategy demonstrates versatility in addressing reaction incompatibility during telescoped flow synthesis, advancing the practical implementation of continuous manufacturing.