Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules

Abstract

Multi-step continuous flow synthesis enables a parallel approach to obtain agrochemicals and pharmaceuticals containing 3-fluoroalkyl pyrazole cores. In this system, fluorinated amines are transformed into pyrazole cores through a telescoped in situ generation and consumption of diazoalkanes. Once synthesized, additional continuous flow and batch reactions add complexity to the pyrazole core via C–N arylation and methylation, TMS cleavage, and amidation. Using this modular assembly line approach, Bixafen and Fluxapyroxad were synthesized in 38 % yield over four continuous flow steps in an overall reaction time of 56 min. Finally, coupling selected continuous flow processes with an offline (batch) Ullmann coupling afforded Celecoxib, Mavacoxib, and SC-560 in 33–54 % yield over two to three steps.