Heterogeneous Catalysis for Dehydrative Condensation of Carboxylic Acids and Amines Bearing Basic Functionalities for Continuous-Flow Synthesis of Flecainide

In acid-catalyzed dehydrative amidation, catalysts must efficiently activate carboxylic acids despite the competitive presence of basic amine substrates. Substrates bearing diverse functional groups—ubiquitous in pharmaceutical synthesis—demand high levels of chemoselective activation. Continuous-flow systems utilizing packed-bed heterogeneous catalysts offer superior contact efficiency, providing an ideal platform to achieve such transformations with enhanced precision. Herein, we demonstrate that a simple mixed-metal oxide with moderate acidity inherently possesses these capabilities and develop a continuous-flow platform that maximizes its catalytic performance. This composite oxide exhibits high activity even in strongly Lewis-basic environments—where more acidic, modified oxides typically suffer from deactivation—enabling the continuous production of pharmaceutical precursors in high yields. Furthermore, by integrating the amidation step with a subsequent aromatic ring hydrogenation (ARH) via customized in-line processing modules, the integrated continuous-flow synthesis of the antiarrhythmic active pharmaceutical ingredient (API), flecainide, was successfully established. This work highlights the importance of balancing surface acidity and adsorption dynamics for the design of robust, sustainable catalytic processes for complex molecule manufacturing.