Sustainable and Atom-Economical Continuous-Flow Synthesis of Iguratimod via Robust Heterogeneous N -Heterocyclic Carbene Catalysis

A robust, heterogeneous N-heterocyclic carbene catalytic flow system was developed for the sustainable synthesis of 3-aminochromones via an intramolecular Stetter-type reaction. By identifying and suppressing a critical benzylic leaching pathway during catalyst preparation, the immobilized triazolium species achieved unprecedented long-term stability and high turnover numbers under high-intensity flow conditions. The integration of in-line HTS-NMR monitoring enabled real-time process optimization and stable, long-term production. This methodology was applied to the synthesis of the anti-rheumatic drug iguratimod, delivering the API in 75% overall yield and high purity (>96%). This work provides an atom-economical framework for the sustainable manufacturing of complex APIs through the synergy of heterogeneous organocatalysis and flow technology.