Supramolecular Interaction-Mediated Diffusion Enhancement for Facilitated Synthesis of the Pharmaceutically Active Ingredient Dantrolene and Its Analogues via Spiral Gas–Solid Two-Phase Flow

Although mechanochemical synthesis has gained widespread application, our understanding and enhancement of the control of the reaction need to be improved. In this work, we confirm that the mechanochemical reaction of the active pharmaceutical ingredient dantrolene is controlled by diffusion-controlled kinetics. On this basis, we demonstrate a novel approach to modulate mechanochemical reactivity through a diffusion enhancement strategy mediated by supramolecular interactions. The method employs a highly efficient spiral gas–solid two-phase flow technique, in which urea, an additive that can establish supramolecular interactions with 1-aminohydantoin hydrochloride, is introduced into the reaction system to substantially enhance diffusion, thus facilitating the efficient synthesis of dantrolene. Notably, in this diffusion enhancement process, the weakening of mechanical forces triggers the nucleation and growth of the active substrate to form structurally well-defined eutectic crystals that inhibit the reaction. This strategy reduces the mechanochemical reaction time of dantrolene and its analogs to less than 30 s. In addition, thiourea and acetamide, which are structurally similar to urea, promote the reaction, and their effects correlate with the number of supramolecular sites of action.