Multigram-Scale Organic Synthesis by Resonant Acoustic Mixing: Application to the Sustainable Preparation of Active Pharmaceutical Ingredients.

Three different reaction types are extensively studied at multi-gram scale by resonant acoustic mixing (RAM): 1) the Knoevenagel condensation to vanillin barbiturate; 2) the Biginelli multicomponent reaction to dihydropyrimidinones, which includes the anticancer drug (±)-Monastrol; and 3) the Biltz synthesis to the antiepileptic drug Phenytoin. The RAM approach demonstrated advantages over traditional solution-based methods by enhancing sustainability and minimizing solvent usage. The processes are assessed by green chemistry metrics and tools (e.g., Chem21 and DOZN 3.0) demonstrating that RAM technology is outperforming compared to the corresponding solution-based methods, representing an environmentally friendly alternative to conventional approaches in organic synthesis and for the preparation of pharmaceuticals in a more sustainable way. The use of milling beads, for grinding-assisted RAM (GA-RAM) processes, alone or in combination with liquid-assisted RAM (LA-RAM), is also investigated, to enhance reaction efficiency.