Scalable Mechanochemical Synthesis of Amides Using Bead Milling Technology

Amide bonds are among the most ubiquitous linkages in pharmaceuticals, agrochemicals, and materials, yet their synthesis is still dominated by solvent-intensive protocols. Mechanochemistry offers a sustainable alternative, but its scalability has remained a critical challenge. Here we demonstrate that amide bond formation can be translated into an industrially relevant process using a standard agitator bead mill. Through systematic optimization, we achieved efficient amidations over a broad substrate scope under liquid-assisted grinding with only minimal ethyl acetate. A 20-fold scale-up delivered productivities of up to 2.89 kg/h, without excess reagents, added base, or bulk solvent, substantially reducing waste. The use of a commercially available equipment that is available from lab to manufacturing-scale establishes bead milling as a practical, scalable, and environmentally responsible platform for scalable amide synthesis.