Scalable mechanochemical synthesis of amides using bead milling technology

Abstract

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⁻¹, without excess reagents, added base, or bulk solvent, substantially reducing waste. The use of commercially available equipment that is available from lab to manufacturing-scale establishes bead milling as a practical, and environmentally responsible platform for scalable amide synthesis.