Abstract

The widespread use of amide bond formation in pharmaceutical synthesis necessitates the development of more sustainable and efficient synthetic strategies. Traditional methods often rely on hazardous solvents and coupling reagents, resulting in significant waste and safety concerns. In this study, we demonstrate a solvent-free, mechanochemical approach to amidation using ball milling technology. A model reaction between benzoic acid and benzylamine was optimized under dry conditions with various coupling agents, including EDC·HCl, CDI, and triphosgene. High yields (85–95%) of amide products were achieved within 30–60 minutes of milling. Scale-up to 10 g batches was successful without loss in efficiency. Reaction scope was further extended to pharmaceutical intermediates such as N-benzylacetamide and fluorenylmethoxycarbonyl-protected amino acids. This approach offers a green, scalable alternative to traditional solvent-based amidation and demonstrates potential for sustainable pharmaceutical manufacturing.