Amide and Peptide Couplings Mediated by Pivaloyl Mixed Anhydrides in Aqueous Media

From the wide range of different chemical transformations used in the pharmaceutical industry, amide and peptide couplings belong to the most important andwidely applied. This is due to the relevance of the amide moiety in pharmaceuticalcompounds. Unfortunately, traditional amidation reaction conditions require hazardousreagents and organic solvents which generate significant amounts of waste. Therefore,finding greener alternatives that are transferrable to industrial applications on a large scaleis an important area of process research and development. This approach is essential forincreasing sustainability in the pharmaceutical and chemical industries. In this article, wedescribe our efforts to develop a sustainable, practical, and scalable protocol for amide andpeptide couplings. Our approach is based on pivaloyl chloride as an inexpensive and readilyobtainable coupling reagent in water as the main reaction media. The conditions developedwere applied to the synthesis of a range of amides and peptides. We then investigated thescope of the transformation and the effect of the surfactant TPGS-750-M by comparing the outcome and the selectivity of reactions carried out in an aqueous solution containing2 wt % of surfactant and solely in aqueous media

Automated summary

Amide and peptide couplings are among the most important and widely applied chemical transformations in the pharmaceutical industry. However, traditional reaction conditions involve hazardous reagents and organic solvents, generating significant waste. Therefore, finding greener alternatives for large-scale industrial applications is crucial.