Elevating 1-tert-Butyl-3-ethylcarbodiimide (TBEC) as a Reagent for Sustainable Peptide Synthesis: Quality Assessment and Minimizing Racemization, Precipitation, and Radical-Induced Side Reactions by TBEC/Oxyma Couplings in an Environmentally Sensible Solvent

Abstract

The finding that the widely used peptide coupling reagents DIC and Oxyma form the toxic H-CN (McFarland, A. D.

N,N‐Dimethyl Formamide European Restriction Demands Solvent Substitution in Research and Development

“…[23] So far, a single solvent able to replace DMF/NMP has not been identified, the mixtures of ethyl acetate (EtOAc) with N-butyl pyrrolidone or DMSO being the most promising candidates. [24][25][26] Industry uses of DMF N,N-Dimethyl formamide accounts for over half of conventional dipolar aprotic solvent use reported in patents (see Supporting Information, Figure S3). The major industry uses of DMF include pharmaceuticals, the production of polyurethane materials, and the spinning of synthetic fibres.…”

“…In the context of peptide synthesis, the development or binary or even ternary solvents is seen as the most promising approach. [24][25][26] The use of solvent mixtures may improve reaction performance but solvent recovery and separation may be compromised and so it remains important to evaluate the impact of solvent substitution from cradle to grave. Telescoped reactions have also been devised to reduce solvent use, minimising risk and waste.…”