Isopropanol‐Dimethyl Sulfoxide, as a Green Solvent Mixture for Solid‐Phase Peptide Synthesis

The increasing industrial demand for peptide therapeutics, together with regulatory and societal pressure to improve the sustainability of chemical processes, has accelerated efforts to replace hazardous solvents used in solid‐phase peptide synthesis (SPPS). N , N ‐Dimethylformamide (DMF), the most widely employed solvent in SPPS, has recently been subject to regulatory restrictions, motivating the search for greener alternatives. In this study, binary mixtures of isopropanol (IPA) and dimethyl sulfoxide (DMSO) are evaluated as sustainable solvent systems for Fmoc‐based SPPS on polystyrene resins. Solubility studies of Fmoc‐protected amino acids, synthesis of model and pharmaceutically relevant peptides, and racemization assessments were performed. IPA–DMSO mixtures (7:3 and 3:1) enabled efficient coupling, washing, and Fmoc deprotection under mild conditions at room temperature. Comparable or improved crude purities relative to DMF were obtained for a range of peptide sequences, including ACP (acyl carrier protein) (6574), afamelanotide analogs, and tirzepatide fragments. Although increased epimerization was observed for histidine‐ and cysteine‐containing sequences in IPA–DMSO compared to DMF, the overall results demonstrate that IPA–DMSO represents a practical and greener solvent platform for SPPS.