N‐Butylpyrrolidinone is an equally good solvent as N,N‐dimethylformamide for microwave assisted solid phase peptide synthesis

Solid‐phase peptide synthesis (SPPS) is the prevailing method for synthesizing research peptides today. However, SPPS is associated with a significant environmental concern due to the utilization of hazardous solvents such as N , N ‐dimethylformamide (DMF) or N ‐methylpyrrolidone, which generate substantial waste. In light of this, our research endeavors to identify more environmentally friendly solvents for SPPS. In this study, we have assessed the suitability of five green solvents as alternatives to DMF in microwave assisted SPPS. The solvents evaluated include Cyrene, ethyl acetate, 1,3‐dioxolane, tetrahydro‐2‐methylfuran, and N ‐Butylpyrrolidinone (NBP). Our investigation encompassed all stages of the synthesis process, from resin swelling, dissolution of reagents, culminating in the successful synthesis of five diverse peptides, including the challenging ACP 65–74, Peptide 18A, Thymosin α1, and Jung‐Redemann peptide. Our findings indicate that NBP emerged as a strong contender, performing on par with DMF in all tested syntheses. Furthermore, we observed that combinations of NBP with either ethyl acetate or tetrahydro‐2‐methylfuran demonstrated excellent results. This research contributes to the pursuit of more sustainable and environmentally conscious practices in peptide synthesis.