SPPS is the method of choice for peptide synthesis. It allows the use of excess reagents to reach a quantitative yield and the excess reagents can be easily removed by several washing from the resin. However, the amount of consumed solvents is a drawback. In fact, solvents are the major component in all reaction mixtures representing 80-90% of the non-aqueous masses as concluded in a survey by GSK at 2007 about the materials used for the manufacturing of APIs. In this regards, the commonly employed solvents is peptide synthesis, DMF (the mostly used), NMP and DCM, are hazardous chemicals according to Several selection guides for greener chemistry.
Herein, we are presenting studies about substituting DMF by greener solvents. Initially, 2-MeTHF and CPME were evaluated for peptide coupling reactions and 2-MeTHF showed promising results. Then, we applied EtOAc and IPA along with 2-MeTHF for full green SPPS (GSPPS) with the objective of totally avoiding DMF from the synthesis. We concluded from that study that the use of 2-MeTHF for coupling and Fmoc removal steps with EtOAc washing steps is the best protocol in combination with ChemMatrix resin and DIC/OxymaPure. However, we found that Fmoc removal is problematic during SPPS of a peptide that tend to aggregate which required performing the Fmoc removal at 40 °C. Therefore, another independent study was achieved for that purpose where others green solvents were evaluated for the Fmoc removal step. Furthermore, the use of green solvents in automatic peptide synthesizer with microwave heating were also evaluated.
We can conclude that there are green alternatives for the hazardous solvents and in several cases with even superior results.