Green Solvents Mixtures for Solid Phase Peptide Synthesis (GM-SPPS). A DMF free high efficient synthesis of pharmaceutical grade peptides.

To replace DMF in Fmoc solid-phase peptide synthesis, we explored the application of mixtures of green solvents (GM-SPPS) as combinations of CyreneTM, sulfolane or anisole with dimethyl carbonate or diethyl carbonate, in different proportions. Their ability to swell differently functionalized polystyrene and polyethylene glycol resins was explored and solubility of amino acids and coupling reagents was studied. Moreover, the synthesis of the model peptide Aib-enkephalin was performed in the new green mixtures, confirming the possibility to fully replace DMF all over SPPS. The two established best green protocols were then successfully applied to the synthesis of a longer peptide (Aib-ACP). Finally, the green solvent-based procedure was applied to the synthesis of the reduced form of the API Octreotide. After oxidative cyclization and a single high pressure column chromatography, the pharmaceutical grade compound was isolated in comparable high yield to that obtained with the standard procedures.