Greening peptide chemistry by using NBP as solvent for SPPS

Sammanfattning

The preferred method for synthesising therapeutic peptides today is by Solid-Phase Peptide Synthesis (SPPS). SPPS is a wasteful process, where the main component of the waste is hazardous solvents, i.e., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP) or dichloromethane (DCM). 3 It is therefore desirable to search for new and greener solvents to use for SPPS, which is what has been studied in this project. Five different solvents were chosen for this study: dihydrolevoglucosenone (Cyrene), ethyl acetate (EtOAc), 1,3-dioxolane (DOL), 2-methyl tetrahydrofuran (2-Me-THF) and N-butylpyrrolidinone (NBP). By systematic evaluation of the solvents, or binary mixtures of these, for their resin swelling capacity and ability to dissolve amino acids and reagents, it was possible to find solvents and solvent systems to be used in SPPS. Eight solvents and binary mixtures of varying “greenness” were identified as possible replacements for today’s solvents. Three of these solvents and binary mixtures were found to perform better than DMF by producing higher yield and purity in synthesis of [Asp5]-vasopressin, i.e., NBP, NBP:EtOAc (1:1), NBP:2-Me-THF (1:1). NBP was further investigated for its utility in SPPS and was found to be successful with various coupling reagents and resins in synthesis of [Asp5]-vasopressin. NBP was lastly used in synthesis of [Asp26]-calcitonin, which gave good yield of 28.7% and high purity of 97.9%. This further proved that NBP shows great potential for replacing DMF in SPPS.