Steps towards sustainable solid phase peptide synthesis: use and recovery of N-octyl pyrrolidone

The investigation of new green biogenic pyrrolidinones as alternative solvents to N,N-dimethylformamide (DMF) for solid phase peptide synthesis (SPPS) led to the identification of N-octyl pyrrolidone (NOP) as the best candidate. NOP showed good performances in terms of swelling, coupling efficiency and low isomerization generating peptides with very high purity. A mixture of NOP with 20% dimethyl carbonate (DMC) allowed a decrease in solvent viscosity, making the mixture suitable for the automated solid-phase protocol. Aib-enkephalin and linear octreotide were successfully used to test the methodologies. It is worth noting that NOP, DMC and the piperidine used in the deprotection step could be easily recovered by direct distillation from the process waste mixture. The process mass intensity (PMI), being reduced by 63–66%, achieved an outstanding value representing a clear step forward in achieving green SPPS.