Developing greener synthesis processes is an inescapable necessity to transform the industrial landscape, mainly in the pharmaceutical sector, into a long-term, sustainable reality.

Solid Phase Peptide Synthesis (SPPS) is a key technology for the production of pharmaceutical grade peptides, although it represents the worst modality in the pharma segment when considering its Process Mass Intensity (PMI). Consequently, academic and industrial research teams have focused their attention on greening SPPS protocols by introducing more sustainable alternatives to the most common reagents and solvents. In this context, 3-(diethylamino)propylamine (DEAPA) was identified to be a viable alternative to piperidine for Fmoc removal. In addition, the use of DEAPA in N-octyl-pyrrolidone (manual synthesis) or N-octyl pyrrolidone/dimethyl carbonate 8/2 v/v (automated synthesis) was proved to be able to minimize the formation of side products like diastereoisomers and aspartimide-containing derivatives.

The replacement of toxic solvents with greener alternatives in Heck–Cassar–Sonogashira (HCS) cross-couplings was investigated. The fine-tuning of the HCS protocol allowed to achieve complete conversions and high speed under mild conditions. N-Hydroxyethylpyrrolidone (HEP) gave the best results. Moreover, the methodology was successfully applied to the synthesis of an intermediate of the anticancer drug Erlotinib, demonstrating the versatility of the new green protocol.