Abstract: A novel hydrophobic silyl tag bis(4-((tert-butyldiphenylsilyl)oxy)phenyl)methanamine (BPPM) was proposed for rapid liquid-phase peptide synthesis under continuous flow in a microreactor. The designed continuous flow device consists of a coupling unit (micro-channel reactor), a deprotection unit (packed-bed reactor) and a washing unit (micro-channel mixer). In this process, a green solvent (ethyl acetate instead of N,N-dimethylacetamide) and Cbz-protected amino acids (clean deprotection instead of piperidine Fmoc-deprotection) were used. Vialox peptide with high purity (>95% crude) was synthesized in an environmentally friendly way, with high synthesis efficiency (each amino acid per coupling <5min). The results of this work are easy to scale up and provide a new strategy for large-scale green and efficient synthesis of peptides.

Key words: Hydrophobic silyl tag, Continuous flow, Liquid-phase peptide synthesis