基于绿色溶剂体系的集成化标签辅助连续流多肽合成及过程强化OA

This study reports an integrated tag-assisted continuous-flow liquid-phase peptide synthesis(CF-TAPS)platform based on a green solvent system,achieving a 3.7-fold reduction in process mass intensity(PMI)relative to the solid-phase peptide synthesis(SPPS)benchmark.The core innovation lies in a"dual-flow intensification"framework:first,a fixed-bed reactor was utilized for the efficient continuous-flow hydrogenation of the hydrophobic amino-tag carrier(BTPM),establishing the material foundation for end-to-end automation;second,a tunable binary solvent system(EA/DMSO)was synergized with a static-mixer-incorporated tubular reactor(SMTR)to ensure robust solvation and ultrafast reaction kinetics.This modular architecture integrated automated in-line membrane separa-tion,transforming emulsion-prone washing into a high-throughput workflow and significantly compressing cycle time for coupling(52 s)and deprotection(38 s).The utility of this tag-based flow strategy was validated through the total synthesis of cell-penetrating peptide 5R,requiring only 1.05～1.2 mol of amino acids.Notably,the platform achieved a transformative 4-fold reduction in organic solvent consumption(OSC),providing a sustainable paradigm for green peptide manufacturing that effectively integrates the high atom economy of liquid-phase strategies with the automated industrial scalability of continuous processes.