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

Integrated Tag-assisted Continuous-flow Peptide Synthesis in Green Solvents: Circumventing Solubility Bottlenecks and Minimizing Process Mass Intensity

摘要

报道了一种基于绿色溶剂体系的集成化标签辅助连续流液相多肽合成(CF-TAPS)平台, 其过程质量强度(PMI)比固相多肽合成(SPPS)基准降低 3.7 倍 . 该平台的核心创新在于构建了“双重流动强化”体系: 首先, 利用固定床反应器实现了疏水性氨基标签载体(BTPM)的高效连续流加氢制备, 为全流程自动化奠定了物料基础; 其次, 通过二元溶剂工程(EA/DMSO)协同静态混合管式反应器(SMTR), 实现了多肽序列在流动体系下的稳健溶剂化与极速反应动力学. 该模块化架构集成自动化在线膜分离技术将传统易乳化的洗涤过程转化为高通量工作流, 显著缩短了偶联(52 s)和脱保护(38 s)的循环时间. 通过细胞穿膜肽5R 全合成实验验证了该策略的实用性, 且氨基酸用量仅需1.05~1.2 mol. 此外, 该平台实现了有机溶剂消耗(OSC) 39倍的减幅, 为多肽绿色制造提供了新思路, 有效整合了液相合成的高原子经济性与自动化连续生产的工业可扩展性.

Abstract

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 separation, 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 scalable production.

关键词

连续流动化学 / 液相多肽合成 / 可溶性载体 / 在线膜分离 / 过程质量强度(PMI)

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基金资助

江苏高校优势学科建设工程项目(PAPD38701021)