氟离子敏感疏水标签辅助连续流动绿色合成胸腺五肽  

Continuous Flow Liquid Phase Synthesis of Thymopentin Using Fluoride-labile Hydrophobic Tag

作　　者：刘冬梅 徐元强 夏超 郑晶晶 苏贤斌 LIU Dongmei;XU Yuanqiang;XIA Chao;ZHENG Jingjing;SU Xianbin(College of Chemical Engineering,Nanjing Tech University,Nanjing 210009,China)

机构地区：[1]南京工业大学化工学院,南京210009

出　　处：《高等学校化学学报》2025年第4期26-34,共9页Chemical Journal of Chinese Universities

基　　金：江苏高校优势学科建设工程资助项目资助。

摘　　要：设计并合成了一种新型氟离子敏感的羧基保护基——2-苯基-2-三乙基硅乙醇(PTESE)作为疏水性标签,结合连续流动化学技术,在微反应器中实现了高效绿色的多肽药物合成.该策略采用绿色溶剂乙酸乙酯替代传统固相合成中使用的环境不友好溶剂N,N-二甲基甲酰胺,避免了潜在的生殖毒性风险.实验中使用Cbz保护的氨基酸进行偶联反应,并通过连续流钯碳填充柱加氢实现快速、清洁的脱保护,有效规避了Fmoc脱保护中对受控试剂哌啶的依赖.基于该方法快速高效地合成了高纯度的胸腺五肽(粗品纯度>98%),与传统固相合成方法相比,过程质量强度(PMI)大幅度降低.同时,正交保护基团PTESE可通过氟离子试剂有效脱除,为全保护肽链的合成提供一种新策略,并在绿色可持续多肽合成领域具有巨大的应用潜力.A novel fluoride-sensitive carboxyl protecting group,2-phenyl-2-triethylsilylethanol(PTESE),as a hydrophobic tag was designed and synthesized.By integrating it with continuous flow chemistry,an efficient and green synthesis of peptide drugs was achieved in a microreactor system.The proposed approach employed ethyl acetate,a green solvent,to replace the environmentally unfriendly solvent N,N-dimethylformamide,thereby avoiding its potential reproductive toxicity.Cbz-protected amino acids were used for coupling reactions,and rapid and clean deprotection via hydrogenation was accomplished through a continuous flow palladium-carbon packed column,effectively circumventing the dependence on piperidine,a controlled substance required in Fmoc deprotection.Using this approach,high-purity thymopentin(crude purity>98%)was synthesized rapidly and efficiently.Compared to traditional solid-phase synthesis methods,this strategy reduced the Process Mass Intensity(PMI).Additionally,the orthogonal protecting group PTESE can be removed with fluoride reagents,offering a new approach to synthesizing fully protected peptides,with significant potential in green,sustainable peptide synthesis.

关 键 词：氟离子敏感 疏水标签 胸腺五肽 连续流动液相多肽合成 

分 类 号：O629.72[理学—有机化学]