A cost- and time-effective synthetic method is a prerequisite to producing therapeutic peptides on a commercial scale. Herein we demonstrate that a soluble-tag-assisted liquid-phase peptide synthesis (LPPS) using a hydrophobic benzyl alcohol as a support is applicable to the 100 g scale production of therapeutic peptides using the bradykinin receptor antagonist icatibant acetate as a model. The use of sacrificial propylamine to trap the activated amino acids enables one-pot sequential couplings and deprotections without detectable double hits. With the modified procedure, precipitations at every other step are sufficient for the overall process, significantly reducing the amount of MeCN required. The complete consumption of starting materials (<0.05% remaining) at each step can be confirmed by a facile in-process control using HPLC, realizing the preparation of icatibant acetate with high purity (>99%).

中文翻译：

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改进的标签辅助液相肽合成：在缓激肽受体拮抗剂依卡替班醋酸盐的合成中的应用。

具有成本效益和时间效益的合成方法是以商业规模生产治疗性肽的先决条件。在本文中，我们证明了使用疏水性苄醇作为载体的可溶性标签辅助液相肽合成（LPPS）适用于以缓激肽受体拮抗剂醋酸依卡替班酯为模型的100 g规模的治疗性肽生产。使用牺牲丙胺捕获活化的氨基酸可实现一锅式顺序偶联和脱保护，而没有可检测到的双重打击。通过改进的程序，每隔一个步骤的沉淀就足以完成整个过程，从而大大减少了所需的MeCN量。每一步骤中原料的完全消耗（剩余<0.05％）可以通过使用HPLC进行的简便的过程中控制来确认，