Improved Tag-Assisted Liquid-Phase Peptide Synthesis: Application to the Synthesis of the Bradykinin Receptor Antagonist Icatibant Acetate

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%).