Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 23, Issue 11, Pages 2576-2581Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.9b00397
Keywords
medium molecule; peptide; soluble tag; LPPS; icatibant acetate
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Funding
- JSPS KAKENHI [17K19222, 19H00930, 16H06193, 17K19221]
- Grants-in-Aid for Scientific Research [19H00930, 17K19222] Funding Source: KAKEN
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A cost- and time-effective synthetic method is a prerequisite to producing therapeutic peptides on a commercial scale. Herein we demonstrate that a solubletag-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%).
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