Optimized Stepwise Synthesis of the API Liraglutide Using BAL Resin and Pseudoprolines

Area of Science:

• Pharmaceutical Chemistry
• Organic Synthesis
• Medicinal Chemistry

Background:

• Peptide-based active pharmaceutical ingredients (APIs) are increasingly complex and larger.
• Traditional Wang and chlorotrityl chloride (CTC) resins present drawbacks for industrial solid-phase peptide synthesis.
• Resins forming amide bonds offer greater robustness for C-carboxylic acid peptide synthesis.

Purpose of the Study:

• To evaluate the efficacy of the backbone (BAL) resin for synthesizing the peptide liraglutide.
• To demonstrate an improved method for industrial-scale peptide synthesis.
• To overcome aggregation issues in complex peptide synthesis.

Main Methods:

• Utilized the backbone (BAL) resin for solid-phase synthesis.
• Incorporated pseudoprolines to mitigate peptide aggregation.
• Applied stepwise synthesis for liraglutide production.

Main Results:

• Achieved excellent purity and yield in liraglutide synthesis using BAL resin.
• Demonstrated the robustness of BAL resin compared to Wang and CTC resins.
• Successfully managed aggregation in a complex peptide synthesis.

Conclusions:

• The BAL resin is a superior alternative for solid-phase synthesis of complex peptide APIs.
• Pseudoproline incorporation is effective in preventing aggregation during synthesis.
• This method facilitates the efficient industrial production of large peptide drugs like liraglutide.