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

The number of peptide-based active pharmaceutical ingredients (APIs) has increased enormously in recent years. Furthermore, the emerging new peptide drug candidates are more complex and larger. For the industrial solid-phase synthesis of C-carboxylic acid peptides, the two main resins available, Wang and chlorotrityl chloride (CTC), have a number of drawbacks. In this context, resins that form an amide bond with the first amino acid are more robust than Wang and CTC resins. Here, we address the use of the backbone (BAL) resin for the synthesis of the peptide liraglutide. The BAL resin, in conjunction with the use of pseudoprolines to avoid aggregation, allows the stepwise solid-phase synthesis of this API in excellent purity and yield. © 2019 American Chemical Society.Funding This work was funded in part by the following: Lonza AG (Visp, Switzerland), the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) (CTQ2015-67870-P and RTC-2014-2207-1), CIBER-BBN and the Generalitat de Catalunya (2017 SGR 1439) (Spain), and the International Scientific Partnership Program ISPP at King Saud University (ISPP# 0061) (Saudi Arabia). Notes The authors declare no competing financial interest.Peer reviewe