A Novel Method for Liraglutide Synthesis and Purification

ABSTRACT Liraglutide, developed by Novo Nordisk, is applied in Type 2 diabetes and obesity treatment. Several solid‐phase peptide synthesis protocols were designed for its production. However, current protocols are expensive and many of them are difficult to scale‐up. In this study, a novel alternative for liraglutide production was developed. The peptide was elongated by Fmoc/tBu solid‐phase peptide synthesis on 4‐hydroxymethylbenzoyl–ChemMatrix (HMBA‐CM) resin using the chaotropic agent LiCl as an additive to prevent peptide aggregation. After elongation, removal of side‐chain protecting groups and peptide cleavage from the resin was performed by a two‐stage procedure. Side‐chain protecting groups were removed with 92.5% TFA, leaving the unprotected peptide attached to the solid support. The resin was thoroughly washed to eliminate the contaminants. Next, peptide release was achieved by treating the peptidyl resin with NaOH 0.1 N. This two‐stage procedure assures a high‐purity product without the need of using a large amount of ether as in previous protocols. Finally, liraglutide was purified by hydrophobic interaction with low‐pressure liquid chromatography (HI‐LPLC) instead of using the expensive RP‐HPLC applied in reported methods. This simple and economic method resulted in a high yield and a purity product while overcoming the high cost and difficulties of current processes.