Scalable and Sustainable DMF-Free Solid-Phase Synthesis of Liraglutide by 1-Tert-Butyl-3-Ethylcarbodiimide-Mediated Couplings and Catch-and-Release Acylation and Purification Strategies

Abstract

Introduction: The growing need for sustainable practices in pharmaceutical manufacturing has stimulated advancements in peptide synthesis. This study focuses on applying green chemistry principles to the synthesis of the Glucagon-Like Peptide-1 analog liraglutide. Material and Methods: The safer coupling reagent 1-tert-butyl-3-ethylcarbodiimide (TBEC) was tested in combination with eco-friendly binary solvents such as dimethyl sulfoxide and butyl acetate to propose novel and sustainable solid-phase synthetic and purification strategies of liraglutide. Results: Two synthetic strategies were developed for liraglutide production. The first strategy was based on a “direct synthesis”, incorporating a lipidated lysine building block into the peptide sequence, achieving 86% HPLC purity after catch-and-release purification. The second strategy based on “catch-lipidation-and-release” approach, allowed to obtain the peptide precursor without the lipid moiety, which was later linked during a controlled lipidation step. This latter strategy yielded purities exceeding 90% and reduced reliance on preparative HPLC. TBEC minimizes hazardous byproducts, such as hydrogen cyanide, and enhances solvent compatibility, achieving crude purities and yields comparable to conventional syntheses. Conclusion: This work underscores the potential of green chemistry to align pharmaceutical innovation with environmental responsibility. In particular our findings highlight the effectiveness of TBEC and green solvent systems optimizing scalable and sustainable SPPS processes and improving resource efficiency. Thus, we propose a viable pathway to produce the therapeutic peptide ingredient liraglutide significantly reducing the environmental impact while maintaining high efficiency and quality of the synthesis.