Scalable and sustainable DMF-free solid-phase synthesis of liraglutideby 1-tert-butyl-3-ethylcarbodiimide-mediated couplings and catch-and-release acylation and purification strategies

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, using novel and sustainable solid-phase synthetic strategies. By adopting the safer coupling reagent 1-tert-butyl-3-ethylcarbodiimide (T-Bec®) in combination with eco-friendly binary solvents like dimethyl sulfoxide and butyl acetate, we demonstrated that it is possible to significantly reduce the environmental impact while maintaining high efficiency and quality of the synthesis. T-Bec® minimizes hazardous byproducts, such as hydrogen cyanide, and enhances solvent compatibility, achieving crude purities and yields comparable to conventional syntheses. Two synthetic strategies were developed for liraglutide production. The first strategy 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. These findings highlight the effectiveness of T-Bec® and green solvent systems to optimize scalable and sustainable SPPS processes. These methods improve resource efficiency and reduce environmental impact, to allow a viable pathway to produce therapeutic peptide ingredients like liraglutide. This work underscores the potential of green chemistry to align pharmaceutical innovation with environmental responsibility.