Hydrophobic Tag-Assisted Liquid-Phase Synthesis of Tirzepatide

The synthesis of tirzepatide relies heavily on solid phase peptide synthesis (SPPS), a process that is both costly and time-consuming. In this paper, a novel soluble liquid-phase assisted (LPPS) strategy for the efficient synthesis of tirzepatide is presented. The efficacy of the method is based on the distinct solubility properties of the soluble tag, which enables high yield synthesis while significantly reducing wastage of amino acids and solvents. The construction of the side chain was achieved by a dual protection strategy utilizing both Cbz and Fmoc groups on lysine. This strategy resulted in a satisfactory improvement in overall yield.