Scalable Hydrophobic Tag-Assisted Convergent Synthesis of Cetrorelix Acetate

We report a scalable and operationally simple synthesis of cetrorelix acetate, a clinically used decapeptide GnRH antagonist (Ac-D-2′Nal1-D-(4-Cl)Phe2-D-3′Pal3-Ser4-Tyr5-D-Cit6-Leu7-Arg8-Pro9-d-Ala10-NH2) employed in in vitro fertilization (IVF) regimens. The peptide was assembled through a convergent [5-mer +5-mer] strategy using tailor-made hydrophobic tags to facilitate fragment anchorage and handling. Pentapeptide intermediates and the final product were constructed via iterative Fmoc-based couplings of suitably protected amino acids. The hydrophobic tags enabled efficient, chromatography-free isolation of intermediates through precipitation and liquid–liquid extraction. This approach provides a practical and scalable route to cetrorelix acetate and demonstrates the utility of tag-assisted peptide synthesis for complex therapeutic peptides.