The present invention relates to the technical field of polypeptide
drug preparation methods. Provided is a
solid-phase preparation method for high-yield and high-purity tirzepatide. An amino resin is used as a starting resin; amino acids and small-fragment peptides are sequentially coupled according to the
amino acid sequence of tirzepatide using a
solid-
phase synthesis method to synthesize a tirzepatide resin; and the tirzepatide resin is cleaved and purified to obtain a pure tirzepatide product. The small-fragment peptides include a 1-4
tetrapeptide fragment Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-OH, a 5-6
dipeptide fragment Fmoc-Thr(tBu)-Phe-OH, a 7-8
dipeptide fragment Fmoc-Thr(tBu)-Ser(tBu)-OH, a 10-11
dipeptide fragment Fmoc-Tyr(tBu)-Ser(tBu)-OH, a 12-13 dipeptide fragment Fmoc-Ile-Aib-OH, a 17-18 dipeptide fragment Fmoc-Ile-Ala-OH, a 20-side-chain
peptide Fmoc-Lys(AEEA-AEEA-γ-Glu(α-OtBu)-Eicosanedioic acid(mon-tBu))-OH, a 28-30
tripeptide fragment Fmoc-Ala-Gly-Gly-OH, a 32-34
tripeptide fragment Fmoc-Ser(tBu)-Ser(tBu)-Gly-OH, and a 36-38
tripeptide fragment Fmoc-Pro-Pro-Pro-OH. A
coupling agent for
coupling the
amino acid and the small-fragment
peptide is selected from Oxyma and DIC, TPTU and TMP, or COMU and DIEA.