Process for preparing a GIP/GLP1 dual agonist

A process of making a purified tirzepatide (SEQ ID NO:

• 1) composition comprising:
• a. synthesizing tirzepatide intermediate SEQ ID NO:
• 24 by solid phase peptide synthesis, conjugating the epsilon-amino group of Lys(20) of tirzepatide intermediate SEQ ID NO:
• 24 with (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(gamma-Glu)1-CO—(CH2)18—CO2H, and conducting resin cleavage to yield a crude tirzepatide composition comprising tirzepatide (SEQ ID NO:
• 1) and 10-15% of depsi peptide isomers of tirzepatide;
• b. adjusting the crude tirzepatide composition to a pH between about pH 7 to about pH 10;
• c. incubating the crude tirzepatide composition at the pH between about pH 7 to about pH 10 for at least one hour to convert the depsi peptide isomers to tirzepatide (SEQ ID NO:
• 1);
• and
• d. adjusting the composition resulting from step (c) to a pH between about pH 1.5 to about pH 2.5, thereby increasing the purity and yield of tirzepatide relative to a process without steps (b)-(d).