Process of preparation of glucagon-like peptide-1 (GLP-1) receptor agonists and their analogs

A process for the preparation of liraglutide comprising the steps of:

• a) anchoring a dipeptide fragment Fmoc-Arg (Pbf)-Gly-OH to a resin and capping it;
• b) selectively deprotecting an amino group of the fragment of step (a);
• c) sequential coupling of the dipeptide fragment Fmoc-Arg (Pbf)-Gly-OH, to amino acid fragments Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Glu (OtBu)-OH, Fmoc-Lys (Dde)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Gln(Trt)-OH;
• dipeptide fragment Fmoc-Glu(OtBu)-Gly-OH, to amino acid fragments Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Val-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH;
• dipeptide fragment Fmoc-Glu(OtBu)-Gly-OH, to amino acid fragments Fmoc-Ala-OH and Boc-His(Trt)-OH in the presence of a coupling agent to obtain an a amino acid sequence of Boc-His(Trt)-Ala-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu) -Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly-Gln(Trt)-Ala-Ala-Lys(Dde) -Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-O-2-resin;
• d) removing a lysine side chain protecting group, followed by coupling the peptide fragment of step (c) with Fmoc-Glu-OtBu followed by Fmoc deprotection and coupling of N-terminal peptide attached to resin with palmitic acid;
• e) cleaving the peptide from the resin using a mixture of trifluoroacetic acid (TFA):
• triisopropylsilane (TIPS):
• 3,6-dioxa-1,8-octanedithiol (DODT):
• water to obtain linear crude liraglutide;
• and
• f) optionally purifying the crude liraglutide.