CPC A61K 38/29 (2013.01) [C07K 1/066 (2013.01); C07K 14/635 (2013.01); C07K 1/04 (2013.01); C07K 1/06 (2013.01); C07K 1/084 (2013.01)] | 28 Claims |
1. A process for the preparation of abaloparatide comprising:
a) providing a peptide bound to a solid resin and having an initial N-terminus, wherein said bound peptide is NH2-Asp(OtBu)-Leu-Arg(Pbf)-Arg20(Pbf)-Arg(Pbf)-Glu(OtBu)-Leu-Leu-Glu25(OtBu)-Lys(Boc)-Leu-Leu-Aib-Lys30(Boc)-Leu-His(Trt)-Thr(tBu)-Ala34-Rink Amide MBHA resin (SEO ID NO: 2);
b) coupling a carboxyl terminus of Fmoc-(Trt)Gln16-OH to the initial N-terminus of the bound peptide, wherein coupling comprises adding to a suspension of the bound peptide in dimethylformamide from about 1.05 to about 2 molar equivalents of Fmoc-(Trt)Gln16-OH, relative to the bound peptide, in the presence of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-Hydroxybenzotriazole (HOBt), N,N′-diisopropylcarbodiimide (DIC), and diisopropylethylamine (DIEA), and allowing the mixture to react for a period of time;
c) adding to the mixture a further from about 1.05 to about 2 molar equivalents of Fmoc-(Trt)Gln16-OH, relative to the bound peptide, in the presence of additional PyBOP, HOBt, DIC, and DIEA;
d) selectively cleaving the Fmoc group with a solution comprising an amine base to provide a peptide bound to a solid resin and having a new N-terminus.
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