US 11,806,387 B1
Process of making abaloparatide
Matt Burke, Wayne, PA (US); and Silvio Campagna, Lehigh Acres, FL (US)
Assigned to Radius Health, Inc., Boston, MA (US)
Filed by Radius Health, Inc., Boston, MA (US)
Filed on May 19, 2023, as Appl. No. 18/320,544.
Claims priority of provisional application 63/344,375, filed on May 20, 2022.
Int. Cl. C07K 1/06 (2006.01); C07K 14/635 (2006.01); A61K 38/29 (2006.01); C07K 1/04 (2006.01); C07K 1/08 (2006.01)
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.