Method for preparing amg 416 (etelcalcetide)

Abstract

A method for preparing AMG 416, or a pharmaceutically acceptable salt thereof, is provided.

What is claimed is: 
     
         1 . A method for preparing etelcalcetide or a pharmaceutically acceptable salt thereof, comprising:
 providing a peptide having the structure of Ac- D -Cys(SPy)- D -Ala- D -Arg- D -Arg- D -Arg- D -Ala- D -Arg-NH 2  (SEQ ID NO:4); and   contacting the peptide with  L -Cys to produce a conjugated product.   
     
     
         2 . The method of  claim 1 , wherein said contacting comprises dissolving the peptide in an aqueous solution comprising  L -Cys and trifluoroacetic acid (TFA). 
     
     
         3 . The method of  claim 2 , wherein said contacting occurs at room temperature for about 15 minutes. 
     
     
         4 . The method of  claim 1 , further comprising lyophilizing the conjugated product. 
     
     
         5 . The method of  claim 4 , further comprising contacting the conjugated product with an aqueous solution comprising isopropyl alcohol and hydrochloride (HCl), thereby producing a precipitate comprising etelcalcetide HCl (SEQ ID NO:1). 
     
     
         6 . The method of  claim 5 , further comprising washing the precipitate comprising etelcalcetide HCl (SEQ ID NO:1) with isopropyl alcohol. 
     
     
         7 . The method of  claim 6 , further comprising dissolving the isopropyl alcohol washed precipitate in water to produce a dissolved precipitate. 
     
     
         8 . The method of  claim 7 , further comprising concentrating the dissolved precipitate via distillation. 
     
     
         9 . The method of  claim 5 , further comprising purifying the precipitate by HPLC. 
     
     
         10 . The method of  claim 1 , wherein the conjugated product is represented by a formula Ac-c(C)rrrar-NH 2  (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 10 , further comprising contacting the conjugated product with an aqueous solution comprising isopropyl alcohol (IPA) and HCl, thereby producing a precipitate a HCl salt of SEQ ID NO: 1. 
     
     
         12 . The method of  claim 4 , wherein the method further comprises deriving the peptide having structure Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH 2  (SEQ ID NO:4) from providing a resin-bound peptide having a structure of Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:3). 
     
     
         13 . The method of  claim 12 , wherein the deriving comprises contacting the resin-bound peptide with a solution comprising water, trifluoroacetic acid, triisopropylsilane and dipyridyldisulfide. 
     
     
         14 . The method of  claim 1 , wherein the peptide comprises a TFA salt of Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH 2  (SEQ ID NO:4).