Methods of making carfilzomib and intermediates thereof

Abstract

Racemization-free methods are disclosed for the synthesis of carfilzomib. Novel intermediates and methods of making carfilzomib employing fragment condensation using the novel intermediates are disclosed. Amorphous carfilzomib and methods of making same are disclosed.

What is claimed is: 
     
         1 . A compound having the formula I 
       
         
           
           
               
               
           
         
         and active esters or salts thereof, wherein Y is selected from the group consisting of 1-hydroxybenzotriazole, azabenzotriazole, succinimidyl, pentafluorophenyl, trichlorophenyl, nitrophenyl, pentachlorophenyl, 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluorenylmethyl. 
       
     
     
         2 . A compound according to  claim 1  comprising an active ester. 
     
     
         3 . A compound according to  claim 2  obtained from a corresponding hydroxy compound and/or substituted phenol. 
     
     
         4 . A method of making an active ester compound according to  claim 1  comprising obtaining a free acid of a compound of formula I and activating a resulting intermediate using a hydroxy and/or phenolic compound. 
     
     
         5 . The method according to  claim 4  wherein the step of obtaining a free acid is selected from one or more of bis-silylation, using at least one silylating agent and an organic base, and/or hydrolysis of esters by using at least one alkali metal hydroxide selected from NaOH, KOH, LiOH and their corresponding carbonates. 
     
     
         6 . The method according to  claim 4  comprising isolating a compound of formula I using an organic solvent.