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 (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluoroenylmethyl (OFm). 
       
     
     
         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. 
     
     
         7 . A compound of the formula IA 
       
         
           
           
               
               
           
         
       
       and active esters or salts thereof
 wherein R1 is Cl or morpholine and R2 is 
 
       
         
           
           
               
               
           
         
       
       or OY and Y is selected from the group consisting of 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluoroenylmethyl (OFm). 
     
     
         8 . A compound according to  claim 7  of the formula II 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 7  of the formula III 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 7  of the formula IV 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound according to  claim 7  obtained from a corresponding hydroxy compound and/or substituted phenol. 
     
     
         12 . A method of making an active ester compound according to  claim 7  comprising obtaining a free acid of a compound of formula IA and activating a resulting intermediate using a hydroxy and/or phenolic compound. 
     
     
         13 . The method according to  claim 12  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. 
     
     
         14 . The method according to  claim 12  comprising isolating a compound of formula IA using an organic solvent. 
     
     
         15 . A method of making carfilzomib comprising employing a compound according to  claim 1  using a 2+2+1 fragment condensation. 
     
     
         16 . A method of making carfilzomib comprising employing a compound according to  claim 7  using a 3+2 fragment condensation. 
     
     
         17 . A method of making carfilzomib comprising employing a compound according to  claim 8  or derivatives thereof using a 3+2 fragment condensation. 
     
     
         18 . A method of making carfilzomib comprising employing a compound according to  claim 9  or derivatives thereof using a 3+2 fragment condensation. 
     
     
         19 . A method of making carfilzomib comprising employing a compound according to  claim 10  or derivatives thereof using a 3+2 fragment condensation. 
     
     
         20 . A method of making amorphous form carfilzomib comprising reacting a compound according to  claim 1  with a compound of formula XIII 
       
         
           
           
               
               
           
         
       
       wherein R is H, methyl, ethyl, benzyl, or isopropyl to obtain a compound of formula IV 
       
         
           
           
               
               
           
         
       
       and 
       reacting a compound of formula IV with a compound of formula 8 
       
         
           
           
               
               
           
         
       
     
     
         21 . A method of making amorphous form carfilzomib comprising the synthetic route: 
       
         
           
           
               
               
           
         
       
       wherein Y is selected from the group consisting of 1-hydroxybenzotriazole (OBt), azabenzotriazole (OAt), O-succinimidyl (OSu), pentafluorophenyl (OPfp), trichlorophenyl (OTcp), nitrophenyl (ONp), pentachlorophenyl (Opcp), 3,4-dehydro-4-oxo-1,2,3-benzotriazinyl (Dhbt), and fluoroenylmethyl (OFm) and X is selected from the group consisting of HCl, TFA, HCOOH, TsOH, and MsOH. 
     
     
         22 . The method according to  claim 21  comprising isolating amorphous carfilzomib using organic solvent extraction. 
     
     
         23 . Amorphous form of carfilzomib. 
     
     
         24 . Carfilzomib according to  claim 23  having an X-ray diffraction (XRD) according to  FIG. 1 .