Process for the manufacture of cyclic undecapeptides

Abstract

The present invention relates to processes and intermediates useful for the manufacture of cyclic undecapeptides, such as Alisporivir.

1 . A process for preparing a compound of formula 3 or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl, the method comprising the steps of acylation of cyclosporin A, to form acetyl-Cyclosporin A; 
         ring opening of the acetyl-Cyclosporin A; and 
         crystallizing the ring opened acetyl-Cyclosporin A to obtain a compound of formula 3. 
       
     
     
         2 . A process according to  claim 1  for preparing a compound of formula 4 or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl, the method comprising the steps of Edman degradation of compound of formula 3; and then 
         crystallizing the compound to obtain a compound of formula 4. 
       
     
     
         3 . A process for preparing a compound of formula 4 or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl, the method comprising the steps of: 
         i) acylation of cyclosporin A to form acetyl-Cyclosporin A; 
         ii) ring opening of the acetyl-Cyclosporin A; and; 
         iii) crystallizing the ring opened acetyl-Cyclosporin A to obtain a compound of formula 3 
       
       
         
           
           
               
               
           
         
         or salt thereof; 
         iv) Edman degradation of the compound of formula 3; and then 
         v) crystallizing the compound to obtain a compound of formula 4 or a salt thereof. 
       
     
     
         4 . A compound of formula 3 or a salt thereof 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl. 
       
     
     
         5 . A compound of formula 4 or a salt thereof 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl and R′ is methyl or ethyl. 
       
     
     
         6 . A process according to  claim 1  wherein the purity of the starting material is >80%, by weight, Cyclosporin A. 
     
     
         7 . A process according to  claim 6  wherein the purity of the starting material is >85%, by weight, Cyclosporin A. 
     
     
         8 . A process according to  claim 1  wherein the purity of the starting material is 60 to 80%, weight % assay, of Cyclosporin A). 
     
     
         9 . A process for preparing a compound of formula 3 or a salt thereof from from Cyclosporin A, Cyclosporin B, or from Cyclosporin D, or from Cyclosporin G, 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R 2  is methyl, ethyl, or propyl, the method comprising the steps of acylation of cyclosporin A, B, D, or G, to form acetyl-Cyclosporin A, B, D, or G; 
         ring opening of the acetyl-Cyclosporin A, B, D, or G; and 
         crystallizing the ring opened acetyl-Cyclosporin A, B, D, or G to obtain a compound of formula 3. 
       
     
     
         10 . A process according to  claim 9  for preparing a compound of formula 4 or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R 2  is methyl, ethyl, or propyl, the method comprising the steps of Edman degradation of compound of formula 3; and then 
         crystallizing the compound to obtain a compound of formula 4. 
       
     
     
         11 . A process for preparing a compound of formula 4 or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R 2  is methyl, ethyl, or propyl, the method comprising the steps of: 
         vi) acylation of cyclosporin A, B, D, or G, to form acetyl-Cyclosporin A, B, D, or G; 
         vii) ring opening of the acetyl-Cyclosporin A, B, D, or G; and 
         viii) crystallizing the ring opened acetyl-Cyclosporin A, B, D, or G to obtain a compound of formula 3 or salt thereof 
       
       
         
           
           
               
               
           
         
         ix) Edman degradation of compound of formula 3; and then 
         x) crystallizing the compound to obtain a compound of formula 4 or a salt thereof. 
       
     
     
         12 . A process according to  claim 9  wherein the purity of the starting material is >90%, by weight, Cyclosporin A. 
     
     
         13 . A process according to  claim 12  wherein the purity of the starting material is >92%, by weight, Cyclosporin A. 
     
     
         14 . A process according to  claim 9  wherein the purity of the starting material is 60 to 80%, weight % assay, of Cyclosporin A). 
     
     
         15 . A compound of formula 3 or a salt thereof 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R 2  is methyl, ethyl, or propyl. 
       
     
     
         16 . A compound of formula 4 or a salt thereof 
       
         
           
           
               
               
           
         
         wherein R is methyl, ethyl, propyl or phenyl, R′ is methyl or ethyl, and R 2  is methyl, ethyl, or propyl.