Semi-synthesis of taxane intermediates and aziridine analogues and their conversion to paclitaxel and docetaxel

Abstract

A process is provided for the semi-synthesis of taxane intermediates and aziridine analogues of cephalomannne and baccatin III intermediates, and the conversion of such intermediates and analogues to paclitaxel and docetaxel.

1 . A process for preparing a taxane comprising the steps of: 
 converting cephalomannine to a taxane intermediate having the structure:                          wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group; and    converting the taxane intermediate to paclitaxel or docetaxel.    
     
     
         2 . The process of  claim 1  wherein the taxane intermediate is converted to paclitaxel.  
     
     
         3 . The process of  claim 1  wherein the taxane intermediate is converted to docetaxel.  
     
     
         4 . The process of  claim 1  wherein the step of converting cephalomannine to the taxane intermediate further comprises the steps of: 
 converting cephalomannine to a cephalomannine aziridine analogue having the structure:                          wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group; and    converting the cephalomannine aziridine analogue to the taxane intermediate.    
     
     
         5 . The process of  claim 1  wherein the step of converting cephalomannine to the taxane intermediate comprises reacting cephalomannine with formic acid.  
     
     
         6 . The process of  claim 1  wherein the step of converting cephalomannine to the taxane intermediate further comprises the reaction sequence:  
       
         
           
           
               
               
           
         
       
       wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group.  
     
     
         7 . The process of  claim 1  wherein the step of converting cephalomannine to the taxane intermediate further comprises the steps of: 
 converting cephalomannine to a cephalomannine epoxide analogue having the structure:                          wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group;    converting the cephalomannine epoxide analogue to a cephalomannine azido alcohol analogue having the structure:                          wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group; and    converting the cephalomannine azido alcohol analogue to the taxane intermediate.    
     
     
         8 . A process for preparing a taxane comprising the steps of: 
 converting cinnamoyl halide to a cinnamoyl halide aziridine intermediate having the structure:                          wherein X is halogen;    reacting the cinnamoyl halide aziridine intermediate with protected baccatin III to provide a protected baccatin III aziridine intermediate having the structure:                          wherein R is selected from hydrogen and a hydroxy-protecting group;    converting the protected baccatin III aziridine intermediate to a taxane intermediate having the structure:                          wherein R is selected from hydrogen and a hydroxy-protecting group; and    converting the taxane intermediate to paclitaxel or docetaxel.    
     
     
         9 . The process of  claim 8 , wherein X is chloro.  
     
     
         10 . A process for preparing a taxane comprising the steps of: 
 converting cinnamoyl halide to a cinnamoyl halide aziridine intermediate having the structure:                          wherein X is halogen;    converting the cinnamoyl halide aziridine intermediate to an open chain cinnamoyl halide intermediate having the structure:                          wherein X is halogen;    reacting the open chain cinnamoyl halide intermediate with protected baccatin III to provide a protected baccatin III intermediate having the structure:                          wherein R is selected from hydrogen and a hydroxy-protecting group;    converting the protected baccatin III intermediate to a taxane intermediate having the structure:                          wherein R is selected from hydrogen and a hydroxy-protecting group; and    converting the taxane intermediate to paclitaxel or docetaxel.    
     
     
         11 . The process of  claim 10 , wherein X is chloro.  
     
     
         12 . The process of  claim 10 , wherein the step of reacting the open chain cinnamoyl halide intermediate with protected baccatin III further comprises the steps of: 
 converting the open chain cinnamoyl halide intermediate to a β-lactam intermediate having the structure:                          reacting the β-lactam intermediate with protected baccatin III to provide the protected baccatin III intermediate.    
     
     
         13 . A process for preparing docetaxel from cephalomannine comprising the reaction sequence:  
       
         
           
           
               
               
           
         
       
       wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group.