Process for C7 silylation of hydroxy substituted taxanes and intermediates thereof

Abstract

Processes for the preparation of taxol and other taxanes through selective derivatization of the C(7) hydroxyl and C(10) hydroxyl groups of 10-DAB, particularly a novel process using a new strategy in which the C(10) hydroxyl group is protected or derivatized prior to the C(7) hydroxyl group; and the provision of C(7) and C(10) derivatized 10-DAB compounds.

1 . A taxane having the structure  
     
       
         
         
             
             
         
       
     
     wherein 
 M is a metal or comprises ammonium:  
 R 1  is hydrogen, hydroxy, protected hydroxy, or together with R 14  or R 2  forms a carbonate;  
 R 2  is keto, —OT 2 , acyloxy, or together with R 1  forms a carbonate;  
 R 4  is —OT 4  or acyloxy;  
 R 7  is —OSi(Me) 2 Ph;  
 R 9  is hydrogen, keto, —OT 9 , or acyloxy;  
 R 10  is hydrogen, keto, —OT 10 , or acyloxy;  
 R 13  is hydroxy, protected hydroxy, keto, or MO—;  
 R 14  is hydrogen, —OT 14 , acyloxy, or together with R 1  forms a carbonate; and  
 T 2 , T 4 , T 9 , T 10 , and T 14  are independently hydrogen or hydroxy protecting group.  
 
   
   
       2 . A taxane having the structure  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydroxy or together with R 14  or R 2  forms a carbonate;  
 R 2  is —OCOZ 2 , —OCOOZ 2 , or together with R 1  forms a carbonate;  
 R 4  is —OCOZ 4 ;  
 R 7  is —OSi(Me) 2 Ph;  
 R 9  is hydrogen or keto;  
 R 10  is hydrogen, keto, hydroxy, protected hydroxy, or acyloxy;  
 R 13  is hydroxy, protected hydroxy, or  
                     
 R 14  is hydrogen, hydroxy, protected hydroxy, or together with R 1  forms a carbonate;  
 X 1  is —OX 6  or —NX 8 X 9 ;  
 X 2  is hydrogen, hydrocarbyl, or substituted hydrocarbyl;  
 X 3  and X 4  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;  
 X 5  is —X 10 , —OX 10 , or —NX 8 X 10 ;  
 X 6  is a hydroxy protecting group;  
 X 8  is hydrogen, hydrocarbyl, or substituted hydrocarbyl;  
 X 9  is an amino protecting group;  
 X 10  is hydrocarbyl, substituted hydrocarbyl, or heteroaryl; and  
 Z 2  and Z 4  are independently hydrocarbyl, substituted hydrocarbyl, or heteroaryl.  
 
   
   
       3 . The taxane of  claim 1  wherein R 10  is hydroxy, protected hydroxy or acyloxy.  
   
   
       4 . The taxane of  claim 2  wherein R 10  is hydroxy, protected hydroxy or acyloxy.  
   
   
       5 . The taxane of  claim 1  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       6 . The taxane of  claim 1  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       7 . The taxane of  claim 1  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       8 . The taxane of  claim 1  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       9 . The taxane of  claim 1  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       10 . The taxane of  claim 2  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       11 . The taxane of  claim 2  having the structure  
     
       
         
         
             
             
         
       
     
   
   
       12 . A process for preparing a C(7) dimethylphenylsilyloxy substituted taxane, the process comprising treating a C(7) hydroxy substituted taxane with a dimethylphenylsilyl halide in the presence of a pyridine, the C(7) dimethylphenylsilyloxy substituted taxane having the structure  
     
       
         
         
             
             
         
       
     
     and the C(7) hydroxy substituted taxane having the structure  
     
       
         
         
             
             
         
       
     
     wherein 
 R 10  is acyloxy, trialkylsilyloxy or hydroxy.  
 
   
   
       13 . The process of  claim 12  wherein R 10  is acetoxy.  
   
   
       14 . The process of  claim 12  wherein R 10  is propionyloxy.  
   
   
       15 . The process of  claim 12  wherein R 10  is cyclopropylcarbonyloxy.  
   
   
       16 . The process of  claim 12  wherein R 10  is hydroxy.  
   
   
       17 . The process of  claim 12  wherein R 10  is dimethyl t-butylsilyloxy.  
   
   
       18 . The process of  claim 12  wherein R 10  is trimethylsilyloxy.  
   
   
       19 . The process of  claim 12  wherein R 10  is triethylsilyloxy.