Novel beta-lactams, methods for the preparation of taxanes, and sidechain-bearing taxanes

Abstract

Novel β-lactams finding utility as intermediates in the preparation of sidechain-bearing taxanes such as taxol and taxol derivatives. The present invention also relates to novel methods of coupling β-lactams to form such sidechain-bearing taxanes, and to novel sidechain-bearing taxanes.

What is claimed is:  
     
         1 . A β-lactam of the following formula I:  
       
         
           
           
               
               
           
         
         where 
 R 1  and R 2  are: 
 (i) both the same alkyl group;  
 (ii) together form a cycloalkyl group;  
 (iii) together form a cycloalkenyl group; or  
 (iv) together form a heterocyclo group;  
 
 R 3  is alkyl;  
 R 4  is aryl;  
 R 5  is hydrogen, arylcarbonyl, or alkyloxycarbonyl, or a salt thereof.  
 
       
     
     
         2 . A β-lactam of  claim 1  which is crystalline at ambient conditions.  
     
     
         3 . A β-lactam of  claim 1  which is substantially free of other isomers and in which the groups —OC(R 1 )(R 2 )(OR 3 ) and R 4  are in the cis position relative to each other.  
     
     
         4 . A β-lactam of  claim 1  where R 1  and R 2  are both the same unsubstituted lower alkyl group, R 3  is unsubstituted lower alkyl, R 4  is phenyl, and R 5  is hydrogen, benzoyl or t-butoxycarbonyl.  
     
     
         5 . A β-lactam of  claim 3  which is (3R-cis)-3-(1-methoxy-1-methylethoxy)-4-phenyl-2-azetidinone.  
     
     
         6 . A β-lactam of  claim 3  which is (3R-cis)-1-benzoyl-3-(1-methoxy-1-methylethoxy)-4-phenyl-2-azetidinone.  
     
     
         7 . A β-lactam of  claim 3  which is (3R-cis)-1-t-butoxycarbonyl-3-(1-methoxy-1-methylethoxy)-4-phenyl-2-azetidinone.  
     
     
         8 . A method for the preparation of a sidechain-bearing taxane of the following formula VII or a salt thereof:  
       
         
           
           
               
               
           
         
         where 
 R 1  and R 2  are: 
 (i) both the same alkyl group;  
 (ii) together form a cycloalkyl group;  
 (iii) together form a cycloalkenyl group;  
 or  
 (iv) together form a heterocyclo group;  
 
 R 3  is alkyl;  
 R 4  is aryl;  
 R 5  is hydrogen, arylcarbonyl, or alkyloxycarbonyl; and  
 T is a taxane moiety bonded directly at C-13 of said moiety;  
 
         comprising the step of contacting a β-lactam of the following formula I or a salt thereof:  
         
           
             
             
                 
                 
             
           
           where R 1 , R 2 , R 3 , R 4  and R 5  are as defined above, with a taxane compound of the following formula VIII or a salt thereof: 
           HO—T  (VIII) 
           where T is as defined above, in the presence of a coupling agent; and optionally, converting the group —OC(R 1 ) (R 2 ) (OR 3 ) of said compound of the formula VII to hydroxyl, thereby forming a sidechain-bearing taxane or a salt thereof of the following formula IX:  
           
             
               
               
                   
                   
               
             
           
           where R 4 , R 5  and T are as defined above.  
         
       
     
     
         9 . The method of  claim 8 , wherein the taxane of the formula VIII is a taxane of the following formula X:  
       
         
           
           
               
               
           
         
         where 
 Bz is benzoyl;  
 Ac is acetyl;  
 R 7  is hydrogen, alkylcarbonyl, or a hydroxyl protecting group; and  
 R 8  is hydrogen or a hydroxyl protecting group.  
 
       
     
     
         10 . The method of  claim 9 , wherein said taxane of the formula X is a 7-O-trialkylsilyl baccatin III.  
     
     
         11 . The method of  claim 8 , wherein said coupling agent is an alkali metal silylamide base or a sterically hindered alkali metal amide base.  
     
     
         12 . The method of  claim 11 , wherein said coupling agent has the following formula XI:  
       
         
           
           
               
               
           
         
         where 
 R 9  and R 10  are trialkylsilyl, cycloalkyl, or together with the nitrogen atom to which they are bonded, form a heterocyclo group; and  
 M is an alkali metal.  
 
       
     
     
         13 . The method of  claim 12 , wherein said coupling agent is an alkali metal hexamethyl disilazide.  
     
     
         14 . The method of  claim 13 , wherein said alkali metal hexamethyl disilazide is lithium hexamethyl disilazide.  
     
     
         15 . The method of  claim 9 , further comprising deprotection of one or more hydroxyl groups on the taxane moiety of the sidechain-bearing taxane formed.  
     
     
         16 . The method of  claim 15 , wherein an acid is employed for said deprotection.  
     
     
         17 . The method of  claim 10 , wherein R 1  and R 2  are both the same unsubstituted lower alkyl group, R 3  is unsubstituted lower alkyl, R 4  is phenyl, and R 5  is benzoyl or t-butoxycarbonyl.  
     
     
         18 . The method of  claim 17 , wherein taxol is prepared.  
     
     
         19 . The method of  claim 17 , wherein taxotere is prepared.  
     
     
         20 . A sidechain-bearing taxane of the following formula VII or a salt thereof:  
       
         
           
           
               
               
           
         
         where 
 R 1  and R 2  are: 
 (i) both the same alkyl group;  
 (ii) together form a cycloalkyl group;  
 (iii) together form a cycloalkenyl group; or  
 (iv) together form a heterocyclo group;  
 
 R 3  is alkyl;  
 R 4  is aryl;  
 R 5  is hydrogen, arylcarbonyl, or alkyloxycarbonyl; and  
 T is a taxane moiety bonded directly at C-13 of said moiety.  
 
       
     
     
         21 . A compound of  claim 20 , wherein R 1  and R 2  are both the same unsubstituted lower alkyl group, R 3  is unsubstituted lower alkyl, R 4  is phenyl, and R 5  is benzoyl or t-butoxycarbonyl.  
     
     
         22 . A compound of  claim 20  which is 2′-MOP-7-triethylsilyl taxol.  
     
     
         23 . A method for the preparation of a taxane bearing a sidechain at C-13, comprising the step of contacting a taxane bearing a hydroxyl group bonded at C-13 with a β-lactam capable of forming said sidechain, in the presence of an alkali metal silylamide base or a sterically hindered metal amide base.