Method for preparation of taxol

Abstract

A β-lactam of the formula: wherein R 1 is aryl, substituted aryl, alkyl, alkenyl, or alkynyl; R 2 is hydrogen, alkyl, acyl, acetal, ethoxyethyl, or other hydroxyl protecting group; and R 3 is aryl, substituted aryl, alkyl, alkenyl, or alkynyl; and process for the preparation of taxol comprising contacting said β-lactam and an alcohol in the presence of an activating agent to provide a taxol intermediate, and converting the intermediate to taxol.

What is claimed is:  
     
         1 . A β-lactam of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is aryl, substituted aryl, alkyl, alkenyl, or alkynyl; R 2  is hydrogen, ethoxyethyl, 2,2,2-trichloroethoxymethoxy or other hydroxyl protecting group; and R 3  is aryl, substituted aryl, alkyl, alkenyl, or alkynyl.  
     
     
         2 . The compound of    claim 1    wherein the hydroxyl protecting group is selected from the group consisting of acetals, ethers, esters, and carbonates.  
     
     
         3 . The enantiomers of the compound of    claim 1   .  
     
     
         4 . The diastereomers of the compound of    claim 1   .  
     
     
         5 . The compound of    claim 1    wherein R 1  is phenyl, substituted phenyl, or aryl; R 2  is ethoxyethyl, or 2,2,2-trichloroethoxymethoxy; and R 3  is phenyl, substituted phenyl, or aryl.  
     
     
         6 . The compound of    claim 1    wherein R 2  is ethoxyethyl.  
     
     
         7 . A β-lactam of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is a hydroxyl protecting group.  
     
     
         8 . The compound of    claim 7    wherein R 2  is selected from the group consisting of acetals, ethers, esters, and carbonates.  
     
     
         9 . The compound of    claim 7    wherein R 2  is ethoxyethyl or 2,2,2-trichloroethoxymethoxy.  
     
     
         10 . The compound of    claim 7    wherein R 2  is ethoxyethyl.  
     
     
         11 . A process for the preparation of a taxol intermediate comprising contacting an alcohol with a β-lactam having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is aryl, substituted aryl, alkyl, alkenyl, or alkynyl,  
 R 2  is a hydroxyl protecting group, and  
 R 3  is aryl, substituted aryl, alkyl, alkenyl, or alkynyl,  
 the contacting of said alcohol and β-lactam being carried out in the presence of a sufficient amount of an activating agent under effective conditions to cause the β-lactam to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol.  
 
     
     
         12 . The process of    claim 11    wherein the hydroxyl protecting group is selected from acetals, ethers, esters, and carbonates.  
     
     
         13 . The process of    claim 11    wherein R 1  is aryl, or substituted aryl; R 2  is ethoxyethyl or 2,2,2-trichloroethoxymethoxy; and R 3  is aryl or substituted aryl.  
     
     
         14 . The process of    claim 11    wherein R 2  is ethoxyethyl.  
     
     
         15 . The process of    claim 11    wherein the alcohol has the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 4  is a hydroxyl protecting group.  
     
     
         16 . The process of    claim 15    wherein R 4  is selected from ethers, esters, carbonates and silyl groups.  
     
     
         17 . The process for    claim 15    wherein R 4  is ethoxyethyl, trimethyl silyl or triethyl silyl.  
     
     
         18 . The process of    claim 15    wherein the activating agent is a tertiary amine.  
     
     
         19 . The process of    claim 15    wherein the activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidizole, or 4-dimethylaminopyridine.  
     
     
         20 . The process of    claim 11    wherein the activating agent is a tertiary amine.  
     
     
         21 . The process of    claim 11    wherein the activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidizole, or 4-dimethylaminopyridine.  
     
     
         22 . A process for the preparation of taxol which comprises contacting an alcohol with a β-lactam of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is aryl, substituted aryl, alkyl, alkenyl, or alkynyl;  
 R 2  is a hydroxyl protecting group; and  
 R 3  is aryl, substituted aryl, alkyl, alkenyl, or alkynyl;  
 the contacting of said alcohol and β-lactam being carried out in the presence of a sufficient amount of an activating agent under effective conditions to cause the β-lactam to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.  
 
     
     
         23 . The process of    claim 22    wherein the hydroxyl protecting group is selected from acetals, ethers, esters, and carbonates.  
     
     
         24 . The process of    claim 22    wherein R 2  is ethoxyethyl.  
     
     
         25 . The process of    claim 22    wherein the alcohol has the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 4  is a hydroxyl protecting group  
     
     
         26 . The process of    claim 25    wherein R 4  is selected from ethers, esters, carbonates and silyl groups.  
     
     
         27 . The process of    claim 22    wherein the activating agent is a tertiary amine.  
     
     
         28 . The process of    claim 22    wherein the activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidizole, or 4-dimethylaminopyridine.  
     
     
         29 . A process for the preparation oil a taxol having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or  
 A and B together form an oxo;  
 L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;  
 E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;  
 E and F together form an oxo;  
 G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or  
 G and M together form an oxo or methylene or  
 G and M together form an oxocyclopropyl ring or  
 M and F together form an oxocyclobutyl ring;  
 J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or  
 I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or  
 I and J taken together form an oxo; and  
 K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and  
 P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or  
 P and Q together form an oxo; and  
 S and T are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or  
 S and T together form an oxo; and  
 U and V are independently hydrogen or lower alkyl, alkenyl, alkynyl, aryl, or substituted aryl; and  
 W is aryl, substituted aryl, lower alkyl, alkenyl, or alkynyl, comprising:  
 contacting a β-lactam of the formula:  
                     
 wherein  
 R 1  is phenyl, substituted phenyl, aryl, alkyl, alkenyl, or alkynyl;  
 R 2  is a hydroxyl protecting group; and  
 R 3  is phenyl, substituted phenyl, aryl, alkyl, alkenyl, or alkynyl; with an alcohol of the formula:  
                     
 wherein said A B, D, E, F, G, I, J, K, L, M and P are as defined above, the contacting of said β-lactam and said alcohol being carried out in the presence of a sufficient amount of an activating agent under effective conditions to cause the β-lactam to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.  
 
     
     
         30 . The process of    claim 29    wherein said alcohol has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 4  is a hydroxyl protecting group.  
     
     
         31 . The process of    claim 30    wherein R 4  is selected from ethers, esters, carbonates and silyl groups.  
     
     
         32 . The process of    claim 30    wherein R 4  is ethoxyethyl, trimethyl silyl or triethyl silyl.  
     
     
         33 . The process of    claim 30    wherein said R 1  is phenyl and said R 3  is phenyl.  
     
     
         34 . The process of    claim 33    wherein said activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidizole, or 4-dimethylaminopyridine.