Process for preparing taxol

Abstract

Process for preparing taxol by the condensation of a (2R, 3S) acid of general formula (I) with a taxan derivative of general formula (II), followed by the removal of the groups R 2 and R 3 protecting the hydroxy groups .Iadd.and intermediates used therein.Iaddend.. ##STR1##

We claim: 
     
       1. A process for preparing taxol of formula: ##STR9## in which a (2R, 3S) 3-phenylisoserine derivative of general formula: ##STR10## in which R 2  is a hydroxy-protecting group, is esterified with a taxan derivative of general formula: ##STR11## in which R 3  is a hydroxy-protecting group, and the protecting groups R 2  and R 3  are then both replaced by hydrogen. 
     
     
       2. A process according to claim 1, in which R 2  is chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy)methyl, tetrahydropyranyl and 2,2,2-trichloroethoxycarbonyl, and R 3  is chosen from trialkylsilyl groups in which each alkyl portion contains 1 to 3 carbon atoms. 
     
     
       3. A process according to claim 2, in which the esterification is performed in the presence of a condensing agent and an activating agent. 
     
     
       4. A process according to claim 3, in which the condensing agent is chosen from carbodiimides and reactive carbonates, and the activating agent is chosen from dialkylaminopyridines. 
     
     
       5. A process according to claim 4, in which the condensing agent is chosen from dicyclohexylcarbodiimide and di-2-pyridyl carbonate and the activating agent is 4-dimethylaminopyridine. 
     
     
       6. A process according to claim 1, in which the reaction is performed in an aromatic organic solvent chosen from benzene, toluene, xylenes, ethylbenzene, isopropylbenzene and chlorobenzene. 
     
     
       7. A process according to claim 1, in which the reaction is performed at a temperature of between 60° and 90° C. 
     
     
       8. A process according to claim 1, in which the replacement of the protecting groups with hydrogen in the intermediate (2'R, 3'S) ester obtained, of general formula: ##STR12## in which R 2  and R 3  are as defined in claim 1, is performed in an acid medium. 
     
     
       9. A process according to claim 8, in which the acid medium comprises and inorganic acid dissolved in an aliphatic alcohol containing 1 to 3 carbon atoms. 
     
     
       10. A process according to claim 9, in which the inorganic acid is hydrochloric acid. 
     
     
       11. A process according to claim 8, in which the reaction is performed at a temperature in the region of 0° C. .Iadd. 
     
     
       12.  A taxan derivative of the formula: ##STR13## wherein R 3  is a trialkylsilyl group in which each alkyl portion contains 1 to 3 carbon atoms. .Iaddend. .Iadd. 
     
     
       13.  A taxan derivative of the formula: ##STR14## wherein R 3  is a trialkylsilyl group in which each portion contains 1 to 3 carbon atoms. .Iaddend. .Iadd. 
     
     
       14.  A taxan derivative of the formula: ##STR15## wherein R 2  is a hydroxy-protecting group and R 3  is a trialkylsilyl group in which each portion contains 1 to 3 carbon atoms. .Iaddend. .Iadd. 
     
     
       15.  A taxan derivative according to claim 14 wherein R 2  is chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy)methyl, tetrahydropyranyl and 2,2,2-trichloethoxycarbonyl. .Iaddend. .Iadd. 
     
     
       16.  A process for preparing taxol of the formula: ##STR16## comprising the following steps: A. reacting a compound of the following formula: ##STR17## with a halotrialkylsilane wherein each alkyl portion contains 1 to 3 carbon atoms, to form a compound of the following formula: ##STR18## in which R 3  is chosen from trialkylsilyl groups in which each alkyl portion contains 1 to 3 carbon atoms; B. acetylating the compound so obtained with acetyl chloride to give a compound of the following formula: ##STR19## C. esterifying the compound so obtained with a (2R, 3S) 3-phenylisoserine derivative of the general formula: ##STR20## in which R 2  is a hydroxy-protecting group; and D. replacing both of the protecting groups R 2  and R 3  by hydrogen. .Iaddend. .Iadd.   
     
     
       17.  A process according to claim 16 in which R 2  is methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy)methyl, tetrahydropyranyl or 2,2,2-trichloroethoxycarbonyl. .Iaddend.