Process for the preparation of taxane derivatives

Abstract

Taxane derivatives and a method of preparing taxane derivatives of formula (I): are disclosed. In general formula (I), Ar represents an aryl radical; R represents a phenyl radical or a radical R 5 —O— in which R 5 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or saturated or unsaturated nitrogenous heterocylcyl radical, R 1 and R 2 , which are identical or different, each represent a hydrogen atom or an alkyl, phenylalkyl, phenyl, alkoxyphenyl, or dialkoxyphenyl radical, or else R 1 and R 2 form, together with the carbon atom to which they are bonded, a ring having from 4 to 7 members; R 3 represents an acetyl radical or a protecting group of the hydroxyl functional group; and R 4 represents a protecting group of the hydroxyl functional group.

1 . Process for the preparation of taxane derivatives of general formula:  
       
         
           
           
               
               
           
         
       
       in which 
 Ar represents an aryl radical,  
 R represents the phenyl radical or a radical R 5 —O— in which R 5  represents 
 a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by one or a number of substituents chosen from the halogen atoms and the hydroxyl radical, alkoxy radical containing 1 to 4 carbon atoms, dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms, piperidino radical, morpholino radical, 1-piperazinyl radical (optionally substituted in the 4-position by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6 carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms, phenyl cyano radical, carboxyl radical or alkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms,  
 or a phenyl radical optionally substituted by one or a number of atoms or radicals chosen from the halogen atoms and the alkyl radicals containing 1 to 4 carbon atoms or the alkoxy radicals containing 1 to 4 carbon atoms,  
 a saturated or unsaturated nitrogen-containing heterocyclyl radical containing 4 to 6 members and optionally substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally be substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms,  
 
 R 1  and R 2 , which are identical or different, represent a hydrogen atom or an alkyl, phenylalkyl, phenyl, alkoxyphenyl or dialkoxyphenyl radical or else Rl and R2 form, together with the carbon atom to which they are bonded, a ring having from 4 to 7 members,  
 R 3  represents an acetyl radical or a protective group of the hydroxyl functional group and  
 R 4  represents a protective group of the hydroxyl functional group, characterized in that protected baccatin III or protected 10-deacetylbaccatin III of general formula:  
                     
 in which R 3  and R 4  are defined as above, is esterified by means of an acid of general formula:  
                     
 in which Ar, R, R 1  and R 2  are defined as above, or of an activated derivative of this acid.  
 
     
     
         2 . Process according to  claim 1 , characterized in that the esterification is carried out by means of an acid of general formula:  
       
         
           
           
               
               
           
         
       
       in which Ar, R, R 1  and R 2  are defined as in  claim 1 , the reaction being carried out in the presence of a condensation agent and of an activating agent in an organic solvent at a temperature between 0 and 90° C.  
     
     
         3 . Process according to  claim 2 , characterized in that the condensation agent is chosen from imides and reactive carbonates and the activating agent is chosen from aminopyridines.  
     
     
         4 . Process according to  claim 3 , characterized in that the condensation agent is chosen from dicyclohexylcarbodiimide and di-2-pyridyl ketone and the activating agent is chosen from 4-dimethylaminopyridine or 4-pyrrolidinopyridine.  
     
     
         5 . Process according to  claim 2 , characterized in that the solvent is chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons.  
     
     
         6 . Process according to  claim 5 , characterized in that the solvent is chosen from aromatic hydrocarbons.  
     
     
         7 . Process according to  claim 1 , characterized in that the esterification is carried out by means of an anhydride of general formula:  
       
         
           
           
               
               
           
         
       
       in which Ar, R, R 1  and R 2  are defined as in  claim 1 , the reaction being carried out in the presence of an activating agent in an organic solvent at a temperature between 0 and 90° C.  
     
     
         8 . Process according to  claim 7 , characterized in that the activating agent is chosen from aminopyridines.  
     
     
         9 . Process according to  claim 8 , characterized in that the activating agent is chosen from 4-dimethylaminopyridine or 4-pyrrolidinopyridine.  
     
     
         10 . Process according to  claim 7 , characterized in that the solvent is chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons.  
     
     
         11 . Process according to  claim 1 , characterized in that the esterification is carried out by means of an activated acid of general formula:  
       
         
           
           
               
               
           
         
       
       in which Ar, R, R 1  and R 2  are defined as in  claim 1  and X represents a halogen atom or an acyloxy or aroyloxy radical, optionally prepared in situ in the presence of a base, the reaction being carried out in an organic solvent at a temperature between 0 and 90° C.  
     
     
         12 . Process according to  claim 11 , characterized in that the base is chosen from nitrogenous organic bases.  
     
     
         13 . Process according to  claim 12 , characterized in that the nitrogenous organic base is chosen from aliphatic tertiary amines, pyridine and aminopyridines.  
     
     
         14 . Process according to  claim 11 , characterized in that the organic solvent is chosen from ethers, ketones, esters, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons.  
     
     
         15 . Process according to  claim 14 , characterized in that the solvent is chosen from aromatic hydrocarbons.  
     
     
         16 . The acids of general formula:  
       
         
           
           
               
               
           
         
       
       in which Ar, R, R 1  and R 2  are defined as in  claim 1 , optionally in the salt, ester, anhydride, mixed anhydride or halide form.