Semisynthesis Process for the Preparation of 10-Deacytyl-N-Debenzoyl-Paclitaxel

Abstract

The invention relates to a process for the preparation of 10-deacetyl-N-debenzoyl-paclitaxel, a synthon useful for the preparation of taxanes with antitumour activity, and intermediates for the preparation thereof. The invention also discloses a process for the preparation of Docetaxel starting from said compound of formula (I).

1 . A process for the preparation of 10-deacetyl-N-debenzoyl-paclitaxel (I) 
       
         
           
           
               
               
           
         
       
       comprising the following steps:
 a) reaction of 2-(2,4-dimethoxyphenyl)-3-(2-nitrobenzenesulfenyl)-4(S)-phenyl-5(R)-oxazolidinecarboxylic acid (V) 
 
       
         
           
           
               
               
           
         
       
       with 10-deacetyl-bis-7,10-trichloroacetylbaccatin III (VI) 
       
         
           
           
               
               
           
         
       
       to give 2-(2,4-dimethoxyphenyl)-3-(2-nitrobenzensulfenyl)-4(S)-phenyl-5(R)-oxazolidine carboxylic acid, 10-deacetyl-7,10-bis-trichloroacetylbaccatin III 13-yl-ester (VII) 
       
         
           
           
               
               
           
         
         b) hydrolysis of the trichloroacetyl groups at the 7- and 10-positions of the compound of formula (VII) to give 2-(2,4-dimethoxyphenyl)-3-(2-nitrobenzensulfenyl)-4(S)-phenyl-5(R)-oxazolidine carboxylic acid, 10-deacetylbaccatin III 13-yl-ester (VIII) 
       
       
         
           
           
               
               
           
         
         c) acid treatment of the compound formula (VIII) to give 10-deacetyl-N-debenzoyl-paclitaxel (I). 
       
     
     
         2 . A process according to  claim 1  wherein step a) is carried out in a solvent selected from an ether, an ester, an aromatic hydrocarbon or a halogenated aliphatic solvent. 
     
     
         3 . A process according to  claim 2  wherein the aliphatic halogenated hydrocarbon is methylene chloride. 
     
     
         4 . A process according to  claim 1  wherein step a) is carried out in the presence of a condensing agent and an activating agent. 
     
     
         5 . Process according to  claim 4  wherein the condensing agent is dicyclohexylcarbodiimide and the activating agent is 4-dimethylamino-pyridine. 
     
     
         6 . A process according to  claim 1  wherein step b) is carried out with ammonium hydroxide in tetrahydrofuran as the solvent. 
     
     
         7 . A process according to  claim 6  wherein step c) is carried out with a methanol solution of aqueous hydrochloric acid. 
     
     
         8 . 2-(2,4-Dimethoxyphenyl)-3-(2-nitrobenzensulfenyl)-4(S)-phenyl-5(R)-oxazolidine carboxylic acid, 10-deacetyl-7,10-bis-trichloroacetylbaccatin III 13-yl-ester (VII) 
       
         
           
           
               
               
           
         
       
     
     
         9 . 2-(2,4-Dimethoxyphenyl)-3-(2-nitrobenzensulfenyl)-4(S)-phenyl-5(R)-oxazolidine carboxylic acid, 10-deacetylbaccatin III 13-yl-ester (VIII) 
       
         
           
           
               
               
           
         
       
     
     
         10 . A process for the preparation of 10-deacetyl-bis-7,10-trichloroacetylbaccatin III with a content of the corresponding 7- or 10-mono-trichloroacetyl derivatives lower than 0.1% as determined by HPLC, comprising the silica gel chromatography of the reaction mixture. 
     
     
         11 . A process for the preparation of Docetaxel by subjecting the intermediate (I) obtained by the process of  claim 1  to reaction with di-tert-butyl dicarbonate. 
     
     
         12 . A process according to  claim 11  wherein the reaction is carried out in solvents selected from alcohols, chlorinated hydrocarbons or mixtures thereof, in the absence of bases. 
     
     
         13 . A process according to  claim 11  wherein Docetaxel is purified by crystallizations from ethanol/water and/or acetone/hydrocarbon mixtures. 
     
     
         14 . A process for the preparation of docetaxel having a purity degree higher than 99% obtained without chromatographic purification and with a content of corresponding 7-epi or 10-dehydro derivatives lower than 0.1% each. 
     
     
         15 . Docetaxel having a purity degree higher than 99% and with a content of corresponding 7-epi or 10-dehydro derivatives lower than 0.1% each. 
     
     
         16 . Pharmaceutical compositions comprising Docetaxel of  claim 15 .