Process for the preparation of taxanes from 10-deacetylbaccatin III

Abstract

A process for the preparation of taxane derivatives by reacting 10-deacetylbaccatin III protected at the 7-and 1-positions with trichloroacetyl groups with a compound of formula and subsequent removal of the protective groups and hydrolysis of the oxazolidine ring.

1. A compound of Formula (IV) 
                 
 
       wherein R is a tert-butoxycarbonyl, benzoyl, or straight or branched chain alkyl carbonyl group; R 1  is a phenyl or a straight or branched alkyl or alkenyl group; and R 2  is hydrogen or an acetyl group. 
     
     
       2. A process for preparing a compound of formula I 
                 
 
       wherein R is a tert-butoxycarbonyl, benzoyl, or straight or branched chain alkyl carbonyl group; R 1  is a phenyl or a straight or branched alkyl or alkenyl group; and R 2  is hydrogen or an acetyl group, said process comprising
 (a) simultaneously protecting the C-7 and C-10 hydroxyl groups of 10-deacetylbaccatin III with trichloroacetyl groups to provide a protected 10-deacetylbaccatin III,  
 (b) esterifying the C-13 hydroxyl group of the protected 10-deacetylbaccatin III with an oxazolidine 5-carboxylic acid of formula II 
                 
 
 
       wherein R is a tert-butoxycarbonyl, benzoyl, or straight or branched chain alkyl carbonyl group; R 1  is a phenyl or a straight or branched alkyl or alkenyl group to provide a protected C-13 esterified 10-deacetylbaccatin III having an oxazolidine ring at the C-13 position;
 (c) removing the trichloroacetyl groups from the protected C-13 esterified 10-deacetylbaccatin III to provide a C-13 esterified 10-deacetylbaccatin III;  
 (d) optionally acetylating the C-10 hydroxyl group of the C-13 esterified 10-deacetylbaccatin III to provide a C-13 esterified baccatin III; and  
 (e) hydrolyzing the oxazlodine ring of the protected C-13 esterified 10-deacetylbaccatin III or the C-13 esterified baccatin III in the presence of an acid to provide the compound of formula I.  
 
     
     
       3. The process of  claim 2 , wherein step (b) is carried out in the presence of a condensing agent and a base. 
     
     
       4. The process of  claim 3 , wherein the condensing agent is dicyclohexylcarbodiimide. 
     
     
       5. The process of  claim 4 , wherein the base is pyridine. 
     
     
       6. The process of  claim 2 , wherein step (c) is carried out using NH 4 OH/NH 4 Cl in an aliphatic solvent. 
     
     
       7. The process of  claim 2 , wherein step (d) is carried out by reacting the C-13 esterified 10-deacetylbaccatin III with acetic anhydride in the presence of a cerium III, scandium, or ytterbium salt. 
     
     
       8. The process of  claim 2 , wherein step (e) is carried out by reacting the protected C-13 esterified 10-deacetylbaccatin III or the C-13 esterified baccatin III with an organic acid or an inorganic acid in an aliphatic alcohol or tetrahydrofuran. 
     
     
       9. The process of  claim 8 , wherein the acid is formic acid. 
     
     
       10. The process of  claim 2 , wherein R is a benzoyl group, R 1  is a phenyl group, and R 2  is an acetyl group. 
     
     
       11. The process of  claim 2 , wherein R is tert-butoxycarbonyl group, R 1  is a phenyl group, and R 2  is a hydrogen. 
     
     
       12. A compound of Formula ( III )