Process for preparing taxol

• US 4,924,011 A
• Filed: 04/03/1989
• Issued: 05/08/1990
• Est. Priority Date: 04/06/1988
• Status: Expired

• Current Assignee: Rhone-Poulenc Rorer S.A.
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Denis, Jean-Noel, Guenard, Daniel, Greene, Andrew E., Gueritte-Voegelein, Francoise
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): Trinh, Ba K.
• Application Number:
  US07/331,807
• Time in Patent Office: 400 Days
• Field of Search: 549/510, 549/511
• US Class Current: 549/510
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems

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 R₂ and R₃ protecting the hydroxy groups. ##STR1##

Claims

1. A process for preparing taxol of formula:

##STR9## in which a (2R, 3S) 3-phenylisoserine derivative of general formula;

##STR10## in which R₂ is a hydroxy-protecting group, is esterified with a taxan derivative of general formula;

##STR11## in which R₃ is a hydroxy-protecting group, and the protecting groups R₂ and R₃ are then both replaced by hydrogen.

2. A process according to claim 1, in which R₂ is chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β

-trimethylsilylethoxy)methyl, tetrahydropyranyl and 2,2,2-trichloroethoxycarbonyl, and R₃ 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 R₂ and R₃ 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.