Process for preparing taxoids

• US 5,587,493 A
• Filed: 06/07/1995
• Issued: 12/24/1996
• Est. Priority Date: 12/09/1992
• Status: Expired due to Term

• Current Assignee: Aventis Pharma SA (Sanofi )
• Original Assignee: Rhone-Poulenc Rorer S.A.
• Inventors: Commercon, Alain, Bourzat, Jean-Dominique, Bouchard, Herv e
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US08/487,232
• Time in Patent Office: 566 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a process for preparing taxoids of formula I herein that includes the steps of esterifying a baccatin III derivative of the formula VI herein, acylating the compound obtained, and optionally removing a protecting group to give the desired taxoid product.

Claims

1. A process for preparing a taxoid of formula I:

##STR27## in which R represents a hydrogen atom or an acetyl, alkoxyacetyl, or alkyl radical, R₁ represents a benzoyl radical or a radical R₂ --O--CO in which R₂ represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising the steps of

esterifying a compound of the formula VI;

##STR28## in which G₁ represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxy-protecting group, with a free acid of the formula VII;

##STR29## in which Ar and R₁ are as defined above, and R₃ and R₄, which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms or an aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms or an aryl radical, or R₃ represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R₄ represents a hydrogen atom, or R₃ and R₄ form, together with the carbon atom to which they are attached, a 4- or 7-membered ring, to give, after treating in acidic medium, a compound of the formula IV;

##STR30## in which Ar and G₁ are as defined above, acylating the compound with benzoyl chloride or a reactive derivative of the formula;

space="preserve" listing-type="equation">R.sub.2 --O--CO--X

in which X represents a halogen atom or a residue --O--R₂ or --O--CO--O--R₂, and R₂ is as defined above, to give a produce of formula I or a compound of formula III ##STR31## wherein G₁ represents a protecting group that is removed to give a product of formula I.

2. A process of claim 1, wherein the protecting group is replaced by a hydrogen atom.

3. A process of claim 1, wherein the esterifying step further comprises using a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic colvent chosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from -10°

to 90°

C.

4. A process of claim 1, wherein the free acid of the esterifying step is in an anhydride form, and wherein the esterifying step is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°

to 90°

C.

5. A process of claim 1, wherein the free acid of the esterifying step is in a halide form or an anhydride from with an aliphatic or aromatic acid, and wherein the esterifying step is carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°

to 80°

C.

6. A process of claim 5, wherein the anhydride form of the free acid is prepared in situ.

7. A process of claim 1, wherein the acidic medium of the acid treatment step is an inorganic or organic acid in an organic solvent at a temperature ranging from 0°

to 50°

C.

8. A process of claim 7, wherein the acid is chosen from hydrochloric, sulphuric, and formic acids.

9. A process of claim 7, wherein the solvent is chosen from alcohols containing 1 to 3carbon atoms.

10. A process of claim 1, wherein the acylating step further comprises using an inert organic solvent in the presence of an inorganic or organic base.

11. A process of claim 10, wherein the inert organic solvent is chosen from esters and halogenated aliphatic hydrocarbons.

12. A process of claim 1, wherein the esterifying step is carried out at a temperature ranging from 0°

to 50°

C.

13. A process of claim 1, wherein the protecting group G₁ of formula III represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical and is replaced with a hydrogen atom by treating with zinc or zinc combined with copper in the presence of acetic acid at a temperature ranging from 30°

to 60°

C. or by treating with an inorganic or organic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester in the presence of zinc or zinc combined with copper.

14. A process of claim 13, wherein the organic acid is selected from hydrochloric acid and acetic acid.

15. A process of claim 13, wherein the aliphatic ester is selected from at least one of ethyl acetate, isopropyl acetate, and n-butyl acetate.

16. A process of claim 1, wherein G₁ is an alkoxyacetyl radical and is replaced with a hydrogen atom by treating in an alkaline medium using ammonia in an aqueous-alcoholic medium at a temperature of about 20°

C. or by treating with a zinc halide in methanol at a temperature of about 20°

C.

17. A process for preparing a taxoid of formula I:

##STR32## in which R represent a hydrogen atom or an acetyl, alkoxyacetyl, or alkyl radical, R₁ represents a radical R₂ --O--CO-- in which R₂ represents an alkyl radical, and Ar represents an aryl radical, comprising the steps of

esterifying a compound of the formula VI;

##STR33## in which G₁ represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxy-protecting group, with a free acid of the formula VII;

##STR34## in which Ar and R₁ are as defined above, and R₃ and R₄, which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms or a aralkyl radical whose alkyl portion contains 1 to 4 carbon atoms or an aryl radical, or R₃ represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R₄ represents a hydrogen atom, or R₃ and R₄ form, together with the carbon atom to which they are attached, a 4- or 7-membered ring, to give, after treating in acidic medium, a compound of the formula IV;

##STR35## in which Ar and G₁ are as defined above, acylating the compound of formula IV with a benzoyl chloride or a reactive derivative of the formula;

space="preserve" listing-type="equation">R.sub.2 --O--CO--X

in which X represents a halogen atom or a residue --O--R₂ or --O--CO--O--R₂, and R₂ is as defined above, to give a produce of formula I or a compound of formula III ##STR36## wherein G₁ represents a protecting group that is removed to give a produce of formula I.

18. A process of claim 17, wherein the protecting group is replaced by a hydrogen atom.

19. A process of claim 17, wherein the esterifying step further comprises using a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from -10°

to 90°

C.

20. A process of claim 17, wherein the free acid of the esterifying step is in an anhydride form, and wherein the esterifying step is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, eters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°

to 90°

C.

21. A process of claim 17, wherein the free acid of the esterifying step is in a halide form or an anhydride from with an aliphatic or aromatic acid, and wherein the esterifying step is carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°

to 80°

C.

22. A process of claim 21, wherein the anhydride form of the free acid is prepared in situ.

23. A process of claim 17, wherein the acidic medium in the acid treatment step is an inorganic or organic acid in an organic solvent at a temperature ranging from 0°

to 50°

C.

24. A process of claim 23, wherein the acid is chosen from hydrochloric, sulphuric, and formic acids.

25. A process of claim 23, wherein solvent is chosen from alcohols containing 1 to 3 carbon atoms.

26. A process of claim 17, wherein the step of acylating further comprises using an inert organic solvent in the presence of an inorganic or organic base.

27. A process of claim 26, wherein the inert organic solvent is chosen from esters and halogenated aliphatic hydrocarbons.

28. A process of claim 17, wherein the esterifying step is carried out at a temperature ranging from 0°

to 50°

C.

29. A process of claim 17, wherein the protecting group G₁ of formula III represents a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical and is replaced by a hydrogen atom by treating from zinc or zinc combined with copper in the presence of acetic acid at a temperature ranging from 30°

to 60°

C. or by treating with an inorganic or organic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester in the presence of zinc or zinc combined with copper.

30. A process of claim 29, wherein the organic acid is selected from hydrochloric acid and acetic acid.

31. A process of claim 29, wherein the aliphatic ester is selected from at least one of ethyl acetate, isopropyl acetate, and n-butyl acetate.

32. A process of claim 17, wherein G₁ is an alkoxyacetyl radical and is replaced with a hydrogen atom by treating in an alkaline medium using ammonia in an aqueous-alcoholic medium at a temperature of about 20°

C. or by treating with a zinc halide in methanol at a temperature of about 20°

C.