Method for preparing taxane derivatives

Details Method for preparing taxane derivatives Method for preparing taxane derivatives

1994-08-02

2003-07-22

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S511000

Reexamination Certificate

active

06596880

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a new method for preparing taxane derivatives of general formula:
in which Ar represents an aryl radical, R represents a hydrogen atom or the acetyl radical and R
1
represents a benzoyl or tert-butoxycarbonyl radical, which derivatives display noteworthy antitumour properties.
BACKGROUND OF THE INVENTION
It is known, from American Patents U.S. Pat. No. 4,924,011 and U.S. Pat. No. 4,924,012, to prepare taxane derivatives of general formula (I) by esterification of a derivative of baccatine III or of 10-deacetyl baccatine III of general formula:
in which G
1
represents a protecting group for the hydroxyl function such as the 2,2,2-trichloroethoxycarbonyl radical or a replacement, by hydrogen atoms, of the protecting groups G
1
, G
2
and R
2
of the product obtained.
The esterification is carried out in the presence of a condensing agent such as a carbodiimide, for instance dicyclohexylcarbodiimide, or a reactive carbonate, for instance 2-dipyridyl carbonate, and an activating agent such as a dialkylaminopyridine, for instance 4-dimethylaminopyridine, working in an organic aromatic solvent such as benzene, toluene, xylenes, ethylbenzene, isopropylbenzene or chlorobenzene at a temperature between 60 and 90° C.
Replacement of the protecting groups by hydrogen atoms is carried out using zinc in acetic acid or by hydrolysis in an acidic medium.
It has now been found, and this forms the subject of the present invention, that the esterification of the alcohol of general formula (II) using the acid of general formula (III) may be performed at a temperature between −10 and 60° C. (60° C. not inc), preferably between 20 and 35° C., working in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, aliphatic hydrocarbons such as pentane, hexane or heptane, hydrogen atoms is carried out using zinc in acetic acid or by hydrolysis in an acidic medium.
DESCRIPTION OF THE INVENTION
It has now been found, and this forms the subject of the present invention, that the esterification of the alcohol of general formula (II) using the acid of general formula (III) may be performed at a temperature between −10 and 60° C., preferably between 20 and 35° C., working in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dioxane, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile, esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, aliphatic hydrocarbons such as pentane, hexane or heptane, chlorinated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane and aromatic hydrocarbons such as benzene, toluene and xylenes. Esters and aromatic hydrocarbons are very particularly advantageous.
The esterification is generally carried out in the presence of a condensing agent such as a carbodiimide, for instance dicyclohexylcarbodiimide, and an activating agent such as an aminopyridine, for instance 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
It is advantageous to perform the esterification using an excess of acid of general formula (III) relative to the alcohol of general formula (II), but the reaction may also be carried out using a stoichiometric amount of acid of general formula (III) and of alcohol of general formula (II). The condensing agent is generally used in a stoichiometric amount relative to the acid of general formula (III) and the activating agent represents a stoichiometric amount or less relative to the alcohol of general formula (II).
Since the method according to the invention is implemented at a temperature below that of the methods known previously, it allows higher yields of ester to be obtained due to the greater stability of the acid of general formula (III) in the reaction mixture and to the decrease in side reactions.


REFERENCES:
patent: 4924011 (1990-05-01), Denis et al.
patent: 4924012 (1990-05-01), Colin et al.
patent: 0 336 840 (1989-10-01), None
patent: 0 336 841 (1989-10-01), None
Swindell et al, J. Med. Chem., vol. 34, No. 3, pp. 1176-1184., 1991.*
V. Senilh et coll., C.R. Acad. Sci. Paris, t.299, serie II, n° 15, 1039 (1984).
F. Guéritte-Voegelein et al., Tetrahedron, 42 (16), 4451-4460 (1986).
J-N. Denis et coll., J. Amer. Chem. Soc., 110, 5917-5919 (1988).
L. Mangatal et al., Tetrahedron, 45 (13), 4177-4180 (1989).
F. Guéritte-Voeglein et al., J. Med. Chem., 34, 992-998 (1991).

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