Carboxylic acids for synthesis of taxane derivatives

Details Carboxylic acids for synthesis of taxane derivatives Carboxylic acids for synthesis of taxane derivatives

1997-08-08

2002-08-13

Stockton, Laura L. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06433180

ABSTRACT:

DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of taxane derivatives of general formula:
which are particularly advantageous intermediates for preparing taxol, Taxotere and their analogues which have notable antileukaemic and antitumour properties.
In the general formula (I),
Ar represents an aryl radical,
R represents the phenyl radical or a radical R
5
—O— in which R
5
represents
a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted by one or a number of substituents chosen from the halogen atoms and the hydroxyl radical, alkoxy radical containing 1 to 4 carbon atoms, dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms, piperidino radical, morpholino radical, 1-piperazinyl radical (optionally substituted in the 4-position by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6 carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms, phenyl cyano radical, carboxyl radical or alkoxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms,
or a phenyl radical optionally substituted by one or a number of atoms or radicals chosen from the halogen atoms and the alkyl radicals containing 1 to 4 carbon atoms or the alkoxy radicals containing 1 to 4 carbon atoms,
a saturated or unsaturated nitrogen-containing heterocyclyl radical containing 4 to 6 members and optionally substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally be substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms,
R
1
and R
2
, which are identical or different, represent a hydrogen atom or an alkyl, phenylalkyl, phenyl, alkoxyphenyl or dialkoxyphenyl radical or else R
1
and R
2
form, together with the carbon atom to which they are bonded, a ring having from 4 to 7 members,
R
3
represents an acetyl radical or a protective group of the hydroxyl functional group and
R
4
represents a protective group of the hydroxyl functional group.
More particularly, Ar represents a phenyl or &agr;- or &bgr;-naphthyl radical optionally substituted by one or a number of atoms or radicals, identical or different, chosen from the halogen atoms (fluorine, chlorine, bromine, iodine) and the alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms and that the aryl radicals are phenyl or &agr;- or &bgr;-naphthyl radicals, or else Ar represents an aromatic heterocyclic radical having 5 members and containing one or a number of atoms, identical or different, chosen from the nitrogen, oxygen or sulphur atoms, optionally substituted by one or a number of substituents, identical or different, chosen from the halogen atoms (fluorine, chlorine, bromine, iodine) and the alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radical containing 1 to 4 carbon atoms, aryloxy radical containing 6 to 10 carbon atoms, amino radical, alkylamino radical containing 1 to 4 carbon atoms, dialkylamino radical, in which each alkyl part contains 1 to 4 carbon atoms, acylamino radical, the acyl part of which contains 1 to 4 carbon atoms, alkoxycarbonylamino radical containing 1 to 4 carbon atoms, acyl radical containing 1 to 4 carbon atoms, arylcarbonyl, the aryl part of which contains 6 to 10 carbon atoms, cyano radical, carboxyl radical, carbamoyl radical, alkylcarbamoyl radical, the alkyl part of which contains 1 to 4 carbon atoms, dialkylcarbamoyl radical, each alkyl part of which contains 1 to 4 carbon atoms, or alkoxycarbonyl radical, the alkoxy part of which contains 1 to 4 carbon atoms.
More particularly, Ar represents a phenyl, 2- or 3-thienyl or 2- or 3-furyl radical optionally substituted by one or a number of atoms or radicals, which are identical or different, chosen from the halogen atoms and the alkyl, alkoxy, amino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.
More particularly still, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom or by an alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (t-butoxycarbonylamino) or 2- or 3-thienyl or 2- or 3-furyl radical.
More particularly, R. represents an acetyl radical or a protective group of the hydroxyl functional group chosen from the (2,2,2-trichloroethoxy)carbonyl, (2-trichloromethylisopropoxy)carbonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl radicals contain 1 to 4 carbon atoms and the aryl radicals are, preferably, phenyl radicals and R
4
represents a protective group of the hydroxyl functional group chosen from the (2,2,2-trichloroethoxy)carbonyl, (2-trichloromethylisopropoxy)carbonyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl radicals contain 1 to 4 carbon atoms and the aryl radicals are, preferably, phenyl radicals.
A description is given in International Application PCT WO 9209589 of the preparation of the products of general formula (I) by esterification of protected baccatin III or protected 10-deacetylbaccatin III of general formula:
in which R
3
and R
4
are defined as above, by means of an acid of general formula:
in which Ar, R
1
and R
2
are defined as above and Boc represents the t-butoxycarbonyl radical, and of their conversion to taxol, Taxotere or their derivatives of general formula:
in which Ar is defined as above, R
6
represents a hydrogen atom or the acetyl radical and R represents the phenyl radical or a radical R
5
—O— in which R
5
is defined as above, by passing through the intermediacy of a product of general formula:
in which R
3
and R
4
are defined as above.
According to the previously known processes, it was necessary, to obtain the products of general formula (IV), in which the absolute configuration of the side chain is necessary for the antitumoral activity, to use the acid of general formula (III) in which the carbon atoms in the 4- and 5-positions respectively have the S and R configurations.
It has now been found, and it is this which forms the subject of the present invention, that the products of general formula (I) can be obtained, with a stereoselectivity in the region of 100%, by esterification of protected baccatin III or protected 10-deacetylbaccatin III by means of an acid of general formula:
in which Ar, R, R
1
and R
2
are defined as above and in which the carbon atoms in the 4- and 5-positions each have the S configuration, or of an activated derivative of this acid.
The process according to the invention makes it possible to stereoselectively obtain the product of general formula (I) from an acid of general formula (VI)i optionally mixed with an acid of general formula (III).
According to the present invention, the esterification of protected baccatin III or protected 10-deacetylbaccatin III by the acid of general formula (VI) is carried out in the presence of a condensation agent such as an imide, such as dicyclohexylcarbodiimide, or a reactive carbonate, such as di-2-pyridyl ketone, and of an activating agent such as an aminopyri

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