Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-12-14
2002-09-03
Coleman, Brenda (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S216000, C548S230000, C546S208000, C544S137000, C544S369000
Reexamination Certificate
active
06444825
ABSTRACT:
The present invention relates to a process for the preparation of an oxazolidinecarboxylic acid or derivatives thereof, of general formula:
from an acid or derivatives thereof, of general formula:
In the formulae (I) and (II),
R′ represents a hydrogen atom or an alkali metal or alkaline-earth metal atom or an alkyl radical containing 1 to 4 carbon atoms optionally substituted with a phenyl radical,
R
1
represents a benzoyl radical or a radical R
2
—O—CO— in which R
2
represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 3 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino, morpholino and 1-piperazinyl (optionally substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms) radicals, cycloalkyl radicals containing 4 to 6 carbon atoms, alkenyl radicals containing 4 to 6 carbon atoms, phenyl, cyano and carboxyl radicals or alkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms,
or a phenyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms,
or a saturated or unsaturated nitrogen-containing 5- or 6-membered heterocyclic radical optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms,
R
3
and R
4
, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or an aralkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R
3
represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical. substituted with a trihalomethyl radical such as trichloromethyl and R
4
represents a hydrogen atom, or alternatively R
3
and R
4
form, together with the carbon atom to which they are attached, a 4- to 7-membered ring.
The acid of general formula (I) is particularly useful for preparing the therapeutically active taxoids of general formula:
in which:
R represents a hydrogen atom or the acetyl radical,
R
1
is defined as above, and
R
5
represents an iodine atom or an alkenyl radical containing 2 to 8 carbon atoms optionally substituted with a phenyl radical, an alkynyl radical containing 2 carbon atoms or a phenyl, formyl, alkanoyl, aroyl, hydroxymethyl, carboxyl or alkoxycarbonyl radical.
According to Application PCT WO 9209589, the preparation of a product of general formula (III) requires the use of an oxazolidinecarboxylic acid of general formula:
in which R
5
is defined as above, R′
3
and R′
4
, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms optionally substituted with one or more aryl (phenyl) radicals or represent an aryl (phenyl) radical, or alternatively R′
3
and R′
4
form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and Boc represents the t-butoxycarbonyl radical, which is obtained from an aldehyde of general formula:
in which R
5
is defined as above, which, depending on the meanings of R
5
, is not always easily accessible.
According to the invention, the product of general formula (I) in which R′ represents an alkyl radical optionally substituted with a phenyl radical is obtained by iodination, according to the usual methods, of a product of general formula (II) in which R′ represents an alkyl radical optionally substituted with a phenyl radical.
The iodination may generally be carried out either using iodine in the presence of bis(trifluoroacetoxy)iodobenzene by working in an organic solvent such as a halogenated aliphatic hydrocarbon like dichloromethane at a temperature between 0 and 50° C., or alternatively by the action of iodine in the presence of ammonium cerium nitrate in acetic acid or methanol, or alternatively by the action of iodine in the presence of silver trifluoroacetate, or alternatively by the action of N-iodosuccinimide in the presence of hydroxy(tosyloxy)iodobenzene (Koser's reagent) in methanol, or alternatively by the action of benzyltrimethylammonium dichloroiodide in the presence of zinc chloride in acetic acid.
The product of general formula (I) for which R′ represents a hydrogen atom may be obtained by saponification of a product of general formula (I) in which R′ represents an alkyl radical optionally substituted with a phenyl radical.
The product of general formula (II) in which R′ represents an alkyl radical optionally substituted with a phenyl radical, R
3
and R
4
are defined as above, may be obtained by reacting a product of general formula:
in which R
3
and R
4
are defined as above in the form of a dialkyl acetyl or an alkyl enol ether, with an ester of general formula:
in which R
1
and R′ are defined as above, which may be obtained under the conditions described in the Application PCT WO 9209589, corresponding U.S. Pat. No. 5,476,954.
The product of general formula (I) may be converted to a product of general formula (III) according to one of the following methods:
1) after replacing the iodine atom of the product of general formula (I), in which R′ represents an alkyl radical optionally substituted with a phenyl radical, with an alkenyl radical containing 2 to 8 carbon atoms optionally substituted with a phenyl radical, an alkynyl radical containing 2 carbon atoms or a phenyl, formyl, alkanoyl, aroyl, hydroxymethyl, carboxyl or alkoxycarbonyl radical according to the known methods, and saponification, the product obtained of general formula:
in which R
1
, R
3
and R
4
are defined as above, and R′
5
represents an alkenyl radical optionally substituted with a phenyl radical or an alkynyl, phenyl, alkanoyl, aroyl, formyl, hydroxymethyl, carboxyl or alkoxycarbonyl radical, or a derivative of the acid of general formula (VIII), is condensed with a protected baccatin III of general formula:
in which G
1
represents a protecting group for the hydroxyl function and G
2
represents an acetyl radical or a protecting group for the hydroxyl function, in order to obtain a product of general formula:
in which R
1
, R
3
, R
4
, R′
5
, G
1
and G
2
are defined as above, in which the protecting groups represented by G
1
and G
2
are replaced by hydrogen atoms by passing, depending on the meanings of R
3
and R
4
, via an intermediate product of general formula:
in which R′
5
is defined as above, G′
1
represents a hydrogen atom or a protecting group for the hydroxyl function and G′
2
represents a hydrogen atom or an acetyl radical or a protecting group for the hydroxyl function, in which the amine function is acylated before replacing the protecting groups G′
1
and, where appropriate, G′
2
by hydrogen atoms.
2) the product of general formula (I), in which R′ represents a hydrogen atom, is condensed with a protected baccatin III of general formula (IX) in order to give a product of general formula:
in which R
1
, R
3
, R
4
, G
1
and G
2
are defined as above, in which the protecting groups represented by G
1
and G
2
are replaced by hydrogen atoms by passing, depending on the meanings of R
3
and R
4
, via an intermediate product of general formula:
in which G′
1
Bourzat Jean-Dominique
Commerçon Alain
Aventis Pharma S.A.
Coleman Brenda
Finnegan Henderson Farabow Garrett & Dunner LLP
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