Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-11
2001-05-08
Seaman, D. Margaret (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S153000, C546S156000
Reexamination Certificate
active
06229017
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to an improved process for preparing quinolone- and naphthyridonecarboxylic acids and esters thereof starting from benzoyl chlorides and nicotinoyl chlorides, respectively.
BACKGROUND OF THE INVENTION
Quinolone- and naphthyridonecarboxylic acids and esters thereof are intermediates for preparing known, pharmaceutically active quinolone-carboxylic acids and naphthyridonecarboxylic acids, respectively.
EP-A-300,311 (Canadian Patent 1333715) discloses a preparation of quinolone-carboxylic acids where a benzoyl chloride is acylated with an aminoacrylic ester, and an amine exchange is carried out with the aroylacrylic ester. The resulting aminoacrylate is cyclized, the resulting ester is hydrolyzed, and the resulting quinolone-carboxylic acid is precipitated out by addition of an acid. The patent reports that yields between 71 and 79% are obtained. The solvents which are given for the for the acylation step include toluene, xylene, cyclohexane, open-chain hydrocarbons, and polar solvents such as dimethyl formamide (DMF) and dimethyl sulphoxide (DMSO). The solvents which are given for the amine-exchange step include the above-mentioned solvents as well as protic polar solvents, e.g., alcohols such as butyl glycol. Suitable solvents for the cyclization steps include only polar solvents such as higher alcohols, amino alcohols, DMF, DMSO, dioxane and N-methylpyrrolidone.
If non-polar to slightly polar solvents such as hydrocarbons are to be employed for the acylation and the amine exchange, a different polar, optionally even protic solvent, such as butyl alcohol, has to be employed for the cyclization. As such, to carry out the entire reaction in one solvent seems possible only in a strongly polar solvent such as DMF and DMSO. In the examples of EP-A 300 311, for instance, the solvent was changed, namely from the non-polar aprotic toluene or cyclohexane for the first solvent and, if appropriate, the second step to the polar, protic butyl glycol for the third and, if appropriate, second step.
The change of solvent leads to considerable expense for the separate removal of two different solvents, for drying the intermediate at whose stage the solvent exchange is carried out and for disposal or regeneration of two different solvents. Further, the yields which can be obtained are still not entirely satisfactory.
According to EP-A 176,846, for reacting a benzoyl halide with an acrylic acid derivative (=acylation), use is made of methylene chloride, chloroform, toluene, tetrahydrofuran or dioxane.
In Liebigs Ann Chem. 1987, 29-37, a dipolar aprotic solvent, for example, DMF, DMSO or N-methylpyrrolidone, is specified for the cyclocondensation of 3-amino-2-benzoylacrylic esters to 4-quinolone-3-carboxylic esters (=cyclization).
Thus, there is a general bias in the art against using a non-polar to slightly polar solvent for the entire reaction sequence.
DESCRIPTION OF THE INVENTION
The invention relates to a process for preparing quinolone- and naphthyridonecarboxylic acids and esters thereof of the formula (I)
in which
R
1
represents hydrogen or C
1
-C
4
-alkyl groups;
R
2
represents a halogen group;
R
3
represents a halogen group;
R
4
represents hydrogen, halogen and nitro groups;
Y represents C
1
-C
6
-alkyl, 2-fluoroethyl, cyclopropyl, fluorocyclopropyl, isopropyl, 4-fluorophenyl and 2,4-difluorophenyl groups; and
A represents nitrogen atoms or C—R
5
groups, in which R
5
includes hydrogen atoms, methyl groups, methoxy groups, halogen groups, nitro groups or cyano groups,
where Y and R
5
together may also represent —CH
2
—CH
2
—O— or —CH(CH
3
)—CH
2
—O—groups, where the terminal CH
2
— or the CH(CH
3
)— group is attached to the nitrogen atom.
The process generally includes the steps of a) reacting (acylating), in the presence of a base, a benzoyl chloride or a nicotinoyl chloride of the formula (II)
in which R
2
, R
3
, R
4
and A are each as defined under formula (I) and
R
6
represents halogen,
with an aminoacrylic ester of the formula (III)
in which
R
1
represents a C
1
-C
4
-alkyl group; and
Z
1
and Z
2
independently of one another represent a C
1
-C
4
-alkyl group, or together with the linking nitrogen atom form a 5- to 6-membered saturated or unsaturated ring which may optionally contain up to two further hetero groups selected from the group consisting of O atoms, S atoms and SO
2
groups to produce a (Het)-aroylacrylic ester of the formula (IV)
in which
R
1′
represents a C
1
-C
4
-alkyl group and
R
2
, R
3
, R
4
and A each are as defined in formula (I),
R
6
is as defined under formula (II), and
Z
1
and Z
2
are each as defined in formula (III);
b) subjecting the (Het)-aroylacrylic ester of the formula (IV) to an amine exchange with an amine of the formula (V)
H
2
N—Y (V),
in which Y is as defined in formula (I), to produce a (Het)-aroylacrylic ester of the formula (VI)
in which R
1′
represents a C
1
-C
4
-alkyl group and
R
2
, R
3
, R
4
, Y and A are each as defined under formula (I) and
R
6
is as defined under formula (II);
c) cyclizing the (Het)-aroylacrylic ester of the formula (VI) in the presence of a base to produce a quinolone or naphthyridone ester of the formula (I) in which R
1
represents a C
1
-C
4
alkyl group;
d) if a quinolone or napthyridonecarboxylic acid of the formula (I) is to be prepared in which R
1
represents hydrogen, the ester which is present after step c) is hydrolyzed and the acid of the formula (I) in which R
1
represents hydrogen is isolated after addition of an acid;
where the intermediates of the formulae (IV) and (VI) are not isolated and steps a) to c) are carried out in the presence of the same non-polar to slightly polar solvent. Although the same non-polar to slightly polar solvent is used in steps a) to c), it is understood that other solvents can be present in the system.
The symbols used in the formulae (I) to (VI) preferably refer to the following:
if
R
1
represents a C
1
-C
4
-alkyl group, e.g., methyl or ethyl group,
R
2
represents chlorine or fluorine groups,
R
3
represents fluorine groups,
R
4
represents hydrogen, chlorine, fluorine or nitro groups,
R
6
represents fluorine or chlorine groups,
A represents C—R
5
in which R
5
is selected from groups such as hydrogen, methyl, methoxy, halogen or cyano, or N groups.
Y represents ethyl, cyclopropyl, fluorocyclopropyl, 2,4-difluorophenyl or together with R
5
—CH(CH
3
)—CH
2
—O—,
Z
1
and Z
2
each represents methyl or ethyl groups.
Suitable reaction temperatures for step a) are generally in the range from 25 to 120° C. Preference is given to carrying out the reaction at from 30 to 80° C. Suitable bases for step a) are, for example, tertiary amines, like those of the formulae
in which R
7
represents a C
1
-C
14
-alkyl group or a benzyl group.
If a plurality of R
7
groups is present in a molecule, these groups may be identical or different. R
7
preferably represents a C
1
-C
4
-alkyl group. A particularly preferred tertiary amine is triethylamine.
In step a), generally at least one equivalent of base is employed per mole of the acyl chloride of the formula (II). This amount is preferably from 1 to 2 equivalents. Greater amounts are not critical, but uneconomical.
Hydrochloride of the base employed which precipitates out during the reaction can, if required, be removed mechanically, e.g., by filtration, or by extraction with water. Preferably, this hydrochloride is not separated off.
Suitable reaction temperatures for step b) are, for example, in the range from 5 to 100° C. Preference is given to carrying out the reaction at from 10 to 80° C. Preferred amines of the formula (V) are ethylamine, cyclopropyl-amine, 2, 4-difluoroaniline, aminopropanol and fluorocyclopropylamine.
In step b) in general at least one equivalent of amine is employed per mole of ester of the formula (IV). This amount is preferably from 1 to 1.3 equivalents. Greater amounts are not critical, but uneconomical.
The liberated dialkylamine, preferably dimethyl- or diethylamine, is preferably removed from the r
Lui Norbert
Muller Herbert
Panskus Hans
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Seaman D. Margaret
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