MXPA99005403A - Process for preparing quinoloncarboxilic acids and naftiridoncarboxilicos and esteres de los mis - Google Patents

Abstract

The present invention relates to the quinolonecarboxylic acids and naphthyridonecarboxylic acids and esters thereof, which are prepared through a process which is characterized in that a benzoyl chloride or nicotinyl is reacted with an amino acrylic ester providing thus a (Het) -arylacrylic ester which is subjected to to an exchange of amine with a primary amine, thus providing a second ester (Het) -aroylacrylic, which becomes cyclic in the presence of a base, and, if a quinolonecarboxylic acid-a-pyridinecarboxylic acid is to be prepared, a hydrolysis of the ester is subsequently carried out, wherein the intermediate compounds which are present after the acylation and the amine exchange, are not isolated, and wherein the acylation, the amine exchange and the cycle formation, are carried out in the presence of the same solvent with features from non-polar to slightly polar

Description

PROCESS FOR PREPARING QUINOLONCARBOXYLIC ACIDS AND NAFTIRIDONCARBOXÍLICOS And ESTERS OF THEMSELVES FIELD OF THE INVENTION The present invention relates to an improved process for preparing quinoline oncarboxylic acids and naphthylcarboxylic acids and esters thereof, starting from benzoyl chlorides and nicotinyl chlorides, respectively.

BACKGROUND OF THE INVENTION The quinolonecarboxylic acids and naphthyridonecarboxylic acids and esters thereof are intermediates for the preparation of the known pharmaceutically active quinolonecarboxylic acids and naphthyridonecarboxylic acids, respectively. EP-A-300311 describes a preparation of quinolonecarboxylic acids wherein a benzoyl chloride is acylated with an aminoacrylic ester, an exchange of REF .: 30546 amine with the aroyl acrylic ester, the formation of cycles is carried out in the resulting amino acrylate, the resulting ester is hydrolysed and the resulting quinolonecarboxylic acid is precipitated by the addition of an acid. Here, the yields are between 71 and 1%. The solvents that are provided for the individual reaction steps are: for acylation, toluene, xylene, cyclohexane, open chain hydrocarbons, DMF and DMSO, for the amine exchange additionally alcohols and butyl glycol and for the formation of only higher alcohols cycles , aminoalcohols, DMF, DMSO, dioxane and N-me ti lpirro 1 idona. If for the acylation and the exchange of amine are going to use solvents with characteristics from non-polar to slightly polar, for example hydrocarbons, a polar solvent, different, including optionally a protic solvent, must be used for the formation of cycles. To carry out the complete reaction in a single solvent, it seems possible to do so only in a strongly polar solvent, for example DMF or DMSO. In all the examples of EP-A-300 311, it was changed the solvent, especially toluene or cyclohexane, aprotic, non-polar, for the former and, if appropriate, for the second step, butyl glycol, protic, polar, for the third step, and if appropriate, for the second step. The change of the solvent leads to a considerable expense for the separate removal of two different solvents, for the drying of the intermediate product in the stage in which the exchange of the solvent is carried out and for the disposal or regeneration of two different solvents. In addition, the yields that can be obtained are still not satisfactory enough. According to EP-A 176 846, to react a benzoyl halide with an acrylic acid derivative (= acylation), use is made of methylene chloride, chloroform, toluene, t-hydrohydrofuran or dioxane. In Liebigs Ann Chem. 1987, 29-37, a dipolar aprotic solvent, for example DMF, DMSO or N-met i Ipirroli dona, is specified for cyclocondensation. of esters 3-amino-2-benzoilacrí lieos in esters 4-quinolon-3-carboxílicos (= formation of cycles).

Thus, there is a general inclination in the art against the use of a solvent with characteristics from non-polar to slightly polar, for the entire reaction sequence. Accordingly, this invention provides a process for preparing quinoline oncarboxylic acids and naphthyridonecarboxylic acids and esters thereof of the formula (I) wherein R 1 represents hydrogen or alkyl of 1 to 4 carbon atoms, R 2 represents halogen, R 3 represents halogen, R 4 represents hydrogen or nitro, Y represents alkyl of 1 to 6 carbon atoms, 2 -fluoroethyl, cyclopropylo, fluoropropyl, isopropyl, 4-fluorophenyl or 2,4-di fluorophenyl and A represents nitrogen or C-R5 wherein R5 = hydrogen, methyl, methoxy, halogen, nitro or cyano, wherein Y and R5 can also represent together -CH2-CH2-0 or -CH (CH3) -CH -0- , wherein the CH2-terminal or the group CH (CH3) - is attached to the nitrogen atom, characterized because a) a benzoyl or nicotionyl chloride of the formula (II) in which R2, R3, R4 and A are each as defined under formula (I) and R6 represents halogen, is reacted in the presence of a base, with an aminoacrylic ester of the formula (III) CH-COOR1 CH-NZ1Z2 (ni), wherein R1 represents alkyl of 1 to 4 carbon atoms and Z1 and Z2, independently of each other, each represents alkyl of 1 to 4 carbon atoms or together with the linking nitrogen atom forms a saturated or unsaturated ring of 5 to 6 members which may optionally contain up to 2 additional hetero groups selected from the group consisting of the O atoms, S atoms and S02 groups, thus providing an ester (He t) - aroi l'air ílico of the formula (IV) wherein R1 represents alkyl of 1 to 4 carbon atoms and R2, R3, R4 and A are each as defined under formula (I), R6 is as defined under formula (II) and Z1 and Z2 are each as defined under formula (III), b) the ester (Het) -aroylacrylic of the formula (IV) is subjected to an exchange of amine with an amine of the formula (V) H2N-Y (v: where Y is as defined under (I) thus providing an ester (Het) - aroi 1 acri 1 ico of the formula (VI) wherein R1 represents alkyl of 1 to 4 carbon atoms and R2, R3, R4, Y and A are each as defined under the formula (I) and R6 is as defined under the formula (II), c) the ester (Het) - aroyl lacrylate of the formula (VI) becomes cyclic in the presence of a base, thus providing a quinolone or naphthyridone ester of the formula (I) in which R 1 represents alkyl of 1 to 4 carbon atoms and d) if a quinolonecarboxylic or naphidocarboxylic acid of the formula (I) is to be prepared, in which R1 represents hydrogen, the ester that is present after step c) is hydrolyzed and the acid of the formula (I) wherein R1 represents hydrogen, is isolated after the addition of an acid, wherein intermediate compounds (IV) and (VI) are not isolated, and steps of a) to c) are carried out in the presence of the same solvent, with characteristics from non-polar to slightly polar. The symbols used in the formulas of (I) to (VI) preferably have the following meanings: if R 1 represents alkyl of 1 to 4 carbon atoms: methyl or ethyl. R2 chlorine or fluorine. R3 fluorine. R4 hydrogen, chlorine, fluorine or nitro. R6 fluorine or chlorine. A C-R5 wherein R5 = hydrogen, methyl, methoxy, halogen or cyano or N.Y: ethyl, cyclopropyl, fluorocyclopropyl, 2,4-fluorophenyl or together with R5-CH (CH3) -CH2-0-. Z1 and Z2: methyl or ethyl.

The reaction temperatures suitable for step a) are, for example, in the range from 25 to 120 ° C. Preference is given to carry out the reaction at a temperature of 30 to 80 ° C. Suitable bases for step a) are, for example, tertiary amines, such as those of the formulas wherein R7 represents alkyl of 1 to 14 carbon atoms or benzyl. If a plurality of R7 groups are present in a molecule, these may be identical or different. R7 preferably represents alkyl of 1 to 4 carbon atoms. A particularly preferred tertiary amine is triethyl sheet. In step a), at least one equivalent of base per mole of acyl chloride of the formula (II) is generally used. This amount is preferably 1 to 2 equivalents. Larger amounts are not critical but neither are they economical. The hydrochloride of the base used which is precipitated during the reaction can, if required, be removed mechanically (for example by filtration) or by extraction with water. Preferably, this hydrochloride is not separated. The reaction temperatures suitable for step b) are found, for example, in the interval from 5 to 100 ° C. Preference is given to carry out the reaction at a temperature of 10 to 80 ° C. Preferred amines of the formula (V) are ethylamine, cyclopropylamine, 2-di-fluoroaniline, aminopropanol and fluorocyclopropi lamin. In step b), in general, at least one equivalent of amine per mole of ester of the formula (IV) is used. This amount is preferably from 1 to 1.3 equivalents. Larger amounts are not critical but neither are they economical. The dialkylamine released, preferably dimethylamine or diethylamine, is preferably removed from the reaction mixture, for example by the addition of an acid equivalent and by mechanical removal, for example by filtration, or by extraction with water . If appropriate, the hydrochloride produced in step a) can also be separated in this step. The released dialkylamine can also be removed, for example, from the reaction mixture by distillation removal at low temperatures.

Suitable reaction temperatures for step c) are, for example, in the range of 50 to 200 ° C. For step c) they are, for example, in the range of 50 to 200 ° C. The respective optimal reaction temperature depends on the substitution pattern and can be easily determined by preliminary routine experiments. Suitable bases for step c) are, for example, potassium carbonate, sodium carbonate, sodium hydride and sodium tert-butoxide. Preference is given to potassium carbonate. On the basis of 1 mole of the compound of the formula (VI) it is possible to use, for example, from * 1 to 4 molar equivalents of the base. This amount is preferably from 1.1 to 1.5 molar equivalents. When using potassium carbonate or sodium carbonate it is advantageous to remove the water that is released from the reaction, using for example a water separator. Step c) can be carried out, if appropriate, in the presence of a phase transfer catalyst. The appropriate phase transfer catalysts are, for For example, the halides of the tetrahalide. The ester of the formula (I) wherein R 1 = alkyl of 1 to 4 carbon atoms can be isolated, for example, as follows: initially a fraction of the solvent is distilled, for example from 40 to 60% by weight, then water is added, whereby, in general, the ester starts to precipitate, the rest of the solvent is then removed by distillation and the ester is then separated, for example, through filtration, washed with an alcohol, for example with an alkyl alcohol of 1 to 4 carbon atoms, and subsequently dried under reduced pressure. The hydrolysis of an ester to prepare the acids of the formula (I) wherein R 1 = hydrogen, from the esters of the formula (I) wherein R alkyl of 1 to 4 carbon atoms, can be carried out at through customary methods, in an acidic or alkaline medium. If the esters in question are base-sensitive esters of the formula (I), preference is given, of course, to the hydrolysis of the esters in an acid medium. To separate and isolate acids of the formula (I) it is possible to add, for example, acetic acid, sulfuric acid or hydrochloric acid. The precipitated acid can be separated, for example, by filtration. An essential feature of the process according to the invention is that the intermediate compounds of the formulas (IV) and (VI) obtained after carrying out steps a) and b) are not isolated. Another essential characteristic of the process according to the invention is that the steps from a) to c) are carried out without solvent exchange in the same solvent, with characteristics from non-polar to slightly polar. Suitable solvents are, for example, alkylbenzenes, in particular those containing de. 1 to 3 alkyl groups of 1 to 4 carbon atoms, per molecule, the halogenobenzenes, in particular those containing 1 to 2 halogen atoms, preferably chlorine atoms, per molecule, the halogenoalkylbenzenes, in particular those containing 1 to 2 halogen atoms, preferably chlorine atoms, and 1 to 2 alkyl groups of 1 to 4 carbon atoms, per molecule, the alicyclic hydrocarbons, and particularly those containing from 5 to 7 carbon atoms in the ring and which are optionally substituted with an amount of 1 to 2 alkyl groups of 1 to 4 carbon atoms, the saturated or unsaturated hydrocarbons of open chain, in particular those which are straight or branched chain and containing from 5 to 18 carbon atoms, and any mixtures of those solvents. Care should be taken in selecting those solvents whose boiling points at atmospheric pressure are above the reaction temperature to be handled, or in the case of reaction temperatures above the boiling point of the solvent that is going To use at atmospheric pressure, use closed pressure-proof devices. If the boiling point of the solvent, at atmospheric pressure, substantially exceeds the reaction temperature to be handled, it is also possible to work under reduced pressure. Particular examples of solvents are: toluene, xylenes, mesitylene, ethylbenzene, diethylbenzenes, isopropylbenzene, chlorobenzene, dichlorobenzenes, chloro toluenes, cyclohexane and mixtures of hydrocarbons containing at least 80% by weight of one or more straight or branched chain hydrocarbons of 6 to 12 atoms of carbon. The preferred solvents are toluene, xylenes, mesitylene, isopropylbenzene, chlorobenzene and di chlorobenzenes. It is possible to use, for example, 300 to 1,000 ml of solvent per mole of acyl chloride of the formula (II). This amount is preferably 400 to 800 ml. Greater quantities of the solvent are not critical but it is not economical to use them. The process according to the invention has the advantages that three reaction steps can be carried out without isolating the intermediates and without changing the solvent, and that higher yields can be obtained than in the prior art. The yields that can be obtained are above 80% of the theoretical, frequently by over 85% of the theoretical. This means that the process according to the invention can be carried out in a technically simple manner and particularly effectively, since the expense incurred for the removal and disposal or regeneration of a second solvent and for the insulation is not incurred. and drying of the intermediate compounds, and it is still possible to obtain higher yields than those that were achieved up to now. These advantages that can be obtained are extremely surprising because until now it had been thought that the use of polar solvents was dominant, at least for the cycle formation reaction (step c). Particularly preferred compounds which can be prepared by the process according to the invention, starting from the corresponding compounds of the formulas (II), (III) and (V) are the following: l-cyclopropyl-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxy liic acid, 1-cyclopropyl-β, 7,8-trifluoro-1,4-dihydro-4-oxo- Ethyl 3-quinoline-carboxylate, ethyl l-cyclopropyl-6,7-difluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylate, 1-cyclopropyl-β, 7-difluoro-8-methoxy-l, 4-dihydro-4-oxo-3-quinoline-ethyl carboxylate, ethyl l-cyclopropyl-6,7-difluoro-8-cyano-l, 4-dihydro-4-oxo-3-quinolinecarboxylate, 1- (2-Fluoro) cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinol-1-carboxylic acid ethyl ester, I-cyclopropyl-8-chloro-6,7-difluoro-1,4-dilf "idro-4-oxo-3-quinol in-carboxy 1 to ethyl, ethyl l-ethyl-6,7,8-trifluoro-l, 4-dihydro-4-oxo-3-quinol in-c-arboxylate, 7-chloro-l- (2, -dif luorophenyl) -6-fluoro-l, 4-dihydro-4-oxo-1, 8-naphthyridon-3-carboxyethyl ethyl ester, 7-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4- oxo-1, 8-naft-iridon-3-carboxylic acid ethyl, l-cyclopropyl-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylate, and 9,10-difluoro-2,3-dihydro-3-me thi-7-oxo-7H-pyrido (1, 2, 3-de) (1,4) enzoxazin-6-carboxy 1 ethyl acetate .

A specific aspect of the present invention is a process for cyclically converting an ester (He t) -aroylacrylic of the formula (VI) wherein Ra represents alkyl of 1 to 4 carbon atoms, R 2 represents halogen, R 3 represents halogen, R 4 represents hydrogen, halogen or nitro, R represents halogen, Y represents alkyl of 1 to 6 carbon atoms, 2-fluoroethyl, cyclopropylo, f luorocyclopropyl, isopropyl, 4-f luoro-phenyl or 2,4-di-fluorophenyl and A represents nitrogen or C-R5 wherein R5 = hydrogen, methyl, methoxy, halogen, nitro or cyano, wherein Y and R5 may also represent CH2-CH2-0 or -CH (CH3) -CH2-0-, wherein the terminal CH2 or the CH (CH3) group - is attached to the nitrogen atom, in the presence of a base, forming an ester of the formula (I) wherein the symbols used are each as defined above under formula (VI), the process is characterized in that it is carried out in the presence of a solvent with characteristics from non-polar to slightly polar. This process was previously described in greater detail. Solvents with characteristics from non-polar to slightly polar, preferred, are: alkylbenzenes, halogenobenzenes, halogenoalkylbenzenes, alicyclic hydrocarbons, open chain hydrocarbons and any mixtures of these solvents.

Eg emplos Example 1 160 g of 2,4-di-chloro-5-fluorobenzoyl chloride or, dropwise, over a period of 50 minutes, were added at 70 ° C to a solution of 380 g of dichlorobenzene (mixture of isomers), 110 g of ethyl N, N-dimethylaminoacrylate and 77 g of triethyl amine. The mixture was subsequently stirred at 70 ° C for 2 hours and cooled to room temperature. 51 g of acetic acid were added at room temperature and the The mixture was again heated to 70 ° C. Then, at 45 ° C, 45 g of cyclopropylamine were added drop by drop, the reaction mixture was subsequently mixed with 100 ml of water and the organic phase that formed was separated. The organic phase was metered into a mixture of 59 g of potassium carbonate and 190 g of dichlorobenzene (mixture of isomers) at a temperature of 180 to 184 ° C. The water that was released from the reaction was separated through a water separator. After all the water had separated, the mixture was cooled to 80 ° C and, at a pressure of 40 mbar, 340 ml of dichlorobenzene were distilled. Then 80 g of a strong aqueous solution of sodium hydroxide were added at 35%, and then 350 g of water were added, and the remaining dichlorobenzene was distilled off. After the addition of 180 g of acetic acid and 100 g of water, the product was filtered with suction and the isolated solid was washed 3 times with 150 ml of water each time and 3 times with 200 ml of isopropanol each time. Drying under reduced pressure at 60 ° C provided 173 g of l-cyclopropyl-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylic acid. This corresponds to a yield of 87% of the theoretical 2 Initially a mixture of 380 g of xylene (mixture of isomers), 110 g of ethyl N, N-dimethylaminoacrylate and 77.4 g of triethylamine, and 160 g of 2,4-dichloro-5-fluorobenzoyl chloride were added dropwise to 70 ° C, for a period of 60 minutes. The mixture was subsequently stirred at 70 ° C for 2 hours and cooled to room temperature. At room temperature, 51 g of acetic acid were then added and the mixture was again heated to 70 ° C. At 70 ° C, 45 g of cyclopropylane were added dropwise. 100 ml of water was added to the reaction mixture that had been stirred for 15 minutes, and the organic phase that formed was separated. The organic phase was metered into a mixture of 89 g of potassium carbonate and 190 g of xylene (mixture of isomers) at a temperature of 140 to 142 ° C. The liberated reaction water was separated by a water separator. After it had separated all the water cooled the mix up to 80 ° C and, at a pressure of 40 mbar, the xylene was distilled. 80 g of a strong aqueous solution of sodium hydroxide were then added, and 350 g of water were then added and the remaining xylene was distilled off. After the addition of 180 g of acetic acid and 100 g of water the product was filtered with suction and the solid was washed 3 times with 150 ml of water each time and 3 times with 200 ml of isopropanol each time. Drying under reduced pressure at 60 ° C produced 170 g of 1-cyclopropi-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid. This corresponds to a yield of 86% of the theoretical. * " Example 3 380 g of chlorobenzene, 110 g of ethyl N, N-dimet and 1-aminoacrylate and 77.4 g of triethyl amine were charged initially, and 160 g of 2,4-dichloro-5- chloride were added dropwise. fluorobenzoi lo, at 70 ° C, for a period of 60 minutes. The mixture was subsequently stirred at 70 ° C for 2 hours and then cooled to room temperature. Then he 51 g of acetic acid were added at room temperature and the mixture was again heated to 70 ° C. Then 45 g of cyclopropylamine were added dropwise at 70 ° C. 100 ml of water was added to the reaction mixture which had been stirred for 15 minutes, and the organic phase that formed was separated. The aqueous phase was extracted with 50 ml of chlorobenzene and the combined organic phases were metered into a mixture of 119 g of potassium carbonate, 1 g of tributylammonium bromide and 190 g of chlorobenzene at 131 ° C. The water released in the reaction was separated through a water separator. After all the water had separated, the mixture was cooled to 20 ° C and the solid precipitate was filtered off with suction using a nutsche filter. The solid was then washed 3 times with 200 ml of isopropanol each time. Drying under reduced pressure at 60 ° C yielded 186 g of ethyl 1-cyclopropyl 1-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylate. This corresponds to a yield of 86% of the theoretical.

Example 4 280 g of 2, 3, 4, 5-teturofluorobenzoyl chloride were added dropwise over a period of 60 minutes to a solution of 270 g of toluene, 189.8 g of N, N-, dropwise at 45 ° C. ethyl dimethylaminoacrylate and 144.2 g of triethylamine. The mixture was subsequently stirred at 50 ° C for 1 hour and then cooled to room temperature. At room temperature, 95.2 g of acetic acid were added and then, dropwise, 75.2 g of cyclopropi laminate were added at a temperature of 20 to 30 ° C. Then 200 ml of water was added to the reaction mixture, and the organic phase that formed was separated. The aqueous phase was extracted with 82 g of toluene and the combined organic phases were metered into a mixture of 110 g of potassium carbonate and 404 g of toluene, at 111 ° C. The water that formed with the reaction was separated with a water separator. After all the water had separated, the mixture was cooled to 60 ° C and 1280 g of water were added. The toluene was distilled at a temperature of 40 ° C at a pressure of 100 mbar.

The suspension was cooled to 20 ° C and filtered off with suction using a nutsche filter. The solid was then washed 3 times with 200 ml of water each time and 3 times with 250 ml of isopropanol each time and subsequently dried at 50 ° C under reduced pressure. This yielded 374 g of ethyl 1-cyclopropyl-6,7,8-1-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate. This corresponds to a yield of 91% of the theoretical.

At 140 [deg.] C., 140 g of 2, 3, 4, 5, 5-t, and fluoro-benzyl chloride were added, dropwise, over a period of 60 minutes, to a solution of 202 g of toluene, 94.9 g of N, N-dimethyl ethyl laminoacrylate and 72.1 g of triethylamine. The mixture was subsequently stirred at 43 ° C and then cooled to room temperature. Then, 37.6 g of cyclopropylamine were added dropwise at a temperature of 20 to 30 ° C, and the mixture was stirred for 1 hour. The dimethylamine was subsequently distilled at a pressure of 80 mbar. HE they added 100 ml of water to the reaction mixture and separated the organic phase that formed. The aqueous phase was extracted with 41 g of toluene and the combined organic phases were metered into a mixture of 55 g of potassium carbonate and 202 g of toluene at 110 ° C. The water that was released from the reaction was separated through a water separator. After all the water had separated, the mixture was cooled to 60 ° C and 640 g of water were added. The toluene was distilled at a temperature of 40 ° C and at a pressure of 100 mbar. The suspension was cooled to 20 ° C and filtered off with suction using a nutsche filter. The resulting solid was washed 3 times with 150 ml of water each time and 3 times with 150 ml of isopropanol each time and subsequently dried under reduced pressure at 50 ° C. This produced 172 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-l, 4-dihydro-4-oxo-3-quinol. This corresponds to a yield of 84% of the theoretical.

Example 6 Example 2 was repeated but was used isopropylbenzene instead of xylene and cycle formation was carried out at a temperature of 156 to 158 ° C. Drying under reduced pressure at 60 ° C yielded 177 g of 1-cyclopropi-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline n-carboxylic acid. This corresponds to a yield of 89% of the theoretical.

Example 7 Example 2 was repeated but mesitylene was used in place of xylene and the cycling was carried out at a temperature of 166 to 168 ° C. Drying under reduced pressure at 60 ° C yielded 174 g of 1-cyclopropi-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylic acid. This corresponds to a yield of 88% of the theoretical.

Example 8 Initially, 272 g of toluene, 111 g of N, N-dimethylaminoethyl acrylate and 85 g of triethylamine were charged and 156 g of 2,4,5-chloro were added dropwise. trifluorobenzoyl at a temperature of 50 to 55 ° C for a period of 60 minutes. The mixture was subsequently stirred at 55 ° C for 2 hours and then cooled to room temperature. Then 56 g of acetic acid were added and 48.6 g of cyclopropylamine were added dropwise at a temperature of 20 to 30 ° C. Then 250 ml of water was added to the reaction mixture which had been stirred for 15 minutes, and the organic phase was separated. The organic phase was metered into a mixture of 65 g of potassium carbonate and 240 g of toluene at 110 ° C. The water that was released from the reaction was separated through a water separator. After all the water had separated, the mixture was cooled to 30 ° C and 500 ml of water was added. The toluene was distilled at a pressure of 120 to 180 mbar. The mixture was subsequently cooled to 20 ° C and the product was filtered off with suction. The isolated solid was washed 3 times with 100 ml of water each time and 3 times with 100 ml of isopropanol. Drying under reduced pressure at a temperature of 50 ° C produced 206 g of 1-cilopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-. quinoline-carboxylate to ethyl. This corresponds to a yield of 88% of the theoretical.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (10)

1. The process for preparing quinolonecarboxylic acids and naphthyridonecarboxylates and esters thereof, of the formula (I) wherein R1 represents hydrogen or alkyl of 1 to 4 carbon atoms, R2 represents halogen, R3 represents halogen, R4 represents hydrogen or nitro, Y represents alkyl of 1 to 6 carbon atoms, 2-f luoroe tyl, cyclopropyl , fluorociclopropi lo, isopropilo, 4 - f luoro feni lo o

2, 4 -di-fluoro phenyl and A represents nitrogen or C-R5 where R5 = hydrogen, methyl, methoxy, halogen, nitro or cyano, where Y and R5 may also represent together -CH2-CH2-0 or -CH (CH3) -CH2-0-, wherein the terminal CH2-terminal or the group CH (CH3) - is attached to the nitrogen atom, characterized because a) a benzoyl or nicotionyl chloride of the formula (II) in which R2, R3, R4 and A are each as defined under the formula (I) and R6 represents halogen, is reacted in the presence of a base, with an amino acrylic ester of the formula (III) CH-COOR1 HI), Cli (H- -NZ1Z2 wherein R1 represents alkyl of 1 to 4 atoms of carbon and Z1 and Z2, independently of each other, each represent alkyl of 1 to 4 carbon atoms or together with the linking nitrogen atom form a saturated or unsaturated ring of 5 to 6 members which may optionally contain up to 2 additional heterogroups selected from the group consisting of the atoms of 0, S atoms and S02 groups, thus providing an ester (He t) - lactic acid of the formula (IV) wherein R1 represents alkyl of 1 to 4 carbon atoms and R2, R3, R4 and A are each as defined under formula (I), R6 is as defined under formula (II) and Z1 and Z2 are each as defined under the formula (III), b) the ester (He t) - aroyl laccharide of the formula (IV) is subjected to an exchange of amine with an amine of the formula (V) H2N-Y (V) where Y is as defined under (I), thus providing an ester (Het) -lacrolyl ester of the formula (VI) wherein R1 represents alkyl of 1 to 4 carbon atoms and R2, R3, R4, Y and A are each as defined under formula (I) and R is as defined under formula (II), c) the ester (He t) - aroi lacr i 1 i co of the formula (VI) becomes cyclic in the presence of a base, thus providing a quinolone or naphthyridone ester of the formula (I) wherein R 1 represents alkyl of 1 to 4 carbon atoms and d) if a quinolonecarboxylic acid or naphthiocarboxylic acid of the formula (I) is to be prepared, in which R1 represents hydrogen, the ester which is present after step c) is hydrolyzed and the acid of the formula (I) in which R1 represents hydrogen, is isolated after the addition of an acid,? wherein intermediate compounds (IV) and (VI) are not isolated, and steps of a) to c) are carried out in the presence of the same solvent having characteristics from non-polar to slightly polar. 2. The process according to claim 1, characterized in that the »intermediate compounds of the formulas (IV) and (VI) obtained after carrying out the steps a) and b) are not isolated.

3. The process according to claims 1 and 2, characterized in that the solvent used is an alkylbenzene, halogenobenzene, haloalkylbenzene, alicyclic hydrocarbon, open chain hydrocarbon, or any mixture of these solvents.

4. The process according to claims 1 to 3, characterized in that the solvent used is toluene, xylene, mesitylene, isopropylbenzene, chlorobenzene or dichlorobenzene.

5. The process according to claims 1 to 4, characterized in that 300 to 1,000 ml of the solvent are used per mole of acyl chloride of the formula (II).

6. The process of. according to claims 1 to 5, characterized in that the symbols used in the formulas of the (I) to (VI) fiemen the following meanings: R with respect to it, represents alkyl of 1 to 4 carbon atoms: methyl or ethyl. R2 chlorine or fluorine. R; fluoride hydrogen, chlorine, fluorine or nitro. Fluorine or chlorine A C-R5 wherein R5 = hydrogen, methyl, methoxy, halogen or cyano or N, Y: ethyl, cyclopropyl, fluorocyclic opropyl, 2,4-di-fluoro-phenyl or together with R5-CH (CH3) -CH2- 0- and Z1 and Z2: methyl or ethyl

7. The process according to claims 1 to 6, characterized in that step a) is carried out at a temperature of 25 to 120 ° C, step b) is carried out at a temperature of 5 to 100 ° C and step c) is carried out at a temperature of 50 to 200 ° C.

8. The process according to claims 1 to 7, characterized in that the base used in step a) is an amine tertiary, the amine used in step b) is ethylamine, cyclopropylamine, 2,4-difluoroaniline, inpropanol or fluorocyclopropylamine, and the base used in step c) is potassium carbonate, sodium carbonate , sodium hydride or sodium tert-butoxide.

9. The process for cyclically turning an ester (He t) -aroi lacrí 1 i co of the formula (VI) wherein R1 represents alkyl of 1 to 4 carbon atoms, R2 represents halogen, R3 represents halogen, R4 represents hydrogen, halogen or nitro, R represents halogen, Y represents alkyl of 1 to 6 carbon atoms, carbon, 2-f luoroe tyl, cyclopropyl, fluorocyclopropyl, isopropyl, 4-fluorophenyl or 2, -di fluorofenyl and A represents nitrogen or C-R5 wherein R5 = hydrogen, methyl, methoxy, halogen, nitro or cyano, wherein Y and R5 may also together represent CH2-CH2-0 or -CH (CH3) -CH2-0-, wherein the terminal CH2 or the group CH (CH3) - is attached to the nitrogen atom, in the presence of a base, forming an ester of the formula '(I) wherein the symbols used are each as defined above under formula (VI), the process is characterized in that it is carried out in the presence of a solvent with characteristics from non-polar to slightly polar

10. The process according to claim 9, characterized in that the solvent used is an alkyl benzene, halogenobenzene, haloalkylbenzene, alicyclic hydrocarbon, open chain hydrocarbon, or any mixture of these solvents.