RU2794892C2 - Method for hydrolysis of quinolonocarboxic acid ethers - Google Patents

Abstract

FIELD: chemical industry.

SUBSTANCE: method for the hydrolysis of esters of quinolone carboxylic acids of general formula (II) to obtain quinolone carboxylic acids of general formula (I):

where, respectively, in formulas (I) and (II): R² is hydrogen, methyl, methoxy, fluorine, chlorine, nitro or cyano, R³ is fluorine or chlorine, R⁴ is fluorine, R⁵ is hydrogen, methyl, fluorine, chlorine or nitro and Υ is methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2,4-difluorophenyl, and in formula (I) R¹ is methyl or ethyl, which includes the step: A) reacting compounds of formula (II) with a mixture containing acetic acid, sulfuric acid and water, which differs in that in step A) from 30 to 40 mol of acetic acid, from 0.3 to 1 mol of sulfuric acid and from 0.9 up to 2.5 mol of water is used in terms of mol of compounds of formula (II).

EFFECT: improved method of hydrolysis of esters of quinolonecarboxylic acids of general formula (II) with the production of quinolonecarboxylic acids of general formula (I), in which the formation of by-products to be processed is as small as possible and in which the resulting quinolonecarboxylic acid has the highest possible purity.

8 cl, 1 dwg

Description

The present invention relates to a process for the hydrolysis of quinolone carboxylic acid esters to quinolone carboxylic acids. Fluoroquinolonecarboxylic acids are important intermediates for the preparation of known pharmaceutically active compounds from the class consisting of quinolones. Specific examples include: benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, pipemide oic acid temafloxacin, tosufloxacin, sarafloxacin, sparfloxacin and pradofloxacin.

Pradofloxacin is a highly effective quinolone antibiotic in veterinary medicine. Its antibacterial action and indications, forms of application and suitable preparations are given, for example, in WO 97/31001 A1, WO 03/007995 A1, WO 03/101422 A1, WO 04/082658 A1, WO 05/018641 A1, WO 05/044271 A1 and WO 06/061156 A1.

One step in the multi-step synthesis of pradofloxacin is the hydrolysis of ethylquinolone carboxylate. For the hydrolysis of quinolone carboxylic acid esters, the pH can be lowered with hydrochloric acid or sulfuric acid/acetic acid. The disadvantage of the hydrochloric acid method is that the reaction mixture is very corrosive and the reaction equipment must accordingly be resistant to corrosion. This results in high costs. In addition, the mother liquors must be neutralized before disposal, which requires certain costs, since a large amount of waste is generated, and the process requires a relatively large number of stages.

The sulfuric acid/acetic acid process has the advantage that the used acetic acid can be recovered by distillation and that less corrosive media can be used.

WO 98/26779 A1 discloses, in example Z 22 of the description, the synthesis of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. To do this, 3.8 g (0.1 mol) of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was heated under reflux in a mixture of 100 ml of acetic acid, 20 ml of water and 10 ml of concentrated sulfuric acid for 3 hours. After cooling, the mixture was poured into 100 ml of ice water, the precipitate was filtered off with suction, washed with water and ethanol and dried at 60° C. under vacuum. In terms of the mol of ester, 17.3 mol of acetic acid, 1.86 mol of sulfuric acid, and 11 mol of water were used.

EP 0276700 A1 discloses in Example 1 the hydrolysis of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate. 1 g of this compound was heated together with 3.5 ml of acetic acid, 3 ml of water and 0.3 ml of sulfuric acid to 140-145°C for 4 hours. The mixture was then diluted with water and a solid was isolated. Received 0.7 g of free carboxylic acid with a melting point of 281-282°C. In terms of mol of ester, 20 mol of acetic acid, 1.89 mol of sulfuric acid and 55.8 mol of water were used.

EP 0169993 A2 discloses in example A of the description that a mixture of 94 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 600 ml of glacial acetic acid, 450 ml of water and 70 ml of concentrated sulfuric acid was heated under reflux for 1.5 hours. The hot suspension was poured onto ice, the precipitate was filtered off with suction, washed with water and dried in vacuum at 100°C. 88.9 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were thus obtained. In terms of mol of ester, 34.7 mol of acetic acid, 4.35 mol of sulfuric acid and 82.8 mol of water were used.

EP 1319656 A1 discloses in Example 2 the reaction of 29.4 g of ethyl 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.088 mol), 160 ml of acetic acid, 100 ml of water and 18 ml of concentrated sulfuric acid. The mixture was stirred at 100-110°C for 40 minutes. The resulting mixture was cooled and filtered. The precipitate was recrystallized from chloroform-ethanol. This gave 23.8 g of free carboxylic acid. In terms of mol of ester, 31.8 mol of acetic acid, 3.84 mol of sulfuric acid and 61.1 mol of water were used.

EP 1236718 A1 discloses in Example 1 that 300 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 106.8 g of water and 426 g of acetic acid were first charged and 3.8 g of sulfuric acid was added. The mixture was heated under reflux for 3 hours. Then 310 ml of the distillate was distilled off until the lower temperature of 109°C was reached. The mixture was cooled to 80° C. and 157.5 g of 4.8 wt. % sodium acetate solution. Then the pH value was set in the range from 3 to 4. The mixture was then cooled to 20°C and the solid was filtered off with suction. The solid was washed with 200 ml of water and dried under reduced pressure at 50°C. 270.3 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were isolated, which corresponds to a yield of 99% of theory. In terms of mol of ester, 7.4 mol of acetic acid, 0.04 mol of sulfuric acid and 6.2 mol of water were used.

It was an object of the present invention to provide an improved process for the hydrolysis of quinolone carboxylic acid esters in which the formation of by-products to be processed is as small as possible and in which the resulting quinolone carboxylic acid is of the highest possible purity.

The problem is solved in accordance with the invention using a method for the hydrolysis of esters of quinolone carboxylic acids of the general formula (II) to obtain quinolone carboxylic acids of the general formula (I):

where in the formula (II) R ¹ represents C ₁ -C ₄ -alkyl and

respectively in formulas (I) and (II):

R ² is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, halogen, nitro or cyano,

R ³ and R ⁴ are each halogen,

R ⁵ is hydrogen, C ₁ -C ₄ alkyl, halogen or nitro, and

Y represents C ₁ -C ₆ -alkyl, cyclopropyl or phenyl, each of which may optionally be substituted with halogen,

where R ² and Y together may also represent -CH ₂ -CH ₂ -O- or -CH(CH ₃ )-CH ₂ -O- bridge attached to the nitrogen atom via a carbon atom, and

where at least one of the radicals R ² -R ⁵ represents fluorine,

which includes the stage:

A) reacting compounds of formula (II) with a mixture which includes acetic acid, sulfuric acid and water.

At stage A), ≥30-≤40 mol of acetic acid, ≥0.3-≤1 mol of sulfuric acid and ≥0.9-≤2.5 mol of water are used in terms of mol of compounds of formula (II). It is preferable to use ≥32-≤38 mol acetic acid, ≥0.4-≤0.8 mol sulfuric acid and ≥0.9-≤2.3 mol water, more preferably ≥33-≤35 mol acetic acid, ≥0.4-≤0.6 mol sulfuric acid and ≥ 0.9-≤2.2 mol of water in terms of mol of compounds of formula (II).

In the process according to the invention, acetic acid and sulfuric acid can be used in aqueous or anhydrous form. The quantitative data described refer to 100% acetic acid and 100% sulfuric acid. If acetic acid containing water and/or sulfuric acid containing water is used, less water must be used depending on their water content. Acetic acid is preferably used as glacial acetic acid, sulfuric acid is preferably used as 96-100% sulfuric acid.

The addition of water, acetic acid and sulfuric acid is preferably carried out in such a way that the ester (II), acetic acid and sulfuric acid are first charged and then water is added. It is also possible to first load the ester (II), water and acetic acid, and then add sulfuric acid. The reaction mixture is preferably heated for 10-25 hours, more preferably for 12-22 hours, particularly preferably for 16-20 hours.

In step A), preferably no other reactive or catalytically active compounds are used, apart from the ester (II), acetic acid, water and sulfuric acid.

Preferred embodiments of the method according to the invention are described below. They may be combined with each other at will, unless the context is clear to the contrary.

In an embodiment of the method at stage A), ≥95 mol. % of the compounds of formula (II) used are converted into compounds of formula (I). This yield is preferably ≥96 mol. % and more preferably ≥99.5 mol. %.

In another embodiment of the method, the reaction in step A) is carried out at a temperature of ≥90°C to ≤99°C. This temperature is preferably in the range ≥92 to ≤97°C, more preferably ≥94 to ≤95°C. It has been found that higher reaction temperatures in this step result in higher levels of impurities (see analytical data below for examples and comparative examples).

The heating of the reaction mixture can be carried out at reduced, atmospheric or elevated pressure. For example, a pressure in the range of 0.5 to 3 bar is possible. Unless otherwise indicated, all process steps described herein are generally carried out at atmospheric pressure.

One of the advantages of the process according to the invention is that no distillation is required and that the product can be isolated directly from the reaction mixture by filtration. This is more cost effective than methods with a distillation step.

The quinolonecarboxylic acid formed can be isolated from the mixture, for example, in such a way that the precipitate present is then filtered off with suction, washed and dried. Ethanol is preferably used to wash the precipitate, particularly preferably the precipitate is first washed with acetic acid and then with ethanol. Washing with water can be avoided, whereby the collected acetic acid can also be more easily recovered. It is expedient to wash the isolated product several times in order to obtain it sufficiently free and practically free of traces of sulfuric acid. The addition of a base at this stage is not required in the method according to the invention. This again saves waste and costs.

In yet another embodiment of the method, in formulas (I) and (II) respectively, it is assumed that:

R ² is hydrogen, methyl, methoxy, fluorine, chlorine, nitro or cyano,

R ³ represents fluorine or chlorine,

R ⁴ is fluorine,

R ⁵ is hydrogen, methyl, fluorine, chlorine or nitro,

Y is methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2,4-difluorophenyl

and in formula (I) R ¹ is methyl or ethyl.

It is also possible that, respectively, in formulas (I) and (II):

R ² is hydrogen, C1-C4 alkoxy or cyano,

R ³ is a halogen, in particular chlorine,

R ⁴ is fluorine,

R ⁵ is hydrogen,

Y is cyclopropyl,

and in formula (I) R ¹ is methyl or ethyl.

In yet another embodiment of the method, formula (I) is 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro-8-cyano-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-(2-fluoro )cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid, 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid or 1-cyclopropyl-6-fluoro-7-chloro-8-cyano-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid.

In yet another embodiment of the method, formulas (II) and (I) have the following definitions in accordance with formulas (11-1) and (I-1), respectively:

In yet another embodiment of the method, compounds of formula (II) are obtained by reacting compounds of general formula (III):

where R ¹ -R ⁵ and Y have the above definitions and X is halogen.

In yet another embodiment of the method, compounds of formula (III) are obtained by reacting compounds of general formula (IV):

and where R ¹ -R ⁵ , X and Y have the above definitions and R ⁶ represents C ₁ -C ₄ -alkyl.

In another embodiment of the method, compounds of formula (IV) are obtained by reacting compounds of general formula (V):

and where R ¹ -R ⁶ , X and Y have the above definitions and X' represents halogen.

For the preferred option for obtaining the intermediate compound pradofloxacin (I), the sequence of reactions should be carried out:

(V)→(IV)→(III)→(II)→(I)

and in all relevant compounds of these general formulas, R ¹ is ethyl, R ² is cyano, R ³ is chlorine, R ⁴ is fluorine, R ⁵ is hydrogen, R ⁶ is methyl, X is chlorine, X ' represents chlorine; and Y represents cyclopropyl.

Examples

The present invention is illustrated in detail by the examples below, but is not limited to them. The synthesis scheme is shown in Fig. 1.

Example 1

Synthesis of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (formula (II-2) in Fig. 1)

To 11.8 kg of toluene was added 2.70 kg (18.8 mol) of ethyl (2E)-3-(dimethylamino)acrylate (beta-dimethylaminoacrylate, β-DAASE) and 2.12 kg (20.9 mol) of triethylamine, heated at T _ext. =45°С-55°С. Then a solution of 4.50 kg (17.8 mol) of 2,4-dichloro-3-cyano-5-fluorobenzoyl chloride (formula (V-1) in Fig. 1) in 11.6 kg of toluene was measured at T _ext. =50°С. The reaction mixture was stirred at T _ext. =50°C for 3 hours and cooled to T _ext. =22°C. The suspension was filtered and the filter cake washed with 3.4 kg of toluene. To the filtrate (formula (IV-1) in Fig. 1) measured 1.23 kg (20.5 mol) of acetic acid and a solution of 1.11 kg (19.4 mol) of cyclopropylamine in 2.40 kg of toluene for 2 hours at T _ext. =5-15°C and the mixture was then stirred for 5 hours at T _ext. =10°C. Then 13.5 kg of water was added, the mixture was heated at T _ext. =40°C and stirring was continued at this temperature for 30 minutes. Then the phases were separated at T _ext. =40°С. A solution of 300 g of sodium carbonate in 6.0 kg of water was added to the organic phase, the mixture was heated to T _ext. =40°C, additionally stirred for 30 minutes and the phases were separated at T _ext. =40°С.

The liquid in the amount of 22.6 l was distilled from the organic phase under reduced pressure to a jacket temperature of 60°C. Then added 19.2 kg of N,N-dimethylformamide, and the mixture was stirred for at least 10 minutes at 40°C. Then, the mixture was again distilled under reduced pressure to a jacket temperature Tm=60° C. until no more distillate was formed, and the residue (formula (III-1) in Fig. 1) was cooled to room temperature.

To the residue was added 2.22 kg (16.0 mol) of potash, the suspension was heated to T _ext. =55°C, and the mixture was stirred at this temperature for 5 hours. The mixture was cooled to T _ext. =22°C and 16.5 l of distillate were distilled under reduced pressure to a jacket temperature of 80°C. To the residue was added 18.0 kg of water and the mixture was then stirred at T _ext. =55°C for at least 10 minutes. Then the mixture was cooled for 2 hours to T _ext. =5°C and further stirred at this temperature for 2 hours.

The resulting product was filtered, washed twice with 6.0 kg of water each time and stirred with 9.9 kg of ethyl acetate for at least 3 hours at T _ext. =22°C. The suspension was filtered and the filter cake was washed twice with 4.8 kg of ethyl acetate each time, and the crude product (formula (II-1) in Fig. 1) was dried at 50° C. under reduced pressure for at least 12 hours.

Yield: 5.08 kg; 85.1% of theory based on 2,4-dichloro-3-cyano-5-fluorobenzoyl chloride.

2.96 kg of crude product was heated in 29.4 kg of N,N-dimethylformamide at 60° C. and insoluble impurities were filtered off at this temperature. 3.8 kg of water was added to the filtrate which was then stirred for 1.5 hours and then 13.9 kg of water was measured out over 1.5 hours. The resulting suspension was cooled to T _ext. =22°C, stirred for 30 minutes and the solid was filtered off. The suction filter cake was washed with 3.1 kg of water, then twice with 2.8 kg of ethanol, and dried at 50°C under reduced pressure for at least 12 hours (formula (II-2) in Fig. 1). The process described here has the advantage that the ester (II-2) can be obtained in high purity. This makes it possible to obtain the preferred quinolone carboxylic acids of high purity. (The ester of formula (II-2) is obtained from the ester (II-1) in a purification step. Thus, both formulas describe the same chemical structure. The different functional formulas are only intended to illustrate the different degrees of purity.)

Yield: 2.87 kg; approx. 97% of theoretical in terms of crude product.

Example 2

Hydrolysis of the product of Example 1

To 20.0 g (59.8 mmol) of the product from Example 1 (formula (II-2) in Fig. 1) was added 122.8 g (2.04 mol) of acetic acid, 3.37 g (33.0 mmol) of sulfuric acid and 1.1 g (63.0 mmol) of water. The mixture was heated to 95° C. and stirred at this temperature for 18.5 hours. The suspension was cooled to 10° C., the solid was filtered off with suction, washed with 48 ml of acetic acid and then with 48 ml of ethanol and dried overnight at 60° C. under vacuum. drying cabinet.

In terms of the mol of compound (II-2), the following were used: 34.11 mol of acetic acid, 0.55 mol of sulfuric acid, and 1.05 mol of water.

Yield: 17.6 g; (96.1% of theoretical)

See table below for purity data.

Example 3

Hydrolysis of the product of Example 1

To 20.0 g (59.8 mmol) of the product from Example 1 (formula (II-2) in Fig. 1) was added 122.8 g (2.04 mol) of acetic acid, 3.37 g (33.0 mmol) of sulfuric acid and 2.3 g (126.0 mmol) of water. The mixture was heated to 95° C. and stirred at this temperature for 18.5 hours. The suspension was cooled to 10° C., the solid was filtered off with suction, washed with 48 ml of acetic acid and then with 48 ml of ethanol and dried overnight at 60° C. under vacuum. drying cabinet.

In terms of the mol of compound (II-2), the following were used: 34.11 mol of acetic acid, 0.55 mol of sulfuric acid, and 2.10 mol of water.

Yield: 17.8 g; (97.1% of theoretical)

See table below for purity data.

Comparative Example 1

In accordance with the procedure from Example 1 of document EP 1236718

To 30.0 g (89.6 mmol) of the product from Example 1 (formula (II-2) in Fig. 1) was added 39.6 g (656.1 mmol) of acetic acid, 0.20 ml (3.5 mmol) of sulfuric acid and 9.9 g (549.5 mmol) of water. The mixture was heated under reflux for 3 hours Then 14.1 g of the distillate was distilled to reach the lower temperature of 109°C. The mixture was cooled to 80°C and 40.1 g of 4.8 wt. % sodium acetate solution. Then the pH value was set in the range from 3 to 4. The mixture was then cooled to 20°C and the solid was filtered off with suction. The solid was washed with 50 ml of water and dried under reduced pressure at 50°C.

In terms of the mol of compound (II-2), the following were used: 7.32 mol of acetic acid, 0.04 mol of sulfuric acid, and 6.13 mol of water.

Yield: 26.7 g; (97.2% of theoretical)

See table below for purity data.

Comparative Example 2

In accordance with the procedure from Example 2 of document EP 1236718

To 30.0 g (89.6 mmol) of the product from Example 1 (formula (II-2) in Fig. 1) was added 78.9 g (1.31 mol) of acetic acid, 0.51 ml (9.1 mmol) of sulfuric acid and 2.25 g (124.9 mmol) of water. The mixture was heated under reflux for 4 hours Then 8.1 g of the distillate was distilled to reach the lower temperature of 109°C. The mixture was cooled to 80°C and 75.3 g of 4.8 wt. % sodium acetate solution. Then the pH value was set in the range from 3 to 4. The mixture was then cooled to 20°C and the solid was filtered off with suction. The solid was washed with 50 ml of water and dried under reduced pressure at 50°C.

In terms of the mol of compound (II-2), the following were used: 14.62 mol of acetic acid, 0.10 mol of sulfuric acid, and 1.39 mol of water.

Yield: 27.0 g; (98.2% of theoretical)

See table below for purity data.

Comparative Example 3

According to the procedure of Example Z 22 of WO 98/26779

To 9.5 g (28.4 mmol) of the product from Example 1 (formula (II-2) in Fig. 1) was added 29.5 g (490.9 mmol) of acetic acid, 5.2 g (52.5 mmol) of sulfuric acid and 5.6 g (310.2 mmol) of water. The mixture was heated under reflux for 3 h and cooled to 20°C. The mixture was then added to 28 g of ice water and the solid was filtered off with suction. The solid was washed with 100 ml of water and 10 ml of ethanol and dried under reduced pressure at 60°C.

In terms of the mol of compound (II-2), the following were used: 17.28 mol of acetic acid, 1.85 mol of sulfuric acid, and 10.92 mol of water.

Yield: 8.5 g; (97.7% of theoretical)

The following table shows the degrees of purity of the hydrolysis products of formula I-1 obtained in the examples and comparative examples.

Clearly, in the process according to the invention, products are obtained in greater purity than in comparative processes where the required ratios of reagent (II-2), acetic acid, sulfuric acid and water are not observed.

Claims (27)

1. Method for the hydrolysis of esters of quinolone carboxylic acids of general formula (II) to obtain quinolone carboxylic acids of general formula (I):

, where, respectively, in formulas (I) and (II): R ² is hydrogen, methyl, methoxy, fluorine, chlorine, nitro or cyano, R ³ represents fluorine or chlorine, R ⁴ is fluorine, R ⁵ is hydrogen, methyl, fluorine, chlorine or nitro, and Υ represents methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2,4-difluorophenyl, and in formula (I) R ¹ is methyl or ethyl, which includes the step: A) reacting compounds of formula (II) with a mixture containing acetic acid, sulfuric acid and water, which is different in that in stage A) from 30 to 40 mol of acetic acid, from 0.3 to 1 mol of sulfuric acid and from 0.9 to 2.5 mol of water are used in terms of mol of compounds of formula (II). 2. The method according to p. 1, where in stage A) ≥95 mol. % of the compounds of formula (II) used are converted into compounds of formula (I). 3. The method according to p. 1 or 2, where the reaction in stage A) is carried out at a temperature of ≥90-≤99°C. 4. The method according to any one of paragraphs. 1-3, where formula (I) is 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro-8-cyano-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-(2-fluoro)cyclopropyl -6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid , 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid or 1-cyclopropyl-6-fluoro-7-chloro-8-cyano-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid. 5. The method according to any one of paragraphs. 1-4, where formulas (II) and (I) have the following definitions in accordance with formulas (II-1) and (I-1), respectively:

6. The method according to any one of paragraphs. 1-5, where the compounds of formula (II) are obtained by introducing compounds of general formula (III) into the reaction:

where R ¹ -R ⁵ and Υ have the above definitions and X is halogen. 7. The method according to p. 6, where the compounds of formula (III) are obtained by introducing compounds of general formula (IV) into the reaction:

and where R ¹ - R ⁵ , X and Υ have the above definitions and R ⁶ represents C ₁ -C ₄ -alkyl. 8. The method according to p. 7, where the compounds of formula (IV) are obtained by introducing compounds of general formula (V) into the reaction:

and where R ¹ -R ⁶ and X have the above definitions and X' represents halogen.

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