RU2044734C1 - Method of synthesis of quinoline carboxylic acid or its pharmaceutically acceptable salts and compounds - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: quinoline carboxylic acid of the formula (I)

where radicals R₁-R₆ have the corresponding meanings. Synthesis is carried out by interaction of quinoline derivative of the formula (II)

where R have the corresponding meanings with piperazine derivatives of the formula (III)

Description

(I) и их фармацевтически приемлемых солей.The invention relates to a new method for the preparation of derivatives of 1- (possibly halo-substituted) -ethyl-7- (3,4,5-substituted piperazine) -6,8-difluoro-4-oxo-1,4-dihydroquinolin-3 -carboxylic acid of the general formula

(I) and their pharmaceutically acceptable salts.

In the general formula (I)
R ₁ and R _{3 are} hydrogen or C _1-4 alkyl,
R ₂ C _1-4 -alkyl,
R ₄ , R ₅ and R _{6 are} each hydrogen or halogen.

, 854; Drugs of Fur. 1986,

, 578; 25-th Intersci Conf. Antimicrob Agents Chemother, 1985, 567; 26-th Intersci Conf. Antimicrob Agents Chemother. 1986, Abstr, 430-431]
Соединения группы могут быть получены путем реакции 6,7,8-трифтор-4-оксо-1,4-дигидро-хинолин-3-карбоновой кислоты и циклических аминов (см. патент ФРГ N 3433924, С 07 В 401/04, заявки Японии N 60-142980, N 61-85381 и N 61-65882).It is known that the group of 7- (3, 4, 5-substituted piperazine) -quinoline-3-carboxylic acid derivatives of the general formula (I) exhibits high antibacterial activity [Antimicrob Agents Chemother. 1987,

854; Drugs of Fur. 1986,

, 578; 25-th Intersci Conf. Antimicrob Agents Chemother, 1985, 567; 26-th Intersci Conf. Antimicrob Agents Chemother. 1986, Abstr, 430-431]
The compounds of the group can be obtained by the reaction of 6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines (see Germany patent N 3433924, C 07 B 401/04, applications Japan N 60-142980, N 61-85381 and N 61-65882).

(II) где R галоген, алифатическая ацилокси-группа, содержащая от 2 до 6 атомов углерода, или ароматическая ацилокси-группа, содержащая от 7 до 11 атомов углерода; R₄, R₅ и R₆ имеют вышеуказанное значение, с амином общей формулы
R

NH (III) где R₁, R₂ и R₃ имеют вышеуказанные значения, или с его солью и гидролиз полученного таким образом соединения общей формулы

(IV) где R, R₁-R₆ такие, как указано выше, после или без выделения и, по желанию, превращение полученного таким образом соединения общей формулы (I) в его соль или его освобождение из его соли.According to the present invention, a new method for the preparation of quinoline-3-carboxylic acid derivatives of the general formula (I), wherein R ₁ and R _{3 are} hydrogen or C _1-4 alkyl, R ₂ C _1-4 alkyl; R ₄ , R ₅ and R ₆ each hydrogen or halogen, and their pharmaceutically acceptable salts provides for the reaction of compounds of General formula

(II) where R is halogen, an aliphatic acyloxy group containing from 2 to 6 carbon atoms, or an aromatic acyloxy group containing from 7 to 11 carbon atoms; R ₄ , R ₅ and R ₆ have the above meaning, with an amine of the general formula
R

NH (III) where R ₁ , R ₂ and R ₃ have the above meanings, or with its salt and hydrolysis of the compound of the general formula thus obtained

(IV) where R, R ₁ -R ₆ are as defined above, after or without isolation, and, if desired, converting the compound of general formula (I) thus obtained into its salt or liberating it from its salt.

 An advantage of the method of the present invention is that it simplifies the preparation of compounds of the general formula (I), provides a very high yield with a short reaction time. Boron derivatives of the general formula (IV) are new compounds.

 According to a preferred embodiment of the invention, boron derivatives of the general formula (IV) are converted to the desired quinoline-3-carboxylic acid of the general formula (I) without prior isolation.

 Boron derivatives of the general formula (II) can be reacted with an amine of the general formula (III), if desired, in the presence of an inert organic solvent and an acid binding agent.

 As the organic solvent, an acid amide (e.g., dimethyl-formamide, dimethyl-acetamide), ketone (e.g., acetone, methyl-ethyl-ketone), ether (e.g., dioxane, tetrahydrofuran, diethyl ether), ester (e.g. ethyl acetate, methyl acetate, ethyl propionate), sulfoxide (e.g. dimethyl sulfoxide), alcohol (e.g. methanol, ethanol, 1-decanol, butanol), as well as halogenated nitrile (e.g. acetonitrile) organic solvents (e.g. chloroform, dichloroethane).

 An organic or inorganic base may be used as an acid binding agent. From the group of organic bases, mention should be made of trialkyl amines (e.g. triethylamine; tributylamine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo (5.4.0) -undec-5-ene, 1,5-diazabicyclo (4.3.0 ) -non-5-ene, 1,4-diazabicyclo (2.2.2) octane), and alkali or alkaline earth metal hydroxides or carbonates can be used as an inorganic base. Thus, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc. are preferably used as an acid binding agent. or an excess of an amine of general formula (III).

Boron-derivative of the general formula (II) and the amine of general formula (III) are reacted at a temperature of from 10 ^to 200 ° C depending on the solvent used. The reaction time can vary from 0.1 to 10 hours. The reaction time also depends on the temperature. If the reaction is carried out at a higher temperature, then the reaction time can be shortened. These conditions are preferred, but other conditions may also be used.

 Compounds of general formula (IV) can be hydrolyzed to the desired quinoline-3-carboxylic acids of general formula (I) after or without isolation, in an acidic or basic medium. Compounds of general formula (IV) can, if desired, be precipitated from the reaction mixture, for example by cooling, and can be separated, for example, by filtration or centrifugation.

 Basic hydrolysis can be carried out preferably by heating, using hydroxide of an alkali or alkaline earth metal in the form of its aqueous solution. An aqueous solution of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, calcium hydroxide is preferably used. At the hydrolysis stage, however, organic amines (triethylamine) can also be used.

Acid hydrolysis is preferably carried out using aqueous mineral acid. The hydrolysis of the compounds of general formula (IV) is preferably carried out by heating these compounds with an aqueous solution of HCl, HBr, H ₂ SO ₄ and H ₃ PO ₄ . Hydrolysis can also be carried out using an organic acid (for example, acetic, propionic, etc.).

 The hydrolysis of the compounds of general formula (IV) can be carried out in an aqueous medium in the presence of an organic solvent capable of mixing with water. For this purpose, for example, alcohols (e.g., methanol, ethanol), ketone (e.g., acetone), ether (e.g., dioxane), acid amide (e.g., dimethylformamide), sulfoxide (e.g., dimethyl sulfoxide) or pyridine can be used.

 The quinoline-3-carboxylic acid thus obtained of the general formula (I) can be isolated by adjusting the pH to a suitable value and separating the precipitated crystals, for example by filtration or centrifugation or lyophilization of the aqueous reaction mixture.

 The compounds of general formula (I) can be converted into their pharmaceutically acceptable salts by a known method. Thus, preferably, these salts can be formed by the addition of an acid, for example by reaction with hydrogen halide, sulfonic acids, sulfuric acid or organic acids. Chlorides, bromides, arylsulfonates, methanesulfonates, maleates, fumarates, benzoates, etc. can preferably be formed. Compounds of the general formula (I) also form salts with ions of alkali, alkaline earth and other metals. Accordingly, salts of sodium, potassium, magnesium, silver, copper, and the like can be obtained.

 The compounds of general formula (I) and their pharmaceutically acceptable salts can be converted into hydrates (e.g., hemihydrates, trihydrates, etc.) by known methods.

A further aspect of the present invention is the preparation of new compounds of general formula (IV), wherein R, R ₁ -R ₆ are as defined above.

(V) где R водород или алифатическая ацилокси-группа, содержащая от 2 до 6 атомов углерода, или ароматическая ацилокси-группа, содержащая от 7 до 11 атомов углерода, или с фторборатом в водной или органической среде.Starting materials of the general formula (II) can be prepared by reacting 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinolin-3-carboxylic acid (UK patent N 2,057.440) with a boron derivative for example with a compound of general formula (V)
B

(V) where R is hydrogen or an aliphatic acyloxy group containing from 2 to 6 carbon atoms, or an aromatic acyloxy group containing from 7 to 11 carbon atoms, or with fluoroborate in an aqueous or organic medium.

 Details of the present invention are set forth in the examples without limiting the scope of protection of these examples.

,

)-дифторбора реагируют с 57,1 г 2,6-диметил-пиперазина в 150 мл диметил-сульфоксида при 100^оС в течение 3 ч. Добавляют 400 мл 3% -ного (мас. или об.) водного раствора гидроксида натрия и проводят гидролиз нагреванием в течение 2 ч. Реакционную смесь фильтруют, уровень рН доводят до 7 96%-ной уксусной кислотой.PRI me R 1. 31.9 g (1-ethyl-6,7,8-tri-fluoro-1,4-dihydro-4-hydroxy-quinoline-3-carboxylate-

,

) -diftorbora reacted with 57.1 g of 2,6-dimethyl-piperazine in 150 ml of dimethyl sulfoxide at ¹⁰⁰ ° C for 3 hours. Add 400 ml of 3% (wt. or vol.) aqueous sodium hydroxide solution and hydrolysis is carried out by heating for 2 hours. The reaction mixture is filtered, the pH level is adjusted to 7 with 96% acetic acid.

 The crystalline reaction mixture was cooled overnight and the precipitated crystals were filtered off, washed with water and dried. 29.9 g of 7- (3,5-dimethyl-piperazino) -1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained.

Mp 232-234 ^about S.

,

)дифторбора реагируют с 50,1 г 2-метил-пиперазина в 150 мл диметилсульфоксида. При этом получают 30,6 г 1-этил-6,8-дифтор-1,4-дигидро-4-оксо-7-(3-метил-пиперазино)хинолин- 3-карбоновой кислоты.Analysis according to the formula C ₁₈ H ₂₁ F ₂ N ₃ O ₃ :
calculated, C = 59.17, H = 5.80, N = 11.49
found, C = 59.05, H = 5.91, N = 11.45
PRI me R 2. According to example 1, 31.9 g (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate -

,

) difluoroboron is reacted with 50.1 g of 2-methyl-piperazine in 150 ml of dimethyl sulfoxide. This gives 30.6 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methyl-piperazino) quinoline-3-carboxylic acid.

Mp 238-240 ^about C.

,

) -бис(ацетато-

)-бора реагируют с 50,1 г 2-метил-пиперазина в 150 мл диметилсульфоксида. При этом получают 30,2 г 1-этил-6,8-дифтор-1,4-дигидро-4-оксо-7-(3-метил-пиперазино)-хи- нолин -3-карбоновой кислоты.Analysis according to the formula C ₁₇ H ₁₉ F ₂ N ₃ O ₃ :
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 58.01, H = 5.55, N = 12.07
PRI me R 3. According to example 1, 39.9 g (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate -

,

) bis (acetate

) -boron are reacted with 50.1 g of 2-methyl-piperazine in 150 ml of dimethyl sulfoxide. 30.2 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methyl-piperazino) -quinoline-3-carboxylic acid are obtained.

Mp 237-239 ^about S.

,

) -бис-(пропионато-

)-бора реагируют с 50,1 г 2-метилпиперазина. При этом получают 28,7 г 1-этил-6,8-дифтор-1,4-дигидро-4-оксо-7- (3-метил-пиперазино)хинолин-3-карбоновой кислоты.Analysis according to the formula C ₁₇ H ₁₉ F ₂ N ₃ O ₃ :
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 57.97, H = 5.53, N = 11.90
PRI me R 4. According to example 1, 42.7 g (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate -

,

) -bis- (propionato-

) -boron are reacted with 50.1 g of 2-methylpiperazine. This gives 28.7 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methyl-piperazino) quinoline-3-carboxylic acid.

Mp 237-239 ^about S.

Analysis according to the formula C ₁₇ H ₁₉ F ₂ N ₃ O ₃ :
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 57.99, H = 5.52, N = 12.10
PRI me R 5. To a solution of 3.99 g (0.01 mol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 ³ , 0 ⁴ (bis) acetate-0) -boron in 40 ml of chloroform add 3.0 g (0.03 mol) of 2-methyl-piperazine and the solution is stirred at room temperature for 1.5 hours. Chlorophorin is distilled off in in a vacuum and to an oily residue, resinous, yellowish, add 40 ml of 4% NaOH and the mixture is heated with stirring for 1 h. The resulting solution is filtered, cooled to room temperature and the pH of the solution is adjusted to 6.5-7 96% - acetic acid (1.5 ml). After cooling, a crystalline precipitate formed which was washed with water (5 ml), ethanol (5 ml) and dried. Thus, 3.16 g (90%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methyl-piperazine) -quinolin-3-carboxylic acid are obtained. Melting point 241-242 ^about C.

Analysis calculated for C ₁₇ H ₁₉ F ₂ N ₃ O ₃ :
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 58.02, H = 5.54, N = 11.94
PRI me R 6. To a solution of 3.99 g (0.01 mol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate 0 ³ , 0 ⁴ -bis- (acetate-0) -boron in 20 ml of dimethyl sulfoxide add 3.0 g (0.03 mol) of 2-methyl-piperazine. The solution was stirred at room temperature for 10 min, after which 20 ml of 8% aqueous NaOH and the mixture was heated at ⁸⁰ ° C for 1 hour. The resulting solution was filtered, cooled to room temperature and the pH adjusted to 6.5-7 using 96 % acetic acid. After cooling, the precipitated crystals are filtered, washed with water (5 ml), then with methanol (5 ml) and dried. Thus, 3.19 g (91%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methylpiperazine) quinoline-3-carboxylic acid are obtained. Melting point 241-242 ^about C.

Analysis for C ₁₇ H ₁₉ F ₂ N ₃ O ₃ :
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 57.98, H = 5.50, N = 12.00
PRI me R 7 (comparative). A mixture of 2.71 g (0.01 mol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 3.0 g (0.03 mol) 2-methyl-piperazine in 100 ml of chloroform was stirred at room temperature for 8 hours. The reaction was investigated by TLC. No product other than the original was defined. The starting 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is again obtained in 90% yield
PRI me R 8 (comparative). A solution of 2.0 g of (2-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 ³ , 0 ⁴ ) -bis (acet-0) -boron and 1.3 g of piperazine in 20 ml of DMSO was stirred at room temperature for 3 hours. The reaction products were investigated by TLC. No product was found other than the original. After hydrolysis in 94% yield, the starting 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is recovered. Melting point 272 ^about C.

Analysis for C ₁₂ H ₉ ClFNO ₃ :
calculated C = 53.45; H = 3.36; N = 5.19; Cl = 13.14
found, C = 53.41; H = 3.43; N = 5.18; Cl = 13.31.

PRI me R 9. To a mixture of 4.2 g of 1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 ³ , 0 ⁴ -bis- (acet-0) -boron and 35 ml of chloroform, 3.4 g of 2-methyl-piperazine are added and the mixture is stirred at room temperature for 3 hours. The solvent is removed in vacuo and 4% is added to the precipitate. aqueous NaOH solution (40 ml) and the mixture was stirred for 1 hour. The resulting solution was acidified to pH = 6.5 with 96% acetic acid. The crystals are collected, washed with cold methanol and dried. Thus, 3.06 g (84.6%) of 1- (0-fluoroethyl) -7- (3-methylpiperazinyl) -6.8-difluoro-1,4-dihydro-4-oxo-quinolin-3 are obtained -carboxylic acid. Melting point 238-240 ^about C.

,

) -бис (ацет-

)-бора и 1,3 г (0,015 моль) пиперазина в 20 мл диметилсульфоксида, перемешивают при комнатной температуре в течение 8 ч.Analysis of the formula C ₁₇ H ₁₃ N ₃ O ₃ F ₃ :
calculated, C = 55.28, H = 4.91, N = 11.37
found, C = 55.20, H = 4.94, N = 11.40
PRI me R 10 (comparative). A mixture of 2.82 g (0.01 mol) of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2.58 g (0.03 mol) piperazine in 100 ml of chloroform was stirred at room temperature for 8 hours. Liquid thin layer chromatography did not show any product other than the starting products. After that, the starting 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained back in 92% yield
PRI me R 11 (comparative). Solution 4.1 g (0.01 mol) (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-1-oxoquinoline-3-carboxylic silate-

,

) bis (acet-

) -boron and 1.3 g (0.015 mol) of piperazine in 20 ml of dimethyl sulfoxide, stirred at room temperature for 8 hours

 The reaction mixture was subjected to TLC. Apart from the starting products, no others were found.

After hydrolysis, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinolin-3-carboxylic acid is obtained in 91% yield. Mp. 241-243 ^about S.

Analysis of the formula: C ₁₃ H ₉ ClFNO ₃ :
Calculated, C = 55.43; H = 3.22; N = 4.9; Cl = 12.59; F = 6.74.

,

) -бис-(ацето-

)Бора в 20 мл диметилсульфоксида добавляют 3,0 г (0,003 моль) 2-метилпиперазина. Раствор перемешивают при комнатной температуре в течение 10 мин, добавляют смесь 10 мл воды и 5,4 мл HCl и реакционную смесь нагревают при 100^оС в течение 30 мин. Смесь фильтруют, фильтрат нейтрализуют 4,0 мл 25% (мас./об) раствора аммиака. После охлаждения осажденные кристаллы отфильтровывают, промывают водой (5 мл), метанолом (5 мл) и сушат. Таким образом получают 3,16 г (90%) 1-этил-6,8-дифтор-1,4-дигидро-4-оксо-7-(3-метилпи- перазинхинолин) -3-карбоновой кислоты.Found, C = 54.81, H = 3.03; N = 4.67; Cl = 12.67, F = 6.97
PRI me R 12. To 3.99 g (0.01 mol) of a solution of (1-ethyl-6,7,8-trifor-1,4-dihydro-4-oxoquinoline-3-carboxylate -

,

) -bis- (aceto-

) Boron in 20 ml of dimethyl sulfoxide add 3.0 g (0.003 mol) of 2-methylpiperazine. The solution was stirred at room temperature for 10 min, the mixture was added 10 ml of water and 5.4 ml of HCl and the reaction mixture was heated at ¹⁰⁰ ° C for 30 min. The mixture is filtered, the filtrate is neutralized with 4.0 ml of a 25% (w / v) ammonia solution. After cooling, the precipitated crystals are filtered off, washed with water (5 ml), methanol (5 ml) and dried. Thus, 3.16 g (90%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methylpiperazinequinoline) -3-carboxylic acid are obtained.

,

) -бис-(ацето-

)бора в 40 мл хлороформа добавляют 3,0 г (0,03 моль) 2-метилпиперазина и раствор перемешивают при комнатной температуре в течение 1,5 ч. Хлороформ отгоняют в вакууме и оставшуюся желтоватую маслянистую смолу обрабатывают н.гексаном (20 мл). Полученный кристаллический материал отделяют, промывают н.гексаном (5 мл). Таким образом получают 4,55 г (95%) промежуточного хелата, 1-этил-6,8-дифтор-7-(3-метилпиперазин)-1,4-дигидро-4-оксохинолин- 3-карбоксилат-

,

)-бис-(ацето-

)-бора.Т.пл. > 280^оС.Analysis of C ₁₇ H ₁₉ F ₂ N ₃ O ₃ :
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 58.05, H = 5.50, N = 11.91
PRI me R 13. To a solution of 3.99 g (0.01 mol) (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate -

,

) -bis- (aceto-

) boron in 40 ml of chloroform add 3.0 g (0.03 mol) of 2-methylpiperazine and the solution is stirred at room temperature for 1.5 hours. Chloroform is distilled off in vacuo and the remaining yellowish oily resin is treated with n. hexane (20 ml) . The obtained crystalline material was separated, washed with N. hexane (5 ml). Thus, 4.55 g (95%) of the intermediate chelate, 1-ethyl-6,8-difluoro-7- (3-methylpiperazine) -1,4-dihydro-4-oxoquinoline-3-carboxylate, are obtained

,

) -bis- (aceto-

) -bor. > 280 ^about C.

 The intermediate chelate (4.55 g) is hydrolyzed into a system of dimethyl sulfoxide (3.0 ml) and an 8% (w / v) NaOH solution (20 ml) by heating the mixture under reflux for 1.5 hours. The resulting solution is filtered, cooled. to room temperature and the pH of the solution was adjusted to 6.5-7 with 96% acetic acid (1.5 ml). The mixture was allowed to stand overnight in a refrigerator, then the crystals were removed, washed with water (5 ml), then ethanol (5 ml) and dried.

Thus, 3.1 g (88%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (3-methylpiperazine) -quinoline-3-carboxylic acid are obtained. Mp 242-243 ^about S.

,

] -бис-(ацето-

)-бора и 35 мл хлороформа добавляют 3,4 г 2-метилпиперазина и смесь перемешивают при комнатной температуре в течение 3 ч. Растворитель удаляют в вакууме и к остатку добавляют 40 мл 4%-ного (мас./об) водного раствора NaOH, и смесь перемешивают в течение часа. Полученный раствор подкисляют до рН=6,5 96%-ной (мас/об) уксусной кислотой.Analysis for C ₁₇ H ₁₉ F ₂ N ₂ O ₃
calculated, C = 58.11, H = 5.45, N = 11.96
found, C = 58.05, H = 5.52, N = 11.95
PRI me R 14. To a mixture of 4.2 g of [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate-

,

] -bis- (aceto-

) -boron and 35 ml of chloroform, 3.4 g of 2-methylpiperazine are added and the mixture is stirred at room temperature for 3 hours. The solvent is removed in vacuo and 40 ml of a 4% w / v aqueous solution of NaOH is added to the residue. and the mixture was stirred for one hour. The resulting solution was acidified to pH = 6.5 with 96% (w / v) acetic acid.

 The crystals are collected, washed with cold methanol and dried.

Thus, 3.06 g (84.6%) of 1- (2-fluoroethyl) -quinoline-3-carboxylic acid are obtained. Mp 238-240 ^about C.

Analysis for C ₁₇ H ₁₈ N ₃ O ₃ F ₃ :
calculated, C = 55.28, H = 4.91, N = 11.37
found, C = 55.20, H = 4.94, N = 11.40.

Claims (10)

1. The method of obtaining quinolinecarboxylic acid of General formula I

where R ₁ and R _{3 are} hydrogen or C ₁ -C ₄ alkyl;
R ₂ C ₁ -C ₄ alkyl;
R ₄ , R ₅ and R _{6 are} hydrogen or halogen,
or its pharmaceutically acceptable salts by the interaction of a quinoline derivative with a piperazine derivative, characterized in that a compound of the general formula II is used as a quinoline derivative

where R is halogen, an aliphatic C ₂ -C ₆ acyloxy group or an aromatic C ₇ -C _{1 1} acyloxy group;
R ₄ , R ₅ , R ₆ have the indicated meanings,
as a piperazine derivative, a compound of general formula III

where R ₁ R ₃ have the indicated meanings,
or its salt, the process is carried out at a temperature from room temperature to 100 ^{° C.} in an organic solvent medium, followed by hydrolysis of the compound of general formula IV thus obtained

where R, R ₁ R ₃ have the indicated meanings,
and isolate the target product in free form or in the form of salt.  2. The method according to p. 1, characterized in that the reaction of the compounds of General formula II with an amine of General formula III is carried out in the presence of an organic solvent, preferably an amide of an acid, sulfoxide, ketone, alcohol, ether, ester or nitrile.  3. The method according to p. 2, characterized in that dimethyl sulfoxide is used as an organic solvent.  4. The method according to p. 1, characterized in that the reaction of compounds of General formulas II and III is carried out in the presence of an acid binding agent.  5. The method according to p. 4, characterized in that as the acid binding agent, an amine or an excess of the compound of general formula IV is used.  6. The method according to p. 1, characterized in that the hydrolysis is carried out in an acidic environment.  7. The method according to p. 6, characterized in that the reaction is carried out using an organic or inorganic acid, preferably hydrochloric, sulfuric or acetic.  8. The method according to p. 1, characterized in that the hydrolysis is carried out in an alkaline environment.  9. The method according to p. 8, characterized in that to create an alkaline environment using alkali metal or alkaline earth metal hydroxide or an organic base, preferably an aqueous solution of triethylamine. 10. The compound of General formula

where R ₁ and R _{3 are} hydrogen or C ₁ -C ₄ alkyl;
R ₂ C ₁ -C ₄ alkyl;
R ₄ , R ₅ and R _{6 are} hydrogen or halogen.