WO2001034595A1 - Alkali metal salts of quinolinecarboxylic acid derivatives and process for purifying quinoline-carboxylic acid derivatives by using the salts - Google Patents

Abstract

A process for purifying quinolinecarboxylic acid derivatives of general formula (I) (wherein R is halogeno or methyl), characterized by reacting a quinolinecarboxylic acid derivative of general formula (I) with an alkali metal compound to form an alkali metal salt of the derivative, isolating the salt, and treating the resulting salt with an acid; alkali metal salts of quinolinecarboxylic acid derivatives (I); and antimicrobial agents containing the salts as the active ingredient. The process makes it possible to purify quinolinecarboxylic acid derivatives (I) in a short time at a sufficiently high purity and a high recovery, thus being industrially useful as a simple and efficient purification process for the derivatives (I). Further, the alkali metal salts of the derivatives (I) are useful as intermediates for the purification and as antimicrobial agents.

Description

 Description Metallic salts of quinoline carboxylic acid derivatives, and methods for purifying quinoline carboxylic acid derivatives using the same

 TECHNICAL FIELD The present invention relates to a novel quinoline carboxylic acid derivative metal salt suitable for purification of a quinoline carboxylic acid derivative and a method for purifying a quinoline carboxylic acid derivative using the same. Background art

 Among compounds having quinoline carboxylic acid as a basic skeleton, many compounds useful as synthetic antibacterial agents are known because of their excellent antibacterial activity and broad antibacterial spectrum. 533-14141286), enoxacin (Japanese Patent Application Laid-Open No. 55-31042), ofloxacin (Japanese Patent Application Laid-Open No. 57-46898), Ciprof Loxacin (Japanese Patent Application Laid-Open No. 58-74667), Tosfloxacin (Japanese Patent Application Laid-Open No. 60-22849), and the like are widely used clinically as therapeutic agents for infectious diseases. . However, these compounds are not necessarily sufficient in terms of antibacterial activity, intestinal absorption, and metabolic stability, and many problems still remain to be solved.

Under such circumstances, the present inventors have reported that a quinoline carboxylic acid derivative having a nitrogen-containing heteroaromatic group substituted at the 1-position with an amino group has strong antibacterial activity and low toxicity. It has been found that it retains excellent properties and has extremely high photostability (WOZ97Z11068), and further has a 3-hydroxyazetidine-1-yl group at the 7-position. The compound has a very strong antibacterial activity against Gram-positive bacteria and is characterized by a marked enhancement of this activity, especially under acidic conditions. (The 37th International Conference on Science and Technology, On Micro Anti-Viral Agents and Chemoterabi, 1977, Toronto. The 3rd InterConference on Science, On. Anti-micro vial (I.J. and Chemotherapy, 1989, San Diego).

 However, quinoline carboxylic acid compounds generally have low solubility in various solvents, which limits the solvent used to recrystallize the compound, and also restricts solvents due to restrictions on residual solvents that are acceptable for pharmaceuticals. However, problems such as the final step of compound purification becoming complicated and insufficient purification are left. Disclosure of the invention

 An object of the present invention is to provide a simple and efficient purification method for obtaining a high-purity quinoline carboxylic acid derivative.

Therefore, the present inventors examined various purification methods other than recrystallization of the quinoline carboxylic acid derivative, and found that the quinoline carboxylic acid salt was almost always an acid addition salt, and was isolated as an alkali metal salt. Although no examples have been found, it is possible to convert the quinoline carboxylic acid derivative represented by the following formula (I) to an alkali metal salt very easily by reacting it with various alkali metal compounds. A high-purity purified quinoline carboxylic acid derivative can be obtained by subjecting the alkali metal salt to acid treatment and desalting, and further, it is not necessary to use a special solvent in the purification means via the alkali metal salt. This led to the completion of the present invention. That is, the present invention provides the following formula (Π)

[Wherein, R represents a halogen atom or a methyl group, and X represents an alkali metal] The present invention provides an alkali metal salt of a quinoline carboxylic acid derivative represented by the following formula: The present invention also provides an antibacterial agent containing an alkali metal salt of compound (II) as an active ingredient.

 The present invention also provides an antibacterial agent composition comprising the metal salt of Compound II and a pharmaceutically acceptable carrier.

 The present invention also provides the use of an alkaline metal salt of Compound II as an antibacterial agent.

 The present invention also provides a method for treating infectious diseases, comprising administering a metal salt of Compound III.

 Further, the present invention provides the following formula (I)

[Wherein, R represents a halogen atom or a methyl group] Reacting the quinoline carboxylic acid derivative represented by the formula (I) with an alkali metal compound, isolating the quinoline carboxylic acid derivative as an alkali metal salt, and then subjecting the alkali metal salt to acid treatment. It provides a method for purifying the compound. BEST MODE FOR CARRYING OUT THE INVENTION

 The purification method of the present invention uses an alkali metal salt of quinoline carboxylic acid as an intermediate thereof.

 Here, most of the quinoline carboxylic acid derivatives are amphoteric compounds, and it is expected that they form salts with acids or bases as described above. However, most of the examples actually reported are acid addition salts, and no salts with bases are found. Even in the compounds of the present invention, there are examples of production of salts with organic amines as salts with bases. It has only been reported (WOZ9711068), but no production example of an alkali metal salt is given.

 The quinoline carboxylic acid derivative represented by the formula (I) is very easily converted to an alkali metal salt by reacting with various alkali metal compounds in various solvents that hardly dissolve the compound. Surprisingly, it could not be predicted at all that the treatment of the alkali metal salt with various acids produced purified quinoline carboxylic acid of high purity.

 The alkali metal salt of the quinoline carboxylic acid derivative represented by the formula (II) of the present invention can exist not only in an unsolvated form but also as a hydrate or a solvate. Accordingly, the compounds of the present invention include all crystal forms and hydrates or solvates thereof.

Further, in the present invention, it has been shown that the alkali metal salt is useful as an intermediate in the purification operation, but the alkali metal salt itself exhibits an excellent antibacterial action as shown in the test examples described later, Needless to say, it is useful as an agent. The alkali metal salt of the quinoline carboxylic acid derivative represented by the formula (π) according to the present invention is obtained by, for example, adding a quinoline carboxylic acid represented by the formula (I) to various solvents together with a base containing various alkali metals. It can be obtained by separating the precipitate deposited by stirring at an appropriate temperature for an appropriate time.

 The solvent used here is not limited to a special solvent as described above, and may be any solvent that does not react with a base containing an alkali metal. For example, water; methanol, ethanol, propanol, etc. Alcohols; ethers such as getyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and the like; and mixed solvents thereof.

 Among such solvents, ordinary quinoline carboxylic acid is hardly dissolved in water, alcohols (methanol, ethanol, propanol, etc.) and ethers (getyl ether, tetrahydrofuran, etc.), and the solvent for recrystallization is used. However, according to the purification method of the present invention, such a solvent, particularly water, ethanol, or the like can be used as a suitable solvent.

 Examples of the alkali metal compound include hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate and potassium carbonate, lithium methoxide, lithium ethoxide, sodium methoxide, sodium methoxide, and the like. Alkoxides such as sodium propoxide, potassium methoxide, and potassium tert-butoxide, and the like, particularly lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium methoxide are preferred. Better.

 The amount of the base containing an alkali metal is preferably at least equimolar to the quinoline carboxylic acid represented by the formula (I), particularly preferably about 1 to 10 moles.

This reaction is carried out usually at 0 to 150 ° C, preferably at 0 to 100 ° C, and the reaction time is usually 10 minutes to 48 hours. In order to separate and acquire the generated alkali metal salt, a usual solid-liquid separation method, for example, a method such as filtration or centrifugal separation may be used, and if necessary, treatment such as washing and dehydration, recrystallization operation, etc. Purification can be performed by commonly used purification means.

 To isolate free quinoline carboxylic acid from an alkali metal salt of a quinoline carboxylic acid represented by the formula (II), add the alkali metal salt to various solvents together with various acids, and stir at an appropriate temperature for an appropriate time. I just need.

 Examples of the solvent used here include the same solvents as those used in the above steps, for example, water; alcohols such as methanol, ethanol, propanol, etc .; ethyl ether, tetrahydrofuran, dioxane, monoglyme, Ethers such as diglyme; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and the like and mixed solvents thereof can be used, and water and alcohols (methanol, ethanol, propanol, etc.) which hardly dissolve alkali metal compounds ) Can also be used as a suitable solvent.

 Examples of the acid used here include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; organic carboxylic acids such as formic acid, acetic acid, propionic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid; Examples thereof include sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid, and particularly preferred are hydrochloric acid, formic acid, and acetic acid.

 The amount of the acid to be used is preferably at least equimolar, particularly preferably about 1 to 10 moles per mole of the alkali metal salt of the quinoline carboxylic acid represented by the formula (II).

 This reaction is usually carried out at 0 to 120 ° (preferably 0 to 80 ° C), and the reaction time is usually 10 minutes to 10 hours.

The resulting free quinoline carboxylic acid (I) can be separated and obtained by a conventional solid-liquid separation method, for example, a method such as filtration or centrifugation. If necessary, washing and dehydration are performed. be able to. Although the isolated quinoline carboxylic acid is sufficiently pure as it is, it can be used as a usual purification means such as recrystallization if necessary. It can be further purified.

 The thus obtained purified quinoline carboxylic acid derivative represented by the formula (I) has a high purity of 98% or more by HPLC without recrystallization, as shown in Examples described later.

 The quinoline carboxylic acid represented by the formula (I) is a known compound, and can be produced by an arbitrary method in addition to the method already reported (WOZ97 / 11068). It is as follows.

 (D) (E)

 (I)

(F) [In the formula, R ¹ R ² represents a lower alkyl group, and R ³ represents a hydrogen atom or an amino-protecting group removable by acid treatment or hydrogenation (eg, tert-butyl group, 1,1,3,3-tetratol) Methylbutyl, benzyl, p-methoxybenzyl, 1-phenyletyl, etc., and R is the same as above.)

That is, the compound (A) is reacted with an orthoformate such as ethyl orthoformate or methyl orthoformate to form an acrylate derivative (B), and then reacted with the amino compound (C) to obtain a compound (D). Subsequently, the compound is subjected to a cyclization reaction, and when R ³ is an amino protecting group, the compound is further deprotected to obtain a compound (E), and then reacted with 3-hydroxyazetidine to obtain (F). By compound

(I) can be obtained.

The reaction of the compound (A) with the orthoformates is usually carried out at 0 to 160 ° C, preferably at 50 to 150 ° C, and the reaction time is usually 10 minutes to 48 hours, preferably 1 to 10 hours. The amount of orthoformate to be used is preferably at least equimolar to compound (A), particularly preferably about 1 to 10 moles. It is desirable to add a carboxylic anhydride such as anhydrous acetic acid as a reaction aid. The amount of the reaction aid is preferably at least equimolar to compound (A), particularly preferably about 1 to 10 moles. The reaction between compound (B) and amino compound (C) is carried out without a solvent or in a suitable solvent. Any solvent may be used as long as it does not affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, tetrahydrofuran, dioxane, monoglyme, and the like. Ethers such as jiglime; aliphatic hydrocarbons such as pentane, hexane, heptane, rigoin; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc .; dimethyl Aprotic polar solvents such as formamide and dimethyl sulfoxide; alcohols such as methanol, ethanol and propanol; This reaction is carried out usually at 0 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is usually 10 minutes to 48 hours. Amino compounds The amount of (C) used is preferably close to equimolar to the compound (A).

 Alternatively, compound (A) is reacted with acetal compounds such as N, N-dimethylformamide dimethyl acetal and N, N-dimethylformamide decyl acetal, and then with an amino compound (C). It can also lead to compound (D). As the solvent used in the reaction with the acetal, any solvent may be used as long as it does not affect the reaction, and examples thereof include those described above. This reaction is carried out usually at 0 to 150 ° C, preferably at room temperature to 100 ° C, and the reaction time is 10 minutes to 48 hours, preferably 1 to 10 hours.

Next, the reaction of subjecting compound (D) to a cyclization reaction to give compound (E) is carried out in a suitable solvent in the presence or absence of a basic compound. As the solvent used in this reaction, any solvent can be used as long as it does not affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, etc .; Ethers such as lahydrofuran, dioxane, monoglyme, diglyme, etc .; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc .; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, etc .; methanol And alcohols such as ethanol, propanol and the like. Examples of the basic compound used include alkali metals such as sodium metal and potassium metal; metal hydrides such as sodium hydride and calcium hydride; lithium hydroxide, sodium hydroxide, and potassium hydroxide. Inorganic salts such as sodium carbonate, sodium carbonate and potassium carbonate; alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal fluorides such as sodium fluoride and potassium fluoride; Organic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] indene (DBU) and the like. Further, a reaction auxiliary such as lithium chloride can be added as a reaction auxiliary. The amount of the reaction aid is at least equimolar to the compound (A), and In particular, about 1 to 10 moles is preferable. The temperature of this reaction is usually 0 to 200 ° C, preferably room temperature to 180 ° C, and the reaction is usually completed in 5 minutes to 24 hours. The amount of the basic compound to be used is 1 mol or more, preferably 1 mol to 2 mol, per 1 mol of compound (D).

When R ³ is an amino-protecting group, it is deprotected by a conventional method.For example, when R ³ is a protecting group that can be removed with an acid, tetrahydrofuran, dioxane, and the like in the presence of an acid such as trifluoroacetic acid, methanesulfonic acid, or hydrochloric acid And the like, ketones such as acetone, methyl ethyl ketone and the like, a solvent such as acetic acid and the like, or in the presence or absence of a mixed solvent thereof. This reaction is carried out usually at room temperature to 150 ° C, preferably at room temperature to 80 ° C, and the reaction time is usually 1 to 24 hours. When R ³ is a protecting group that can be removed by hydrogenation, an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, acetone, or methyl ester in a hydrogen atmosphere in the presence of a palladium catalyst or a platinum catalyst. The reaction is performed in the presence or absence of a solvent such as ketones such as tyl ketone, acetic acid, or a mixed solvent thereof. This reaction is carried out usually at room temperature to 150 ° C., preferably at room temperature to 80 ° C., the hydrogen pressure is from normal pressure to 10 atm, and the reaction time is usually from 1 to 24 hours.

 Further, the compound (F) is obtained by reacting the compound (E) with 3-hydroxyazetidine.

In this reaction, alcohols such as methanol, ethanol, etc .; ethers, such as tetrahydrofuran, dioxane, monoglyme, etc .; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, etc .; dimethylformamide Aprotic polar solvents such as dimethylsulfoxide, N-methylpyrrolidone, etc .; solvents such as acetonitrile, pyridine, etc., which do not affect the reaction; if necessary, a deoxidizing agent, for example, sodium carbonate, calcium carbonate, triethylamine , N-methylpyrrolidine, 1,8-diazabicyclo [5.4.0] indene (DBU), potassium carbonate, etc., at room temperature to 160 ° C. reaction The time is several minutes to 48 hours, preferably 10 minutes to 24 hours. The amount of 3-hydroxyazetidine to be used is 1 mol or more, preferably 1 mol to 5 mol, per 1 mol of compound (F).

Compound (I) can be obtained by hydrolyzing compound (F) and removing the carboxy protecting group of R ¹ .

 For the deprotection reaction, a generally known reaction is used, and examples thereof include hydrolysis, and basic compounds such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and lithium carbonate; hydrochloric acid, sulfuric acid, Mineral acids such as hydrobromic acid; or! 1) In the presence of an organic acid such as toluenesulfonic acid, water, alcohols such as methanol, ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane, etc., ketones such as acetone, methylethylketone, etc. And acetic acid or a mixed solvent thereof. This reaction is carried out usually at room temperature to 180 ° C, preferably at room temperature to 140 ° C, and the reaction time is usually 1 to 24 hours. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1

 Synthesis of 2_amino-3,5-difluoro-6- (rac-1-phenylethylamino) pyridine

Add 7.5 g of 2-amino-1,3,5,6-trifluoropyridine to 20 g of N, N'-dimethyl-1-oxazolidinone together with 15.0 g of rac-1-phenylethylamine. The mixture was stirred at 170 ° C. for 66 hours under a nitrogen atmosphere. After allowing to cool, 30 OmL of black-mouthed form was added, and the mixture was washed twice with 1.5 L of a 5% aqueous solution of citric acid. The black-mouthed form layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 62 g of the crude title compound were obtained as a dark green oil showing almost a single spot by TLC. _{'HNMR (CDC 1 3) δ} ;

 1.53 (d, J = 7Hz, 3H), 4.10 (brs, 2H), 4.52 (brs, 1H), 5.15 (m, 1H), 6.96 (t , J = 10 Hz, 1 H), 7.21 -7. 37 (m, 5H)

Example 2

 Ethyl 3 — [(3,5-difluoro-6— (rac—1-phenylethylamino) pyridine_2—yl) amino] —2— (3-chloro-1,2,4,5-trifluorobenzoyl) acrylate Synthesis of

 Ethyl 3-chloro-2,4,5-trifluorotrifluorobenzoyl acetate To 5.6 O g, add 5.60 g of acetic anhydride and 5.00 g of triethyl orthoformate and put in an oil bath at 140 ° C for 1 hour Heated for 15 minutes. The solvent was distilled off under reduced pressure. 6 OmL of toluene was added to the residue, and the mixture was concentrated under reduced pressure. This operation was repeated twice more. To the residue was added 15 mL of chloroform, 5.20 g of 2-amino-3,5-difluoro-6- (rac-1-phenylenylamino) pyridine was added, and the mixture was concentrated under reduced pressure. 1 OmL of methanol was added, and the mixture was allowed to stand for several days. The precipitated solid was collected by filtration and washed with methanol to obtain 8000 g of the title compound as a yellow powder.

 Melting point: 138-140 ° C

_{'HNMR (CDC 1 3) (} 5;

 1.21 (t, J = 7Hz, 3H), 1.62 (d, J = 7Hz, 3H), 4.20 (q, J = 7Hz, 2H), 5.01 (brs , 1H), 5.14 (q, J = 7Hz, 1H), 7.15 (t, J = 9Hz, 1H), 7.21 (m, 2H), 7 35 (m, 2H), 7.42 (m, 2H), 9.02 (d, J-13Hz, 1H), 12.48 (brs, 1H)

Example 3

Etyl 3-[(6-amino-3,5-difluoropyridine-2-yl) amino] —2- (3-chloro-1,2,4,5-trifluorobenzoyl) acrylate Synthesis of

 Ethyl 3-chloro-2,4,5-tritrifluorobenzoyl acetate 2.60 g, acetic anhydride 2.60 g, triethyl orthoformate 2.50 g, and put in a 140 ° C oil bath Heated for 1 hour. The solvent was distilled off under reduced pressure. 15 mL of toluene was added to the residue, and the mixture was concentrated under reduced pressure. This operation was repeated twice more. To the residue was added 5 mL of chloroform, 1.40 g of 2,6-diamino-3,5-difluoropyridine was added, and the mixture was concentrated under reduced pressure. The precipitated solid was dispersed in methanol, collected by filtration, and washed with methanol to obtain 2.96 g of the title compound as a yellow powder.

 Melting point: 149-150 ° C

 'HNMR (CDC 13) δ;

 1.02 (t, J = 7 Hz, 3 H), 4.13 (q, J = 7 Hz, 2 H), 4.61 (brs, 2 H), 7.2 1 (t, J = 9 Hz, 1 H), 7.38 (m, 1H), 8.97 (d, J = 13 Hz, 1H), 11.28 (brs, 1 H)

Example 4

 Synthesis of ethyl 3_ [(6-amino-3,5-difluoropyridine-12-yl) amino] —2 -— (2,4,5_trifluoro-3-methylbenzoyl) acrylate

 2.60 g of ethyl 2,4,5-trifluoro-3-methylbenzoyl acetate, 2.60 g of acetic anhydride and 2.50 g of triethyl orthoformate were added and heated in a 140 ° C oil bath for 1 hour. . The solvent was distilled off under reduced pressure. 15 mL of toluene was added to the residue, and the mixture was concentrated under reduced pressure. This operation was repeated twice more. To the residue was added 5 mL of chloroform-form, 1.43 g of 2,6-diamino-3,5-difluoropyridine was added, and the mixture was concentrated under reduced pressure. The precipitated solid was dispersed in methanol, collected by filtration, and washed with methanol to obtain 3.26 g of the title compound as a yellow powder.

Melting point: 155-156 ° C _{'HNMR (CDC 1 3) (} 5;

 1. 00 (t, J = 7Hz, 3H), 1.56 (s, 3H), 4.11 (q, J = 7Hz, 2H), 4.62 (brs, 2H), 7.20 (t, J = 9Hz, 1H), 7.27 (m, 1H), 8.90 (d, J = 13Hz, 1H), 11.17 (brs, 1H) H)

Example 5

 Ethyl 1- (6-amino-3,5-difluoropyridine-12-yl) -18-chloro-6,7-difluoro41-oxo-1,4-dihydroquinoline-13-force Synthesis

 Ethyl 3-[(6-amino-3,5-difluoropyridine_2-2-yl) amino] _2_ (3-chloro-1,2,4,5-trifluorobenzoyl) acrylate

2.18 g, together with 60 mg of lithium salt and 250 mg of lithium hydroxide, were added to 7.0 g of dimethyl sulfoxide, and the mixture was stirred under a nitrogen atmosphere at 60 ° C. for 1.5 hours. After cooling, the reaction solution was added to 4 OmL of a 10% aqueous solution of citric acid with stirring. The precipitate was collected by filtration and washed with water. The obtained solid was dispersed in 7 mL of ethanol and heated under reflux for 15 minutes. The precipitate was collected by filtration and washed with ethanol. 1.85 g of the title compound were obtained as a yellow powder.

 Melting point: 204-208 ° C

_{'HNMR (CDC 1 3) δ} ;

 1.27 (t, J = 7Hz, 3H), 4.24 (d, J-7Hz, 2H), 6.76 (brs, 2H), 7.97 (t, J = 9Hz, 1 H), 8.21 (t, J = 9Hz, 1H), 8.63 (s, 1H)

Example 6

Ethyl 1- (6-amino-3,5-difluoropyridine-2-yl) -1-6,7-difluoro-8-methyl-4-oxo-1 1,4-dihydroquinoline-13-force Synthesis of ropoxylate Ethyl 3- [(6-amino-3,5-difluoropyridine-1-yl) amino] _2 _ (2,4,5-trifluoro-3-methylbenzoyl) acrylate

83 Omg was added to 2.5 mL of dimethyl sulfoxide together with 43 Omg of lithium chloride and 90 mg of lithium hydroxide, and the mixture was stirred under a nitrogen atmosphere at 60 ° C for 5 hours and at 80 ° C for 2 hours. After cooling, the reaction solution was added to 1 OmL of a 10% aqueous solution of citric acid with stirring. The precipitate was collected by filtration and washed with water. The obtained solid was dispersed in 1 mL of ethanol and heated under reflux for 15 minutes. The precipitate was collected by filtration and washed with ethanol. 662 mg of the title compound was obtained as a yellow powder.

 Melting point: 22 1—224 ° C

'HNMR (d ₆ — DMS〇) δ;

 1.29 (t, J = 7Hz, 3H), 1.79 (s, 3H), 4.25 (q, J = 7Hz, 2H), 6.87 (brs, 2H), 8.00 (t, J = 9Hz, 1H), 8.07 (t, J = 9Hz, 1H), 8.60 (s, 1H)

Example 7

 Ethyl 1 _ (3,5-difluoro-6- (rac-1-phenylethylamino) pyridine _2-yl) 1-8-cloth _ 6,7-difluoro-1 4-oxo-1 1,4-dihydro Synthesis of quinoline-3-carboxylate

Ethyl 3 _ [(3,5-difluoro-6- (rac-1 -phenylethylamino) pyridine- 1-2-yl) amino] 1-2-(3-1,2-, 5-tribenzoyl) To a solution of 73.6 g of acrylate in 125 mL of dimethylformamide was added 45 g of potassium carbonate, and the mixture was stirred at 80 ° C for 1 hour. The reaction solution was added to 1 L of distilled water, the solution was discarded leaving a precipitate, 1 L of distilled water was newly added, and the mixture was stirred and allowed to stand. Then, the solution was removed with decantation. The residue was dissolved in 30 OmL of chloroform and washed twice with 80 OmL of distilled water. The black-mouthed form layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was dispersed in 10 OmL of ethanol and heated under reflux for 10 minutes. The precipitate is collected by filtration and washed with ethanol. W

 Was. 66 g of the title compound were obtained as a colorless powder.

 Melting point: 224—229 ° C

_{'HNMR (CDC 1 3) δ} ;

 1.40 (t, J = 7Hz, 3H), 1.55 (m, 3H), 4.87, 5.01 (m, 2H), 7.11-7.34 (m, 7H), 8.24 (t, J = 9Hz, 1H), 8.41 (s, 1H)

 Example 8

 Ethyl 1_ (3,5-difluoro-6 _ (rac _1 phenylethylamino) pyridine-12 mol) _6,7-Difluoro-8-methyl-14-oxo-1,4-dihydroquinoline-13-carboxy Rate synthesis

 26.0 g of ethyl 2,4,5 trifluoro-3-methylbenzoyl acetate, 26.0 g of acetic anhydride and 25.0 g of triethyl orthoformate were added and heated in an oil bath at 140 ° C for 1 hour. did. The solvent was distilled off under reduced pressure. 100 mL of toluene was added to the residue, and the mixture was concentrated under reduced pressure. This operation was repeated twice more. To the residue was added 5 OmL of chloroform, and 2-amino-3,5-difluoro-6- (rac-1_phenylethylamino) pyridine 27.Og was added, and the mixture was concentrated under reduced pressure. The residue was added to 8 OmL of dimethyl sulfoxide together with 12.O g of lithium chloride and 4.5 g of lithium hydroxide, and the mixture was stirred at 60 ° C for 4 hours. The reaction was added to 1 L of ice water. The precipitate was collected by filtration and washed with water. The obtained solid was dispersed in 15 OmL of ethanol and heated under reflux for 10 minutes. The precipitate was collected by filtration and washed with ethanol. 33.5 g of the title compound were obtained as a light brown powder.

 Melting point: 238—241 ° C

 'HNMR (CDC 13) δ;

1.17 (d, J = 2Hz, 3H), 1.40 (t, J = 7Hz, 3H), 1.52 (d, J = 7Hz, 3H), 4.89, 5.05 , 5.11, 5.18 (m, 2H), 7.1 1-7. 34 (m, 6H), 8.16 (t, J = 9 Hz, 1 H), 8.22 (brs, 1 H), 8.37 (s, 1 H)

Example 9

 Ethyl 11- (6-amino-3,5-difluoropyridine-12-yl) 1,6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-force Synthesis of lipoxylate

 Ethyl 1- (3,5-difluoro-6- (rac-1 phenylethylamino) pyridine-2-yl) _6,7-Difluoro-8-methyl-4-oxo-1,4-dihydroquinoline 1-3 112 mg of carboxylate was added to 0.5 mL of trifluoroacetic acid and heated to 80 ° C for 2 hours. Concentrated under reduced pressure. 1 mL of n-hexane was added to the residue and stirred. Hexane was removed by decantation. This operation was repeated once. The title compound was obtained quantitatively as a colorless solid residue.

'HNMR (d ₆ -DMSO) δ;

 1.29 (t, J = 7Hz, 3H), 1.79 (s, 3H), 4.25 (q, J = 7Hz, 2H), 6.87 (brs, 2H), 8.00 (t , J = 9Hz, 1H), 8.07 (t, J = 9Hz, 1H), 8.60 (s, 1H)

Example 10

 Ethyl 1- (6-amino-3,5-difluoropyridine-12-yl) -1-fluoro-7- (3-hydroxyazetidine-1-yl) -18-methyl-1,4 dihydro-41 Synthesis of oxoquinoline-3-carboxylate.

Ethyl 1- (6-amino-3,5-difluoropyridine-12-yl) -1,6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-13-force Rupoxylate 399 mg, 3-hydroxy Azetidine 'hydrochloride (137 mg), N-methylpyrrolidine (370 mg), and lithium chloride (11 Omg) were added to 70 Omg of dimethyl sulfoxide, and the mixture was stirred at 60 ° C for 17 hours and at 85 ° C for 3 hours. The reaction solution was added to 6 mL of a 10% aqueous solution of citric acid with stirring. The precipitate was collected by filtration and washed with water. The obtained solid was dispersed in 1 mL of ethanol and heated under reflux for 15 minutes. sediment Was collected by filtration and washed with ethanol. 204 mg of the title compound was obtained as a pale yellow powder. Melting point: 242-245 ° C

'HNMR (d ₆ -DMSO) δ;

 1.25 (t, J = 7Hz, 3Η), 1.58 (s, 3H), 3.84 (m, 1H), 3.92 (m, 1H), 4.21 (q, J = 7Hz, 2 H), 4.44 (m, 3 H), 5.62 (d, J = 5 Hz, 1 H), 6.79 (brs, 2

H), 7.62 (d, J = 14 Hz, 1H), 7.93 (t, J = 9 Hz, 1

H), 8.42 (1H, s)

Example 11

 1- (6-Amino-3,5-difluoropyridine-1-2-yl) 1-6-Fluoro-7- (3-Hydroxyazetidine-1-yl) 1-8_Methyl-1, 4-dihydro Synthesis of Mouth-4-oxoquinoline-3-carboxylic acid

 Ethyl 1 _ (6-amino-1,3,5-difluoropyridine-12-yl) 1,6,7-difluoro-8 _methyl-4-oxo-1 1,4-dihydroquinoline-3 -force Rupoxylate 910 mg, 3 —Hydroxyazetidine (240 mg), N-methylpyrrolidine (410 mg), and lithium chloride (23 Omg) were added to 161 Omg of dimethyl sulfoxide, and the mixture was stirred at 60 ° C. for 22 hours. The reaction solution was added to 6 mL of a 10% aqueous solution of citric acid with stirring. The precipitate was collected by filtration and washed with water. The obtained solid was added to a mixture of 3 mL of water and 3 mL of ethanol together with 20 Omg of sodium hydroxide, and the mixture was stirred at 60 ° C for 2 hours under a nitrogen atmosphere. After returning to room temperature, concentrated hydrochloric acid was added to adjust the pH to 1. After stirring at room temperature for one day, the precipitate was collected by filtration and washed with water.

 The obtained solid was dispersed in 1.5 mL of ethanol and stirred at room temperature for 19 hours. The precipitate was collected by filtration and washed with ethanol. The title compound (65 Omg) was obtained as a yellow powder.

'HNMR (d “DMSO) δ; 1.64 (s, 3H), 3.94 (m, 1H), 4.03 (m, 1H), 4.49 (m, 3H), 5.69 (d, J = 5Hz, 1H ), 6.85 (brs, 2H), 7.77 (d, J = 14Hz, 1H), 7.96 (t, J = 10Hz, 1H), 8.72 (s, 1H)

Example 12

 1- (6-amino-3,5-difluoropyridine-1-yl) 1-6-fluoro-1 7- (3-hydroxyazetidine-1-yl) 1-8-methyl-1, 4-1 Synthesis of dihydro-4-oxoquinoline-3-lithium ribonate · lithium salt

 1- (6-amino-3,5-difluoropyridine-12-yl) 1-6_fluoro-17- (3-hydroxyazetidine-1f1) 1-8-methyl-1,4-dihydrochloride — 4-oxoquinoline — 214 mg (purity 98.8%) of 3-carboxylic acid was added to 1.10 g of ethanol together with 63 mg of lithium hydroxide, and the mixture was heated to reflux while stirring for 6 hours. During this time, most of the solids remained dispersed. After cooling, the precipitate was collected by filtration and washed with ethanol. Drying over phosphorus pentoxide under reduced pressure gave 21 Omg (purity: 99.3%) of the title compound as a colorless powder.

 The purity of the compound was determined by high-performance liquid chromatography using a reversed-phase column under the following conditions and the area ratio of the target substance to the sum of all detected peak areas (hereinafter referred to as Examples). The same applies to 13 to 17).

 Conditions:

 Column; LUNA 5u C18 (2) 150 X 4.60 mm (Phenomenex)

 UV detection; 254 nm or 290 nm

 Mobile phase; 20mM SDS solution in phoshoric acid (1 → 10000) ： aceton itrile (67:33)

 Flow rate; 1.2 mL / min

 Melting point: 280 ° C or higher (colored at 275 ° C or higher)

'HNMR (d ₆ —DMSO: Chemical shift depends on concentration: 3.8 mg Dissolve in 0.8 mL and measure) δ ；

 1.60 (s, 3H), 3.85 (m, 1H), 3.94 (m, 1H), 4.35—4.45 (m, 3H), 5.65 (brs, 1H) ), 6.77 (brs, 2H), 7.69 (d, J = 14Hz, 1H), 7.93 (t, J = 9Hz, 1H), 8.55 (s, 1H)

Example 13

 1-1- (6-amino-1,3,5-difluoropyridine-1-yl) 1-6-fluoro-7- (3-hydroxyazetidine-1-yl) _8-methyl-1,4-dihydro Mouth—4-oxoquinoline—Synthesis of 3-Rubonic acid and Rhidium salt

 1- (6-Amino-3,5-difluoropyridine-1-yl) 16-Fluoro — 7— (3-Hydroxyazetidine-1-yl) 18-Methyl-1,4-dihydrid 403 mg of Rho 4-oxoquinoline-13-carboxylic acid (purity 92.8%) was added to 2.5 mL of ethanol together with 15 Omg of potassium hydroxide, and the mixture was heated to reflux while stirring for 2 hours. During this time, most of the solids remained dispersed. After cooling, the precipitate was collected by filtration and washed with ethanol. Drying over phosphorus pentoxide under reduced pressure gave 220 mg of the title compound (purity 95.6%) as a colorless powder. Melting point: 280 ° C or higher (colored at 260 ° C or higher)

'HNMR (d ₆ — DMS〇: Chemical shift value depends on concentration: measured by dissolving 5.6 mg in 0.8 mL) δ;

 1.55 (s, 3Η), 3.80 (m, 1H), 3.85 (m, 1H), 4.35 (m, 2H), 4.43 (m, 1H), 5. 71 (brs, 1Η), 6.66 (brs, 2H), 7.57 (d, J = 14Hz, 1H), 7.88 (t, J = 9Hz, 1H), 8.09 (s , 1 H)

Example 14

1- (6-amino-3,5-difluoropyridine-1 2 ^^) 18-chloro-6-fluoro-7- (3-hydroxyazetidine_1-yl) _1, 4—Jihid Synthesis of Rho 4-oxoquinoline-3-carboxylic acid · lithium salt

1- (6-amino-1,3,5-difluoropyridine-1-yl) 1-8-chloro-6-fluoro-7- (3-hydroxyazetidine-1yl) 1-1,4- 222 mg of dihydrofuran-4-oxoquinoline-3-carboxylic acid (purity: 97.4%) was added to 1.2 mL of ethanol together with 63 mg of lithium hydroxide, and the mixture was heated to reflux while stirring for 6 hours. During this time, most of the solids remained dispersed. After cooling, the precipitate was collected by filtration and washed with ethanol. Drying over phosphorus pentoxide under reduced pressure gave 215 mg of the title compound (purity 97.8%) as a colorless powder.

 Melting point: 280 ° C or higher (colored at 200 ° C or higher)

'HNMR (d ₆ -DMSO: Chemical shift depends on concentration: measured by dissolving 3.2 mg in 0.8 mL) δ;

 4.10 (m, 2H), 4.35 (m, 1H), 4.64 (m, 2H), 6.67 (brs, 2H), 7.80 (d, J = 13Hz, 1H ), 7.92 (t, J = 9Hz, 1H), 8.48 (s, 1H)

Example 15

 1- (6-amino-3,5-difluoropyridine-1-yl) 18-chloro-1-6-fluoro-7- (3-hydroxyazetidine-11-yl) 1,4 _Synthesis of 4-hydroxyquinoline-3-carboxylic acid · sodium salt

 1- (6-Amino-1,3,5-difluoropyridine-1T) 18-Chloro-6-Fluoro_7— (3-Hydroxyazetidine_1-yl) — 1,4-Dihide 310 mg of 4-oxoquinoline-3-carboxylic acid (purity 95.8%) was added to 2.5 mL of methanol together with 9 Omg of sodium hydroxide, and the mixture was heated and refluxed for 2 hours with stirring. During this time, most of the solids remained dispersed. After cooling, the precipitate was collected by filtration and washed with methanol. The residue was dried over phosphorus pentoxide under reduced pressure to give 294 mg of the title compound (purity: 98.2%) as a colorless powder.

Melting point: 280 ° C or higher 'HNMR (d ₆ -DMSO: Chemical shift value depends on concentration: measured by dissolving 7.6 mg in 0.8 mL) δ;

 4.07 (m, 2H), 4.44 (m, 1H), 4.59 (m, 2H), 5.74 (brs, 1Η), 6.63 (brs, 2H), 7.72 (d, J = 13Hz, 1H), 7.89 (t, J = 9Hz, 1H), 8.26 (s, 1H) Example 16

 1- (6-Amino-3,5-difluoropyridine-12-yl) -1-6-Fluoro-7- (3-hydroxyazetidine-11-yl) -18-Methyl_1,4-dihydro Regeneration of Rho-4oxoquinoline-3-carboxylic acid

 1- (6-amino-3,5-difluoropyridine-1-yl) 1-6-fluoro-1 7- (3-hydroxyazetidine-1_yl) 1-8_methyl-1,4 180 mg of dihydro 4-oxoquinoline-l-carboxylic acid sodium salt (purity 92.6%) was added to 1.OmL of distilled water together with 57mg of acetic acid, and the mixture was stirred at room temperature for 2 hours and at 60 ° C for 1 hour. . During this time, most of the solids remained dispersed. After cooling, the precipitate was collected by filtration and washed with ethanol. Drying over phosphorus pentoxide under reduced pressure gave 148 mg of the title compound (purity 94.3%) as a pale yellow powder. Melting point: 232—235

'HNMR (d ₆ -DMSO) δ;

 1.64 (s, 3Η), 3.94 (m, 1 H), 4.03 (m, 1 H), 4.49 (m, 3H), 5.69 (d, J = 5 Hz, 1 H ), 6.85 (brs, 2H), 7.77 (d, J = 14Hz, 1H), 7.96 (t, J = 10Hz, 1H), 8.72 (s, 1H)

Example 17

1-(6-amino-3,5-difluoropyridine-1-yl) -18-chloro-6-fluoro-7- (3-hydroxyazetidine-1-yl) _1,4_dihydro 4 Regeneration of monooxoquinoline-3-butyric acid 1- (6-amino-1,3,5-difluoropyridine-1-yl) 18-chloro-6-fluoro-7- (3-hydroxyazetidine-1-yl) 1,1,1-dihydrofluoride —4-oxoquinoline-3-lithium sulfonic acid · lithium salt (purity: 97.8%) 107 mg was added to 1.0 mL of ethanol together with 55 mg of acetic acid, and the mixture was heated under reflux with stirring for 4 hours. During this time, most of the solids remained dispersed. After cooling, the precipitate was collected by filtration and washed with ethanol. Drying over phosphorus pentoxide under reduced pressure gave 90 mg of the title compound (purity 98.1%) as a colorless powder.

 Melting point: 280 ° C or higher

 'HNMR (d “DMSO) δ;

 4.18 (m, 2H), 4.51 (m, 3Η), 5.75 (brs, 1H), 6.76 (brs, 2H), 7.79 (d, J = 13Hz, 1 H), 7.99 (t, J = 9Hz, 1H), 8.75 (s, 1H) Test example (antibacterial action)

1- (6-Amino-3,5-difluoropyridine-1-yl) 1-6-Fluoro-7- (3-Hydroxyazetidine-1 ^ F) — 8-Methyl—1,4— Minimum growth inhibitory concentration (MIC: g / mL) of dihydro 4-oxoquinoline-13-carboxylic acid sodium salt in accordance with the Japanese Society of Chemotherapy Standard Method (CHEMOTHERAPY, 29 (1), 76, 1981) Was measured. Table 1 shows the results. In the table, CPFX is 1-cyclopropyl-6-fluoro-7 _ (1-pirazinyl) — 1,4-dihydro-14-oxoquinoline-3 —capillonic acid, LVF X is S (-) One 9-Fluoro-2,3-dihydro-1-methyl_10— (4-Methyl_1-piperazinyl) —7-oxo-1H-pyrido [1,2,3-de] [1,4] Benzoxazine-1 6 —Indicates liponic acid. table 1

Industrial applicability

 When the method for purifying a quinoline carboxylic acid derivative of the present invention is used, the quinoline carboxylic acid derivative represented by the formula (I) hardly dissolves, and the compound can be prepared in a short time even from a solvent that could not be used as a recrystallization solvent. It can be purified with sufficiently high purity and high recovery. Therefore, the purification method of the present invention is industrially useful as a simple and efficient method for purifying the quinolinecarbonic acid derivative represented by the formula (I). In addition, the alkali metal salt of the quinoline carboxylic acid derivative represented by the formula (Π) is useful as an intermediate for purifying the quinoline carboxylic acid derivative represented by the formula (I) and an antibacterial agent.

Claims

The scope of the claims The following formula (II)

 [In the formula, R represents a halogen atom or a methyl group, and X represents an alkali metal.] An alkali metal salt of a quinoline carboxylic acid derivative represented by the following formula:  2. The metal salt of a quinoline carboxylic acid derivative according to claim 1, wherein the alkali metal is lithium, sodium or potassium.  3. An antibacterial agent containing the metal salt of the quinoline carboxylic acid derivative according to claim 1 or 2 as an active ingredient.  4. An antimicrobial composition comprising the metal salt of the quinoline carboxylic acid derivative according to claim 1 or 2 and a pharmaceutically acceptable carrier.  5. Use of an alkali metal salt of the quinoline carboxylic acid derivative according to claim 1 or 2 as an antibacterial agent. 6. A method for treating an infectious disease, comprising administering the metal salt of a quinoline carboxylic acid derivative according to claim 1 or 2. 7. The following formula (I)

 [Wherein, R represents a halogen atom or a methyl group] Reacting a quinoline carboxylic acid derivative represented by the following formula with an alkali metal compound to isolate the quinoline carboxylic acid derivative as an alkali metal salt, and then subjecting the alkali metal salt to an acid treatment, thereby purifying the quinoline carboxylic acid derivative. Law.  8. The method for purifying a quinoline carboxylic acid derivative according to claim 7, wherein the alkali metal is lithium, sodium or potassium.