JPH0665671B2 - Novel process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative or salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention has a general formula showing a strong antibacterial action against Gram-positive and Gram-negative bacteria. 1-substituted aryl-1,4-dihydro-4-represented by
Process for producing oxonaphthyridine derivative or salt thereof, more specifically, general formula "In the formula, R ¹ and X each have the same meaning as described above; R ² is substituted with one or more groups selected from an azido group or a halogen atom, a nitro group, an alkyl group and an alkoxy group. Which represents an optionally substituted arylthio, alkylsulfinyl, arylsulfinyl, alkanesulfonyl, arenesulfonyl, alkanesulfonyloxy, arenesulfonyloxy, dialkoxyphosphinyloxy or diaryloxyphosphinyloxy group. And a compound represented by the general formula R ³ H (II) [wherein R ³ has the same meaning as described above] or a salt thereof is reacted, and the carboxyl protecting group is eliminated or converted to a salt, if desired. The 1-substituted aryl-1,4-dihydro-4-oxo represented by the general formula (III) It relates Fuchirijin derivatives or manufacturing process to obtain the salt thereof.

[Conventional technology]

The 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (III) and its salt are the 24th Interscience Conference on Antimicrovial Agents and Chemotherapy (ICAAC) Pages 102-104 and JP-A-60
-228479 has a strong antibacterial action against Gram-positive and Gram-negative bacteria, especially antibiotic-resistant bacteria, and has high blood concentration by oral or parenteral administration, and is highly safe. It has been shown to have properties. And, as a method for producing these compounds, a method of using a novel 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (I) or a salt thereof as an intermediate is not known at all.

[Problems to be solved by the invention]

An object of the present invention is to provide a process for producing a 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (III) or a salt thereof in a high yield and easily industrially. To do.

[Means for solving problems]

As a result of earnest research to achieve the above-mentioned objects, the present inventors have
A compound represented by the general formula (I) or a salt thereof is reacted with a compound represented by the general formula (II) or a salt thereof to give a 1-substituted aryl-1,4-dihydro-group represented by the general formula (III). The inventors have found a method for obtaining a 4-oxonaphthyridine derivative or a salt thereof in high yield, and completed the present invention.

Hereinafter, the present invention will be described in detail.

In the present specification, the carboxyl protecting group represented by R ¹ is ^one commonly used in the art, for example, an alkyl group, a benzyl group, a pivaloyloxymethyl group, a trimethylsilyl group, and the like. Ordinary protecting groups for a carboxyl group described in, for example, Japanese Patent No. 80665 can be used.

Examples of the arylthio group for R ² include phenylthio, naphthylthio, etc .; Examples of the alkylsulfinyl group include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, tert.-butylsulfinyl, etc .; Examples of the arylsulfinyl group include phenylsulfinyl, Naphthylsulfinyl, etc .; as an alkanesulfonyl group, for example, methanesulfonyl, ethanesulfonyl, 1-methylethanesulfonyl, 1,1-dimethylethanesulfonyl, etc .; as an arenesulfonyl group, for example, benzenesulfonyl, naphthalenesulfonyl, etc .; alkanesulfonyl. Examples of the oxy group include methanesulfonyloxy, ethanesulfonyloxy, 1-methylethanesulfonyloxy and 1,1-dimethyoxy. Ethane sulfonyloxy; The arenesulfonyl group, for example,
Benzenesulfonyloxy, naphthalenesulfonyloxy, etc .; As the dialkoxyphosphinyloxy group,
For example, dimethoxyphosphinyloxy, diethoxyphosphinyloxy, dipropoxyphosphinyloxy, dibutoxyphosphinyloxy and the like; examples of diaryloxyphosphinyloxy groups include diphenoxyphosphinyloxy and the like. Can be mentioned.

Examples of the halogen atom as the substituent of R ² described above include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl and the like; as the alkoxy group,
For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy and the like can be mentioned.

Further, the amino group in R ³ may be protected 3-
Examples of the protecting group for the amino group and imino group in the piperazinyl group in which the aminopyrrolidinyl group and the imino group may be protected include those usually used in the art, for example, formyl, acetyl, N, N. -Dimethylaminomethylene and the like include the usual protecting groups for amino and imino groups described in JP-A-59-80665.

Examples of the salt of the compounds represented by the general formulas (I) and (III) include commonly known salts of a basic group such as amino group or an acidic group such as carboxyl group and hydroxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as oxalic acid, citric acid and trifluoroacetic acid; methanesulfonic acid, p- Examples of salts of acidic groups include salts with sulfonic acids such as toluenesulfonic acid and naphthalenesulfonic acid; salts with alkaline metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium; Salt; procaine, dibenzylamine, N, N-
Examples thereof include salts with nitrogen-containing organic bases such as dibenzylethylenediamine, triethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, diethylamine and dicyclohexylamine.

Further, as the salt of the compound represented by the general formula (II),
The salts of the same basic group as those explained for the compounds represented by the general formulas (I) and (III) can be mentioned.

Next, the production method of the present invention will be described in detail.

The 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (III) or a salt thereof of the present invention is obtained by adding a deoxidizing agent to a compound represented by the general formula (I) or a salt thereof. In the presence or absence of the general formula (II)
It can be obtained by reacting an amine represented by: or a salt thereof.

When this reaction is carried out in a solvent, the solvent used is
It is not particularly limited as long as it is a solvent inert to the reaction, and specifically, methanol, ethanol, n-propanol,
2-propanol, n-butanol, isobutanol,
tert.-Alcohols such as butyl alcohol; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether; ketones such as acetone and methyl ethyl ketone; nitroalkanes such as nitromethane and nitroethane; esters such as methyl acetate and ethyl acetate Nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide Examples thereof include sulfoxides such as dimethyl sulfoxide, and these may be used as a mixture of two or more kinds.

Further, as the deoxidizing agent, for example, triethylamine,
Diisopropylethylamine, 1,8-diazabicyclo-
Examples include organic or inorganic bases such as [5.4.0] -undec-7-ene (DBU), pyridine, potassium tert.-butoxide, potassium carbonate, sodium carbonate, sodium hydride.

The amount of the amines represented by the general formula (II) or a salt thereof is preferably 2.0 to 5.0 times mol with respect to the compound represented by the general formula (I) or a salt thereof, when a deoxidizing agent is not used. However, the amount of the amines represented by the general formula (II) or a salt thereof can be reduced by appropriately using a deoxidizing agent. This reaction may be carried out usually at 0 to 150 ° C., preferably 0 to 100 ° C. for 5 minutes to 30 hours.

In the above reaction step, R ² is a halogen atom, a nitro group,
In the case of a compound represented by the general formula (I) or a salt thereof, which is an alkanesulfonyloxy or arenesulfonyloxy group which may be substituted with one or more groups selected from an alkyl group and an alkoxy group, R ² is bulky. A high alkanesulfonyloxy or arenesulfonyloxy group, especially one or more groups in which at least one or more carbon atoms adjacent to the carbon atom to which the oxysulfonyl group is attached are selected from halogen atom, nitro group, alkyl group and alkoxy group. It is preferably a substituted arenesulfonyloxy group.

The thus obtained compound represented by the general formula (III) can be derivatized into a free carboxylic acid of the corresponding compound, if desired, by subjecting the protecting group to a reaction of eliminating by a known method. Furthermore, if desired, these free carboxylic acids can be converted into salts or esters of the corresponding compounds by subjecting them to salt formation reactions or esterification reactions known per se.

Next, a method for producing the raw material compound represented by the general formula (I) will be described. This compound can be produced, for example, according to the production method shown below.

Formulas (IV), (V), (VI), (VIIIa), and (I
Examples of the salt of the compound represented by a) include the same salts as those described for the compounds represented by the general formulas (I) and (III). Examples of the salt of the compound represented by the general formula (VII) include salts with alkali metals such as lithium, potassium and sodium, salts with alkaline earth metals such as magnesium and salts with ethoxymagnesium. To be

The compound represented by the general formula (VI) or a salt thereof is obtained by converting the compound represented by the general formula (IV) or a salt thereof prepared according to the method described in British Patent No. 1409987 into a bretane de la society.・ Simik de France (Bull.S
oc.Chim.Fr.) 1165-1169 (1975), it can be produced by reacting with a compound represented by the general formula (V) or a salt thereof produced according to the method.

The compound represented by the general formula (VIIIa) or a salt thereof is
A compound represented by the general formula (VI) or a salt thereof is reacted in a manner known per se with a reactive derivative at a carboxyl group, for example, acid halide such as acid chloride or acid bromide; acid anhydride; monoalkyl carbonate such as monoethyl carbonate. Mixed acid anhydride with ester; active ester such as dinitrophenyl ester, cyanomethyl ester, succinimide ester; converted to active acid amide with imidazole, etc., and then reacted with compound represented by general formula (VII) or salt thereof And then decarboxylated. The solvent used in this reaction is not particularly limited as long as it is an inert solvent for the reaction, and for example, methanol, ethanol, 2-
Alcohols such as propanol; Aromatic hydrocarbons such as benzene and toluene; Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane; Ethers such as diethyl ether, tetrahydrofuran, dioxane; Nitriles such as acetonitrile; N, Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide, and two or more kinds of these solvents may be mixed and used. The amount of the compound represented by the general formula (VII) or the salt thereof used is equimolar or more, preferably 1.0 to 2.5 times the molar amount of the compound represented by the general formula (VI) or the salt thereof. This reaction is usually -50 ~
It may be carried out at 100 ° C, preferably -20 to 70 ° C, for 5 minutes to 30 hours.

The compound represented by the general formula (Ia) or (I) or a salt thereof is the same as the compound represented by the general formula (VIIIa) or a salt thereof or the compound represented by the general formula (VIII), for example, N, N- It can be obtained by reacting a trialkyl orthoformic acid ester in the presence or absence of an acetal of dimethylformamide or acetic anhydride. This reaction is carried out in the presence or absence of a solvent, and the solvent used is not particularly limited as long as it is an inert solvent for the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as dioxane, tetrahydrofuran and diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; N, N-dimethylformamide , N, N-dimethylacetamide and the like amides; dimethyl sulfoxide and the like sulfoxides, and the like, and two or more kinds thereof may be mixed and used.
Further, as the acetal of N, N-dimethylformamide, for example, N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide diethyl acetal, N, N-dimethylformamide dinopenpentyl acetal, or trialkyl orthoformate is also used. Examples of the ester include trimethyl orthoformate and triethyl orthoformate, and these reagents may be used as a solvent. The amount of these used is the compound represented by the general formula (VIIIa) or a salt thereof or the general formula (VIII)
It is preferably equimolar or more to the compound represented by. This reaction is generally 0 to 150 ° C, preferably 15 to 110 ° C.
Then, it may be carried out for 5 minutes to 30 hours.

Further, in the compound represented by the general formula (VIII) or the compound represented by the general formula (I) or a salt thereof, R ²
Is an alkanesulfonyloxy, arenesulfonyloxy, dialkoxyphosphinyloxy or diaryloxyphosphinyl which may be substituted with one or more groups selected from an azido group, a halogen atom, a nitro group, an alkyl group and an alkoxy group. The compound that is an oxy group is
It can be obtained by reacting a compound represented by the general formula (VIIIa) or (Ia) or a salt thereof with an azidating agent, a sulfonylating agent or a phosphorylating agent, respectively.

(1) Sulfonylation A compound represented by the general formula (VIII) or the general formula (I)
In the compound represented by or a salt thereof, R ² is a halogen atom, a nitro group, a compound which is an alkanesulfonyloxy or arenesulfonyloxy group optionally substituted with one or more groups selected from an alkyl group and an alkoxy group, General formula (VIIIa) or (Ia) respectively
It can be obtained by reacting the compound represented by or a salt thereof with a sulfonylating agent in the presence or absence of a deoxidizing agent. The solvent used in this reaction is not particularly limited as long as it is an inert solvent for the reaction, but for example, water; aromatic hydrocarbons such as benzene, toluene, xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, etc. Ethers; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; acetone,
Ketones such as methyl ethyl ketone; N, N-dimethylformamide, amides such as N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; hexamethylphosphoramide; pyridine and the like. You may mix and use the solvent of 2 or more types. As the sulfonylating agent,
For example, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride,
1-methylethanesulfonyl chloride, 1,1-dimethylethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, nitrobenzenesulfonyl chloride, chlorobenzenesulfonyl chloride,
2,5-dichlorobenzene sulfonyl chloride, 2,3,4-trichlorobenzene sulfonyl chloride, 2,4,5-trichlorobenzene sulfonyl chloride, mesitylene sulfonyl chloride, 2,4,6-triisopropylbenzene sulfonyl chloride, naphthalene sulfonyl chloride Examples thereof include alkanesulfonyl halides or arenesulfonyl halides, alkanesulfonic anhydrides such as methanesulfonic anhydride, toluenesulfonic anhydride, or arenesulfonic anhydrides. Examples of the deoxidizing agent include triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] -undec-7-ene (DBU), pyridine, potassium tert.-butoxide, alkali hydroxide, alkali carbonate and the like. And organic or inorganic bases.

The amount of the sulfonylating agent and optionally the deoxidizing agent used is equimolar or more with respect to the compound represented by the general formula (VIIIa) or (Ia) or a salt thereof,
It is preferably 1.0 to 2.0 times mol. This reaction is usually 0
It may be carried out at 150 ° C, preferably 0 to 50 ° C, for 5 minutes to 30 hours.

(2) Azido and phosphorylation The compound represented by the general formula (VIII) or the general formula (I)
In the compound represented by or a salt thereof, R ² is dialkoxyphosphinyloxy or diaryloxyphos optionally substituted with one or more groups selected from an azido group or a halogen atom, a nitro group, an alkyl group and an alkoxy group. The compound having a finyloxy group is obtained by reacting the compound represented by the general formula (VIIIa) or (Ia) or a salt thereof with an azidating agent or a phosphorylating agent in the presence or absence of a deoxidizing agent, respectively. Can be obtained by The solvent used in these reactions is not particularly limited as long as it is a solvent inert to the reaction, and specifically, the same solvents as those used in the above-mentioned sulfonylation can be mentioned. Examples of the azidating agent include dialkylphosphoric acid azides such as diethylphosphoric acid azide and diarylphosphoric acid azides such as diphenylphosphoric acid azide. In addition, examples of the phosphorylating agent include dialkyl phosphate halogenides such as dimethyl phosphate chloride, diethyl phosphate chloride, dipropyl phosphate chloride, dibutyl phosphate chloride, and diaryl phosphate halides such as diphenyl phosphate chloride. Also, in these reactions,
Specific examples of the deoxidizing agent used include the same deoxidizing agents used in the sulfonylation described above.

The amount of the azidating agent and optionally the deoxidizing agent used in the azidation is represented by the general formula (VIIIa) or (Ia)
It is an equimolar amount or more, preferably 1.0 to 3.0 times the molar amount of the compound represented by or a salt thereof. This reaction is usually 0 to 150 ° C, preferably 15 to 100 ° C for 5 minutes to
It should be carried out for 30 hours. Further, the amount of the phosphorylating agent used in phosphorylation and the deoxidizing agent optionally used is
The amount is equimolar or more, preferably 1.0 to 1.5 times the molar amount of the compound represented by the general formula (VIIIa) or (Ia) or a salt thereof. This reaction is usually 0-150 ℃,
Preferably, it may be carried out at 0 to 50 ° C. for 5 minutes to 30 hours.

Further, in the compound represented by the general formula (VIII) or (I) or a salt thereof, R ² may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group. The compound which is an arylthio group, R ² obtained above is a halogen atom, a nitro group, an alkanesulfonyloxy or arenesulfonyloxy group which may be substituted with one or more groups selected from an alkyl group and an alkoxy group. In a compound,
It can be obtained by reacting a thiol such as thiophenol or naphthalenethiol or a salt thereof in the presence or absence of a deoxidizing agent. Examples of the salts of thiols include those represented by the general formulas (I) and (II
Salts having the same acidic group as those described for the compound represented by I) can be mentioned. The solvent used in this reaction is not particularly limited as long as it is an inert solvent for the reaction, and for example, aromatic hydrocarbons such as benzene, toluene, xylene; dioxane, tetrahydrofuran,
Ethers such as anisole and diethylene glycol diethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide For example, two or more kinds of these solvents may be mixed and used. Examples of the deoxidizing agent include inorganic bases such as alkali hydroxide and alkali carbonate, and organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine and collidine. The amount of the thiols or salts thereof and the optional deoxidizing agent used is R ²
Is a compound represented by the general formula (VIII) or a general formula (VIII) in which is an alkanesulfonyloxy or arenesulfonyloxy group which may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group. It is an equimolar amount or more, preferably 1.0 to 2.0 times the molar amount of the compound represented by I) or a salt thereof. This reaction is usually 0 to 150 ℃, preferably 0 to 70 ℃
Then, it may be carried out for 5 minutes to 30 hours.

Further, a compound represented by the general formula (VIII) or a general formula (VIII) in which R ² is an alkylsulfinyl or alkanesulfonyl group which may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group R ₂ which is a raw material of the compound represented by the formula (I) or a salt thereof generally corresponds to an alkylthio group which may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group. The compound represented by the formula (VIII) or the compound represented by the general formula (I) or a salt thereof is, for example, methanethiol, ethanethiol, n-propanethiol, isobutanethiol,
It can be obtained by reacting a thiol such as pentanethiol, hexanethiol, heptanethiol, octanethiol, dodecanethiol or a salt thereof in the same manner as described above.

R ² thus obtained is a halogen atom, a nitro group,
A compound represented by the general formula (VIII) or a compound represented by the general formula (I), which is a group corresponding to an alkylthio group which may be substituted with one or more groups selected from an alkyl group and an alkoxy group, or an arylthio group. Alternatively, a salt thereof is an alkylsulfinyl, arylsulfinyl, alkanesulfonyl or arene in which R ² may be substituted by one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group by subjecting to an oxidation reaction. It is possible to derive a compound having a sulfonyl group or a salt thereof. The solvent used in this reaction is not particularly limited as long as it is an inert solvent for the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated carbonization such as methylene chloride, chloroform and dichloroethane. Examples thereof include hydrogens; ethers such as diethyl ether, tetrahydrofuran and dioxane; fatty acids such as formic acid and acetic acid; water and the like, and two or more kinds of these solvents may be mixed and used. Examples of the oxidizing agent include organic peracids such as performic acid, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide, periodic acid, sodium metaperiodate, potassium metaperiodate. , Potassium permanganate, ozone and the like. In the general formula (VIII) or (I)
In order to obtain a compound (sulfoxide) in which R ² is an alkylsulfinyl or arylsulfinyl group optionally substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group, or a salt thereof, Preferable oxidizing agents include organic peracids, sodium metaperiodate, potassium metaperiodate, etc., and the amount thereof is the general formula (VIII) or (I).
In the compound or salt thereof, R ² is a group corresponding to an alkylthio group which may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group, or an arylthio group. ~ 1.2
It is twice the mole. Further, a compound in which R ² in the general formula (VIII) or (I) is an alkanesulfonyl or arenesulfonyl group which may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group and an alkoxy group. In order to obtain (sulfone) or a salt thereof, particularly preferable oxidizing agents include organic peracids, hydrogen peroxide and the like. The amount used is such that in the general formula (VIII) or (I), R ² is a halogen atom. A compound or a salt thereof which is a group corresponding to an alkylthio group which may be substituted with one or more groups selected from a nitro group, an alkyl group and an alkoxy group, or an arylthio group.
It is 2.0 to 2.5 times mol. Furthermore, the compound that is a sulfoxide in the general formula (VIII) or the compound that is a sulfoxide in the general formula (I) or a salt thereof can be further oxidized to a compound that is a sulfone, if desired. These reactions are usually 0 to 100 ° C., preferably 0
It may be carried out at -30 ° C for 5 minutes to 30 hours.

When the compound represented by the general formula (VI), (Ia) or (I) described above or a salt thereof has a protecting group, the elimination reaction of the protecting group is carried out by a known method, if desired, and the corresponding free Can be induced to the compound. Further, when the compound represented by the general formula (VI), (Ia) or (I) is a free compound, it may be subjected to a salt-forming reaction or an esterification reaction known per se and corresponding thereto, respectively. It can be derived into a salt or ester of the compound.

Furthermore, when the compound represented by the general formula (VI), (Ia) or (I) has a protecting group, it may be subjected to a salt forming reaction known per se to give a salt of the corresponding compound. Can be induced.

The compound obtained by each reaction described above can be isolated or separated by a conventional method, or can be used in the next reaction without isolation or separation.

Next, the antibacterial action of typical compounds obtained by the method of the present invention will be shown.

Test Method Japanese Society of Chemotherapy Standard Method [CHEMOTHERAP
Y) Vol. 29, No. 1, pp. 76-79 (1981)], Heart InfuSion broth
(Eiken Chemical Co., Ltd.) at 37 ℃, 20 hours cultured bacterial solution containing Heart Infusion agar (Heart Infusi
on agar) medium (manufactured by Eiken Chemical Co., Ltd.) and incubated at 37 ° C. for 20 hours, and then observed for the growth of bacteria. The minimum concentration at which the growth of bacteria was inhibited was determined as MIC (μg / ml). did. However, the inoculum size was 10 ⁴ cells / plate (10 ⁶ cells / ml).
The results are shown in Table-1. The symbols used in Table 1 have the following meanings.

* Penicillinase-producing bacteria ** Cephalosporinase-producing bacteria [Examples] Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

The symbols used in Reference Examples and Examples have the following meanings.

Me; methyl group, Et; ethyl group, i-Pr; isopropyl group Example 1 150 mg of 3-aminopyrrolidine dihydrochloride in 5 ml of ethanol
And dissolve it by adding 310 mg of triethylamine. Then 1- (2,4-difluorophenyl) -6-
Fluoro-1,4-dihydro-4-oxo-7- (2,4,6-
Triisopropylbenzenesulfonyloxy) -1,8-
Naphthirizine-3-carboxylic acid ethyl ester (500 mg) is added, and the mixture is reacted at room temperature for 2 hours. Then, 6 ml of water is added to remove the precipitated crystals, and the crystals are washed with 5 ml of water to give a melting point of 200 to 20.
7- (3-amino-1-pyrrolidinyl) -1 showing 2 ° C.
-(2,4-Difluorophenyl) -6-fluoro-1,4-
330 mg (yield 96.3%) of ethyl dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ester are obtained. By recrystallizing this with a mixed solvent of ethyl acetate-ethanol (volume ratio 1: 1), crystals having a melting point of 206 to 209 ° C are obtained.

NMR (TFA-d ₁ ) δ value; 1.48 (3H, t, J = 7Hz), 2.19 to 2.86 (2H, m), 3.33 to 4.90 (7H, m), 6.89 to 7.85 (3H, m), 8.18 ( 1H, d, J = 11Hz), 9.04 (1H, s) The same reaction is performed to obtain the results shown in Table-2.

Example 2 270 mg of anhydrous piperazine was dissolved in 4 ml of methylene chloride, and 1
-(2,4-Difluorophenyl) -6-fluoro-1,4-
Dihydro-4-oxo-7- (2,4,6-triisopropylbenzenesulfonyloxy) -1,8-naphthyridine-
400 mg of 3-carboxylic acid ethyl ester is added, and the mixture is reacted under ice cooling for 1 hour. Add 20 ml of ethyl acetate and 10 to the reaction mixture.
ml was added, the organic layer was separated, washed successively with 10 ml of saturated aqueous sodium hydrogen carbonate solution and 10 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 5 ml of diethyl ether was added to the obtained crystalline substance, and crystals were taken to show a melting point of 208 to 211 ° C. 1- (2,4
250 mg (91.2% yield) of -difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. By recrystallizing this with a mixed solvent of acetone-methanol (volume ratio 1: 1), crystals having a melting point of 220 to 223 ° C are obtained.

NMR (TFA-d ₁ ) δ value; 1.50 (3H, t, J = 7Hz), 3.39 to 3.93 (4H, m), 3.93 to 4.44 (4H, m), 4.66 (2H, q, J = 7Hz), 6.89 to 7.82 (3H, m), 8.32 (1H, d, J = 12Hz), 9.14 (1H, s) Perform the same reaction to obtain the results shown in Table-3.

Example 3 70 mg of N-acetylpiperazine-hydrochloride was added to methylene chloride.
Suspend in 2 ml and add triethylamine 80 mg to dissolve. Then, 1- (2,4-difluorophenyl) -6
-Fluoro-1,4-dihydro-4-oxo-7- (2,4,6
-Triisopropylbenzenesulfonyloxy) -1,8
-Naphthyridine-3-carboxylic acid ethyl ester 200 mg
Is added and reacted at room temperature for 2 hours. Methylene chloride (8 ml) and water (10 ml) were added to the reaction solution, the organic layer was separated, washed successively with water (10 ml) and saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 5 ml of diethyl ether was added to the obtained residue and the precipitated crystals were collected to give 7- (4-acetyl-1) having a melting point of 217-219 ° C.
-Piperazinyl) -1- (2,4-difluorophenyl)
140 mg (yield 93.1%) of ethyl 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ester are obtained. If this is recrystallized with acetone, a crystal having a melting point of 219 to 220 ° C is obtained.

Example 4 (1) 64 mg of 3-aminopyrrolidine dihydrochloride was suspended in 2 ml of ethanol, and 130 mg of triethylamine was added and dissolved. Then 1- (2,4-difluorophenyl)-
7-diphenoxyphosphinyloxy-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-
Add 200 mg of carboxylic acid ethyl ester and react at room temperature for 1 hour. Then, 3 ml of water was added to collect the precipitated crystals, and the crystals were washed with 3 ml of water to give 7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6.
-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 110 mg (yield 75.
9%). The physical properties of this compound were the same as those obtained in Example 1.

(2) 1- (2,4-difluorophenyl) -7-diphenoxyphosphinyloxy-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester Instead, 7-diethoxyphosphinyloxy-1- (2,4-difluorophenyl) -6-
When 170 mg of fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was used and reacted under the same conditions, 7- (3-amino-1-pyrrolidinyl)- 1- (2,4-difluorophenyl) -6
-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 105 mg (yield 71.
5%). The physical properties of this compound were the same as those obtained in Example 1.

Example 5 400 mg of anhydrous piperazine was dissolved in a mixed solution of 4.5 ml of ethanol and 4.5 ml of N, N-dimethylformamide, and 7-azido-1- (2,4-difluorophenyl) -6-fluoro-1,4- Dihydro-4-oxo-1,8-naphthyridine-
Add 450 mg of 3-carboxylic acid ethyl ester and add 1 at 80 ° C.
After reacting for a time, the solvent is distilled off under reduced pressure. Ethyl acetate (30 ml) and water (30 ml) were sequentially added to the obtained residue, and 2N-
Adjust the pH to 1.0 with hydrochloric acid and separate the aqueous layer. Chloroform (15 ml) was added to the aqueous layer, and the pH was adjusted to 8 with a 1N aqueous sodium hydroxide solution.
Adjust to 5 and separate the organic layer. The organic layer is washed successively with 10 ml of water and 10 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 5 ml of diethyl ether was added to the obtained residue and the precipitated crystals were collected to give 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro- 420 ml of 4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester (yield 84.0%) is obtained. The physical properties of this compound were the same as those obtained in Example 2.

Example 6 1- (2,4-Difluorophenyl) -6-fluoro-1,4
400 mg of ethyl dihydro-4-oxo-7-phenylthio-1,8-naphthyridine-3-carboxylic acid and 380 mg of anhydrous piperazine were added to N, N-dimethylformamide 12
It is suspended in ml and reacted at 95-100 ° C for 6 hours. Then, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue.
ml and 30 ml of water are sequentially added, and the pH is adjusted to 0.5 with 6N-hydrochloric acid. The aqueous layer is separated, 30 ml of ethyl acetate is added, the pH is adjusted to 9.0 with a 10% aqueous potassium carbonate solution, and the organic layer is separated. The aqueous layer is extracted twice with 20 ml of ethyl acetate, combined with the above organic layer, washed with 20 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 5 ml of diethyl ether was added to the obtained crystalline substance, and crystals were taken to give 1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro- 230 mg (yield 60.7%) of 4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. The physical properties of this compound were the same as those obtained in Example 2.

Example 7 (1) 120 mg of 3-aminopyrrolidine dihydrochloride is suspended in 3 ml of ethanol, and 250 mg of triethylamine is added and dissolved. Then, 7-benzenesulfinyl-1-
300 mg of (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is added, and the mixture is reacted at room temperature for 3 hours. After 10 ml of diethyl ether was added to the reaction solution to collect crystals, it was washed with 12 ml of water to give 7- (3-amino-1).
-Pyrrolidinyl) -1- (2,4-difluorophenyl)
230 mg (yield 83.8%) of 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. The physical properties of this compound were the same as those obtained in Example 1.

(2) 7-benzenesulfinyl-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-
Instead of oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 1- (2,4-difluorophenyl)
If 270 mg of -7-ethylsulfinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was used and reacted under the same conditions, 7- (3 -Amino-1-pyrrolidinyl) -1-
230 mg (yield 83.6%) of (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. The physical properties of this compound were the same as those obtained in Example 1.

Example 8 (1) 120 mg of 3-aminopyrrolidine dihydrochloride is suspended in 3 ml of ethanol, and 250 mg of triethylamine is added and dissolved. Then, 7-benzenesulfonyl-1- (2,
4-Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (300 mg) is added, and the mixture is reacted at 45-50 ° C for 4 hours. After 10 ml of diethyl ether was added to the reaction solution to collect crystals, it was washed with 12 ml of water to give 7- (3-amino-1).
-Pyrrolidinyl) -1- (2,4-difluorophenyl)
230 mg (yield 86.6%) of ethyl 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ester are obtained. The physical properties of this compound were the same as those obtained in Example 1.

(2) Instead of 7-benzenesulfonyl-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 1- (2,4-difluorophenyl)-
If 270 mg of 7-ethanesulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was used and reacted under the same conditions, 7- (3- Amino-1-pyrrolidinyl) -1- (2,
225 mg (yield 84.9%) of 4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. The physical properties of this compound were the same as those obtained in Example 1.

Example 9 7- (3-Amino-1-pyrrolidinyl) -1- (2,4-
Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (1.00 g) was suspended in 6N-hydrochloric acid (6 ml) and reacted under heating under reflux for 2 hours. Let Then, 6 ml of water was added to collect crystals, and the crystals were washed with 2 ml of water to give 7- (3-amino-1-pyrrolidinyl) -1 having a melting point of 247 to 250 ° C. (decomposition).
-(2,4-Difluorophenyl) -6-fluoro-1,4-
920 mg (yield 90.2%) of the hydrochloride of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. When this is recrystallized with a mixed solvent of concentrated hydrochloric acid-ethanol (volume ratio 1: 3), crystals having a melting point of 247 to 250 ° C (decomposition) are obtained.

NMR (TFA-d ₁ ) δ value; 2.23 to 2.95 (2H, m), 3.38 to 4.83 (5H, m), 6.95 to 7.90 (3H, m), 8.22 (1H, d, J = 11Hz), 9.18 ( 1H, s) Similarly, the following compound is obtained.

○ 7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-
Hydrochloride of 4-oxo-1,8-naphthyridine-3-carboxylic acid Yield: 90.7% Melting point: 210-217 ° C (decomposition) NMR (TFA-d ₁ ) δ value; 2.20-2.85 (2H, m), 3.48 to 4.98 (5H, m), 7.07 to 7.78 (4H, m), 8.18 (1H, d, J = 11Hz), 9.18 (1H, s) Example 10 1- (2,4-difluorophenyl)- 6-fluoro-1,4
-Dihydro-4-oxo-7- (1-piperazinyl)-
1,8-Naphthyridine-3-carboxylic acid ethyl ester 200
mg is suspended in 1.2 ml of 6N-hydrochloric acid, and the mixture is reacted under heating under reflux for 2 hours. Then, after adding 2 ml of water to collect crystals,
If washed with 1 ml of water, it shows a melting point of 249-252 ° C (decomposition) 1
-(2,4-Difluorophenyl) -6-fluoro-1,4-
Dihydro-4-oxo-7- (1-piperazinyl) -1,
190 mg (yield 93.2%) of the hydrochloride of 8-naphthyridine-3-carboxylic acid are obtained. Concentrated hydrochloric acid-ethanol (volume ratio
1: 2) Recrystallization with a mixed solvent gives crystals with a melting point of 249-252 ° C (decomposition).

NMR (TFA-d ₁ ) δ value; 3.33 to 3.92 (4H, m), 3.92 to 4.50 (4H, m), 6.90 to 7.90 (3H, m), 8.30 (1H, d, J = 12Hz), 9.18 ( 1H,
s) Example 11 7- (4-acetyl-1-piperazinyl) -1- (2,4
-Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (100 mg) is dissolved in 6N-hydrochloric acid (1 ml) and reacted for 2 hours under heating under reflux. Then, add 1 ml of ethanol to collect crystals, and wash with 1 ml of water to obtain 1- (2,4
-Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid-hydrochloride 85 mg (yield 91.5
%). The physical properties of this compound were the same as those obtained in Example 10.

Reference Example 1 23.0 g of N- (2,4-difluorophenyl) -amidinoacetic acid methyl ester-hydrochloride was dissolved in a mixed solution of 92 ml of water and 92 ml of methylene chloride, and the pH was adjusted to 13.0 with a 2N-aqueous sodium hydroxide solution. adjust. The organic layer is separated, washed successively with 50 ml of water and 50 ml of saturated saline and then dried over anhydrous magnesium sulfate. 27.1 g of sodium salt of hydroxymethylenefluoroacetic acid ethyl ester is added to this solution at room temperature, and the mixture is reacted under heating under reflux for 4 hours, and then the solvent is distilled off under reduced pressure. 92 ml of water and 46 of ethyl acetate were added to the obtained residue.
ml is sequentially added to collect precipitated crystals, and the crystals are suspended in 184 ml of water. The pH was adjusted to 1.0 with 6N-hydrochloric acid, and the resulting precipitated crystals were mixed with water 4
When 6 ml and 46 ml of 2-propanol were added to collect crystals, 15.0 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester having a melting point of 222 to 223 ° C. Rate 57.9%). By recrystallizing this with ethyl acetate, crystals having a melting point of 222 to 223 ° C. are obtained.

IR (KBr) cm ^-1 ; νC = O 1700 NMR (TFA-d ₁ ) δ value; 4.06 (3H, s), 6.71 to 7.65 (3H, m), 8.12 (1H, d, J = 11Hz) To obtain the following compound.

○ 5-fluoro-2- (4-fluorophenylamino)
-6-Hydroxynicotinic acid methyl ester Melting point; 227 to 228 ° C (resolving solvent; ethyl acetate) IR (KBr) cm ^-1 ; νC = O 1690 NMR (TFA-d ₁ ) δ value; 4.05 (3H, s) , 6.89 to 7.53 (4H, m), 8.11 (1H, d, J = 11Hz) Reference Example 2 3.00 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester After suspending in 30 ml of methanol and adding 16.1 ml of 2N-sodium hydroxide aqueous solution at room temperature, the mixture is reacted under heating under reflux for 4 hours. Then, the reaction solution is added to a mixed solution of 60 ml of ethyl acetate and 60 ml of water to separate the aqueous layer. The aqueous layer was adjusted to pH 1 with 6N hydrochloric acid.
After adjusting to 0, the precipitated crystals were collected and washed successively with 15 ml of water and 15 ml of 2-propanol to give 2- (2,4-difluorophenylamino) -5-fluoro-6 having a melting point of 213 to 216 ° C. -Hydroxynicotinic acid 2.68 g (yield 93.7%)
To get By recrystallizing this with a mixed solvent of acetone-ethanol (volume ratio 1: 1), crystals having a melting point of 215 to 216 ° C are obtained.

IR (KBr) cm ^-1 ; νC = O 1700 NMR (DMSO-d ₆ ) δ value; 6.65 to 7.58 (2H, m), 7.86 (1H, d, J = 11Hz), 8.12 to 8.68 (1H, m) , 10.49 (1H, bs) Similarly, the following compound is obtained.

○ 5-fluoro-2- (4-fluorophenylamino)
-6-Hydroxynicotinic acid, melting point; 216-217 ° C (resolving solvent; acetone: methanol =
1: 1 (capacity ratio)) IR (KBr) cm ^-1 ; νC = O 1685 (sh) NMR (DMSO-d ₆ ) δ value; 6.84 to 7.94 (5H, m), 10.33 (1H, bs) Reference example 2.34-g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid was suspended in 94 ml of anhydrous tetrahydrofuran, and 2.00 g of N, N'-carbonyldiimidazole was added under ice cooling. And react at room temperature for 2 hours. Then, magnesium salt of ethoxycarbonylacetic acid
After adding 3.50 g and reacting for 1.5 hours under heating under reflux, the reaction solution was added to a mixed solution of 150 ml of ethyl acetate and 150 ml of water,
Adjust to pH 2.0 with 6N hydrochloric acid. The organic layer is separated, washed successively with 80 ml of saturated aqueous sodium hydrogen carbonate solution and 80 ml of water, then 80 ml of water is added, and the pH is adjusted to 2.0 with 6N-hydrochloric acid. The organic layer is separated, washed successively with 80 ml of water and 80 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Diethyl ether was added to the obtained crystalline substance.
When 8 ml was added and crystals were collected, 2- [2- (2,4-difluorophenylamino) -5- having a melting point of 161-162 ° C was obtained.
Fluoro-6-hydroxynicotinoyl] acetic acid ethyl ester (1.93 g, yield 66.2%) is obtained. If this is recrystallized with benzene, a crystal having a melting point of 161.5 to 162 ° C is obtained.

IR (KBr) cm ^-1 ; νC = O 1725,1665 NMR (CDCl ₃ ) δ value; 1.29 (3H, t, J = 7Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7Hz) , 6.57 to 7.69 (4H, m), 10.17 (1H, bs), 11.52 (1H, bs) In the same manner, the following compound is obtained.

○ 2- [5-Fluoro-2- (4-fluorophenylamino) -6-hydroxynicotinoyl] acetic acid ethyl ester melting point; 185 ° C (decomposition) (resolving solvent; ethyl acetate) IR (KBr) cm ^-1 νC = O 1715,1685 NMR (CDCl ₃ ) δ value; 1.30 (3H, t, J = 7Hz), 3.75 (2H, s), 4.25 (2H, q, J = 7Hz), 7.08 to 7.34 (4H, m), 7.48 (1H, d, J = 11Hz), 11.68 (1H, bs) Reference Example 4 2- [2- (2,4-difluorophenylamino) -5-
400 mg of fluoro-6-hydroxynicotinoyl] acetic acid ethyl ester was dissolved in 4 ml of methylene chloride, and 2,2
300 mg of 4,6-trimethylbenzenesulfonyl chloride and 150 mg of triethylamine are added, and the mixture is reacted at room temperature for 2 hours. Methylene chloride (4 ml) and water (4 ml) were added to the reaction solution, the organic layer was separated, washed successively with water (4 ml) and saturated saline (4 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained crystalline substance.
When 2 ml was added and crystals were collected, 2- [2- (2,4-difluorophenylamino) -5- having a melting point of 158-159 ° C was obtained.
Fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetic acid ethyl ester 520 mg
(Yield 85.8%) is obtained. If this is recrystallized with benzene, a crystal having a melting point of 160 to 160.5 ° C is obtained.

IR (KBr) cm ^-1 ; νC = O 1730 NMR (CDCl ₃ ) δ value; Reference Example 5 2- [2- (2,4-difluorophenylamino) -5-
Fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetic acid ethyl ester 100 mg
It is dissolved in 1 ml of N, N-dimethylformamide, 17 mg of ethanethiol and 28 mg of triethylamine are added, and the mixture is reacted at room temperature for 4 hours. The reaction solution was mixed with ethyl acetate (3 ml) and water (3 ml).
The pH of the mixture is adjusted to 1.0 with 2N hydrochloric acid, and the organic layer is separated. The organic layer is washed successively with 2 ml of water and 2 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Wako silica gel C-200, eluting solvent; benzene:
Hexane = 1: 2 (volume ratio)]
50 mg (yield 67.4%) of 2- [2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetic acid ethyl ester showing 1 ° C. are obtained. If recrystallized with diisopropyl ether, the melting point is 102.5-103.
Crystals showing ° C are obtained.

IR (KBr) cm ^-1 ; νC = O 1730 NMR (CDCl ₃ ) δ value; 1.29 (6H, t, J = 7Hz), 3.06 (2H, q, J = 7Hz), 3.90 (2H,
s), 4.22 (2H, q, J = 7Hz), 6.62 to 7.35 (2H, m), 7.52 (1H, d, J = 11Hz), 7.70 to 8.20 (1H, m), 10.86 (1H,
bs) Similarly, the following compound is obtained.

○ 2- [2- (2,4-difluorophenylamino) -5
-Fluoro-6-phenylthionicotinoyl] acetic acid ethyl ester Melting point; 132.5 to 134 ° C (resolving solvent; ethyl acetate: n-hexane = 10: 1 (volume ratio)) IR (KBr) cm ^-1 ; νC = O 1725 NMR (CDCl ₃ ) δ value; 1.27 (3H, t, J = 7Hz), 3.89 (2H, s), 4.20 (2H, q, J = 7Hz), 5.98 to 8.03 (9H, m), 11.12 ( 1H, b
s) Reference example 6 2- [2- (2,4-difluorophenylamino) -5-
200 mg of fluoro-6-hydroxynicotinoyl] acetic acid ethyl ester was suspended in 4 ml of toluene, and 200 mg of N, N-dimethylformamide dinopenpentyl acetal was added,
After reacting for 1 hour at room temperature, precipitated crystals are collected. To the obtained crystals, 5 ml of ethanol and 5 ml of water were added, and the pH was adjusted to 1.0 with 2N-hydrochloric acid.
1- (2,4-difluorophenyl) -6-indicating ~ 248 ° C
155 mg (yield 75.4%) of fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. If this is recrystallized with a mixture of acetone-methanol (volume ratio 1: 1), the melting point is 250-
Crystals showing 252 ° C. are obtained.

IR (KBr) cm ^-1 ; νC = O 1720 NMR (TFA-d ₁ ) δ value; 1.51 (3H, t, J = 7Hz), 4.70 (2H, q, J = 7Hz), 7.00-8.10
(3H, m), 8.30 (1H, d, J = 8Hz), 9.11 (1H, s) Similarly, the following compound is obtained.

○ 6-fluoro-1- (4-fluorophenyl) -1,4
-Dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester melting point; 252-253 ° C (resolving solvent; acetone: methanol =
1: 1 (capacity ratio)) IR (KBr) cm ^-1 ; νC = O 1730 (sh), 1700 NMR (TFA-d ₁ ) δ value; 1.50 (3H, t, J = 7Hz), 4.64 (2H, q, J = 7Hz), 7.15 to 7.84
(4H, m), 8.20 (1H, d, J = 9Hz), 9.02 (1H, s) Reference Example 7 2- [2- (2,4-difluorophenylamino) -6-
160 mg of ethylthio-5-fluoronicotinoyl] acetic acid ethyl ester is dissolved in 3 ml of benzene, 72 mg of N, N-dimethylformamide dimethyl acetal is added, and the mixture is reacted for 2.5 hours while heating under reflux. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Wako silica gel C-200, eluting solvent; benzene: ethyl acetate = 10: 1.
(Volume ratio)] shows a melting point of 169.5-171 ° C.
-(2,4-Difluorophenyl) -7-ethylthio-6
-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 115 mg (yield 70.
1%). If this is recrystallized from ethyl acetate, the melting point is 1
Crystals showing 70-171 ° C are obtained.

IR (KBr) cm ^-1 ; νC = O 1730 NMR (CDCl ₃ ) δ value; 1.08 (3H, t, J = 7Hz), 1.38 (3H, t, J = 7Hz), 2.79 (2H,
q, J = 7Hz), 4.38 (2H, q, J = 7Hz), 6.88 to 7.83 (3H, m), 8.10 (1H, d,
J = 9Hz), 8.48 (1H, s) Similarly, the following compound is obtained.

○ 1- (2,4-difluorophenyl) -6-fluoro-
1,4-dihydro-4-oxo-7-phenylthio-1,8-
Naphthyridine-3-carboxylic acid ethyl ester melting point; 218.5 to 220 ° C. (resolving solvent; acetone: methanol = 1: 1 (volume ratio)) IR (KBr) cm ⁻¹ ; νC═O 1730,1700 (sh) NMR ( CDCl ₃ ) δ value; Reference Example 8 1- (2,4-difluorophenyl) -6-fluoro-1,4
3.00 g of -dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was suspended in 30 ml of methylene chloride, and triethylamine 1.
02g and ortho nitrobenzene sulfonyl chloride 2.2
0 g is added, and the mixture is reacted at the same temperature for 30 minutes and at room temperature for 6 hours.
The reaction solution is washed 3 times with 50 ml of water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, a mixed solution of 6 ml of ethyl acetate and 12 ml of diethyl ether was added to the obtained residue, and the precipitated crystals were collected to give a melting point of 157 to 160 ° C. 1- (2,4-difluoro) (Phenyl) -6-fluoro-1,4
Obtained 4.40 g (yield 97.2%) of -dihydro-7- (2-nitrobenzenesulfonyloxy) -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. By recrystallizing this with a mixed solvent of acetone-n-hexane (volume ratio 10: 1), crystals having a melting point of 162 to 163 ° C are obtained.

IR (KBr) cm ^-1 ; νC = O 1730,1700 (sh) NMR (DMSO-d ₆ ) δ value; 1.30 (3H, t, J = 7Hz), 4.24 (2H, q, J = 7Hz), 7.03 ~ 8.26
(7H, m), 8.64 (1H, d, J = 9Hz), 8.72 (1H, s) Similarly, the compounds shown in Table 4 are obtained.

Reference Example 9 1- (2,4-difluorophenyl) -6-fluoro-1,4
-Dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (500 mg) was suspended in anhydrous acetonitrile (5 ml), triethylamine (150 mg) and diphenylphosphoric acid chloride (410 mg) were added under ice-cooling, and the mixture was allowed to stand at room temperature for 2 hours. React for hours. Methylene chloride (25 ml) and water (25 ml) were added to the reaction solution, and the organic layer was separated, washed with water (20 ml) twice and saturated saline (20 ml) once, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 15 ml of diethyl ether was added to the obtained residue, and the precipitated crystals were collected to show a melting point of 144 to 147 ° C. 1- (2,4
-Difluorophenyl) -7- (diphenoxyphosphinyloxy) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 700 mg (yield 85.5% ) Get. This is ethyl acetate
Recrystallization of n-hexane (volume ratio 10: 1) with a mixed solvent gives crystals having a melting point of 147 to 148 ° C.

IR (KBr) cm ^-1 ; νC = O 1725 (sh), 1680 NMR (DMSO-d ₆ ) δ value; 1.30 (3H, t, J = 7Hz), 4.26 (2H, q, J = 7Hz), 6.60 ~ 8.11
(13H, m), 8.56 (1H, d, J = 9Hz), 8.75 (1H, s) Similarly, the following compound is obtained.

○ 7- (diethoxyphosphinyloxy) -1- (2,4
-Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester melting point; 133-134 ° C (resolving solvent; ethyl acetate: n-hexane = 10: 1 (capacity ratio)) IR (KBr) cm ^-1 ; νC = O 1730 (sh), 1685 NMR (CDCl ₃ ) δ value; 1.27 (6H, t, J = 7Hz), 1.38 (3H, t, J = 7Hz), 3.98 (4H,
q, J = 7Hz), 4.37 (2H, q, J = 7Hz), 6.81 to 7.82 (3H, m),
8.43 (1H, d, J = 8.5Hz), 8.50 (1H, s) Reference Example 10 1- (2,4-Difluorophenyl) -6-fluoro-1,4
-Dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (500 mg) was suspended in pyridine (5 ml), diphenylphosphoric acid azide (770 mg) was added, and the mixture was reacted at 80 ° C for 4 hours, and then depressurized. The solvent is distilled off underneath. Ethyl acetate (10 ml) and water (10 ml) were added to the obtained residue, the pH was adjusted to 2.0 with 6N-hydrochloric acid, and the organic layer was separated. The organic layer is washed successively with 5 ml of saturated aqueous sodium hydrogen carbonate solution and 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 5 ml of diethyl ether was added to the obtained residue and the precipitated crystals were collected.
440 mg of 7-azido-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester showing 76 to 177.5 ° C. Yield 82.3%).

IR (KBr) cm ^-1 ; νN ₃ 2110, νC = O 1725 (sh), 1680 NMR (CDCl ₃ ) δ value; 1.39 (3H, t, J = 7Hz), 4.36 (2H, q, J = 7Hz) , 6.84 ~ 7.75
(3H, m), 8.29 (1H, d, J = 9Hz), 8.48 (1H, s) Reference Example 11 1- (2,4-difluorophenyl) -7-ethylthio-
1.00 g of 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was dissolved in 10 ml of methylene chloride, and m-chloroperbenzoic acid (purity
80%) 0.58 g is added, and the mixture is reacted for 5 hours under ice cooling. After removing the precipitate, 10 ml of water was added to the solution, the pH was adjusted to 7.5 with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer is washed with 10 ml of water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako silica gel C-20.
0, elution solvent; toluene: ethyl acetate = 10: 1 (volume ratio)]
1- (2,4-difluorophenyl) -7-ethylsulfinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 having a melting point of 150-151 ° C. -Carboxylic acid ethyl ester 0.81 g (yield 77.9%)
To get If recrystallized with ethyl acetate, the melting point is 151-1.
Crystals showing 52 ° C. are obtained.

IR (KBr) cm ^-1 ; νC = O 1730,1695 NMR (CDCl ₃ ) δ value; 1.22 (3H, t, J = 7Hz), 1.37 (3H, t, J = 7Hz), 3.07 (2H,
q, J = 7Hz), 4.34 (2H, q, J = 7Hz), 6.92 to 7.93 (3H, m), 8.42 (1H, d, J = 9Hz), 8.66 (1H,
s) Similarly, the following compound is obtained.

○ 1- (2,4-difluorophenyl) -6-fluoro-
1,4-Dihydro-4-oxo-7-phenylsulfinyl-1,8-naphthyridine-3-carboxylic acid ethyl ester melting point; 194 to 196 ° C (resolving solvent; acetone: methanol =
5: 1 (capacity ratio)) IR (KBr) cm ^-1 ; νC = O 1735,1695 (sh) NMR (CDCl ₃ ) δ value; 1.36 (3H, t, J = 7Hz), 4.34 (2H, q, J = 7Hz), 6.81 to 7.75 (8H, m), 8.36 (1H, d, J = 8.5Hz), 8.55 (1H, s) Reference Example 12 1- (2,4-difluorophenyl) -7-ethylthio −
1.00 g of 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was dissolved in 15 ml of methylene chloride, and m-chloroperbenzoic acid (purity
80%) 1.06 g is added, and the mixture is reacted under ice cooling for 30 minutes and at room temperature for 4 hours. After removing the precipitate, 10 ml of water was added to the solution,
After adjusting to pH 7.5 with saturated aqueous sodium hydrogen carbonate solution,
Separate the organic layer. The organic layer was mixed with 10 ml of water and 10 ml of saturated saline.
After washing with ml sequentially, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 ml of diethyl ether was added to the obtained residue to collect precipitated crystals.
1- (2,4-difluorophenyl) -7-
Ethanesulfonyl-6-fluoro-1,4-dihydro-4
0.94 g (yield 87.2%) of -oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester is obtained. This is recrystallized with a mixed solvent of ethyl acetate-ethanol (volume ratio 1: 1) to obtain crystals having a melting point of 216.5 to 217.5 ° C.

IR (KBr) cm ^-1 ; νC = O 1730,1700 (sh) NMR (CDCl ₃ ) δ value; 1.21 (3H, t, J = 7Hz), 1.37 (3H, t, J = 7Hz), 3.22 (2H ,
q, J = 7Hz), 4.36 (2H, q, J = 7Hz), 6.91 to 7.82 (3H, m), 8.57 (1H, d,
J = 9Hz), 8.62 (1H, s) Similarly, the following compound is obtained.

○ 7-benzenesulfonyl-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester melting point; 212-213 ° C (Reconstituted solvent; acetone: ethanol =
1: 1 (capacity ratio)) IR (KBr) cm ^-1 ; νC = O 1740,1700 (sh) NMR (CDCl ₃ ) δ value; 1.35 (3H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 6.58 ~ 7.86
(8H, m), 8.50 (1H, d, J = 8.5Hz), 8.50 (1H, s)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mikako Shinagawa 916 Dogenji, Tateyama-cho, Nakashinagawa-gun, Toyama Prefecture (72) Inventor Yoshinori Konishi Sano (Takamachi, Takaoka-shi, Toyama Prefecture) 1000-72 (72) Invention Person Narita Hirokazu 6-40, Okudahonmachi, Toyama City, Toyama Prefecture (72) Inventor Shuntaro Takano 3-chome 8-44, Inarimoto Town, Toyama City, Toyama Prefecture (72) Inventor Isamu Saikawa 7-52, Oizumi Nakamachi, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents a hydrogen atom or a carboxyl protecting group;
² is an azido group or a halogen atom, a nitro group, an arylthio optionally substituted with one or more groups selected from an alkyl group and an alkoxy group, alkylsulfinyl, arylsulfinyl, alkanesulfonyl, arenesulfonyl, alkanesulfonyloxy, An arenesulfonyloxy, dialkoxyphosphinyloxy or diaryloxyphosphinyloxy group; and X represents a hydrogen atom or a fluorine atom, respectively. Compound or a salt thereof of the general formula R ³ H "formula represented by", R ³ is an amino group may be protected 3-aminopyrrolidinyl group or piperazinyl be imino group is protected A general formula characterized by reacting with a compound represented by the formula: or a salt thereof to remove a carboxyl protecting group or convert it to a salt if desired. 1-substituted aryl-1,4-dihydro-4-represented by "wherein R ¹ , R ³ and X have the same meanings as described above."
A method for producing an oxonaphthyridine derivative or a salt thereof.