JPH07116154B2 - Reactive derivatives at the carboxyl group of new 5-fluoronicotinic acids - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has a general formula (2) showing a strong antibacterial action against Gram-positive and Gram-negative bacteria.

[Chemical 2] "In the formula, R ² represents a hydrogen atom or a carboxyl protecting group; R ³ represents 3-amino-1-pyrrolidinyl group in which an amino group may be protected or 1-piperazinyl in which an imino group may be protected. And X represents a hydrogen atom or a fluorine atom. ", Which is an important intermediate of the 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof represented by the general formula (1 )

[Chemical 3] “In the formula, X has the same meaning as described above; R ¹ is a hydroxyl group or an alkoxy which may have a substituent,
It represents an alkanesulfonyloxy, arenesulfonyloxy, alkylthio or arylthio group. And a reactive derivative at the carboxyl group of 5-fluoronicotinic acids.

[0002]

2. Description of the Related Art The 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives represented by the general formula (2) and salts thereof are available at the 24th Interscience Conference on Antimicrovial Agents. A strong antibacterial action against Gram-positive and Gram-negative bacteria, especially antibiotic-resistant bacteria, in And Chemotherapy (I.C.A.A.C.) Abstracts, pages 102 to 104 and JP-A-60-228479. It has been shown that oral administration or parenteral administration provides high blood concentration and has excellent properties such as high safety. However, as a method for producing these compounds, no method is known at all through a reactive derivative at the carboxyl group of the novel 5-fluoronicotinic acid represented by the general formula (1) as an intermediate.

[0003]

The object of the present invention is to provide a novel intermediate for producing a 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula (2) or a salt thereof. To provide the body.

[0004]

[Means for Solving the Problems] Under such circumstances,
As a result of intensive studies, the present inventors have found that the reactive derivative at the carboxyl group of 5-fluoronicotinic acids represented by the general formula (1) is useful as an intermediate, and to complete the present invention. I arrived.

The present invention will be described in detail below. In the present specification, examples of the alkoxy group for R ¹ include, for example,
Methoxy, ethoxy, n-propoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, dodecyloxy and the like; as the alkanesulfonyloxy group, for example, methanesulfonyloxy, ethanesulfonyloxy, 1-methylethanesulfonyloxy, 1,1-dimethylethanesulfonyloxy and the like; arenesulfonyloxy groups such as benzenesulfonyloxy, naphthalenesulfonyloxy and the like; alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, isobutylthio, tert. .-Butylthio, pentylthio, hexylthio, heptylthio, octylthio, dodecylthio, etc .; examples of arylthio groups include phenylthio and naphthylthio. Which can be mentioned.

The above-mentioned alkoxy, alkanesulfonyloxy, arenesulfonyloxy, alkylthio and arylthio groups of R ¹ are, for example, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; nitro group; methyl, ethyl, n -Propyl, isopropyl,
Lower alkyl groups such as n-butyl, isobutyl, sec.-butyl, tert.-butyl; methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.
It may be substituted with one or more substituents selected from lower alkoxy groups such as -butoxy and tert.-butoxy. Examples of the reactive derivative at the carboxyl group of the compound represented by the general formula (1) include acid halides such as acid chloride and acid bromide; acid anhydrides; mixed acids with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester. Anhydrides: active acid amides with imidazole and the like can be mentioned.

The carboxyl protecting group represented by R ² is one commonly used in the art, for example, an alkyl group, a benzyl group, a pivaloyloxymethyl group, a trimethylsilyl group and the like, JP-A-59-80665. Ordinary protective groups for carboxyl groups described in, for example, can be mentioned.

Examples of the salt of the compound represented by the general formula (2) include salts of a generally known basic group such as amino group or acidic group such as carboxyl group and hydroxyl group. As the salt of the basic group,
For example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid;
Salts with organic carboxylic acids such as oxalic acid, citric acid, trifluoroacetic acid; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid,
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as magnesium and calcium; ammonium salts; procaine, dibenzylamine, N, N-dibenzylethylenediamine, Triethylamine, pyridine,
Examples thereof include salts with nitrogen-containing organic salts such as N, N-dimethylaniline, N-methylpiperidine, diethylamine and dicyclohexylamine.

Next, the method for producing the compound of the present invention will be described in detail. The reactive derivative at the carboxyl group of the compound represented by the general formula (1) can be produced, for example, according to the following production route.

[Chemical 4] "In the formula, R ¹ , R ² and X have the same meanings as described above;
R ^1b represents an alkoxy group which may have a substituent similar to that described for R ¹ ; R ^1C represents an alkanesulfonyloxy which may have a substituent similar to that described in R ^1. An arenesulfonyloxy group; R ^1d represents an alkylthio or arylthio group which may have the same substituent as described for R ¹ . General formula (3),
(4), (5a), (5b), (5c) and (5d)
Examples of the salt of the compound represented by are the same salts as those described for the compound represented by the general formula (2).

Hereinafter, each manufacturing route will be described in detail. (1) The compound represented by the general formula (5a) or a salt thereof is a compound represented by the general formula (3) or a salt thereof produced according to the method described in British Patent No. 1409987.
A compound represented by the general formula (4) produced according to the method described in Bulletin de la Societe Chimic de France (Bull.Soc.Chim.Fr.) pp. 1165-1169 (1975) or It can be produced by reacting with the salt.

(2) Alkylation A compound represented by the general formula (5b) or a salt thereof can be prepared by adding an alkylating agent to the compound represented by the general formula (5a) or a salt thereof in the presence or absence of a deoxidizing agent. It can be obtained by reacting. The solvent used in this reaction is not particularly limited as long as it is an inert solvent for the reaction, and for example, water; methanol, ethanol, 2-
Alcohols such as propanol; diethyl ether,
Ethers such as tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; N , N-dimethylformamide, N, N-dimethylacetamide, and other amides; dimethyl sulfoxide, and other sulfoxides, and the like, and two or more of these solvents may be mixed and used. Examples of the alkylating agent include diazoalkanes such as diazomethane and diazoethane; dialkyl sulfates such as dimethyl sulfate and diethyl sulfate; alkyl halides such as methyl iodide, methyl bromide and ethyl bromide. When dialkyl sulfate or alkyl halide is used as the alkylating agent, inorganic bases such as alkali hydroxide and alkali carbonate, amines such as trimethylamine, triethylamine and pyridine may be used as deoxidizing agents. The amount of the alkylating agent such as dialkyl sulfate or alkyl halide and the deoxidizing agent optionally used is equal to or more than equimolar with respect to the compound represented by the general formula (5a) or a salt thereof.
It is 1.0 to 2.0 times mol. In this case, the reaction is usually 0-50 ° C.
Then, it may be carried out for 5 to 30 hours. When diazoalkane is used as the alkylating agent, the amount used is equimolar or more, preferably 1.0 to 1.5 times the molar amount of the compound represented by the general formula (5a) or a salt thereof. In this case, the reaction is usually 0 to 50 ℃, preferably 0 to 25 ℃, 5 minutes to 3
It should be carried out for 0 hours.

(3) Sulfonylation A compound represented by the general formula (5c) or a salt thereof is prepared by adding a sulfonylating agent to the compound represented by the general formula (5a) or a salt thereof in the presence or absence of a deoxidizing agent. It can be obtained by reacting. 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; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Examples thereof include sulfoxides such as dimethyl sulfoxide; hexamethylphosphoramide; pyridine and the like, and two or more kinds of these solvents may be mixed and used. Examples of the sulfonylating agent include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 1-methylethanesulfonyl chloride,
1,1-dimethylethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, nitrobenzenesulfonyl chloride, chlorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,3,4-trichlorobenzenesulfonyl chloride, 2,4,5 -Trichlorobenzene sulfonyl chloride, mesitylene sulfonyl chloride, 2,4,6
Alkanesulphonylhalides or arenesulfonylhalides such as triisopropylbenzenesulphonyl chloride, naphthalenesulphonyl chloride; methanesulphonic anhydrides; alkanesulphonic anhydrides or arenesulphonic anhydrides such as toluenesulphonic anhydride. Examples of the deoxidizing agent include triethylamine, diisopropylethylamine, 1,8-
Diazabicyclo [5.4.0] undec-7-ene (D
BU), pyridine, potassium tert.-butoxide, alkali hydroxides, alkali carbonates and other organic or inorganic bases. The amount of the sulfonylating agent and optionally the deoxidizing agent used is equimolar or more, preferably 1.0 or more with respect to the compound represented by the general formula (5a) or a salt thereof.
~ 2.0 times mole. This reaction may be carried out usually at 0 to 150 ° C., preferably 0 to 50 ° C. for 5 minutes to 30 hours.

(4) Thiolation A compound represented by the general formula (5d) or a salt thereof can be prepared by reacting a compound represented by the general formula (5c) or a salt thereof with or without a deoxidizing agent such as methane. Thiol, ethanethiol, n-propanethiol, 1-methylethanethiol, isobutanethiol, 1,1-dimethylethanethiol, pentanethiol, hexanethiol, heptanethiol, octanethiol, dodecanethiol, thiophenol, naphthalenethiol, etc. It can be obtained by reacting a thiol or a salt thereof. Examples of the salts of thiols include salts with the same acidic groups as described for the compound represented by the general formula (2). The solvent used in this reaction is not particularly limited as long as it is a solvent inert to the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, etc. Ethers; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide, and the like. You may mix and use 2 or more types. Examples of the deoxidizing agent include inorganic bases such as alkali hydroxide and alkali carbonate; trimethylamine, triethylamine, tributylamine, pyridine,
Organic bases such as N-methylpiperidine, N-methylmorpholine, lutidine, collidine and the like can be mentioned. The amount of the thiol or salt thereof and the deoxidizing agent optionally used is equimolar or more, preferably 1.0 to 2.0 times the molar amount of the compound represented by the general formula (5c) or 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.

The general formula (5a) thus obtained,
When the compound represented by (5b), (5c) and (5d) or a salt thereof has a protecting group, the protecting group can be eliminated by a known method, if desired, to give a corresponding free compound. it can. 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. Then, the obtained compounds represented by the general formulas (5a), (5b), (5c) and (5d) or salts thereof are subjected to the general formulas (1a), (1b), (1c) and It can be led to a reactive derivative at the carboxyl group of the compound represented by (1d).

The reactive derivative at the carboxyl group of the compound represented by the general formula (1) of the present invention thus obtained is, for example, a compound represented by the general formula (2) or a salt thereof according to the following route. Can be induced.

[Chemical 5] [In the formula, Y represents a halogen atom; R ^2a represents a carboxyl protecting group similar to that described for R ² ; R ¹ , R ² , R ^2
3 and X have the same meaning as above. The amino group and the imino group-protecting group in the 1-piperazinyl group, in which the amino group in R ³ may be protected, the 3-amino-1-pyrrolidyl group and the imino group may be protected, are generally known in the art. Are used in
For example, there may be mentioned ordinary protecting groups for amino groups and imino groups such as formyl, acetyl, N, N-dimethylaminomethylene and the like described in JP-A-59-80665. Examples of the salt of the compound represented by the general formula (6) include salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as magnesium; salts with ethoxymagnesium.
Moreover, as the salt of the compound represented by the general formula (7) or (8), the same salts as those described for the compound represented by the general formula (2) can be mentioned. Further, as the salt of the compound represented by the general formula (9),
Examples thereof include salts with the same basic group as described for the compound.

[0016]

EXAMPLES The present invention will now be described with reference to examples and reference examples, but the present invention is not limited thereto.
The symbols used in Examples and Reference Examples have the following meanings. Me; methyl group, Et; ethyl group, i
-Pr: isopropyl group, Ph: phenyl group

Example 1 (1) 23.0 g of the hydrochloride salt of 2- [N- (2,4-difluorophenyl) amidino] acetic acid methyl ester was dissolved in a mixed solution of 92 ml of water and 92 ml of methylene chloride, and 2N sodium hydroxide was added. Adjust to pH 13.0 with aqueous solution. 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 to the obtained residue
And ethyl acetate (46 ml) were sequentially added, and the precipitated crystals were collected by filtration,
Suspend in 184 ml of water. After adjusting to pH 1.0 with 6N hydrochloric acid,
The precipitated crystals were collected by filtration, water 46 ml and 2-propanol 46 ml.
If washed sequentially with 2, 2- (2,4)
-Difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester 15.0 g (yield 57.9
%). If recrystallized from ethyl acetate, the melting point is 22.
Crystals showing 2 to 223 ° C. are obtained. IR (KBr) cm ⁻¹ ; ν _{c = 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)

In the same manner, the following compound is obtained. o 2- (2,4-difluorophenylamino) -5-
Fluoro-6-hydroxynicotinic acid ethyl ester melting point; 177 to 178 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{c = o} 1700 NMR (TFA-d ₁ ) δ value; 1.52 (3H, t, J = 7Hz), 4.50 (2H, q, J = 7H
z), 6.80-7.65 (3H, m), 8.15 (1H, d, J = 11Hz) o 5-Fluoro-2- (4-fluorophenylamino) -6-hydroxynicotinic acid methyl ester melting point; 227-228 ° C (Resolving solvent; ethyl acetate) IR (KBr) cm ^-1 ; ν _{c = 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)

(2) 200 mg of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was dissolved in 5 ml of N, N-dimethylformamide, and 110 mg of potassium carbonate and 110 mg of methyl iodide. Is added at room temperature and reacted at the same temperature for 1 hour. 20 ml of water and 20 ml of ethyl acetate are added to the reaction solution, the organic layer is separated, 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 2-propanol was added to the obtained crystalline substance, and the crystals were collected by filtration to give a melting point of 159 to 161 ° C. 2- (2,
4-difluorophenylamino) -5-fluoro-6-
Methoxynicotinic acid methyl ester 190 mg (yield 90.7
%). If it is recrystallized from ethyl acetate, the melting point is 16
Crystals showing 0.5 to 161.5 ° C. are obtained. IR (KBr) cm ⁻¹ ; ν _{c = o} 1690 NMR (CDCl ₃ ) δ value; 3.89 (3H, s), 3.98 (3H, s), 6.57 to 7.08 (2
H, m), 7.81 (1H, d, J = 11Hz), 8.10 ~ 8.97 (1H, m), 10.24 (1H, b
s)

(3) 500 mg of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was suspended in 10 ml of methylene chloride,
Add 440 mg of mesitylene sulfonyl chloride and 220 mg of triethylamine, and react at room temperature for 3 hours. Water (15 ml) is added to the reaction solution, the organic layer is separated, washed with water (15 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 15 ml of diethyl ether was added to the obtained crystalline substance.
Is added and the crystals are filtered to give a melting point of 153-155 ° C.
660 mg (yield 81.9%) of (2,4-difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinic acid methyl ester is obtained. The crystals are recrystallized from ethyl acetate to give crystals having a melting point of 155-156 ° C. IR (KBr) cm ⁻¹ ; ν _{c = o} 1700 NMR (CDCl ₃ ) δ value; 2.33 (3H, s), 2.59 (6H, s), 3.92 (3H, s),
6.32 ~ 6.84 (2H, m), 6.92 (2H, s), 7.35 ~ 7.94 (1H, m), 8.05
(1H, d, J = 9Hz), 10.17 (1H, bs)

In the same manner, the following compound is obtained. o 2- (2,4-difluorophenylamino) -5-
Fluoro-6- (2,4,6-triisopropylbenzenesulfonyloxy) nicotinic acid ethyl ester
Melting point: 147 to 148 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm ⁻¹ ; ν _{c = o} 1700 NMR (CDCl ₃ ) δ value; 1.21 (12H, d, J = 7Hz), 1.28 (6H, 6H, d, J = 7H
z), 1.40 (3H, t, J = 7Hz), 2.55〜3.30 (1H, m), [3.70〜4.60
(m), 4.37 (q, J = 7Hz)] 4H, [6.20 ~ 7.30 (m), 7.20 (s)] 4H, [7.
50〜8.30 (m), 8.10 (d, J = 9Hz)] 2H, 10.33 (1H, bs)

(4) 2- (2,4-Difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinic acid methyl ester 3.89 g was added to N, N-
Dissolve in 39 ml of dimethylformamide, thiophenol
Add 1.34g and 1.23g triethylamine and add 5 at room temperature.
React for hours. Then, 120 ml of ethyl acetate and 120 ml of water are added to the reaction solution, and the pH is adjusted to 2.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with 80 ml of water and 80 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 20 ml of n-hexane was added to the obtained crystalline substance, and the crystals were collected by filtration to show a melting point of 126-128 ° C.
(2,4-Difluorophenylamino) -5-fluoro-6-phenylthionicotinic acid methyl ester 2.85 g
(Yield 90.2%) is obtained. When this is recrystallized from diisopropyl ether, crystals having a melting point of 128 to 128.5 ° C are obtained. IR (KBr) cm ⁻¹ ; ν _{c = o} 1685 NMR (CDCl ₃ ) δ value; 3.90 (3H, s), [6.0 to 8.0 (m), 7.77 (d, J = 1)
0Hz)] 9H, 10.25 (1H, bs)

In the same manner, the following compound is obtained. o 2- (2,4-difluorophenylamino) -6-
Ethylthio-5-fluoro nicotinic acid methyl ester melting point; 113.5 to 114 ° C. (resolving solvent; diisopropyl ether) IR (KBr) cm ⁻¹ ; ν _{c = o} 1680 NMR (CDCl ₃ ) δ value; 1.29 (3H, t, J = 7Hz), 3.07 (2H, q, J = 7Hz),
3.90 (3H, s), 6.50 ~ 7.20 (2H, m), 7.66 (1H, d, J = 10Hz), 7.80
~ 8.50 (1H, m), 10.00 (1H, bs)

(5) 3.00 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was suspended in 30 ml of methanol, and 16.1 ml of 2N aqueous sodium hydroxide solution was added at room temperature. After that, 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 1.0 with 6N hydrochloric acid, and the precipitated crystals were collected by filtration and washed successively with 15 ml of water and 15 ml of 2-propanol to give 2- (2,4-difluorophenyl) having a melting point of 213 to 216 ° C. 2.68 g (yield 93.7%) of amino) -5-fluoro-6-hydroxynicotinic acid are obtained. Acetone-
If recrystallized with a mixed solvent of ethanol (volume ratio 1: 1),
Crystals having a melting point of 215-216 ° C. are obtained. IR (KBr) cm ⁻¹ ; ν _{c = o} 1700 NMR (DMSO-d ₆ ) δ value; 6.65 to 7.58 (2H, m), 7.86 (1H, d, J = 11H
z), 8.12 ~ 8.68 (1H, m), 10.49 (1H, bs)

In the same manner, the following compound is obtained. o 5-Fluoro-2- (4-fluorophenylamino) -6-hydroxynicotinic acid Melting point: 216-217 ° C (resolving solvent; acetone: methanol =
1: 1 (volume ratio)) IR (KBr) cm ⁻¹ ; ν _{c = o} 1685 (sh) NMR (DMSO-d ₆ ) δ value; 6.84 to 7.94 (5H, m), 10.33 (1H, bs)

(6) 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid methyl ester (2.00 g) was dissolved in tetrahydrofuran (60 ml), and 1N aqueous sodium hydroxide solution (25.5 ml) was added at room temperature.
The mixture is reacted under heating under reflux for 7 hours. Then, the solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate and 1 ml of water were added to the obtained residue.
Add 00 ml and adjust to pH 2.0 with 2N hydrochloric acid. The organic layer was separated and washed successively with 50 ml of water and 50 ml of saturated saline,
Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 10 ml of diethyl ether was added to the obtained crystalline substance, and the crystals were collected by filtration to give a melting point of 237 to 240 ° C.
1.40 g (yield 73.3%) of (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid is obtained. If this is recrystallized with acetone, a crystal having a melting point of 239 to 240 ° C is obtained. IR (KBr) cm ⁻¹ ; ν _{c = o} 1665 NMR (DMSO-d ₆ ) δ value; 3.98 (3H, s), 6.76 to 7.48 (2H, m), 7.86
(1H, d, J = 11Hz), 8.10 ~ 8.60 (1H, m), 10.51 (1H, bs)

In the same manner, the following compound is obtained. o 2- (2,4-difluorophenylamino) -5-
Fluoro-6- (mesitylenesulfonyloxy) nicotinic acid Melting point; 179 to 180 ° C. (resolving solvent; benzene) IR (KBr) cm ⁻¹ ; ν _{c = o} 1665 NMR (acetone-d ₆ ) δ value; 2.32 (3H , s), 2.55 (6H, s), [6.37
~ 8.52 (m), 7.05 (s), 8.24, (d, J = 9Hz)] 7H, 10.37 (1H, bs) o 2- (2,4-difluorophenylamino) -5-
Fluoro-6- (2,4,6-triisopropylbenzenesulfonyloxy) nicotinic acid Melting point; 163.5 to 164.5 ° C (resolving solvent; benzene) IR (KBr) cm ^-1 ; ν _{c = o} 1675 NMR (CDCl ₃ + DMSO-d ₆ ) δ value; 1.22 (12H, d, J = 7Hz), 1.30 (6H,
d, J = 7Hz), 2.55〜3.30 (1H, m), 3.70〜4.40 (2H, m), [6.20〜
8.30 (m), 7.22 (s), 8.18 (d, J = 9Hz)] 6H, 9.66 (1H, bs), 10.57
(1H, bs) o 2- (2,4-difluorophenylamino) -6-
Ethylthio-5-fluoronicotinic acid Melting point; 209 to 210 ° C. (resolving solvent; benzene) IR (KBr) cm ⁻¹ ; ν _{c = o} 1665 NMR (acetone-d ₆ ) δ value; 1.30 (3H, t, J = 7Hz), 3.14 (2H, q, J =
7Hz), 6.70 ~ 7.50 (2H, m), [7.60 ~ 8.50 (m), 7.80 (d, J = 9H
z)] 2H, 9.70 (1H, bs), 10.27 (1H, bs) o 2- (2,4-difluorophenylamino) -5-
Fluoro-6-phenylthionicotinic acid Melting point: 264 to 265 ° C. (resolving solvent; ethyl acetate: ethanol = 1: 1 (volume ratio)) IR (KBr) cm ⁻¹ ; ν _{c = o} 1660 NMR (DMSO-d ₆ ) δ value; 6.00〜7.73 (8H, m), 7.85 (1H, d, J = 10H
z), 10.58 (1H, bs)

(7) 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid 5.
Suspend 00 g in 150 ml of methylene chloride and add 5.98 thionyl chloride.
g and 3 drops of N, N-dimethylformamide are added, and the mixture is reacted under heating under reflux for 2 hours. The solvent and excess thionyl chloride were distilled off under reduced pressure, 10 ml of n-hexane was added to the obtained crystalline substance, and the crystals were collected by filtration to give 2- (2,4-difluoro) having a melting point of 153-154 ° C. Phenylamino) -5-
Fluoro-6-methoxynicotinic acid chloride (4.87 g, yield 91.7%) is obtained. When this is recrystallized from methylene chloride, crystals having a melting point of 154-155 ° C are obtained. IR (KBr) cm ^-1 ; ν _{c = o} 1680 NMR (CDCl ₃ ) δ value; 3.98 (3H, s), 6.60 ~ 7.10 (2H, m), [7.70 ~
8.30 (m), 8.06 (d, J = 10Hz)] 2H, 9.65 (1H, bs)

Examples 2 to 5 In the same manner as in Example 1 (7), the compounds shown in Table 1 are obtained. In addition, R ^{1 in} Table 1 is the following formula.

[Chemical 6] The substituents of the compound represented by

[0030]

[Table 1]

The physical properties of the compounds shown in Table 1 are shown below. No.2 melting point; 136.5 to 138 ° C (resolving solvent; n-hexane) IR (KBr) cm ^-1 ; ν _{c = o} 1705 NMR (CDCl ₃ ) δ value; 2.34 (3H, S), 2.57 (6H, s), 6.40 to 7.10 (4
H, m), 7.55-8.05 (1H, m), 8.28 (1H, d, J = 9Hz), 9.55 (1H, bs) No.3 Melting point; 140-142 ° C (resolving solvent; diisopropyl ether) IR ( KBr) cm ^-1 ; ν _{c = o} 1700 NMR (CDCl ₃ ) δ value; 1.23 (12H, d, J = 7Hz), 1.30 (6H, d, J = 7Hz),
2.60 ~ 3.35 (1H, m), 3.75 ~ 4.45 (2H, m), [6.40 ~ 7.40 (m),
7.22 (s)] 4H, [7.80 ~ 8.50 (m), 8.35 (d, J = 9Hz)] 2H, 9.77 (1
H, bs) No.4 Melting point; 85-87 ° C (resolving solvent; n-hexane) IR (KBr) cm ^-1 ; ν _{c = o} 1685 NMR (CDCl ₃ ) δ value; 1.23 (3H, t, J = 7Hz), 3.00 (2H, q, J = 7Hz),
6.60 ~ 7.30 (2H, m), [7.40 ~ 8.05 (m), 7.86 (d, J = 10Hz)] 2
H, 9.32 (1H, bs) No.5 mp; 179-181 ° C. (recrystallization solvent: _{chloroform) NMR (DMSO-d 6)} δ values; [6.00~8.10 (m), 7.63 (s), 7.92 (d , J = 1
0Hz)] 9H, 10.54 (1H, bs)

Example 6 500 mg of 2- (2,4-difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinic acid chloride was dissolved in 10 ml of methylene chloride and then at -20 ° C.
Then, 1 ml of a methylene chloride solution containing 77 mg of imidazole and 120 mg of triethylamine was added dropwise, and the mixture was reacted at room temperature for 30 minutes. Then add 5 ml of water to the reaction mixture and add 2N hydrochloric acid to adjust the pH to 2.0.
Adjust to. Separate the organic layer, and add 5 ml of water and saturated saline solution.
After washing with ml sequentially, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 2 ml of diisopropyl ether was added to the obtained crystalline substance, and the crystals were collected by filtration.
485 mg of 1- [2- (2,4-difluorophenylamino) -5-fluoro-6- (mesitylenesulfonyloxy) nicotinoyl] imidazole showing a melting point of 98-101 ° C.
(Yield 91.1%) is obtained. The crystals are recrystallized from a mixed solvent of diisopropyl ether-diethyl ether (volume ratio 5: 2) to give crystals having a melting point of 103 to 105 ° C. IR (KBr) cm ⁻¹ ; ν _{c = o} 1670 NMR (CDCl ₃ ) δ value; 2.33 (3H, s), 2.60 (6H, s), 6.35 to 8.15 (9
H, m), 9.60 (1H, bs)

Examples 7 to 9 In the same manner as in Example 6, the compounds shown in Table 2 are obtained. In addition, R ^{1 in} Table 2 is the following formula.

[Chemical 7] The substituents of the compound represented by

[0034]

[Table 2]

The physical properties of the compounds shown in Table 2 are shown below. No.7 Melting point; 172.5-173 ° C (resolving solvent; benzene) IR (KBr) cm ^-1 ; ν _{c = o} 1660 NMR (DMSO-d ₆ ) δ value; 3.93 (3H, s), 6.75-8.35 ( 7H, m), 9.75
(1H, bs) No.8 Melting point; 140.5-141 ° C (recrystallization solvent; ethyl acetate: n-hexane = 1: 1 (volume ratio)) IR (KBr) cm ^-1 ; ν _{c = o} 1670 NMR (CDCl ₃ ) δ value; 1.28 (3H, t, J = 7Hz), 3.08 (2H, q, J = 7Hz),
6.65~8.20 (7H, m), 9.62 (1H, bs) No.9 mp; 169.5 to 171 ° C. (recrystallization solvent; ethyl acetate: n-hexane = 1: 1 (volume ratio)) IR (KBr) cm ^{- 1} ; ν _{c = o} 1650 NMR (CDCl ₃ ) δ value; 6.05 to 8.20 (12H, m), 9.88 (1H, bs)

Reference Example 1 200 mg of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid chloride was dissolved in 7 ml of anhydrous tetrahydrofuran, and 45 mg of imidazole and 65 mg of triethylamine were dissolved at -20 to -10 ° C. After adding 1 ml of an anhydrous tetrahydrofuran solution containing the solution, the reaction is carried out at room temperature for 30 minutes. Then, 150 mg of ethoxycarbonylacetic acid magnesium salt was added at room temperature and reacted under heating under reflux for 30 minutes, and then the reaction solution was added to a mixed solution of 10 ml of ethyl acetate and 10 ml of water and adjusted to pH 2.0 with 2N hydrochloric acid. . Separate the organic layer, add 5 ml of water, and p.s. with saturated aqueous sodium hydrogen carbonate solution.
Adjust to H7.5. The organic layer is separated, washed successively with 5 ml of water and 5 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 1 ml of diisopropyl ether was added to the obtained crystalline substance, and the crystals were collected by filtration to give 2- [2- (2,4-difluorophenylamino) having a melting point of 148 to 149 ° C. 190 mg of 5-ethyl-5-fluoro-6-methoxynicotinoyl] acetic acid (yield 81.7%)
To get If this is recrystallized with benzene, the melting point is 149-150.
Crystals showing ° C are obtained. IR (KBr) cm ^-1 ; ν _{c = o} 1745 NMR (CDCl ₃ ) δ value; 1.30 (3H, t, J = 7Hz), 3.90 (2H, s), 4.02 (3
H, s), 4.27 (2H, q, J = 7Hz), 6.65-7.35 (2H, m), 7.73 (1H, d, J
= 10Hz), 7.90 ~ 8.40 (1H, m), 11.19 (1H, bs)

Reference Example 2 To 4 ml of N, N-dimethylformamide, 250 mg of phosphorus oxychloride was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 10 minutes, and then 2
-[2- (2,4-difluorophenylamino) -5-
Fluoro-6-methoxynicotinoyl] acetic acid ethyl ester (200 mg) is added, and the mixture is reacted at 50-60 ° C for 3.5 hours. The reaction solution is poured into 50 ml of ice water, 20 ml of chloroform is added, and the organic layer is separated. After washing the organic layer with 20 ml of water,
Dry 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 collected by filtration to give 7-chloro-6-fluoro-1- (2,4 -Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate ethyl ester 150 mg (yield 72.
2%). The crystals are recrystallized with a mixed solvent of acetone-methanol (volume ratio 1: 1) to obtain crystals having a melting point of 219 to 221 ° C. Elemental analysis _{(C 17 H 10 N 2 O} 3 ClF 3) Calculated (%): C53.35; H2.63; N7.32 Found (%): C53.61; H2.47; N6.96

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mikako Shinagawa 916 Dogenji, Tateyama-machi, Nakashinagawa-gun, Toyama (72) Inventor Yoshinori Konishi Sano (Takamachi, Takaoka-shi, Toyama) 1000-72 (72) Invention Person Hirokazu Narita 6-40 Okudahonmachi, Toyama City, Toyama Prefecture (72) Inventor Shuntaro Takano 3-chome 8-44, Inarimoto Town, Toyama City, Toyama Prefecture (72) Inventor Isakawa 7-52, Oizumi Nakamachi, Toyama City, Toyama Prefecture (56) References Japanese Patent Publication 6-29247 (JP, B2)

Claims (1)

[Claims] 1. A general formula: In the formula, R ¹ represents a hydroxyl group or an optionally substituted alkoxy, alkanesulfonyloxy, arenesulfonyloxy, alkylthio or arylthio group; and X represents a hydrogen atom or a fluorine atom. Reactive derivatives at the carboxyl group of the represented 5-fluoronicotinic acids.