JPH0629246B2 - 2- (5-fluoronicotinoyl) acetic acid derivative and its salt - 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. A 1-aryl-1,4-dihydro-4-oxonaphthyridine derivative represented by And a 2- (5-fluoronicotinoyl) acetic acid derivative and a salt thereof.

[Conventional technology]

The 1-aryl-1,4-dihydro-4-oxonaphthyridine derivatives represented by the general formula (I) and salts thereof can be prepared according to the 24th Interscience Conference on Antimicrovial Agents and Chemotherapy (Interscience). Conference on Antimicrobial Age
nts and Chemotherapy), pages 102-104 and Japanese Patent Publication No. 63-20828, showing strong antibacterial activity against Gram-positive and Gram-negative bacteria and obtaining high blood concentration by oral or parenteral administration. It has been shown to have excellent properties such as being able to do and being highly safe. However, as a method for producing these compounds, a method via a 2- (5-fluoronicotinoyl) acetic acid derivative represented by the general formula (II) or a salt thereof is not known at all.

[Problems to be solved by the invention]

An object of the present invention is to provide a novel intermediate useful in the production of 1-aryl-1,4-dihydro-4-oxonaphthyridine derivatives represented by the general formula (I) and salts thereof.

[Means for solving problems]

Under such circumstances, the present inventors have conducted diligent research, and as a result, found that the 2- (5-fluoronicotinoyl) acetic acid derivative represented by the general formula (II) and its salt are useful as intermediates, The invention was completed.

Hereinafter, the present invention will be described in detail.

As the carboxyl-protecting group represented by R ¹ and R ^1a in the present specification, those usually used in the art, for example, an alkyl group, a benzyl group, a pivaloyloxymethyl group, a trimethylsilyl group, and the like are disclosed. Examples thereof include the usual protecting groups for carboxyl groups described in JP-A-59-80665.

The halogen atom in R ² is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the alkoxy group is, for example, methoxy, ethoxy, n-propoxy, isobutoxy, pentyloxy, hexyloxy,
Heptyloxy, octyloxy, dodecyloxy and the like; examples of the alkylthio group include methylthio,
Ethylthio, n-propylthio, isobutylthio, pentylthio, hexylthio, heptylthio, octylthio, dodecylthio etc .; arylthio groups such as phenylthio, naphthylthio etc .; alkanesulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, 1 -Methylethanesulfonyloxy, 1,1-dimethylethanesulfonyloxy and the like; Examples of the arenesulfonyloxy group include groups such as benzenesulfonyloxy and naphthalenesulfonyloxy.

Among the above, the alkoxy, alkylthio, arylthio, alkanesulfonyloxy and arenesulfonyloxy groups may have a substituent, and these substituents include, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. A halogen atom; a nitro group; an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl; methoxy, ethoxy, n-propoxy, isopropoxy, n- Alkoxy groups such as butoxy, isobutoxy, sec.-butoxy, tert.-butoxy and the like can be mentioned.

Further, as the amino group and the imino group-protecting group in the piperazinyl group, which may protect the 3-aminopyrrolidinyl group and the imino group, which may have the amino group in R ² and R ³ protected, Examples include those used in the field, for example, acyl groups such as formyl and acetyl.

Examples of the salts of the compounds represented by the general formulas (I) and (II) include salts of commonly known basic groups such as amino groups and imino groups, or acidic groups such as carboxyl groups and hydroxyl groups. .

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-toluene. Examples of salts of acidic groups include salts with sulfonic acids such as sulfonic acid and naphthalene sulfonic acid; salts with alkaline metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts. A salt with a nitrogen-containing organic base such as procaine, dibenzylamine, N, N-dibenzylethylenediamine, triethylamine, pyridine, 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 compound represented by the general formula (II) or a salt thereof can be produced, for example, according to the following production route.

Examples of the reactive derivative at the carboxyl group of the compound represented by the general formula (III) include acid chloride,
Acid halides such as acid bromide; acid anhydrides; mixed acid anhydrides with carbonic acid monoethyl ester; active esters such as dinitrophenyl ester, cyanomethyl ester, succinimide ester; active acid amides with imidazole, etc. .

Examples of salts of the compounds represented by the general formulas (IV) and (V) include salts with alkali metals such as lithium, potassium and sodium; salts with alkaline earth metals such as magnesium; and ethoxymagnesium. Examples include salt.

Further, as the salt of the compound represented by the general formula (VI),
The same salts as described for the salts of the compounds represented by the general formulas (I) and (II) can be mentioned.

The compound represented by the general formula (II) or (VI) or a salt thereof is usually added to a reactive derivative at the carboxyl group of the compound represented by the general formula (III) in a suitable solvent, respectively. It can be obtained by reacting a compound represented by IV) or a salt thereof. The solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; alcohols such as methanol, ethanol and 2-propanol; aromatic hydrocarbons such as benzene and toluene. Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as diethyl ether, tetrahydrofuran and dioxane; Nitric acid such as acetonitrile; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide And so on. The amount of the compound represented by the general formula (IV) or (V) or a salt thereof used is at least equimolar to the reactive derivative at the carboxyl group of the compound represented by the general formula (III), preferably It is 1.0 to 2.5 times the molar amount. This reaction is usually -50 to 100 ° C,
Preferably, it is carried out at -20 to 70 ° C for 5 minutes to 30 hours.

To derive the compound represented by the general formula (VI) or a salt thereof into the compound represented by the general formula (II) or a salt thereof, the compound represented by the general formula (VI) or a salt thereof is
For example, p-toluenesulfonic acid in a water-containing solvent or trifluoroacetic acid in anisole may be used to partially eliminate and decarboxylate the carboxyl-protecting group.

Further, in the compound represented by the general formula (II) or a salt thereof, when R ² is a hydroxyl group or a halogen atom, it can be led to another compound of the present invention by the following method.

Further, as the salt of the compound represented by the general formula (VII), the same salts as those described for the salt in the acidic group of the compounds represented by the general formulas (I) and (II) can be further represented by the general formula (VIII). Examples of the salt of the compound represented include the same salts as those described for the salt in the basic group of the compounds represented by formulas (I) and (II).

(1) Method for producing compound represented by general formula (IIb) (alkylation) The compound represented by general formula (IIb) is obtained by subjecting a compound represented by general formula (IIa) or a salt thereof to an alkylation reaction. be able to. The alkylating agent used is not particularly limited, but preferred examples include diazoalkanes, dialkyl sulfates and alkyl halides.

(A) Alkylation with diazoalkane The compound represented by the general formula (IIb) can be obtained by reacting the compound represented by the general formula (IIa) or a salt thereof with a diazoalkane. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, alcohols such as methanol, ethanol and 2-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. You may use these solvents in mixture of 2 or more types. Examples of the diazoalkane include diazomethane, diazoethane and the like, and the use amount thereof is equimolar or more, preferably 1.0 to 1.5 times the molar amount of the compound represented by the general formula (IIa). This reaction is generally 0 to 50 ° C, preferably 0 to 25 ° C.
Then, it may be carried out for 5 minutes to 30 hours.

(B) Alkylation with dialkyl sulfate A compound represented by the general formula (IIb) is obtained by reacting a compound represented by the general formula (IIa) or a salt thereof with a dialkyl sulfate in the presence or absence of a deoxidizing agent. You can get it. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; ketones such as acetone and methyl ethyl ketone; methyl acetate, acetic acid Esters such as ethyl; ethers such as tetrahydrofuran and dioxane; N, N-dimethylformamide,
Examples thereof include amides such as N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide. You may use these solvents in mixture of 2 or more types. Examples of the dialkyl sulfate include dimethyl sulfate and diethyl sulfate. Examples of the deoxidizing agent include inorganic bases such as alkali hydroxide and alkali carbonate.

In this reaction, the amount of the dialkyl sulfate and optionally a deoxidizing agent used is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the general formula (IIa) 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.

(C) Alkylation with an alkyl halide The compound represented by the general formula (IIb) is obtained by reacting the compound represented by the general formula (IIa) or a salt thereof with an alkyl halide in the presence or absence of a deoxidizing agent. It can be obtained. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as diethyl ether, tetrahydrofuran, dioxane; N, N-dimethylformamide, N, N-
Examples thereof include amides such as dimethylacetamide; sulfoxides such as dimethyl sulfoxide. You may use these solvents in mixture of 2 or more types. Examples of the alkyl halide include methyl iodide, methyl bromide, ethyl bromide and the like. As the deoxidizer, for example, an inorganic base such as alkali carbonate,
Alternatively, organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine and the like can be mentioned.

In this reaction, the amount of the alkyl halide and the deoxidizing agent optionally used is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the formula (IIa) or a salt thereof. Is. 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) Method for producing compound represented by general formula (IIc) (sulfonylation) The compound represented by general formula (IIc) is obtained by reacting a compound represented by general formula (IIa) or a salt thereof with a deoxidizing agent or It can be obtained by reacting a sulfonylating agent in the absence.

When this reaction is carried out in a solvent, the solvent used is
It is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether; methylene chloride , Halogenated hydrocarbons such as chloroform, dichloroethane; acetone,
Ketones such as methyl ethyl ketone; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide;
Hexamethylphosphoramide; pyridine and the like. You may use these solvents in mixture of 2 or more types. Examples of the sulfonylating agent include methanesulfonyl chloride, ethanesulfonyl chloride, 1
-Methylethanesulfonyl chloride, alkanesulfonyl halides such as 1,1-dimethylethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, mesitylenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl Examples thereof include arenesulfonyl halogenides such as chloride and naphthalenesulfonyl chloride, alkane- or arene-sulfonic anhydride such as benzenesulfonic anhydride, toluenesulfonic anhydride and methanesulfonic anhydride. Examples of the deoxidizing agent include triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] -undec-7-ene (DBU), pyridine and potassium ter.
Organic or inorganic bases such as t.-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.

The amount of the sulfonylating agent and the deoxidizing agent used as required is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the formula (IIa) or a salt thereof. This reaction is generally -10 to 150 ° C, preferably 0.
It may be carried out at -80 ° C for 5 minutes to 30 hours.

(3) Method for producing compound represented by general formula (IId) (thiolation) The compound represented by general formula (IId) is obtained by reacting a compound represented by general formula (IIc) or (IIe) with a deoxidizing agent. Alternatively, it can be obtained by reacting a thiol represented by the general formula (VII) or a salt thereof in the absence thereof.

When this reaction is carried out in a solvent, the solvent used is
It is not particularly limited as long as it does not adversely affect the reaction, and specifically, aromatic hydrocarbons such as benzene, toluene and 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 Can be mentioned. You may use these solvents in mixture of 2 or more types.

Examples of the thiols represented by the general formula (VII) include methanethiol, ethanethiol, n-propanethiol, isobutanethiol, pentanethiol, hexanethiol, heptanethiol, octanethiol, dodecanethiol, thiophenol and naphthalenethiol. Is mentioned. Examples of the deoxidizing agent include the same inorganic or organic bases as those mentioned in (2).

The amount of the thiol represented by the general formula (VII) or a salt thereof and the deoxidizing agent optionally used is equimolar or more with respect to the compound represented by the general formula (IIc) or (IIe), The molar amount is preferably 1 to 2 times. This reaction is usually at 0 to 150 ° C, preferably at 0 to 70 ° C for 5 minutes to 3
It may be carried out for 0 hours.

(4) Method for producing a compound represented by the general formula (IIf) or a salt thereof A compound represented by the general formula (IIf) or a salt thereof is prepared by adding a deoxidizing agent to a compound represented by the general formula (IIc) or (IIe). It can be obtained by reacting an amine represented by the general formula (VIII) or a salt thereof in the presence or absence.

When this reaction is carried out in a solvent, the solvent used is
It is not particularly limited as long as it does not adversely affect the reaction, but specifically, aromatic hydrocarbons such as benzene, toluene and xylene; methanol, ethanol, n-propanol, 2-propanol, n-butanol, iso Alcohols such as butanol and tert.-butanol; ethers such as dioxane, tetrahydrofuran, anisole and diethylene glycol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane;
Examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. You may use these solvents in mixture of 2 or more types. Moreover, as the deoxidizing agent, the same inorganic or organic bases as those mentioned in (2) can be mentioned.

The amount of the amine represented by the general formula (VIII) or a salt thereof used in the general formula (IIc) or (I
The amount is preferably 2 to 5 times the molar amount of the compound represented by Ie), but the amount of the amines represented by the general formula (VIII) or a salt thereof can be reduced by appropriately using a deoxidizing agent. be able to. This reaction may be carried out usually at 0 to 150 ° C., preferably 15 to 100 ° C. for 5 minutes to 30 hours.

The compound represented by the general formula (III), which is a raw material for producing the compound of the present invention, can be obtained, for example, as follows.

Further, the salts of the compounds represented by the above formulas (IIIa) to (IIIe), (IX), (XI) and (XII) can be represented by the general formula (I)
And the salts similar to those described for the compound represented by (II).

A compound represented by the general formula (XI) or a salt thereof is obtained by reacting a compound represented by the general formula (IX) or a salt thereof with a compound represented by the general formula (X) according to the method described in British Patent No. 1409987. Can be obtained.

In addition, the compound represented by the general formula (XII) or a salt thereof is prepared by the method described in Bulletin de la Societe Simique de France (Bull.Soc.Chim, Fr.) 1165 to 1169 (1975). Therefore, it can be manufactured.

A compound represented by the general formula (IIIa) or a salt thereof can be obtained by converting a compound represented by the general formula (XI) or a salt thereof into a compound represented by the general formula (XII) or a salt thereof in the presence or absence of a condensing agent. Can be obtained by reacting

When this reaction is carried out in a solvent, the solvent used is
It is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; alcohols such as methanol, ethanol, 2-propanol, butanol, ethylene glycol, methyl cellosolve; aromatic carbonization such as benzene and toluene. Hydrogens; methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane; ethers such as tetrahydrofuran, dioxane, anisole, diethylene glycol dimethyl ether, dimethyl cellosolve; nitriles such as acetonitrile; ketones such as acetone and methyl ethyl ketone; ethyl acetate,
Examples thereof include esters such as methyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide. You may use these solvents in mixture of 2 or more types.

As the condensing agent, for example, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium hydride, sodium methoxide, sodium ethoxide,
Examples thereof include potassium methoxide and potassium ethoxide.

In this reaction, the amount of the compound represented by the general formula (XII) or a salt thereof is not particularly limited, but is usually equimolar or more, preferably 1 mol or more with respect to the compound represented by the general formula (XI) or a salt thereof. It is 0.0 to 3.0 times mol. Also,
This reaction is usually performed at 0 to 150 ° C, preferably 25 to 100 ° C, and
It may be carried out for a minute to 30 hours.

Further, the alkylation, sulfonylation, thiolation and the method of deriving the compound represented by the general formula (IIIc) or a salt thereof into the compound represented by the general formula (IIIe) or a salt thereof can be carried out by the same method as described above. It can be carried out.

In the compound represented by the general formula (IIIc) or a salt thereof, when R ¹⁰ is a halogen atom, the compound represented by the general formula (IIIc
It can be obtained by reacting the compound represented by a) or a salt thereof with a halogenating agent. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, aromatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as methylene, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide. You may use these solvents in mixture of 2 or more types. As a halogenating agent,
Examples thereof include phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, thionyl chloride, phosgene, etc. These agents may be used as a mixture of two or more kinds. These halogenating agents may be used as a solvent. The amount of the halogenating agent used is equimolar or more based on the compound represented by the general formula (IIIa) or a salt thereof. This reaction is usually 0 to 150 ° C, preferably 5
It may be carried out at 0 to 110 ° C. for 30 minutes to 30 hours.

The compounds represented by the general formulas (IIIa) to (IIIe) or salts thereof thus obtained are converted into a reactive derivative at the carboxyl group of the compound represented by the general formula (III) by a method known per se. can do.

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

The thus-obtained compound represented by the general formula (II) or a salt thereof can be derived into the compound represented by the general formula (I) or a salt thereof by the route shown below, for example.

In the above-mentioned steps, when R ² of the compound represented by the general formula (XIII) or a salt thereof is a hydroxyl group or an alkoxy group which may have a substituent, this may be, for example, a halogen atom to which R ² corresponds. Alternatively, the compound represented by the general formula (VIII) or a salt thereof is converted to a compound represented by the general formula (XIII) or a salt thereof, which is an alkanesulfonyloxy or arenesulfonyloxy group which may have a substituent. The compound can be allowed to act to induce the compound represented by the general formula (I) or a salt thereof. Further, when R ² of the compound represented by the general formula (XIII) or a salt thereof is alkylthio or arylthio which may have a substituent, the compound represented by the general formula (XIII) in which R ² is the corresponding sulfoxy or sulfone The compound represented by the general formula (VIII) or a salt thereof can be converted to a compound represented by the general formula (I) or a salt thereof by reacting the compound represented by the general formula (VIII) or a salt thereof.

Examples of the salt of the compound represented by the general formula (XIII) include the same salts as those described for the compounds represented by the general formulas (I) and (II).

〔Example〕

Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited thereto.

Example 1 2.00 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid was suspended in 40 m of anhydrous tetrahydrofuran, and N, N'-carbonyldiimidazole was cooled under ice cooling. Add 0.86g, 1.5 at room temperature
React for hours. Then, 1.60 g of magnesium salt of ethoxycarbonylacetic acid was added and reacted at 60 ° C. for 3 hours, and then the reaction solution was mixed with 80 m of ethyl acetate and 80 m of water.
The pH of the mixture is adjusted to 2.0 with 6N hydrochloric acid. The organic layer was separated, washed successively with 40m saturated aqueous sodium hydrogen carbonate solution and 40m water, and then 40m water was added,
Adjust to pH 2.0 with 6N hydrochloric acid. Separate the organic layer and use water 4
The extract is washed successively with 0 m and saturated saline 40 m, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 4 m of diethyl ether was added to the obtained crystalline substance to collect crystals, which had a melting point of 161-162 ° C.
-(2.4-Difluorophenylamino) -5-fluoro-6-hydroxynicotinoyl] acetic acid ethyl ester 0.
43 g (yield 34.5%) are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1725,1665 NMR (CDCl ₃ ) δ value; 1,29 (3H, t, J = 7Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7H
z), 6.57 to 7.69 (4H, m), 10.17 (1H, bs), 11,52 (1H, b
s) Similarly, 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 ; ν _{c = 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) Example 2 6-chloro-2- (2,4-difluorophenylamino)
0.70 g of -5-fluoronicotinic acid is dissolved in 30 m of anhydrous tetrahydrofuran, 1.13 g of N, N'-carbonyldiimidazole is added under ice cooling, and the mixture is reacted at room temperature for 6 hours. Then, 0.99 g of magnesium salt of ethoxycarbonylacetic acid was added and reacted at 55 ° C. for 2 hours, then the reaction solution was added to a mixed solution of 75 m of ethyl acetate and 65 m of water, and the pH was adjusted to 2.0 with 6N-hydrochloric acid. . The organic layer is separated, 30 m of water is added, and the pH is adjusted to 7.5 with a saturated aqueous sodium hydrogen carbonate solution. Separate the organic layer and water 30m
After successively washing with 30 m of saturated saline and drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, eluting solvent: benzene].
0.68 g (yield 78.9%) of 2- [6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester is obtained. This is recrystallized from diisopropyl ether to give crystals having a melting point of 92.5 to 93 ° C.

IR (KBr) cm ₋₁ ; ν _{c = o} 1745 NMR (CDCl ₃ ) δ value; 1.31 (3H, t, J = 7Hz), 3.97 (2H, s), 4.25 (2H, q, J = 7Hz),
6.65 ~ 7.35 (2H, m), 7.85 (1H, d, J = 9Hz), 8.00 ~ 8.50 (1
H, m), 10.91 (1H, bs) Similarly, the following compound is obtained.

2- [2- (2,4-difluorophenylamino) -5
-Fluoro-6-methoxynicotinoyl] acetic acid ethyl ester melting point; 149 to 150 ° C. (resolving solvent; benzene) 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 (3H, s), 4.27 (2
H, q, J = 7Hz), 6.65 to 7.35 (2H, m), 7.73 (1H, d, J = 10H
z), 7.90 to 8.40 (1H, m), 11.19 (1H, bs) 2- [2- (2,4-difluorophenylamino) -6
-Ethylthio-5-fluoronicotinoyl] acetic acid ethyl ester Melting point: 102.5 to 103 ° C (resolving solvent; diisopropyl ether) IR (KBr) cm _-1 ; ν _{c = 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), 7.70-8.20 (1H, m), 10.86 (1H, bs) 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) IR (KBr) cm ⁻¹ ; ν _{c = 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, bs) 2- [2- (2,4-difluorophenylamino) -5
-Fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetic acid] ethyl ester melting point; 160-160.5 ° C (resolving solvent; benzene) IR (KBr) cm ^-1 ; ν ^{c = o} 1730 NMR (CDCl ₃ ) δ value; 1.27 (3H, t, J = 7Hz), 2.32 (3H, s), 2.57 (6H, s), 3.90 (2
H, s), 4.20 (2H, q, J = 7Hz), 10.93 (1H, bs) 2- [6- (4-acetyl-1-piperazinyl) -2
-(2,4-Difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester melting point; 160 to 161 ° C (resolving solvent; benzene) IR (KBr) cm ^-1 ; ν _{c = o} 1730,1640 NMR (CDCl ₃ ) δ value; 1.28 (3H, t, J = 7Hz), 2.12 (3H, s), 3.38〜3.97 (10H, m),
4.22 (2H, q, J = 7Hz), 6.67 ~ 7.20 (2H, m), 7.57 (1H, d, J =
14Hz), 7.77-8.20 (1H, m), 10.98 (1H, bs) 2- [6- (3-acetylamino-1-pyrrolidinyl) -2- (2,4-difluorophenylamino) -5-
Fluoronicotinoyl] acetic acid ethyl ester Melting point: 184 to 185 ° C. (resolving solvent; ethyl acetate: ethanol = 1: 1) IR (KBr) cm ⁻¹ ; ν _{c = o} 1735,1670 NMR (CDCl ₃ ) δ value; Example 3 (1) 0.28 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid was suspended in 3 m of methylene chloride, and 0.58 g of thionyl chloride and N, One drop of N-dimethylformamide is 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, and the obtained crystalline substance was converted into methylene chloride 6
dissolve in m.

(2) 0.59 g of diphenylmethyl-ethyl-malonate was dissolved in 6 m of anhydrous tetrahydrofuran, and 0.09 g of sodium hydride (purity; 50%) was added at -20 ° C to give 0-
React at 10 ° C. for 1 hour. Then, the reaction solution is cooled to -20 ° C, the methylene chloride solution obtained in (1) is added dropwise at the same temperature, and the reaction is allowed to proceed at -20 to -10 ° C for 30 minutes. 0.12 g of acetic acid is added to the reaction solution, the solvent is distilled off under reduced pressure, 20 m of ethyl acetate and 10 m of water are added to the obtained residue, and the pH is adjusted to 2.0 with 2N-hydrochloric acid. Separate the organic layer,
After sequentially washing with 10 m of water and 10 m of saturated saline, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diisopropyl ether 5 was added to the obtained residue.
After adding m and collecting crystals, 0.43 g of diphenylmethyl = ethyl = 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinoyl malonate
(Yield 79.2%) is obtained. This was recrystallized with a mixed solvent of benzene-n-hexane (volume ratio 10: 1) to give a melting point of 130-131.
Crystals showing ° C are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1740,1730 (sh) NMR (CDCl ₃ ) δ value; 1.24 (3H, t, J = 7Hz), 3.94 (3H, s), 4.28 (2H, q, J = 7Hz),
5.14 (1H, s), 6.40 ~ 7.64 (14H, m), 7.70 ~ 8.20 (1H, m), 1
1.10 (1H, bs) (3) Diphenylmethyl = ethyl = 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinoyl malonate (0.20 g) was dissolved in anisole (2 m) and cooled with ice. Then, 2 m of trifluoroacetic acid is added, and the mixture is reacted at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, and 2 m of diisopropyl ether was added to the obtained crystalline substance to collect crystals. 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- 0.12 g (yield 94.3%) of methoxynicotinoyl] acetic acid ethyl ester is obtained.

The physical properties of this compound were the same as those obtained in Example 2.

Example 4 2- [2- (2,4-difluorophenylamino) -5-
Fluoro-6-hydroxynicotinoyl] acetic acid ethyl ester (0.10 g) is dissolved in ethyl acetate (2 m), and a diethyl ether solution containing 0.015 g of diazomethane is added under ice-cooling, followed by reaction at room temperature for 30 minutes. Then, acetic acid is added until foaming does not occur in the reaction solution, and then the solvent is distilled off under reduced pressure. If 2 m of diisopropyl ether was added to the obtained crystalline substance to collect crystals, 2- [2
-(2,4-Difluorophenylamino) -5-fluoro-6-methoxynicotinoyl] acetic acid ethyl ester 0.0
8 g (yield 77.0%) are obtained.

The physical properties of this compound were the same as those obtained in Example 2.

Example 5 0.40 g of 2- [2-2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinoyl] acetic acid ethyl ester was dissolved in 4 m of methylene chloride, and 2,4, 6-Trimethylbenzenesulfonyl chloride 0.3
0 g and triethylamine 0.15 g were added, and 2
React for hours. Then, add 4m of methylene chloride to the reaction mixture.
And 4 m of water are added, the organic layer is separated, washed successively with 4 m of water and 4 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2 m of diethyl ether was added to the obtained crystalline substance to collect crystals. 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- 0.52 g (yield 85.8%) of (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetic acid ethyl ester is obtained.

The physical properties of this compound were the same as those obtained in Example 2.

Similarly, the following compound is obtained.

2- [2- (2,4-difluorophenylamino) -5
-Fluoro-6-methanesulfonyloxynicotinoyl] acetic acid ethyl ester melting point; 98 to 99 ° C. (resolving solvent; benzene) IR (KBr) cm ⁻¹ ; ν _{c = o} 1730 NMR (CDCl ₃ ) δ value; 1.27 ( 3H, t, J = 7Hz), 3.28 (3H, s), 3.93 (2H, s), 4.23 (2
H, q, J = 7Hz), 6.63 to 7.43 (2H, m), 10.78 (1H, bs) Example 6 2- [6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester 0.15 g was added to N, N-dimethylformamide 1. It is dissolved in 5 m, 0.07 g of thiophenol and 0.06 g of triethylamine are added, and the mixture is reacted at room temperature for 1 hour. Then, 20 m of ethyl acetate and 10 m of water are added to the reaction solution, and the pH is adjusted to 2.0 with 2N-hydrochloric acid. Separate the organic layer,
After sequentially washing with 10 m of water and 10 m of saturated saline, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 5 m of n-hexane was added to the obtained crystalline substance to collect crystals. 2- [2- (2,4-difluorophenylamino) -5-fluoro-6 -Phenylthionicotinoyl] acetic acid ethyl ester 0.17 g (yield 94.
6%).

The physical properties of this compound were the same as those obtained in Example 2.

Example 7 2- [2- (2,4-difluorophenylamino) -5-
Fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinoyl] acetic acid ethyl ester 0.10 g
Is dissolved in 1 m of N, N-dimethylformamide, 0.017 g of ethanethiol and 0.028 g of triethylamine are added, and the mixture is reacted at room temperature for 4 hours. Then, the reaction solution was added to a mixed solution of 3 m of ethyl acetate and 3 m of water, and 2N-
Adjust to pH 1.0 with hydrochloric acid. The organic layer is separated, washed successively with 2 m of water and 2 m 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 (volume ratio 1:
2)], 2- [2- (2,4-difluorophenylamino) -6-ethylthio-5-fluoronicotinoyl] acetic acid ethyl ester 0.05 g (yield 67.4%)
To get

The physical properties of this compound were the same as those obtained in Example 2.

Example 8 2- [6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester (0.50 g) was dissolved in chloroform (5 m) to give 3-aminopyrrolidine dihydrochloride. 0.26 g and triethylamine 0.50 g are added, and the mixture is reacted under heating under reflux for 1.5 hours. Then, the reaction solution was mixed with chloroform (5 m) and water (5 m).
The organic layer is separated, washed successively with 5 m of water and 5 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2 m of diisopropyl ether was added to the obtained crystalline substance to obtain crystals. 2- [6- (3-amino-1-pyrrolidinyl) -having a melting point of 140-142 ° C. 2- (2,4-Difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester 0.48 g (yield 84.7%) is obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1730 NMR (DMSO-d ₆ ) δ value; 1.22 (3H, t, J = 7Hz), 1.50 to 2.30 (2H, m), 3.30 to 4.40 (9
H, m), 6.80 to 7.60 (2H, m), 7.81 (1H, d, J = 14Hz), 8.00 to
8.70 (1H, m), 11.45 (1H, bs) Example 9 0.14 g of anhydrous piperazine was dissolved in 1.5 m of ethanol to give 2- [6-chloro-2- (2,4-difluorophenylamino)- 5-Fluoronicotinoyl] acetic acid ethyl ester (0.15 g) is added portionwise, and the mixture is reacted at room temperature for 30 minutes. Then, the reaction solution was mixed with chloroform (5 m) and water (5 m).
The organic layer is separated, washed successively with 3 m of water and 3 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2 m of n-hexane was added to the obtained crystalline substance to collect crystals, and 2- [2- (2,4-difluorophenylamino)-
5-Fluoro-6- (1-piperazinyl) nicotinoyl] acetic acid ethyl ester 0.07 g (yield 41.2%) is obtained. Ethyl acetate-n-hexane (volume ratio 10:
1) Recrystallize with a mixed solvent to obtain crystals having a melting point of 121 to 123 ° C.

IR (KBr) cm ₋₁ ; ν _{c = o} 1745,1730 (sh) NMR (CDCl ₃ ) δ value; 1.30 (3H, t, J = 7Hz), 2.76 to 3.10 (4H, m), 3.55 to 4.00 ( 6
H, m), 4.21 (2H, q, J = 7Hz), 6.40-7.20 (2H, m), 7.47 (1
H, d, J = 14 Hz), 7.75 to 8.35 (1H, m), 11.10 (1H, bs) Example 10 3-aminopyrrolidine dihydrochloride (0.05 g) was suspended in chloroform (1.5 m), and triethylamine (0) was added. After adding 0.11 g and reacting at room temperature for 10 minutes, 2- [2- (2,4-
Difluorophenylamino) -5-fluoro-6- (2,
4,6-Trimethylbenzenesulfonyloxy) nicotinoyl] acetic acid ethyl ester (0.15 g) was added, and the mixture was stirred at room temperature for 1.5.
React for hours. Then, add 5m of chloroform to the reaction mixture.
And 5 m of water are added, the organic layer is separated, washed successively with 5 m of water and 5 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2 m of diisopropyl ether was added to the obtained crystalline substance to collect crystals. 2- [6- (3-amino-1-pyrrolidinyl) -2- (2,4- Difluorophenylamino)-
5-Fluoronicotinoyl] acetic acid ethyl ester 0.11
g (yield 93.2%) are obtained.

The physical properties of this compound were the same as those obtained in Example 8.

Example 11 0.13 g of anhydrous piperazine was dissolved in 2 m of methylene chloride, and 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-trimethyl was dissolved under ice cooling. Benzenesulfonyloxy) nicotinoyl] acetic acid ethyl ester (0.20 g) is added, and the mixture is reacted at the same temperature for 40 minutes.
Then, the reaction solution was mixed with 10 m of ethyl acetate and 10 m of water.
The organic layer is separated, washed successively with 2 m of a saturated aqueous sodium hydrogen carbonate solution and 2 m of a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 1 m of n-hexane was added to the obtained crystalline substance.
Then, the crystals are added to give 2- [2- (2,4-difluorophenylamino) -5-fluoro-6- (1-piperazinyl) nicotinoyl] acetic acid ethyl ester 0.11 g.
(Yield 69.9%) is obtained.

The physical properties of this compound were the same as those obtained in Example 9.

Example 12 2- [6- (3-amino-1-pyrrolidinyl) -2-
0.10 g of (2,4-difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester is dissolved in 1 m of chloroform, 0.026 g of acetic anhydride is added dropwise, and the mixture is reacted at room temperature for 30 minutes. Then, the reaction solution is added to a mixed solution of 1 m of water and 1 m of chloroform, the organic layer is separated, washed successively with 1 m of water and 1 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 0.5 m of diisopropyl ether was added to the obtained crystalline substance to collect crystals, and 2- [6- (3
-Acetylamino-1-pyrrolidinyl) -2- (2,4-
Difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester 0.08 g (yield 72.8%) is obtained.

The physical properties of this compound were the same as those obtained in Example 2.

Similarly, the following compound is obtained.

2- [6- (4-acetyl-1-piperazinyl) -2
-(2,4-Difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester The physical properties of this compound were the same as those obtained in Example 2.

Reference Example 1 (1) 50 g of β-imino-β-phenoxypropionic acid ethyl ester hydrochloride and 27.8 g of 2,4-difluoroaniline were suspended in 300 m of ethyl acetate and reacted under heating under reflux for 2 hours. . If the precipitated crystals are collected and washed twice with 200 m of ethyl acetate, N having a melting point of 196 to 197 ° C is obtained.
47 g (yield 82.2%) of the hydrochloride of-(2,4-difluorophenyl) amidinoacetic acid ethyl ester are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1730 NMR (DMSO-d ₆ ) δ value; 1.26 (3H, t, J = 7Hz), 4.07 (2H, s), 4.19 (2H, q, J = 7Hz ) 、
7.02 ~ 7.78 (3H, m), 9.11 (1H, bs), 10.26 (1H, bs), 12.28
(1H, bs) Similarly, the following compound is obtained.

Hydrochloride of N- (2,4-difluorophenyl) amidinoacetic acid methyl ester Melting point; 192-193 ° C IR (KBr) cm ^-1 ; ν _{c = o} 1735 NMR (DMSO-d ₆ ) δ value; 3.74 (3H , s), 4.09 (2H, s), 6.91 to 7.73 (3H, m), 9.15 (1H,
bs), 10.31 (1H, bs), 12.29 (1H, bs) N- (4-Fluorophenyl) amidinoacetic acid methyl ester hydrochloride Melting point; 134-135 ° C IR (KBr) cm ^-1 ; ν _{c = o} 1730 NMR (DMSO-d ₆ ) δ value; 3.74 (3H, s), 4.05 (2H, s), 7.01 to 7.59 (4H, m), 8.96 (1H,
bs), 10.06 (1H, bs), 12.26 (1H, bs) (2) N- (2,4-difluorophenyl) amidinoacetic acid methyl ester hydrochloride 23.0 g was mixed with water 92 m and methylene chloride 92 m. And is adjusted to pH 13.0 with a 2N sodium hydroxide aqueous solution. Then, the organic layer is separated, washed successively with 50 m of water and 50 m of saturated saline and dried over anhydrous magnesium sulfate. Α in this solution
27.1 g of sodium salt of formyl-α-fluoroacetic acid ethyl ester is added 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. Water (92 m) and ethyl acetate (46 m) are added to the obtained residue, and the precipitated crystals are collected. Then, the obtained crystals were suspended in 184 m of water and adjusted to pH 1.0 with 6N-hydrochloric acid, and then 46 m of water and 46 m of 2-propanol were added to the precipitated crystals to collect the crystals. 4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester 15.0 g (yield 57.9%) is obtained. This is recrystallized from ethyl acetate to give crystals having a melting point of 222-223 ° C.

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) Then, the following compound is obtained.

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) Reference Example 2 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester 0. 20 g
Is dissolved in 6 m of tetrahydrofuran, a diethyl ether solution containing 0.04 g of diazomethane is added under ice cooling, and the mixture is reacted at room temperature for 30 minutes. Then, acetic acid is added until foaming does not occur in the reaction solution, and then the solvent is distilled off under reduced pressure. 2-propanol 6m to the obtained crystalline substance
Is added and the crystals are collected to obtain 0.15 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid methyl ester (yield 71.6%).
This is recrystallized from ethyl acetate to obtain crystals having a melting point of 160.5 to 161.5 ° C.

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 (2H, m), 7.81 (1H,
d, J = 11 Hz), 8.10 to 8.97 (1H, m), 10.24 (1H, bs) Reference Example 3 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester 9 .5g,
A mixture of 26.5 g of phosphorus pentachloride and 46.9 g of phosphorus oxychloride is reacted at 70-80 ° C for 4 hours. Then, the reaction solution is gradually added to 285 m of water, the precipitated crystals are collected, and then washed with 57 m of water. The obtained crystals were purified by column chromatography [Wako Silica Gel C-200, eluting solvent: toluene] to give 6-chloro-2- (2,4
3.5 g (yield 34.7%) of methyl difluorophenylamino) -5-fluoronicotinate are obtained. This was recrystallized from diisopropyl ether to give a melting point of 139.5-14.
Crystals showing 0.5 ° C. are obtained.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1695 NMR (CDCl ₃ ) δ value; 3.93 (3H, s), 6.61 to 7.06 (2H, m), 7.94 (1H, d, J = 9Hz),
8.15-8.57 (1H, m), 10.13 (1H, bs) Reference Example 4 2- (2,4-Difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester 0.50 g
Is suspended in 10 m of methylene chloride, 0.44 g of 2,4,6-trimethylbenzenesulfonyl chloride and 0.22 g of triethylamine are added, and the mixture is reacted at room temperature for 3 hours. Water 15m was added to this solution, the organic layer was separated, and water 15m
After washing with, dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, 15 m of diethyl ether was added to the obtained crystalline substance to collect crystals, and 2- (2,
4-difluorophenylamino) -5-fluoro-6-
0.66 g (yield 81.9%) of (2,4,6-trimethylbenzenesulfonyloxy) nicotinic acid methyl ester is obtained. This is recrystallized from ethyl acetate to obtain 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 to 6.84 (2H,
m), 6.92 (2H, s), 7.35 to 7.94 (1H, m), 8.05 (1H, d, J = 9H
z), 10.17 (1H, bs) Reference Example 5 6-chloro-2- (2,4-difluorophenylamino)
0.70 g of -5-fluoronicotinic acid methyl ester was suspended in 7 m of N, N-dimethylformamide, and 0.34 g of triethylamine and 0.2 of ethanethiol were added at room temperature.
1 g is added and reacted at 50 ° C. for 4 hours. Then, 40 m of ethyl acetate and 30 m of water were added to the reaction solution, and 2
Adjust to pH 2.0 with N-hydrochloric acid. Separate the organic layer and add water 20
m and saturated saline solution (20 m), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 m of n-hexane was added to the obtained crystalline substance to collect crystals. 6-ethylthio-2- (2,4-difluorophenylamino) -5-fluoronicotine 0.62 g (yield 81.9%) of acid methyl ester is obtained. This is recrystallized from diisopropyl ether and the melting point is 113.5 to 114 ° C
To obtain crystals.

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 to 7.20 (2H, m), 7.66 (1H, d, J = 10Hz), 7.80 to 8.50 (1
H, m), 10.00 (1H, s) Similarly, the following compound is obtained.

2- (2,4-Difluorophenylamino) -5-fluoro-6-phenylthionicotinic acid methyl ester Melting point; 128-128.5 ° C (resolving solvent; diisopropyl ether) IR (KBr) cm ^-1 ; ν _{c = O} 1685 NMR (CDCl ₃ ) δ value; 3.90 (3H, s), 10.25 (1H, bs) Reference Example 6 0.12 g of 3-aminopyrrolidine dihydrochloride was suspended in 3 m of N, N-dimethylformamide, 0.25 g of triethylamine was added, and the mixture was reacted at room temperature for 5 minutes, and then 2 −
(2,4-difluorophenylamino) -5-fluoro-
6- (2,4,6-trimethylbenzenesulfonyloxy)
Add 0.30 g of nicotinic acid methyl ester and add 1.5 at room temperature.
React for hours. Chloroform (10 m) and water (10 m) were added to the reaction solution, the organic layer was separated, washed successively with water (10 m) and saturated brine (10 m), and dried over anhydrous magnesium sulfate. Then add 0.10 g of acetic anhydride,
After reacting for 10 minutes at room temperature, the solvent is distilled off under reduced pressure. 5 m of diethyl ether was added to the obtained crystalline substance to collect crystals, and 6- (3-acetylamino-1-
Pyrrolidinyl) -2- (2,4-difluorophenylamino) -5-fluoronicotinic acid methyl ester 0.21 g
(Yield 82.4%) is obtained. This is recrystallized from ethyl acetate to give crystals having a melting point of 202-203 ° C.

IR (KBr) cm ^-1 ; ν _{c = o} 1675 NMR (CDCl ₃ -DMSO-d ₆ ) δ value; 6.63 to 7.17 (2H, m), 7.62 (1H, d, J = 14Hz), 7.83 to 8.60 (2
H, m), 10.30 (1H, bs) Similarly, the following compound is obtained.

6- (4-acetyl-1-piperazinyl) -2- (2,
4-difluorophenylamino) -5-fluoronicotinic acid methyl ester melting point; 172-173 ° C (resolving solvent; ethyl acetate) IR (KBr) cm ^-1 ; ν _{c = o} 1680,1650 NMR (CDCl ₃ ) δ Value; 2.13 (3H, s), 6.57 to 7.07 (2H, m), 7.68 (1H, d, J = 13Hz), 7.77 to 8.18 (1
H, m), 10.05 (1H, bs) Reference Example 7 2- (2,4-Difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester 3.00 g
Is suspended in 30 m of methanol, 16.1 m of 2N-sodium hydroxide aqueous solution is added at room temperature, and the mixture is reacted under heating under reflux for 4 hours. Then, the reaction solution was mixed with 60 m of ethyl acetate.
And 60 m of water are added to the mixture, and the aqueous layer is separated.
This aqueous layer was adjusted to pH 1.0 with 6N-hydrochloric acid, and the precipitated crystals were collected and washed successively with 15 m of water and 15 m of 2-propanol to give 2- (2,4-difluorophenylamino) -5- Fluoro-6-hydroxynicotinic acid 2.68
g (yield 93.7%) are obtained. This was recrystallized from a mixed solvent of acetone-ethanol (volume ratio 1: 1) to give a melting point of 215-215.
Crystals showing ° 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 = 11Hz), 8.12 to 8.68 (1
H, m), 10.49 (1H, bs) Similarly, the following compound is obtained.

5-fluoro-2- (4-fluorophenylamino)
-6-Hydroxynicotinic acid Melting point; 216 to 217 ° C (resolving solvent; acetone: methanol =
1: 1) 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) Reference Example 8 2- (2,4-Difluorophenylamino) -5-fluoro-6-methoxynicotinic acid methyl ester 2.00 g was dissolved in 60 m of tetrahydrofuran, and 1N-at room temperature.
25.5 m of sodium hydroxide aqueous solution is added, and the mixture is reacted under heating under reflux for 7 hours. Then, the solvent was distilled off under reduced pressure,
100 m of ethyl acetate and 100 ml of water were added to the obtained residue.
m is added and the pH is adjusted to 2.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with 50 m of water and 50 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 m of diethyl ether was added to the obtained crystalline substance to collect crystals. 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid 1.40 g (yield 73.3%) are obtained. This is recrystallized with acetone to obtain crystals having a melting point of 239 to 240 ° C.

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 to 8.60 (1H, m), 10.51 (1H, bs) Similarly, the following compound is obtained.

6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid Melting point; 226 to 228 ° C (resolving solvent; benzene) IR (KBr) cm ^-1 ; ν _{c = o} 1680 NMR ( Acetone-d ₆ ) δ value; 6.60〜7.41 (2H, m), 10.30 (1H, bs), 10.64 (1H, bs) 2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinic acid Melting point; 179- 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), 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 to 7.50 (2
H, m), 9.70 (1H, bs), 10.27 (1H, bs) 2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotinic acid Melting point: 264-265 ° C (resolving solvent; ethyl acetate) : Ethanol = 1: 1) IR (KBr) cm ⁻¹ ; ν _{c = o} 1660 NMR (DMSO-d ₆ ) δ value; 6.00 to 7.73 (8H, m), 7.85 (1H, d, J = 10Hz), 10.58 (1H, bs) Reference Example 9 6- (3-Acetylamino-1-pyrrolidinyl) -2-
(2,4-Difluorophenylamino) -5-fluoronicotinic acid methyl ester 0.98 g was suspended in a mixed solution of tetrahydrofuran 30 m, methanol 10 m and water 4 m, and 1N-sodium hydroxide aqueous solution 5.3 m was added, React at 65 ° C. for 3 hours. Then, the reaction solution is added to a mixed solution of 50 m of ethyl acetate and 50 m of water, the aqueous layer is separated, and then adjusted to pH 2.0 with 1N-hydrochloric acid. The precipitated crystals were collected and washed successively with 2 m of water and 2 m of ethanol to give 6- (3-acetylamino-1-pyrrolidinyl) -2- (2,4-difluorophenylamino) -5-
0.888 g of fluoronicotinic acid (yield 93.0%) is obtained.
This is recrystallized with a mixed solvent of acetone-methanol (volume ratio 1: 1) to obtain a crystal having a melting point of 233.5 to 236 ° C.

IR (KBr) cm ⁻¹ ; ν _{c = o} 1645 NMR (TFA-d ₁ ) δ value; 3.62 to 5.03 (5H, m), 6.82 to 7.80 (3H, m), 8.27 (1H, d, J = 1
(3 Hz) Similarly, the following compound is obtained.

6- (4-acetyl-1-piperazinyl) -2- (2,
4-difluorophenylamino) -5-fluoronicotinic acid Melting point: 243 to 244 ° C (resolving solvent; ethyl acetate: ethanol = 1: 1) IR (KBr) cm ⁻¹ ; ν _{c = o} 1670,1635 (sh ) NMR (TFA-d ₁ ) δ value; 2.48 (3H, s), 3.47 to 4.40 (8H, m), 6.83 to 7.82 (3H, m), 8.
47 (1H, d, J = 13Hz) Reference Example 10 2- [6- (3-Acetylamino-1-pyrrolidinyl)
-2- (2,4-Difluorophenylamino) -5-fluoronicotinoyl] acetic acid ethyl ester (0.20 g) was suspended in benzene (2 m), N, N-dimethylformamide dimethylacetal (0.10 g) was added, and the mixture was heated under reflux. React under 7 hours. Then, the precipitated crystals were collected and washed with 2 m of diethyl ether to give 7- (3-acetylamino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro. -4-oxo-1,8
-Naphthyridine-3-carboxylic acid ethyl ester 0.18
g (yield 88.1%) is obtained. This was recrystallized from a mixed solvent of acetone-methanol (volume ratio 1: 1) to give a melting point of 234-236.
Crystals showing ° C are obtained.

NMR (CDCl ₃ ) δ value; 1.33 (3H, t, J = 7Hz), 3.13 ~ 4.02 (4H, m), 6.78 to 7.70 (4H, m), 8.10 (1H, d, J = 8Hz), 8.31 (1H, s) Reference Example 11 7- (3-Acetylamino-1-pyrrolidinyl) -1-
(2,4-Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 0.50 g was dissolved in 6 N-hydrochloric acid 5 m and heated under reflux. Allow to react for 4 hours under. Then, the precipitated crystals are collected and washed with 1 m of water to obtain 7- (3-amino-
1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8
0.39 g (yield 84.0%) of the hydrochloride of naphthyridine-3-carboxylic acid is obtained. This is recrystallized with a mixed solvent of concentrated hydrochloric acid-ethanol (volume ratio 1: 3) to obtain crystals having a melting point of 247 to 250 ° C (decomposition).

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) Reference Example 12 In the same manner as in Reference Examples 10 and 11, the following compound was obtained.

1- (2,4-difluorophenyl) -6-fluoro-
Hydrochloride of 1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid Melting point: 249-252 ° C (decomposition) (resolving solvent; concentrated hydrochloric acid: methanol = 1: 2) 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)

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yoshinori Konishi Sano (Takaoka Shinmachi), Takaoka City, Toyama 1000-72 (72) Inventor Hirokazu Narita 6-40, Okudahonmachi, Toyama City, Toyama (72) Inventor Takano Shuntaro 3-8-44, Inarimoto-cho, Toyama-shi, Toyama (72) Inventor Isamu Saikawa 7-52 Oizumi-naka-cho, Toyama-shi, Toyama Examiner Shinichi Akasaka

Claims (1)

[Claims] 1. A general formula A 2- (5-fluoronicotinoyl) acetic acid derivative represented by and a salt thereof.