JPS61189269A - 2-(5-fluoronicotinoyl)acetic acid derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:The 2-(5-fluoronicotinoyl)acetic acid derivative of formula I (R<1> is group capable of forming carboxyl-protecting group; R<2> is halogen, hydroxy, 3-aminopyrrolidinyl, piperazinyl, alkoxy, alkylthio, arylthio, alkanesulfonyloxy, or arenesulfonyloxy; X is H or F) and its salt. EXAMPLE:2-(2,4-Difluorophenylamino)-5-fluoro-6-hyroxynicotinoylacetic acid ethyl ester. USE:Intermediate for 1-aryl-1,4-dihydro-4-oxonaphthyridine derivative exhibiting strong bactericidal effect against Gram-positive bacteria and Gram-negative bacteria, and its salt. PREPARATION:The compound of formula I can be produced e.g. by reacting the reactive derivative of the compound of formula II at the carboxyl group with the compound of formula III or its salt.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides 1-aryl-1,4-dihydro- The present invention relates to 2-(5-fluoronicotinoyl)acetic acid derivatives represented by the general formula and salts thereof, which are important intermediates for 4-oxonaphthyridine derivatives and salts thereof.

[Conventional technology]

1-aryl-1,4-dihydro-4-oxonaphthyridine derivatives represented by general formula (I) and their mu,
24th Interscience Conference on
Antimicrobial Agents and Chemotherapy (Interscience Conference
ce on Anttmicrobial Agent
s and Chemotherapy) Abstracts No. 10
In pages 2 to 104 and Japanese Patent Application No. 59-84963, it is shown that it has strong antibacterial activity against Durum-positive bacteria and Durum-negative bacteria, can obtain high blood concentrations by oral or parenteral administration, and is safe. It has been shown to have excellent properties such as high durability. However, as a method for producing these compounds, 2-(5-
There is no known method using fluoronicotinoyl) acetic acid derivatives or their salts.

[Problem that the invention seeks to solve]

An object of the present invention is to provide a novel intermediate useful in producing 1-aryl-1,4-dihydro-4-oxonaphthyridine derivatives represented by general formula (I) and salts thereof. [Means for Solving the Problems] Under such circumstances, the present inventors have conducted extensive research and have developed a 2-(5-fluoronicotinoyl)acetic acid derivative represented by general formula (II) and its salts. was found to be useful as an intermediate, leading to the completion of the present invention.

The present invention will be explained in detail below.

In this specification, the carboxyl protection-forming groups represented by R1 and R111L include those commonly used in the art, such as alkyl groups, benzyl groups, pivaloyloxymethyl groups, trimethylsilyl groups, and JP-A No. 5
Examples include the usual carboxyl group-protecting groups described in Japanese Patent No. 9-80665 and the like.

Examples of the halogen atom in R2 include fluorine atom, chlorine atom, odor atom, and iodine atom; examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy. , dodecyloxy, etc.; examples of the alkylthio group include methylthio,
Ethylthio, n-propylthio, isobutylthio, pentylthio, hexylthio, heptylthio, octylthio, dodecylthio, etc.; Arylthio groups include phenylthio, naphthylthio, etc.; alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy , 1-71 thylethanesulfonyloxy, 1. Examples of the arenesulfonyloxy group include l-dimethylethanesulfonyloxy, hensensulfonyloxy, and naphthalenesulfonyloxy.

Among the above, alkoxy, alkylthio, arylthio, alkanesulfonyloxy, and arenesulfonyloxy groups may have a substituent, and examples of these substituents include fluorine atom, chlorine atom, odor atom, and iodine atom. Halogen atoms such as; nitro group; methyl, ethyl, n-propyl, isopropyl, n-butyl,
Alkyl groups such as isobutyl, see, -butyl, tert, -butyl; methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 8
Examples include alkoxy groups such as ee, -butoxy, tert, and -butoxy.

In addition, as protecting groups for the amino group and imino group in the 3-aminopyrrolidinyl group in which the amino group in R2 and R3 may be preserved and the piperazinyl group in which the imino group may be protected, Those commonly used in the field include, for example, acyl groups such as formyl and acetyl.

In addition, as salts of the compounds represented by general formulas (I) and (II), commonly known salts of basic primary groups such as amino groups and imino groups or acidic groups such as carboxyl groups and hydroxyl groups are used. Can be mentioned.

Examples of salts with basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; oxalic acid.

Salts with organic carboxylic acids such as citric acid and trifluoroacetic acid; salts with sulfonic acids such as mecnesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; salts with acidic groups include, for example, sodium, potassium, etc. Salts with alkali metals; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; brocaine, dibenzylamine, N,N-dibenzylethylenediamine, triethylamine, pyridine, N,N-dimethylaniline, N-methyl Salts with nitrogen-containing organic bases such as piperidine, diethylamine, and dicyclohexylamine can be mentioned.

Next, the method for producing the compound of the present invention will be explained in detail.

The compound represented by the general formula (■) or a salt thereof can be produced, for example, according to the following production route.

(Blank below C) r゛(II) or its salt = 8 = Reactive derivatives at the carboxyl group of the compound represented by the general formula (III) include, for example, acid herogenides such as acid chloride and acid bromide; acid anhydrides; ; Mixed acid anhydrides with carbonic acid monoethyl ester, etc.; Active esters, such as dinitrophenyl ester, cyanomethyl ester, succinimide ester; Active acid amides, with imidazole, etc.;

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

Further, examples of the salt of the compound represented by the general formula (VI) include the same salts as explained for the salts of the compound represented by the general formulas (I) and (n).

The compound represented by the general formula (III) or (VI) or a salt thereof is usually prepared in a suitable solvent.
) The reactive derivative at the carboxyl group of the compound represented by formula (V) or (IV) is not particularly limited as long as it does not adversely affect the reaction, but specifically, water; methanol can be used. , ethanol, 2-7”
Alcohols such as lovanol; Aromatic hydrocarbons such as benzene and toluene; Salt, methylene, chloroform,
Examples include halokenated hydrocarbons such as dichloroethane; ethers such as diethyl ether, te)rahydrofuran, and dioxane; nitriles such as acetonitrile; amides such as iN, N-dimethylformamide, and N,N-dimethylacetamide; and the like. Further, the amount is equal to or more, preferably 1.0 to 2.5 times the mole of the reactive derivative in the carboxyl group of general metals. This reaction may be carried out normally at -50 to 100°C, preferably -20 to 70°C, for 5 minutes to 30 hours.

In order to derive the compound represented by general formula (VI) or a salt thereof into a compound represented by general formula (I[) or a salt thereof, the compound represented by general formula (VI) or a salt thereof is treated with The carboxyl protection-forming group may be partially removed and decarboxylated using p-toluenesulfonic acid or trifluoroacetic acid in anisole.

Furthermore, in the compound represented by general formula (n) or a salt thereof, when R2 is a hydroxyl group or a halogen atom, it can also be led to other compounds of the present invention by the method shown below.

(Left below) 1l- (I[a) or its salt (
IIb) (ITf) or its salt
(Ile)=12= Also, as a salt of the compound represented by the general formula (■),
The same salts as those explained for the acidic group salts of the compounds represented by general formulas (I) and (II) can be further added to the general formulas (
Examples of the salts of the compounds represented by (2) include the same salts as explained for the basic group salts of the compounds represented by formulas (I) and (n).

(1) Method for producing a compound represented by general formula (IIb) (
alkylation) The compound represented by the general formula (nb) is a compound represented by the general formula (I[a
) or a salt thereof can be obtained by subjecting it to an alkyl reaction.

The alkylating agent used is not particularly limited, but
Preferred examples include diazoalkanes, dialkyl sulfates, and alkyl halides.

(a) Alkylation with diazoalkane General formula (II
The compound represented by Ib) can be obtained by reacting the compound represented by the general formula (IIa) 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, but specifically, methanol,
Alcohols such as ethanol and 2-propanato; ethers such as diethyl ether, 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 Examples include. Two or more of these solvents may be used in combination. Examples of the diazoalkane include diazomethane and diazoethane, and the amount used is equal to or more, preferably 1.0 to 1.5 times the mole of the compound represented by the general formula (IIa). This reaction may be carried out usually at 0 to 50°C, preferably 0 to 25°C, for 5 minutes to 30 hours.

can be obtained by reacting a salt of with dialkyl sulfate in the presence or absence of an acid absorber. 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, but 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,
Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethylsulfoxide; two or more of these solvents may be used in combination. 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 the deoxidizing agent used as desired is equal to or more, preferably 1 to 2 times the mole of the compound represented by the general formula (IIa) or its salt. . This reaction is usually 0 to 150
What is necessary is just to carry out at 0-50 degreeC, preferably 5 minutes to 30 hours.

, Ci Alkyl halogenation The compound represented by the general formula (nb) is prepared by adding a 710 alkyl halide to the compound represented by the general formula (I[a) or a salt thereof in the presence or absence of a deoxidizing agent. It can be obtained by reaction. 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, but specifically, water; methylene chloride, chloroform fx, tonohalogen, hydrocarbons; diethyl Ethers such as ether, tetrahydrofuran and dioxane; N,N-dimethylformamide, N.

Amides such as N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide, and the like. Two or more of these solvents may be used as a mixture. Examples of the halogenated alkyl include methyl iodide, methyl bromide, and ethyl bromide. Examples of the deoxidizing agent include inorganic bases such as carbonic acid and organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, and collidine.

In this reaction, the amount of the alkyl halide and the deoxidizing agent used if desired is equal to or more, preferably 1 to 2 times the amount of the compound represented by the general formula (]Ta) or its salt. It is a mole. This reaction is usually O~
What is necessary is just to carry out at 150 degreeC, preferably 0-50 degreeC for 5 minutes to 30 hours.

(2) Process for producing a compound represented by the general formula (ffc) (sulfonylation) The compound represented by the general formula (I[c)
It can be obtained by reacting the compound represented by Ia) or a salt thereof with a sulfonylating agent in the presence or absence of a deoxidizing agent.

When this reaction is carried out in a solvent, the solvent used is
There is no particular limitation as long as it does not adversely affect the reaction, but specifically, water; aromatic hydrocarbons such as benzene, toluene, and xylene; dioxane, tetrahydrofuran, anisole, thiethylene glycol dimethyl ether natonoethers; chloride Halogenated hydrocarbons such as methylene, chloroform, dichloroethane; acetone,
Methyl ethyl ketone-/x which ketones; N,N-dimethylformamide-N.

Amides such as N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; hexamethylphosphoramide; and pyridine. These solvents may be used in combination of two or more. Sulfonyl additives include, for example, alkanesulfonyl halokeates such as methanesulfonyl chloride, ethanesulfonyl chloride, 1-methylethanesulfonyl chloride, 1,1-dimethylethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl Chloride, 2-nitrobenzenesulfonyl chloride, mesitylenesulfonyl chloride, 2,4.6-)lyisoprobylbenzenesulfonyl chloride, arenesulfonyl halogenates such as naphthalenesulfonyl chloride, benzenesulfonic anhydride, toluenesulfonic anhydride, Alkanes or arenes such as methanesulfonic anhydride
Examples include sulfonic acid anhydride. As a deoxidizing agent,
For example, triethylamine, pyruethyl 7
min, 1,8-diazabicyclo-[5,4,0]-undec-7-ene (DBU), viriciso, cariou-IA
tert.

organic or inorganic bases such as -butoxide, potassium carbonate, sodium carbonate, hydride, and the like.

The amount of the sulfonylating agent and the deoxidizing agent used as desired is equal to or more, preferably 1 to 2 moles, relative to the compound represented by the general formula (mn) or its salt.
It is twice the mole. This reaction may be carried out normally at -10 to 150°C, preferably at 0 to 80°C, for 5 minutes to 30 hours.

(3) Manufacturing method (thiolation) of the compound represented by the general formula (nd) The compound represented by the general formula (nd) is manufactured by the general formula (me
) or (IIe) with a thiol represented by the general formula (■) or a salt thereof in the presence or absence of a deoxidizing agent.

When this reaction is carried out in all solvents, the solvent used is 1
There is no particular limitation as long as it does not adversely affect the reaction, but specific examples include 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; N.

Amides such as N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; and the like.

These solvents may be used in combination of two or more.

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

or the compound represented by (IIe), respectively, in an equimolar amount or more, preferably 1 to 2 times the molar amount.

This reaction is usually carried out at a temperature of 0 to 150°C, preferably 0 to 70°C,
It may be carried out for 5 minutes to 30 hours.

(4) Method for producing the compound represented by the general formula (IIf) or its salt The compound represented by the general formula (If) or its salt is:
A compound represented by the general formula (IIc) or (Ice) in the presence or absence of a deoxidizer.

It can be obtained by reacting amines represented by the general formula (vIll) or salts thereof.

When this reaction is carried out in a solvent, the solvent used is
There is no particular limitation as long as it does not adversely affect the reaction, but specific examples include aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, ethanol, n-gropanol, 2-gropanol, n-butanol, and Alcohols such as butanol, tert, -butanol; dioxane, tetrahydrofuran, anisole, diethylene glycol, etc. (D ethers; methylene chloride,
Examples include halogenated hydrocarbons such as chloroform and dichloroethane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These solvents may be used in combination of two or more. Furthermore, examples of the deoxidizing agent include the same inorganic or organic bases as mentioned in (2).

When no deoxidizing agent is used, the amount of the amine represented by the general formula (■) or its salt is preferably 2
The amount of the amine represented by formula (■) or its salt can be reduced by appropriately using a deoxidizing agent. This reaction is usually 0 to 150℃
, preferably at 15 to 100°C for 5 minutes to 30 hours.

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

(Left below) (Illa) or a salt thereof (me) or a salt thereof, or the above formula (Ha) to (me), (IX)
, (XI) and (■),
Examples include the same salts as explained for the compounds represented by general formulas (I) and (n).

A compound represented by the general formula (5) or a salt thereof can be prepared by the general formula (5) according to the method described in British Patent No. 1409987.
General formula (X) to the compound represented by IX) or its salt
It can be obtained by reacting a compound represented by

In addition, the compound represented by the general formula (■) or a salt thereof is prepared by Pretane de Uφ Société Chimique Tou France (Bull, Soc, Chim, Fr,) 1165
1169 (1975), a compound represented by the general formula (■a) or a salt thereof, in the presence or absence of a condensing agent, a compound represented by the general formula (X[) When a compound or a salt thereof is reacted with a compound represented by the general formula (■), fc can be obtained by the following procedure.

When this reaction is carried out in a solvent, the solvent used is
There are no particular limitations as long as it does not adversely affect the reaction, but specifically, water; methanol.

Alcohols such as ethanol, 2-7' lovanol, butanol, ethylene glycol, methyl cellosolve;
Aromatic hydrocarbons such as benzene and toluene; Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; Ethers such as tetrahydrofuran, dioxane, anisole, diethylene glycol dimethyl ether, and dimethyl cellosolve; Nitriles such as acetonitrile; Acetone , Ketones such as methyl ethyl ketone; Esters such as ethyl acetate and methyl acetate; N,
Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. Two or more of these solvents may be used in combination.

Suitable condensing agents include, for example, sodium hydroxide, potassium hydroxide, potassium tert, -butoxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and the like.

In this reaction, the amount of the compound represented by the general formula (■) or its salt used is not particularly limited, but is usually at least equimolar to the compound represented by the general formula (XI) or its salt, preferably It is 1.0 to 3.0 times the mole.

1, this reaction is usually carried out at 0 to 150°C, preferably 25 to 1
What is necessary is just to carry out at 00 degreeC for 5 minutes - 30 hours.

The method for converting a compound represented by formula (IIIc) or a salt thereof into a compound represented by general formula (IITe) or a salt thereof may be carried out by the same method as described above. I can do it.

In addition, in the compound represented by the general formula (Illc) or a salt thereof, when R10 is a halogen atom, it can be obtained by reacting the compound represented by the general formula (Illa) or a salt thereof with a halogenating agent. be able to. 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, but specifically, aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane; N, N-
Examples include amides such as dimethylformamide%N, N-dimethylacetamide, and the like. These solvents may be used in combination of two or more. Examples of the halogenating agent include phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, thionyl chloride, and phosgenate, and two or more of these agents may be used. These halogenating agents may also be used as solvents. The amount of the halogenating agent used is at least equimolar to the compound represented by general formula (IIIa) or its salt. This reaction is usually 0~
150℃, preferably 50-110℃, 30 minutes to 30 minutes
All you have to do is time it.

General formulas (Ha) to (IIIe) thus obtained
The compound represented by or a salt thereof can be converted into a reactive derivative at the carboxyl group of the compound represented by general formula (III) by a method known per se.

The compounds obtained in each of the reactions described above can be isolated or separated by conventional methods, or can be used in the next reaction without being isolated or separated.

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

(Left below) =30- (III) or a salt thereof ■ (I) or a salt thereof In the above-mentioned process, R2 of the compound represented by the general formula (X]Ir) or a salt thereof is a hydroxyl group or a substituent. In the case of an alkoxy group which may have an alkoxy group, for example, R2 is a corresponding norogen atom or an arenesulfonyloxy group which may have a substituent. After converting to the compound represented by (■) or its salt, the general formula (■)
The compound represented by or its salt is reacted with the general formula (
The compound represented by I) or a salt thereof can be derived. In addition, in the case where R2 of the compound represented by the general formula (X[II) or a salt thereof is alkylthio or arylthio which may have a substituent, this is replaced by the general formula (■ ) or its salt, the general formula (■
) or a salt thereof can be reacted with the compound represented by formula (I) to induce a salt of shikadobutaba represented by general formula (I).

Examples of the salt of the compound represented by the general formula αm) include the same salts as explained for the compounds represented by the general formulas (I) and (n).

〔Example〕

Next, the present invention will be explained with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 1.0Of 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid was suspended in anhydrous tetrahydrofuran 40-, and N,N'- was added under water cooling.
0.8611 l of carbonyl diimidazole was added and the mixture was allowed to react at room temperature for 185 hours. Next, 1.601 ml of magnesium salt of ethoxycarbonylacetic acid was added, and the reaction was carried out at 60°C for 3 hours. The reaction m' was then added to a mixture of 80 ml of ethyl acetate and 80 ml of water, and the pH was adjusted to 2 with 6N hydrochloric acid. Adjust to 0. The organic layer is separated and washed successively with 40 g of saturated aqueous sodium bicarbonate solution and 40 g of water, then 40 g of water is added, and the pH is adjusted to 2.0 with 6N hydrochloric acid. The organic layer is separated, sequentially washed with 40 g of water and 40 g of saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, and diethyl ether is added to the resulting crystalline substance to form crystals, which gives a melting point of 161~
2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoylacetic acid ethyl ester 0143f exhibiting 162°C! (yield 34.5%).

IR(KBr)B-1; νc =01725.1665
NMR (CDCJa) δ value; 1.29 (3H, t, J = 7Hz), 3.74 (2'H
,s).

4.20 (2H,q, J=7Hz), 6
．． 57-7.69 (4H.

m), 10.17 (IH, bs), 11.52 (IH,
bs) Compound 2 is obtained in the same manner.

05-Fluoro-2-(4-fluorophenylamino)
-6-Hydroxynicotinoyl acetic acid ethyl ester melting point; 185°C (decomposition) (reconsolidation solvent; ethyl acetate) I
R(KB r ), , -1; νc=o 1715
, 1685 NiviR (CDCI3) δ value; 1.30 (3H, t, J = 7Hz), 3.75 (2
H,s).

4.25 (2H, q, J=7Hz), 7.80~7
．． 34 (41 (, m), 7.48 (IH, d, J=
11Hz).

11.68 (IH, bs) Example 2 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotine mo, 70t was dissolved in anhydrous tetrahydrofuran 30-, and N and N' were dissolved under water cooling. −
Add 1.13 f of carbonyldiimidazole and react at room temperature for 6 hours. Next, 0.99 f of magnesium salt of ethoxycarbonylacetic acid was added and the reaction was allowed to proceed at 55°C for 2 hours.
Add to the mixed solution of a/ and adjust to p'H2,o with 116N-hydrochloric acid. The organic layer is separated, 30% of water is added, and the pH is adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed successively with 30 d of water and 30 d of saturated brine, 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-200, elution solvent: benzene]
2-[6-chloro2-(2,4-difluorophenylami/)-s-fluoronicotinoyl] f
f[ethyl ester 0.68r (yield 789)'fi
:obtain. This was recrystallized from diisopropyl ether to give a crystalline phase having a melting point of 92.5 to 93°C.

I R (KB r ) cm-″1; c=o1745N
MR (CDC13) 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 (in, d, J=9Hz), 8.00~
In the same manner as in 8.50 (IH, m) and 10.91 (IH, bs), a compound of Tsa is obtained.

02-[2-(2,4-difluorophenylamino)-
5-Fluoro-6-medoxynicotinoyl]acetic acid ethyl ester melting point; 149-150°C (recrystallization solvent: benzene) IR
(KBr)crc” ishic=o1745NMR(C
DCIa) δ value; 1.30 (3H, t, J=7Hz), 3.90 (2
H,s).

4.02 (3H,s), 4.27 (2H,q
, J=7Hz).

6゜65~7.35 (2H, m), 7.73 (IH
,d.

J=10Hz), 7.90-8.40 (IH, m)
.

11.19(IH, bs) 0 2-[2-(2,4-difluorophenylamino)
-6-ethylthio-5-fluoronicotinoyl]acetic acid ethyl ester melting point; 102.5-103°C (reconsolidation solvent; diisopropyl ether) IR (KBr), -71-1; c=
o173ONMR (CDCIa) δ value; 1.29 (6H, t, J = 7Hz), 3.06 (2
H,q.

J=7Hz), 3.90 (2H, s), 4.2
2 (2H.

q, J”=7Hz), 6.62-7.35 (2H,
m).

7.52 (IH, d, J=11Hz), 7.70~
8.20 (IH, m), 10.86 (1) 1. bs
)0 2-1:2-(2,4-difluorophenylamino)-5-fluoro-6-phenylthionicotinoyl]
Ethyl acetate melting point: 132.5-134°C (reconsolidation solvent; ethyl acetate:
n-hexane=10:1)=37-IR(KBr),,,-i; νc=o
1725NMR (CDC13) δ value; 1.27 (3H, t, J = 7Hz), 3.89 (2
H,s).

4.20 (2H, q, J”7Hz), 5
．． 98-8.03 (9H, m), 11.12 (IH
, bs)02-C2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-)limethylbenzenesulfonyloxy)nicotinoylacetic acid]ethyl ester Melting point: 160-160.5°C (Recrystallization solvent; benzene) I
R(KBr), L-'''; νc=o
173QNMR (CDCIa) δ value; 1.27 (3H, j, J”7Hz), 2.32 (3H,
s).

2.57 (6H, s), 3.90 (2H, s), 4.2
0 (2H.

02-C6-(4-acetyl-1-piperazinyl)-2
-(2,4-difluorophenylamino)-5-fluoronicotinoyl]ethylnistylacetate melting point; 160-161'C: (reconsolidation solvent; benzene) I
R(KB r )c@-” rνc=o 1730
, 164ONMR (CDCIs) δ value; 1.28 (3H, t, J=7Hz), 2.12 (3
H,s).

3.38-3.97 (IOH, m), 4.22 (2
H,q.

J=7Hz), 6.67-7.20 (2H, m).

7.57 (IH-dtJ=14Hz), 7.77~8
．． 20 (IH, m), 10.98 (IH, ba) 0
2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenyl 7mi/)-5-
Fluoronicotinoyl]ethyl acetate ester melting point; 184-185°C (reconsolidation solvent; ethyl acetate:
Ethanol = 11) I R (K B r ) crn-”; νc = o
1735,167 ONMR (CDOla) δ value; 1.27 (3H,t, J"7Hz).

11.25 (IH, bs) Example 3 fi+ 2-(2,4-difluorophenylamino)
-5-Fluoro-6-medoxynicotine eo, 28t, was suspended in methylene chloride 3- and 0.0% thionyl chloride at room temperature.
Add 1 drop of 58F and N,N-dimethylformamide and react under heating under reflux for 2 hours. The solvent ν and excess thionyl chloride are distilled off under reduced pressure, and the obtained crystalline material is dissolved in chloride and methylene 6atlK.

(21cyphenylmethyl-ethylmalona-1-0,5
91 was dissolved in 6 ml of anhydrous tetrahydrofuran.

Sodium hydrogen (purity 750%) 0.09 at -20℃
9 is added and reacted at 0 to 10°C for 1 hour. Then,
The reaction solution is cooled to -20'C, and the methylene chloride solution obtained in (1) is added dropwise at the same temperature, followed by reaction at -20 to -10C for 30 minutes. 0.125' of acetic acid in the reaction solution? The solvent was distilled off under reduced pressure, and 20 m7 of ethyl acetate was added to the resulting residue. and 10 IntTh of water were added, and the pH was adjusted to 2.0 with 2N-hydrochloric acid. The organic layer is separated, sequentially washed with water and saturated brine, and then dried over magnesium acetate. The solvent was distilled off under reduced pressure.

Add 5 rnl of diisopropyl ether to the resulting residue and crystallize it to form diphenylmethyl-ethyl=2-
(2,4-difluorophenylamino)-5-fluoro-6-medoxynicotinoyl malonor) 0.43r (yield 79.2t) is obtained. This was recrystallized from a mixed solvent of benzene-n-hexane (volume ratio 10:1) to a melting point of 13.
Crystals exhibiting 0-131'C are obtained.

IR(KBr)"L-"; c=01740.
1730 (ah) NMR (CDCl2) δ value; 1.24 (3H, t, J = 7H2), 3.94 (
3H,s).

4.28 (2H, q, J=7Hz), 5.14 (I
H,s).

6.40~7.64 (14H, m), 7.7C)~
8.204l- (IH,m), 11.10(11(,bs)(3
) Diphenylmethyl-ethyl-2-(2,4-difluorophenylamino)-5-fluoro-6-medoxynicotinoyl malonor) 0.2Or was dissolved in anisole 2g, and trifluoroacetic acid 2d was added under water cooling. In addition, if the reaction was carried out for 10 minutes at the same temperature, 2-C2-C2,4-difluorophenylamino)-5-fluoro-5-methoxynicotinoyl]acetic acid ethyl ester 0.129 (yield 94.3%) was obtained. ) get f.

The physical properties of this compound were consistent with those obtained in Example 2.

Example 4 2-[2-(2,4-difluorophenylamino)-5
-Fluoro-6-hydroxynicotinoyl]acetic acid ethyl ester o, 1ofi ethyl acetate 21nt [dissolved,
After adding a diethyl needle solution containing 0.015 f of diazomethane under ice cooling, the mixture is allowed to react at room temperature for 30 minutes. Next, acetic acid was added to the first reaction solution until foaming ceased, and the solvent was distilled off under reduced pressure. Adding 2d of diisopropyl ether to the obtained crystalline substance and dividing the number of crystals gives 2
-[2-(2,4-difluorophenylamino)-5-
Fluoro-6-medoxynicotinoyl]acetic acid ethyl ester 0.08? (yield: 77.0%).

The physical properties of this mixture were consistent with those obtained in Example 2.

Example 5 2-[2-(2,4-difluorophenyl 7mi/)-5
-Fluoro-6-hydroxynicotinoyl]acetic acid ethyl ester 0.40SF'e salt dissolved in ichmethylene 4- and cooled with water 2.4.6-)limethylbenzenesulfonyl chloride 0.30f and triethylamine 0.15
Add r and allow to react at room temperature for 2 hours.

After washing, add 4 g of methylene chloride and 4 d of water to the reaction mixture, separate the entire organic layer, wash sequentially with 4 d of water and 4 d of saturated brine, and then dry over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and diethyl ether 2 is added to the obtained crystalline substance to obtain crystals, resulting in 2-[2-(2
,4-difluorophenylamino)-5-fluoro-6
-(2,4,6-drimethylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester 0.52F (yield: 85.8%) is obtained.

The physical properties of this compound were consistent with those obtained in Example 2.

In the same manner, a compound of Tsusa is obtained.

02-[2-(2,4-difluorophenylamino)-
5-Fluoro-6-methanesulfonyloxynicotinoyl]acetic acid ethyl ester melting point: 98-99°C (reconsolidation bath medium: benzene) I R (KB r ) (1-”; c:
0173ONMR (CDCIa) δ value; 1.27 (3H, t, J = 7Hz), 3.28 (3
H,s).

3.93 (2H, s), 4.23 (2H, q, J=
7Hz).

6.63-7.43 (2H, m).

Example 6 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester 0. l 5 y k L>J, N-dimethylformamide 1.5mtiC dissolved, thiophenol 0°072 and triethylamine 0.06
Add f and react at room temperature for 1 hour. Next, 20 m of ethyl acetate and water Low/ were added to the reaction solution, and 2N-4
Adjust the pH to 2.0 with acid. Separate the organic layer and add 10-
After washing with IiM and 10rnt of saturated saline, it is dried over anhydrous magnesium sulfate. The solvent was completely distilled off under reduced pressure, and 5d of n-hexane was added to the obtained crystalline substance to form crystals, yielding 2-[2-(2,4-difluorophenylamino)-5-fluoro. -6-phenylthionicotinoyl]acetic acid ethyl ester 0.17r (yield 94.6
LI)) is obtained.

The physical properties of this compound were consistent with those obtained in Example 2.

Example 7. 2-[2-(2,4-difluorophenylamine)-
5-Fluoro-6-(2,4,6-)limethylbenzenesulfonyloxy)nicotinoyl]ff+[ethyl ester O,'l OreN, N-dimethylformamide 1rrLl! and ethanethiol 0.017
f and 0.021'l'i of triethylamine are added and allowed to react at room temperature for 4 hours. Then, the reaction solution was added to a mixture of ethyl acetate and water, and the pH was adjusted with %2N-4 acid.
Adjust to 1,0. The organic layer is separated, sequentially washed with 2 d of water and 2 d of saturated brine, 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-200
, elution solvent; benzene:hexane (volume-H ratio: 2)] to obtain ethyl 2-[2-(2,4-difluorophenylamino)-〇-ethylthio-5-fluoronicotinoyl]acetic acid ethyl ester. 05y (yield 67.4%) was obtained.

The physical properties of this compound were consistent with those obtained in Example 2.

Example 8 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester o, sor was dissolved in chloroform 5mi! Dissolve in 3
- Add 0.261 l of dihydrochloride of aminopyrrolidine and 0.5 Or of triethylamine, and react under heating under reflux for 1.5 hours. Next, the reaction solution was added to a mixture of 5 d of chloroform and 5 t of water, the organic layer was separated, and 5 d of water was added.
and 5 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2 portions of diisopropyl ether were added to the obtained crystalline material to give 2-[
6-(3-amino-1-pyrrolidinyl)-2-(2,4
-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester o, 4sr (yield 84.7%) fjc was obtained.

IR(KBr), -@-1iνc=o 173ONMR
(DMSO-d6) δ value; 1.22 (3H, t, J=7Hz), 1.50-2
．． 30 (2H, m).

3.30-4.40 (9H, m), 6. RO~7.
60 (2H, m).

7.81 (IH, d, J=14Hz), 8.00~
8.70 (IH, m).

11.45 (IH, bs) Example 9 Anhydrous piperazine O,l4f was dissolved in ethanol 1.5- and 2-[6-chloro-2-(2,4-difluorophenylamino)-5-fluoro 0.15 f of ethyl nicotinoyl acetate was added in portions.

Let react for 30 minutes at room temperature. Next, 1 reaction solution is added to a mixed solution of 5 d of chloroform and 5 d of water, and the organic layer is separated, washed successively with 3 d of water and 3 d of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2 g of n-hexane was added to the obtained crystalline substance to form a crystal. -(1-piperazinyl)
Nicotinoyl]acetic acid ethyl ester 0.07t (yield 4
1.2%). This was mixed with ethyl acetate-n-hexane (
Recrystallize with a volume ratio of 1 (Ml) mixed solvent to obtain a melting point of 121-1
Crystals exhibiting a temperature of 23°C are obtained.

IR (KBr), 77,. 1 Niji c = o 1745.
1730 (ah) NMR (CDC1a) δ value; 1.30 (3H, t, J = 7Hz), 2.76-3
．． 10 (4H, m).

3.55-4.00 (6H, m), 4.21 (2H
, q, J"'7Hz).

6.40-7.20 (2H, m), 7.47 (IH,
d, J=14Hz).

7.75-8.35 (IH, m), 11.10 (I
H, bs) Example 10 3-aminopyrrolidine dihydrochloride 0.05f suspended in 1.5 g of total chloroform, triethylamine 0,11
After adding F and reacting at room temperature for 10 minutes, 2-[2-(
2,4-difluorophenylamino)-5-fluoro-
6-(2,4,6-drimethylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester 0.1! Add M and allow to react at room temperature for 1.5 hours. Next, 5 mg of chloroform and 5111 tons of water are added to the reaction solution, and the organic layer is separated, washed successively with 5 mg of water and 5 mg of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, diisopropyl ether 2 is added to the obtained crystalline substance, and the crystals are collected to obtain 2-[6-(3-amino-1-pyrrolidinyl)-2-(2, 4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester 0.11 ? (yield: 93.2).

The physical properties of this compound were "in agreement" with those obtained in Example 8.

Example 11 0.13f of anhydrous piperazine was dissolved in dichloromethane 2-[2-(2,4-difluoro)] under water cooling.

lophenylamino)-5-fluoro-6-(2,4゜6
-drimethylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester 0.2Of was added.

React at the same temperature for 40 minutes. Then, the reaction solution was added to a mixture of 1Qd of ethyl acetate and 10d of water, and the organic layer was separated and washed with 2d of saturated hydrogen carbonate solution and 2d of saturated brine, and then dried over anhydrous magnesium sulfate. let The solvent is distilled off under reduced pressure, and n-hexane 1- is added to the obtained crystalline substance to form a crystal.
-C2-(2,4-difluorophenylami/ )-5
-Fluoro-6-(1-piperazinyl)nicotinoyl]
Ethyl acetate 0.11? (yield 69.9%).

The physical properties of this compound were consistent with those obtained in Example 9.

Example 12 2-[6-(3-amino-1-pyrrolidinyl)-2-(
2,4-Difluorophenylami/)-5-fluoronicotinoyl]acetic acid ethyl ester 0,10y is dissolved in chloroform 1d, acetic anhydride o, oMGr are added dropwise, and the mixture is allowed to react at room temperature for 30 minutes.

Next, 1 reaction solution was added to a mixture of water 1 and chloroform, the organic layer was separated, and water 1 and saturated saline were added.
- and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

Diinobrobyl ether 0.5-
If you add and calculate the number of crystals, 0.08 f of 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester ( A yield of 72.8% was obtained.

The physical properties of this compound were consistent with those obtained in Example 2.

In the same manner, a compound of Tsusa is obtained.

02-[6-(4-acetyl-1-piperazinyl)-2
-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester The properties and properties of this compound were consistent with those obtained in Example 2.

Reference Example 1 (1) Hydrochloride of β-imino-β-phenoxybrobionic acid ethyl ester 50f and 2,4-difluoroaniline 27.8 f 'ff'' ethyl acetate 300 In
The mixture was suspended in water and reacted under heating and reflux for 2 hours.

If the precipitated crystals are separated and washed twice with 200°C of ethyl acetate, N-(2°4-
The hydrochloride salt of difluorophenyl) amidinoacetic acid ethyl ester 471 (yield 82.21) is obtained.

IR(KB r ), WL-1; νc=o 173O
NMR (DMSO-da) 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 (IH, bs), 10.26 (IH, bs
).

12.28 (IH, bll) Similarly, the following compound is obtained.

ON -(2,4--)fluorophenyl)amidinoacetic acid methyl ester hydrochloride melting point; 192-193°C I R(KB r ) crn-”; 'c=0173
5NMR (DMSO-da) δ value; 3.74 (3H, s), 4.09 (2H, s),
6.91-7.73 (3H, +n), 9.15 (I
H, bs), 10.31 (IH, bs).

12.29 (LH, bs) ON-(4-fluorophenyl)amidinoacetic acid methyl ester salt 1! &salt melting point; 134-135°C IR(KB r ) crn-1; c=o173ON
MR (DMSO-(16) δ value; 3.74 (3H, s), 4.05 (2H, s),
7.01-7.59 (4H, m), 8.96 (IH
, bs), 10.06 (IH, bs).

12.26 (IH, b8) (21N-(2,4-difluorophenyl)amidinoacetic acid methyl ester hydrochloride 23.Of is dissolved in a mixture of 92g of water and 92a/methylene salt, and 2N-hydroxyl The pH is adjusted to 13.0 with an aqueous sodium chloride solution.Then, the organic layer is separated, washed successively with 50 ml of water and 50 ml of saturated sodium chloride water, and dried over anhydrous magnesium sulfate. After adding 27.1 r of the sodium salt of α-fluoroacetic acid ethyl ester at room temperature and reacting under heating and reflux for 4 hours, the solvent was distilled off under reduced pressure.The resulting residue was mixed with 92 g of water and ethyl acetate. Add 46ml of water and count the precipitated crystals.Then, add 18ml of water to the resulting crystals.
Suspend in 4 vessels.

After adjusting the pH to 1.0 with 6N hydrochloric acid, add 4 ml of water to the precipitated crystals.
6d and 2-propertool 4611t are added to form a few crystals, 2-(2,4-difluorophenylamino)-5-A/O-5-hydroxynicotinic acid methyl ester 15. Of (yield 57.9%) is obtained. This is recrystallized from ethyl acetate to obtain crystals having a melting point of 222-223°C.

IR (KBr) (@-1; νc=o 170ONMR
(TFA-di) δ value; 4.06 (3H, s), 6.71 to 7.65 (3H
, m).

8.12 (IH, d, J = 11 Hz) Similarly, the following compound is obtained, 0 5-7) L/olor 2-(4-fluorophenylamino)-6-hydroxynicotinic acid methyl ester melting point; 227 ~228°C (reconsolidation solvent: ethyl acetate) I
R(K B r ) ”;ν.=0169ONM
R(TFA-dl) δ value; 4.05 (3H, s), 6.89-7.53 (4H
, m).

8.11 (IH, d, J = 11 Hz) Reference Example 2 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid methyl ester 0.2
After dissolving in 6 d of 0fft tetrahydrofuran and adding a diethyl ether acid solution containing 0.04 y of diazomethane under ice cooling, the mixture is allowed to react at room temperature for 30 minutes. Next, acetic acid was added to the first reaction solution until foaming ceased, and the solvent was distilled off under reduced pressure.

If 61 nt'f of 2-propanol is added to the obtained crystalline substance and the crystals are counted, 0.15 f of 2-(2,4-difluorophenylamino)-5-fluoro-6-medoxynicotinic acid methyl ester is obtained. (yield: 871.6 yen). This was recrystallized from ethyl acetate with a melting point of 160.5~
Crystals exhibiting a temperature of 161.5°C are obtained.

IR(KBr), -1;ν(!=0169ONMR(
CDCJa) δ value; 3.89 (3H, s>, 3.98 (3H, s),
6.57-7.08 (2H,, m), 7.81 (
IH, d, J = 11Hz).

8.10-8.97 (IH, m), 10.24-(
], II, bs) Reference Example 3 2-(2,4-difluorophenylamine)-5-fluoro-6-hydroxynicotinic acid methyl ester 9.5
f, five salts 26.59 and oxysalts 46.
The mixture of 9r is reacted at 70-80°C for 4 hours. Next, the reaction mixture was gradually added to 285 g of water, and the precipitated crystals were collected and washed with 57 g of water. If the obtained crystals are purified by column chromatography [Wako silica gel C-200, elution solvent: toluene], 6-chloro-2-(
2,4-cyfluorophenylamino)-5-fluoronicotinic acid methyl ester 3.5 f (Yield: $34.7
4) Obtain. This is recrystallized from diisopropyl ether to obtain crystals having a melting point of 39.5 to 140.5°C.

IR (KBr), 71-” ;shic:oi 695N
MR (CDCla) δ value 3.93 (3H, a), 6.61 to 7.06 (2H
, m), 7.94 (IH, d, J=9Hz),
8.15-8.57 (H(, m).

10.13(i, I(, bs) Reference Example 4 2-(2,4-difluorophenyl 7mi/)-s-fluoro-6-hydroxynicotinic acid methyl ester 0.5
0? Suspend it in 10 ml of methylene chloride, 2.4.6
Add 0,441 f of -drimethylbenzene sulfonyl chloride and 0.22 f of triethylamine, and react at room temperature for 3 hours. Add 15 ml of water to this solution. The organic layer was separated, washed with 15 g of water, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 15d of diethyl ether is added to the obtained crystalline substance, and the crystals are collected to give 2-(2゜4-difluorophenylamino)-
5-Fluoro-6-(2,4,6-drimethylbenzenesulfonyloxy)nicotinic acid methyl ester 0.66
f (yield: 81.9). This is recrystallized from ethyl acetate to obtain crystals having a melting point of 155-156°C.

I R(KB r )(Hm-" r I'c==6
170ONMR (CI)Cla) 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 (IH, m), 8.
05 (IH, d, J=9Hz).

10.17 (IH, bs) Reference Example 5 6-chloro0-2-(2,4-difluorophenylamine)-5-fluoronicotinic acid methyl ester o, toy
suspended in 7rnl of N,N-dimethylformamide,
Add 0.34 f of triethylamine and 0.211 f of yohyethanethiol at room temperature, and react at 50° C. for 4 hours. Then, 40≧≧40≧ ethyl acetate and 30≧water are added to the reaction solution, and the pH is adjusted to 2.0 with 2N hydrochloric acid. The organic layer is separated, sequentially washed with 20 ml of water and 20 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and n-hexane 10- is added to the obtained crystalline substance to obtain crystals, resulting in 6-ethylthio 2-(2,4
-difluorophenylamino)-5-fluoronicotinic acid methyl ester Q, 62y (yield 81.9%) is obtained. This was recrystallized from diisopropyl ether and melted A, 1
Crystals exhibiting a temperature of 13.5-114°C are obtained.

I R (KB r ) Tan-1; 'c==+) 168
ONMR (CDCla) δ value; 1.29 (3H, t, J=7Hz), 3.07 (2H,
(1, J=7Hz).

3.90 (3H, s), 6.50-7.20 (2
H, m), 7.66 (IH.

d, J"l0I(z), 7.80~8.50(II
(, m), io, 00 (LH, s) In the same manner, the compound with ゛ is obtained.

02-(2,4-difluorophenylamino)-5-fluoro-6-phenylthionicotinic acid methyl ester melting point; 128-J285°C (reconsolidation solvent; diisopropyl ether) IR (/(Br), fn-1; C-=
o 1685NMf (CI) C13') δ value; 10.25 (IH, bs) Reference Example 6 Dihydrochloric acid field of 3-aminopyrrolidine 0.121N.

After suspending in N-dimethylformamide 3 and adding 0.259% of triethylamine and reacting at room temperature for 5 minutes,
Add 0.3 Or of 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,,6-drimethylbenzenesulfonyloxy)nicotinic acid methyl ester and react at room temperature for 1.5 hours. let Add 10 ml of chloroform and 10 m/ml of water to the reaction solution, separate the organic layer, and add 1.0 d/ml of water and 1.0 m/ml of saturated food! After sequentially washing the eggs with water, the eggs are dried with anhydrous magnesium sulfate. Then, 0.1Of acetic anhydride was added and the mixture was allowed to react at room temperature for 10 minutes, and then the solvent was distilled off under reduced pressure. Add diethyl ether 5d to the obtained crystalline substance and count the crystals to obtain 6-(
3-acetylamino-1-pyrrolidinyl)-2-(2,
4-difluorophenylamino)-5-fluoronicotinic acid methyl ester 0.21 y (yield R2.4U was obtained. This i was recrystallized from ethyl acetate to give a melting point of 202-20
Crystals showing a temperature of 3°C are obtained.

IR(KBr), ;@-] ;shic=o1675NMR
(CDC1a-DMSO-d6) δ value: 6.63-7.
1.7 (2H, m), 7.62 (LH, d, J=14
Hz).

7.83-8.60 (2H, m), 10.30
(II(, bs)) In the same manner, obtain the compound proboscis.

06-(4-acetyl-1-piperazinyl)-2-(2
, 4-difluorophenylamino)-5-fluoronicotinic acid methyl ester melting point: 172-173'C (reconsolidation solvent: ethyl acetate) I
R(KBr), -1, νc=o 1680,16
5ONMR (CDC13) δ value; 6.57-7.07 (2H, m), 7.68 (IH, d
, J=13Hz).

7.77-8.18 (IH, m), 1.0.05 (IH
, bs) Reference Example 7 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid methyl ester 3.0
Of is suspended in 30 g of methanol, 16.1 g of a 2N aqueous solution of sodium hydroxide is added at room temperature, and the mixture is allowed to react under heating under reflux for 4 hours. Then, the reaction solution was diluted with 60% ethyl acetate.
- and 60 g of water, and separate the aqueous layer. This aqueous layer was adjusted to pI (1,0) with 6N-hydrochloric acid, and after removing the precipitated crystals, 15 me of water and 15 of 2-propanol were added.
After sequential washing with -, 2.68f of 2-(2,4-difluorophenylami/)-5-fluoro-6-hydroxynicotinic acid (yield 93.7%) is obtained. This is recrystallized from a mixed solvent of acetone and ethanol (volume ratio 1:1) to obtain crystals having a melting point of 215-216°C.

I R(KB r ) crn-1; νc=o1.70
ONMR (DMSO-d6) δ value; 6, fi5-7.58 (2H,m), 7.8
6 (IH, d, J=11Hz).

8.12-8.68 (IH, m), 10.49 (I
H, bs) In the same manner, obtain a Tsuza mixture.

Q5-fluoro-2-(4-fluorophenylamino)
-6-hydroxynicotinic acid melting point; 216-217°G (reconsolidation solvent; acetoso:methanol = 111) IR (KBr) g-4;
) NMR (DMSO-d6) δ value; 6.84-7.94 (5H, m), 10.33 (I
H, bs) Reference Example 8 2-(2,4-difluorophenylamino)-5-fluoro-6-medoxynicotinic acid methyl ester 2.0O
Dissolve f in 60 tnl of tetrahydrofuran and add 25.5# of IN-sodium hydroxide aqueous solution at room temperature. Add /,
The reaction is allowed to proceed under heating under reflux for 7 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate 100II+/
Add 100 g of water and adjust the pH to 2 with 2N hydrochloric acid. The organic layer is separated, washed sequentially with 50+d of water and 50% of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 10 g of diethyl ether is added to the obtained crystalline substance, and the crystals are collected.
-(2,4-difluorophenylamino)-5-fluoro-6-medoxynicotinic acid 1.40t (yield 73.3
9G) t'-obtain. This is recrystallized with acetone and has a melting point of 2.
Crystals exhibiting a temperature of 39-240°C are obtained.

I R (K B r ) (Hg-”; c=o166
5′ NMR (DMS O-da) δ value; 3.98 (3H, s), 6.76-7.48 (2H,
m).

7.86 (IH, d, J=11Hz), 8.10~8
．． 60 (IH, m).

10.51 (IH, bs) In the same manner, the compound of Tsuza is obtained.

06-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid Melting point: 226-2286C (Recrystallization solvent: Benzene) I
R(KB r ) cm-” iνQ=Q 168ON
MR (acetone-da) δ value: 6.60-7.41 (2H, m).

10.30 (IH, bs), 10.64 (IH, bS)
0 2-(2,4-difluorophenylamino)-5-
Fluoro-6-(2,4,6-drimethylbenzenesulfonyloxy)nicotinic acid melting point +179-180°C (reconsolidation solvent; benzene) IR (
KBr), H@-1; c=o1665 NMR (acetone-da) δ value; 2.32 (3H, 8), 2.55 (6H, s).

02-(2,4-difluorophenylamino)-6-ethylthio-5-fluoronicotinic acid Melting point: 209-21
0°C (recrystallization solvent; benzene) = 65-IR (KBr), -1 di-c- = o1665 NMR
(acetone-da) δ value; 1.30 (3H, t, J-”7Hz), 3.14 (2H
, q, J=7Hz).

6.70-7.50 (2H, m).

9.70 (IH, bs), 10.27 (IH, bs
)0 2-(2,4-difluorophenyl7mi/)-5
-Fluoro-6-phenylthionicotinic acid Melting point; 264
~265°C (reconsolidation solvent; ethyl acetate: ethanol = 1 concentration 1) IR (KBr)C@-” Ishic=o166ONMR
(DMSO-da) δ value; 6.00 to 7.73 (J(H,m), 7.F+5(IH
, d, J=10Hz).

10.58 (IH, bs) Reference Example 9 6-(3-acetylamino-1-pyrrolidinyl)-2-
(2,4-difluorophenylamino)-5-fluoronicotinic acid methyl ester 0.981 F't-Tetrahydrofuran 30 d, methanol 10 d and water 4 d suspended in a mixture of 5.3 ml of IN-sodium hydroxide aqueous solution
Add 1 nt and react at 65°C for 3 hours. Then, the reaction solution was diluted with ethyl acetate 507! and 50 ILt of water, and after separating the aqueous layer, the pH was adjusted to 2.0 with IN-hydrochloric acid. The precipitated crystals were poured into the bottom of the furnace and mixed with 2 d of water and 2 d of ethanol.
-, 6-(3-acetylamino-1-
PyroIJ (cynyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid o, 88yc, yield 93.0h) is obtained. This was recrystallized from a mixed solvent of acetone-methanol (volume ratio 1:1), with a melting point of 233.5-2.
Crystals exhibiting a temperature of 36°C are obtained.

IR(KBr), -1; c=o1645NMR(T
FA-di) δ value; 6.82 to 7.80 (3H, m), 8.27 (IH
, d, J=13Hz) In the same manner, the compound with t is obtained.

06-(4-acetyl-1-piperazinyl)-2-(2
, 4-difluorophenylamino)-5-fluoronicotinic acid Melting point: 243-244°C (reconsolidation solvent: ethyl acetate = ethanol = 11) I R (KB r ) z-1; νc = o 1670,1
635 (sh) NMR (TFA-dx) δ value; 2.48 (3H, s), 3.47-4.40 (l(
H, m).

64 (3-7.R2(3)(,m), 8.47(IH,
d, J=13Hz) Reference Example 10 6-(3-acetylamino-1-pyrrolidinyl)-2-
(2,4-difluorophenyl 7/)-5-fluoronicotinoyl acetic acid ethyl ester 0o20f'z-Suspension in benzene 2-, add 0.1Of N,N-dimethylformamide dimethyl acetal, and heat under reflux. Let it react for 7 hours at a lower temperature. Then, the precipitated crystals are collected and washed with diethyl ether 2d 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 0.182 (yield: 88.1) is obtained. This is recrystallized with a mixed solvent of acetone-methanol (volume ratio 1:1) to obtain crystals having a melting point of 234-236°C.

NMR (CDC) a) δ value; 1.33 (3H, t, J=7Hz).

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 fft) is dissolved in 6N hydrochloric acid (5-) and reacted under heating under reflux for 4 hours. Then, if the precipitated crystals are separated and washed with 1 int of water, 7-
(3-Amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1°8-naphthyridine-3-carboxylic acid hydrochloride 0. 39f (yield: 84.0). This is recrystallized from a mixed solvent of #hydrochloric acid and ethanol (volume ratio 1:3) to obtain crystals having a melting point of 247-250°C (decomposed)'fr.

NMR (TFA-di) δ value; 2.23-2.95 (2H, m), 3.38-4.
83 (5H, m).

6.95-7.90 (3) i, m), 8.22 (I
H, dIJ=lIHz)e9.18(IH,s) Reference Example 12 In the same manner as Reference Examples 10 and 11, the mixture 'f
obtain.

0l-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride Melting point: 249~ 252℃ (decomposition) (reconsolidation solvent; #hydrochloric acid:
Methanol=1:2) NMR (TFA-dx) δ value; 3.33-3.92 (4H, m), 3.92-4.
50 (4H, m).

6.90-7.90 (3H, m), 8.30 (], H,
d, J=12Hz).

9.18 (IH, 5) -71-+-+

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a carboxyl protection forming group; R^2 is 3-, which may have a halogen atom, hydroxyl group, or amino group protected. An aminopyrrolidinyl group, a piperazinyl group where the imino group may be protected, an alkoxy, alkylthio, arylthio, alkanesulfonyloxy or arenesulfonyloxy group which may have a substituent; and X is a hydrogen atom or fluorine Indicates an atom. ] A 2-(5-fluoronicotinoyl)acetic acid derivative and a salt thereof.