JPS61289088A - Novel method for producing 1,4-dihydro-4-oxonaphtyridine derivative or salt thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an antibacterial agent can be produced by reacting a specific 2-(5-fluoronicotinoyl)-acetic acid derivative or its salt with an acetal of a specific N,N-disubstituted formamide. CONSTITUTION:The objective compound of formula III (R<1> is protecting group) or its salt can be produced by reacting (A) the compound of formula I (R<1a> is protecting group; R<2> is halogen, hydroxyl, azido, alkoxy, alkylthio, 3-amino-1- pyrrolidinyl, 1-piperazinyl, etc.; X is H or F) or its salt with (B) the compound of formula II (R<3> and R<4> are alkyl or cycloaralkyl or R<3> and R<4> together form an alkylene; R<5> and R<6> are alkyl or R<5> and R<6> together with N form a heterocyclic group in the presence or absence of a solvent, usually at 0-150 deg.C for 5min-3hr, and if necessary, subjecting the product to deprotecting, etc. The amount of the compound B is usually >=1mol per 1mol of the compound A.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to general formula (I), lukansulfonyl, arenesulfonyl, ai deletion.

[Conventional technology and its problems]

Among the 1,4-dihydro-4-oxonaphthyrisine derivatives represented by the general formula flll, the following general formula (■), 1-substituted aryl-1,4-dihydro-4-oxonaphthyrisine derivatives and salts thereof is the 24th Interscience Conference on Antimicrobial φAzoents and Chemosera g-(I, C, Human, A, C) Collection of Proceedings, pp. 102-104 and the patent application filed in 1983.
Further, the compound represented by the general formula (Ib) or a salt thereof is useful as an intermediate in producing the compound of the formula (Ilm).

Conventionally, a method using 2-[2,6-zochloro-5-fluoronicotinoyl]acetic acid ethyl ester as an intermediate is known as a method for producing the compound of formula (1&), but there are still more industrially advantageous methods. It was hoped that a new method would be developed.

[Means for solving problems]

That is, the present invention provides 2-(
5-Fluoronicotinoyl) acetic acid derivative or its salt and an acetal of N,N-disubstituted formamide represented by general formula (I) are reacted, and if necessary, the protecting group is removed or converted to a salt or ester. This is a method for producing a 1,4-dihydro-4-oxonaphthyrisin derivative or a salt thereof represented by the general formula (2).

In the method of the present invention, a compound of general formula (+) is added to a compound of general formula (
When the compound (2) is reacted, an intermediate compound represented by the general formula (n5) or its salt is formed, and this further reacts to form a l,4-dihydro-4-okyne represented by the formula (U+). A naphthyridone derivative or a salt thereof is obtained.

The present invention will be explained in detail below.

In this specification, carboxyl protecting groups represented by Bl and FLIIL include those commonly used in the field, such as alkyl groups, benzyl groups, pivaloyloxymethyl groups, trimethylsilyl groups, etc. 8
Examples include the usual carboxyl group-protecting groups described in Publication No. 0665 and the like.

Examples of the halogen atom in R2 and Rlb include fluorine atom, chlorine atom, bromine atom, and iodine atom, and examples of the alkoxy group include methoxy, ethoxy, n-7'rosexy, inbutoxy, pentyloxy, Hexyloxy, hexyloxy, octyloxy, dodecyloxy, etc.; Examples of alkylthio groups include methylthio, ethylthio, n-7' pyrthio, isobutylthio, isobutylthio, tart,
-butylthio, pentylthio, hexylthio, henotylthio, octylthio, dodecylthio, etc.; Examples of arylthio groups include phenylthio, naphthylthio, etc.; alkanesulfinyl groups, teha, ri,! : For example, methanesulfinyl, ethanesulfinyl, 1-methylethanesulfinyl, 1,1-dimethylethanesulfinylnato; arenesulfinyl group: ri,!
: Eha, benzenesulfinyl, naphthalenesulfinyl nato; alkanesulfonyl group, for example, methanesulfonyl, ethanesulfonyl, l-methylethanesulfonyl, 1,1-dimethylethanesulfonylnato;
Examples of the arenesulfonyl group include benzenesulfonyl and naphthalenesulfonyl; examples of the alkanesulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, 1-methylethanesulfonyloxy, and 1,1-dimethylethanesulfonyloxy. Examples of the arenesulfonyloxy group include benzenesulfonyloxy and naphthalenesulfonyloxy; Examples of the zoalkoxyphosphinyloxy group include dimethoxyphosphinyloxy, shedoxyphosphinyloxy, and zozolo? xyphosphinyloxy, zoptoxyphosphinyloxy, etc.; Examples of the sialyloxyphosphinyloxy group include diphenoxyphosphinyloxy.

The above alkoxy, alkylthio, arylthio, alkanesulfinyl, arenesulfinyl, alkanesulfonyl-arenesulfonyl, alkanesulfonyloxy, arenesulfonyloxy, dialkoxyphosphinyloxy and sialyloxyphosphinyloxy groups are, for example, fluorine atoms, Halogen atoms such as chlorine atom, bromine atom, iodine atom; Nitro group; Methyl,
Lower alkyl groups such as ethyl, n-zologyl, isozorobyl, n-butyl, inbutyl, aac, -butyl, tart, -butyl; methoxy, ethoxy, n-globoxy, inf71ro? One or more substituent groups selected from lower alkoxy groups such as oxy-butoxy, isobutoxy, see, -butoxy, tert, -butoxy, etc.
i [may be done.

In addition, the protecting groups for the amino group and imino group in the 3-amino-1-pyrrolizonyl group in which the amino group in R2 and B11 may be protected and the l-biperazonyl group in which the imino group may be protected are usually Examples include those used in the field, such as formyl, acetyl, ethoxycarbonyl, pencyloxycarbonyl, N,N-dimethylaminomethylene, and other common amino groups described in JP-A-59-80665. and a protecting group for an imino group.

Examples of the acetals of N,N-zo-substituted alumamides in general formula (1) include commonly known acetals of N,N-disubstituted formamides, such as N,N-
Dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-zomethylformamide zoderopyl acetal, N,N-dimethylformamide diptylacetal, N,N-zomethylformamidezoneopentyl acetal, N, N,N-sialkylformamide sialkyl acetals such as N-dimethylformamide dimethyl acetal, N,N-zozolobylformamide dimethyl acetal, N,N-diptylformamide dimethyl acetal; N,N
-N,N-dialkylformamide dicycloalkyl acetals such as dimethylformamide dicyclohexyl acetal; 2-dimethylamino-1,3-zooxolane, 2-dimethylamino-tetramethyl-1,3-dioxolane, 2-dimethyl N,N-sialkylformamide cyclic acetals such as amine-1,3-zooxane; N-formyl heterocycles such as N-dimethoxymethyl-pyrrolidine, N-dimethoxymethyl-morpholine, N-dimethoxymethyl-piperidine nato; Examples include sialkyl acetals.

Furthermore, general formulas (1), (lI), (B[a) and (r
Examples of the salt of the compound r) include commonly known salts with basic groups such as amino groups or acidic groups such as carboxyl groups and hydroxyl groups. Examples of salts for basic groups include hydrochloric acid, hydrobromic acid,
Salts with mineral acids such as sulfuric acid; Salts with organic carboxylic acids such as oxalic acid, citric acid, and trifluoroacetic acid; Salts of sulfonic acids such as methanesulfonic acid, p) luenesulfone & naphthalenesulfonic acid, and acidic groups. Examples of salts include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as magnesium and calcium; ammonium salts; derocaine, zopenzolamine, N-benzo-β-phenethylamine, ■-F, enamine ,N.

N-zopenzoleethylenezoamine, triethylamine,
Examples include salts with nitrogen-containing organic bases such as biricin, N,N-zomethylaniline, N-methylpipericine, N-methylmorpholine, diethylamine, dicyclohexylamine, and the like. Further, as salts of the compound of general formula (I[b), general formulas (+), (fune, (厘a)) and (r
The same salts as the acidic group explained in the compound r) can be mentioned.

To carry out the present invention, a compound of general formula (I) or a salt thereof is reacted with a compound of general formula (1) in the presence or absence of a solvent.

The solvent is not particularly limited as long as it is inert to the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane; Ethers such as dioxane, tetrahydrofuran, and diethylene glycol dimethyl ether; Esters such as methyl acetate and ethyl acetate; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; Alcohols such as methanol and ethanol Class; N.

Amides such as N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; and glycine, and these may be used alone or in combination of two or more.

The amount of the acetal of the N,N-disubstituted formamide of general formula (i) to be used may be at least equimolar to the compound of general formula (1) or its salt, but it may not be used in excess. It can also serve as a solvent. However, the reaction may proceed smoothly by adding an acid anhydride such as acetic anhydride to the reaction system. In this case, the amount of acid anhydride added is preferably at least equimolar, particularly 1.0 to 5.0 times the molar amount of the compound of general formula (■) or its salt. reaction is usually 0
The process is completed after 5 minutes to 30 hours at a temperature of ~150°C. Moreover, the acetal of N,N-disubstituted formamide of the general formula (summer) can also be prepared in the reaction system.

When doing this, the general formula (
+V) or a salt thereof is produced. Although these can be isolated by conventional methods, they can also be induced to the compound of general formula (I) or a salt thereof by further proceeding with the reaction. When the intermediate compound (m or its salt) is isolated, if it is subjected to a ring-closing reaction in the presence or absence of an acid, the compound of the general formula (m or its salt) is obtained. The solvent used is not particularly limited as long as it is inert to the reaction, but for example, in addition to the same solvents used in the above-mentioned reaction,
Examples include fatty acids such as formic acid and acetic acid; water; and these can be used alone or in combination of two or more. Examples of acids that may be used as desired include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; organic carboxylic acids such as oxalic acid and trifluoroacetic acid; methanesulfonic acid, p
) Sulfonic acids such as luenesulfonic acid and naphthalenesulfonic acid are mentioned, and these are usually used in an amount equal to or more than the same mole relative to the compound of general formula (ff) or its salt.

This reaction is usually carried out at 0 to 150°C for 5 minutes to 30 hours using the general formula (
(2) Calholysis of the compound represented by (2) is carried out.

The compound of the general formula (ship) thus obtained can be induced into the corresponding compound by subjecting it to a known protective group elimination reaction, salt formation reaction, or esterification reaction, as desired. .

The compound of general formula (1) or a salt thereof, which is a starting material for the method of the present invention, is produced, for example, by the method shown in the following reaction formula. In the production route, the compounds represented by the following general formula (V!I), their reactive derivatives at the carboxyl group, and their salts are important intermediates for the compounds represented by the general formula (V!I).

[In the formula, Bl, B2 and X have the same meanings as above. [Reactive derivatives of the sil group include general formulas (■a), (■b), (■C) and (■d) described below.
Examples include the same reactive derivatives at the carboxyl group of the compound represented by.

In addition, as a salt of the compound represented by the general formula (■),
Examples include the same salts as explained for the salts of compounds represented by the general formulas (+), (ship) and (rr).

゛ is the lower margin general formula (Ia), (Ie), (v), (VI), (■a
), (■b), (■C), (■d) and (■e) salts of the general formulas (+), (m), (1!Ia
) and (■), as salts of the compound of general formula (ff) -Cm, general formula (■), (IIl), (Illa) and (+V ) The same salts as the basic group explained in the compound are mentioned. Examples of the salt of the compound of general formula (■) include salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline earth metals such as magnesium; and ethoxymagnesium salts.

Each step will be explained in detail below.

(1) The compound of general formula (■a) or a salt thereof is prepared by combining the compound of general formula (v) or a salt thereof produced according to the method described in British Patent No. 1409987 with pretan.
Société Simique de France (Bull
, Soe, Chlm, Fr.), pp. 1165-1169 (1975).
vI) or a salt thereof.

(2) Compounds of the general formula (, I a ) or (Is) or salts thereof or compounds represented by the general formula (Ib) , (Ie) or (Id) are the compounds of the general formula (■a), (■・), (■b), (■C) or (■d
) or their salts by a method known per se to form reactive derivatives at the carboxyl group, such as acid halognides such as acid chlorides and acid bromides; acid anhydrides; and mixed acids with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester. After converting into anhydride; active ester such as dinitrophenyl ester, cyan methyl ester, succinimide ester, etc.; active acid amide such as imidapool, react with a compound of general formula (■) or a salt thereof, and then decardaxylation. You can get it by doing this. The solvent that can be used in this reaction is not particularly limited as long as it is inert to the reaction, but examples include methanol, ethanol, isofropyl alcohol, and
D Alcohols: Aromatic hydrocarbons such as benzene and toluene; Logated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Diethyl ether,
Examples include ethers such as tetrahydrofuran and dioxane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide. Even if two or more of these solvents are used as a mixture, good. However, the amount of the compound of general formula (■) or its salt to be used is as follows: general formula (■&), (■b), (■C),
The amount is at least equimolar, preferably 1.0 to 2.5 times the mole of the compound (■d) or (■·) or a salt thereof.

This reaction is usually carried out at -50 to 100°C, preferably -20 to 100°C.
What is necessary is just to carry out at 70 degreeC for 5 minutes - 30 hours.

(3) Alkylation Compound of general formula (■b) or its structure or general formula (
The compounds of Ib) have the general formula (■&) or ([a
) or a salt thereof with an alkylating agent in the presence or absence of a deoxidizing agent.

Solvents that can be used in this reaction are not particularly limited as long as they are inert to the reaction, but include, for example, water; alcohols such as methanol, ethanol, and lobil alcohol; 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; Halogenated hydrocarbons such as methylene chloride and chloroform; N, N- Examples include amides such as dimethylformamide and N,N-zomethylacetamide; sulfoxides such as dimethyl sulfoxide, and two or more of these solvents may be used as a mixture.As an alkylating agent, for example, Examples include siaalkanes such as diazomethane and diazoethane; sialkyl sulfates such as dimethyl sulfate and diethyl sulfate; and alkyl halides such as methyl iodide, methyl bromide, and ethyl bromide.

When a sialkyl sulfate or an alkyl halide is used as an alkylating agent, an inorganic base such as an alkali hydroxide or an alkali carbonate, or an amine such as trimethylamine, triethylamine, or bilicin may be used as a deoxidizing agent. The amount of the sialkyl sulfate or alkyl halide used as the alkylating agent and the deoxidizing agent used if desired is equal to or more than the equivalent molar amount, preferably, based on the compound of general formula (■a) or (Ia) or a salt thereof. 1
．． It is 0 to 2.0 times the mole. In this case, the reaction is usually 0~
What is necessary is just to carry out at 50 degreeC for 5 minutes - 30 hours.

In addition, when a cyasialkane is used as an alkylating agent, the amount used is equal to or more than the equivalent mole, preferably 1.0 to 1.5 times the mole of the compound of general formula (■a) or (Im) or a salt thereof. It is. In this case, the reaction is usually 0
~50''C1 Preferably, it may be carried out at 0 to 25°C for 5 minutes to 30 hours.

(4) The compound of general formula (■C) or a salt thereof can be obtained by halogenating or sulfonylating the compound of general formula (■a) or a salt thereof. Further, the compound of general formula (Tc') can be obtained by sulfonylating the compound of general formula (1) or a salt thereof.

(1) Halogenation Among the compounds of the general formula (■C) or salts thereof, the compounds or salts thereof in which R8 is a halogen atom are those of the general formula (■a)
It can be obtained by reacting a compound or a salt thereof with a halogenating agent. When carrying out this reaction in a solvent, the solvent is not particularly limited as long as it is inert to the reaction, but specifically, aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform, Halogenated hydrocarbons such as dichloroethane: N,
Examples include amides such as N-zomethylformamide and N,N-zomethylacetamide.
A mixture of 11 or more may be used.

Examples of the halogenating agent include phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride,
Examples include thionyl chloride and phosgene, and two or more of these agents may be used as a mixture, and these halogenating agents may be used as a solvent.

The amount of the halogenating agent used is at least equimolar to the compound of general formula (■a) or its salt.

This reaction is usually carried out at 0 to 150°C, preferably 50 to 110°C.
Then, it may be carried out for 30 minutes to 30 hours.

(i) Sulfonylation Among the compounds of general formula (■C) or salts thereof, FL8 is an alkanesulfonyloxy or arenesulfonyloxy group which may have a transfer group, or a salt thereof or general formula (Ic The compound represented by ') can be obtained by reacting a compound of general formula (■a) or (Im) or a salt thereof with a sulfonylating agent in the presence or absence of an acid absorbing agent.

The solvent that can be used in this reaction is not particularly limited as long as it is inert to the reaction, but 7'c,! :,ttf
, water; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as dioxane, tetotehydrofuran, anisole, diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane; acetone, methyl ethyl ketone, etc. Ketones; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; hexamethylphosphoramide; pyricine; - It is also possible to use a mixture of two or more types. Examples of sulfonyl north shore J include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride/*li)', 1-methylethanesulfonyl chloride, 111-
Zomethylethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, nitrobenzenesulfonyl chloride, chlorobenzenesulfonyl chloride! J) %2#5-zochlorobenzenesulfonyl chloride, 2.3.4-tricfflobenzenesulfonyl chloride)'%2,4.5-) IJ chlorobenzenesulfonyl chloride, 2.4.6-1L% thylbenzenesulfonyl Chloride, 2.4.6-) lynnolobyl benzenesulfonyl chloride, naphthalenesulfonyl chloride, alkanesulfonyloxydi)'-! ii arenesulfonyl halognite; methanesulfonic anhydride;
Examples include alkanesulfonic anhydrides or arenesulfonic anhydrides such as toluenesulfonic anhydride. In addition, as a deoxidizing agent, for example, triethylamine, diisonorobyl ethylamine, 1,8-diazabicyclo-
Examples include organic or inorganic bases such as (5,4,0)-undec-7-ene (DBυ), pyricine, potassium t·rt-butoxide, alkali hydroxide, and alkali carbonate.

The amount of the sulfonylating agent and the optional deoxidizing agent to be used is at least the same molar amount, preferably 1.0 to 2.0 times, relative to the compound of general formula (■a) or (Im) or a salt thereof. It is a mole. This reaction is usually ゛0-1
What is necessary is just to carry out at 50 degreeC, preferably 0-50 degreeC for 5 minutes to 30 hours.

(5) Thiolation Compound of general formula (■d) or its salt or general formula (
The compound of td) is a compound of the general formula (■C) or its salt or a compound of the general formula (Ic) in the presence or absence of a deoxidizing agent, for example, methanethiol, ethanethiol, n-7' Thiols or their salts such as 9-thiol, 1-methylethanethiol, isobutanethiol, l,1-dimethylethanethiol, pentanethiol, hexanethiol, hexanethiol, octanethiol, dodecanethiol, thiophenol, and naphthalenethiol. It can be obtained by reaction. Examples of the salts of thiols include general formulas (■), (I), (II),
Examples include salts at acidic groups as explained in the compounds of ). Solvents that can be used in this reaction are not particularly limited as long as they are inert to the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and pheasant; ethers such as dioxane, tetrahydrofuran, anisole, and diethylene glycol diethyl ether. ; Halodanized hydrocarbons such as methylene chloride, chloroform, and dichloroethannatate; Amides such as N,N-zomethylformamide and N,N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; You may use a mixture of two or more. Examples of the deoxidizing agent include inorganic bases such as alkali hydroxide and alkali carbonate, and organic bases such as trimethylamine, triethylamine, tributylamine, pyricine, N-methylpipericine, N-methylmorpholine, lutidine, and colicin. The amount of thiols or their salts and the deoxidizing agent used if desired is determined according to the general formula (■C
) or a salt thereof or the compound of general formula (re), respectively at least 1.0 to 2 mol, preferably 1.0 to 2.
．． It is 0 times the mole. This reaction may be carried out normally at 0 to 150°C, preferably 0 to 70°C, for 5 minutes to 30 hours.

(6) The compound of general formula (■e) or (1@) or a salt thereof is added to the compound of general formula (■C) or a salt thereof or the compound of general formula (Ic) in the presence of a deoxidizing agent or It can be obtained by reacting an amine of the general formula (l) or a salt thereof in the absence of

When carrying out this reaction in a solvent, the solvent is not particularly limited as long as it is inert to the reaction, but specifically aromatic hydrocarbons such as benzene, toluene, and xylene;
Methanol, ethanol, n-gulono Qnol, isopropyl alcohol, n-butanol, imbutanol,
t@rt, -butyl alcohol natonoalcohols; ethers such as dioxane, tetrahydrofuran, anisole, and soethylene glycol zoethyl , esters such as ethyl acetate; nitriles such as acetonitrile; methylene chloride, chloroform, sochloroethane natonohalogonated hydrocarbons; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; dimethylsulfoxide, etc. sulfoxides, etc., and two or more of these solvents may be used as a mixture. Further, specific examples of the deoxidizing agent include the same inorganic or organic bases as mentioned in the above-mentioned section of sulfonylation.

When no deoxidizing agent is used, the amount of the amine of general formula ([) or its salt to be used is preferably 2 to 20% of the compound of general formula (■C) or its salt or the compound of general formula (re). Although the amount is .0 to 5.0 times by mole, the amount of the amine of general formula (W) or its salt used can be reduced by appropriately using a deoxidizing agent. This reaction is usually 0 to 150
What is necessary is just to carry out at 0-100 degreeC, preferably for 5 minutes to 30 hours.

(7) Phosphorylation and acidification The compound of the general formula (If) or (Ig) is a compound of the general formula (I
It can be obtained by reacting the compound m) or a salt thereof with a phosphorylating agent or an acidifying agent, respectively, in the presence or absence of a deoxidizing agent. Solvents that can be used in these reactions are not particularly limited as long as they are inert to the reactions, but specific examples include the same solvents as those used in the above-mentioned sulfonylation. Examples of the phosphorylating agent include sialkylphosphate nolognides such as dimethylphosphate dichloride, diethylphosphate dichloride, zoglopyruphosphate chloride, and sibutylphosphate chloride, or sialylphosphate halognides such as diphenylphosphate dichloride. Further, examples of the acidifying agent include sialkyl phosphoric acid such as diethyl phosphoric azide or sialyl phosphoric acid such as diphenyl phosphoric azide.

Further, in these reactions, specific examples of deoxidizing agents that can be used include those similar to the deoxidizing agents used in the above-mentioned sulfonylation.

The amount of the phosphorylating agent and optionally used deoxidizing agent used in the phosphorylation is equal to or more than the equivalent mole, preferably 1.0 to 1.0, respectively, based on the compound of general formula (Ia) or its salt.
It is 1.5 times the mole. This reaction (phosphorylation) is usually 0~
What is necessary is just to carry out at 150 degreeC, preferably 0-50 degreeC for 5 minutes to 30 hours.

In addition, the amount of the acidifying agent and the deoxidizing agent used if desired in the acidification is equal to or more, preferably 1 mole or more, respectively, based on the compound of general formula (Ta) or its salt.
．． It is 0 to 3.0 times the mole. This reaction (acidation) is usually carried out at 0 to 150°C, preferably 15 to 100°C, for 5 minutes to
It is sufficient to carry out the test for 30 hours.

(8) Oxidation The compound of general formula (Ih) can be obtained by reacting the compound of general formula (Ia) with an oxidizing agent. Solvents that can be used in this reaction are not particularly limited as long as they are inert to the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane. ethers such as diethyl ether, tetrahydrofuran, and dioxane; fatty acids such as formic acid and acetic acid; and water; two or more of these solvents may be used in combination. Examples of oxidizing agents include performic acid,
Examples include organic peracids such as peracetic acid, perbenzoic acid, and a+-chloroperbenzoic acid, hydrogen peroxide, periodic acid, sodium metaperiodate, potassium metaperiodate, potassium permanganate, and ozone. Among the compounds of general formula (Ih), B11 may have a substituent or alkali/
Preferred oxidizing agents for obtaining a compound (sulfoxide) having a sulfinylmatahaarenesulfinyl group include organic peracids, sodium metaperiodate, potassium metaperiodate, etc., and the amount used is as follows: The amount is 1.0 to 1.2 times the mole of the compound of general formula (Id). Further, among the compounds of general formula (Ih), preferred oxidizing agents for obtaining a compound (sulfone) in which 几11 is an alkanesulfonyl or arenesulfonyl group which may have a substituent include organic peracids, Examples include hydrogen peroxide, and the amount used is 2.0 to 2.5 times the mole of the compound of general formula (Ia). Furthermore, the general formula (
Among the compounds of lh), compounds that are sulfoxides are:
If necessary, it can be further oxidized to form a sulfone compound. These reactions are usually carried out at temperatures between 0 and 100°C.
, preferably at 0 to 30°C for 5 minutes to 30 hours.

The general formulas (■a), (■b), (■C), (
When the compounds of ■d), (■e) and (Is) or their salts have a protecting group, if desired, the protecting group can be removed by a known method to form the corresponding free compound. can be induced. Furthermore, when the compounds of these general formulas (■a), (■b), (■C), (■d), (mu) and (■・) are free compounds, they may be stirred as desired, The salts or esters of the corresponding compounds can be derived by subjecting them to salt-forming reactions or esterification reactions that are known per se.

Furthermore, general formulas (■a), (■b), (■C], (
When the compounds of ■d), (■・) and (■@) have a protecting group, they can be induced into salts of the respective compounds by subjecting them to a known salt-forming reaction, if desired. .

The compounds obtained by 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.

Among the compounds of general formula (I) thus obtained,
Compound where a2 is R2b [compound of general formula (mb)]
or its salt, for example, a compound in which R is empty 21 [compound of general formula (■&)] according to the route shown below.
or its salts.

(Wb) or its salt (1
&)-Matakeso salt In the above-mentioned step, when R2b is a hydroxyl group or an alkoxy group which may have a substituent, for example, when B2b is an alkanesulfonyloxy group which may have a substituent, After converting into a compound having a lane sulfonyloxy group or a halogen atom, the compound of general formula (Im) or a salt thereof can be derived by reacting the compound of general formula (I[) or a salt thereof. In addition, when R2b is an alkylthio or arylthio group that may have a substituent,
For example, a compound of the general formula CI or a salt thereof is reacted or subjected to an oxidation reaction to derive a corresponding sulfoxide or sulfone compound, and then the compound of the general formula (
By reacting the compound of 2) or its salt,
A compound of general formula (llla) or a salt thereof can be derived.

In the step of obtaining the compound of general formula (top &) or its salt from the above-mentioned compound of general formula (ffib) or its salt, Bzb is a bulky arenesulfonyloxy group, especially a carbon atom of an aryl group to which an oxysulfonyl group is bonded. It is preferable that at least one carbon atom adjacent to is an arenesulfonyloxy group substituted with the above-mentioned substituent.

Further, the raw material compound of general formula (I) is, for example, Chew, B@r, 101.

It can be produced according to the method described on pages 41 to 50 (1968).

Below margin 〔Example〕 Next, an example will be given and explained.

Example 1 2-[2-(2,4-difluorophenylamino 1-5
-Fluoro-6-hydroxynicotinoyl]acetic acid ethyl ester 200rn9t) Luene 4r! After suspending the suspension in Lt and adding 200~ of N,N-dimethylformamide dineopentyl acetal and reacting at room temperature for 4 hours, the precipitated crystals were collected. After adding ethanol 5- and water 5-ILt to the obtained crystals and adjusting the pH to 1.0 with 2N-hydrochloric acid, the precipitated crystals had a melting point of 244-248.
1- (2゜4-difluorophenyl 1-6-
Fluoro-1°4-dihydro-7-hydroxy-4-okyne-1°8-cathyridine-3-carboxylic acid ethyl ester 155~ (yield 75.4%) was obtained. If this is recrystallized with a mixed solvent of acetone-methanol (volume ratio 1:1), crystals having a melting point of 250 to 252°C are obtained.

IR(KBr)Crn-': Wcwo1720NM
R(TFA-d,) δ value.

1.51 (3H,t, J==7Hzl, 4.70
(2H, q, J-7Hzl.

7.00-8.10 (3H, m), 8.30 (I
H, d, J-8Hz l.

9.11 (IH,!11 Similarly, the following compound is obtained.

o6-Fluoro-1-(4-fluorophenyl)-11
4-dihydro-7-hydroxy-4-oxo-1,8-
7 tyridine-3-carboxylic acid ethyl ester yield; 7λ8 melting point; 252-253°C (reconsolidation solvent; acetone:methanol = 1:1 (volume ratio)) IR(KBr)Crn-'; νc=0 1730 (
51h), 170ONMR (TFA-d, lδ value; 1.50 (3H,t, J-7Hz l, 4.64
(2H, (1, J-7Hz +.

7.15-7.84 (4H, ml, 8.20 (
LH, d, J -9Hz).

9.02 (IH,s) Example 2 2-[:6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-
Fluoronicotinoyl]acetic acid ethyl ester 200mg
Suspend it in benzene 2p and N.

N-dimethylformamide dimethyl acetal 1011
After adding g, the mixture is reacted under heating and reflux for 7 hours. Then, the precipitated crystal tl-F is collected and washed with 2 ml of diethyl ether to obtain 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-, which has a melting point of 233 to 236°C. 180 η of 6-fluoro-1,4-dihydro-4-oxo-1°8-naphthyridine-3-carboxylic acid ethyl ester (yield 8&1%) is obtained. If this is recrystallized with a mixed solvent of acetone and methanol (volume ratio 1:1), crystals having a melting point of 234 to 236°C are obtained.

NMR (CDCl, lδ value; 1.33 (3H, t, J-7Hz).

8.10 (LH, d, J-8Hz l, 8.31
(IH,s The following compound is obtained in the same manner as 1.

07-(4-acetyl-1-piperazinyl)-1-(2
,4-difluorophenyl)-6-fluoro-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester yield, 84.2% Melting point: 219-220°C (reconsolidation solvent: acetone) Example 3 +l) 2-(2-(2 , 4-difluorophenylamine)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester 300 IQ was dissolved in methylene chloride 6d,
N,N-dimethylformamide dimethyl acetal 13
After adding 5 ■ and 115 da of acetic anhydride, 30
Let it react for a minute. Then, 0.31% of 2N-hydrochloric acid was added to the reaction solution.
After adding Ill and 3 ml of ethanol and reacting at room temperature for 1 hour, 6N methylene chloride and 6N water are added, and the organic layer is separated, washed with 6 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diimpropyl ether 2-
When the crystals are added, the melting point is 170 to 173'C.
, 6-toIJmethylbenzenesulfonyluogish)-1,
8-naphthyridine-3-carboxylic acid ethyl ester 26
0~(yield 85.1%) was obtained. If this is recrystallized from chloroform, crystals having a melting point of 174 to 177°C are obtained.

IR (KBr) Rust-';'(-g 1740.1
700 (sh)N kite (CDC1,) δ value; 1.35 (3H,t, J-7Hz l,';L3
5 (3H, s l, 2..46 (614°s)
, '4.34 (2H,q, J-7Hz l, 6
．． 62-7.57 (sH, m).

8.41 (IH,s), 8.47 (IH,d,
J-8Hz) Compounds shown in Table 2 are obtained in the same manner.

(2) In place of N,N-dimethylformamide dimethyl acetal in (above), the nine N,N listed in Table 3 below can be used.
The reaction is carried out in the same manner as in (1) using the acetal of -disubstituted formamide to obtain the results shown in Table 3.

Table 3 Example 4 (1) Add 540 m9 of (N,N-dimethylformamide-dimethyl sulfate) complex compound to 4rnl of toluene,
After adding 85 μ of sodium methoxide at 0 to 1
React at 0°C for 1 hour. Then, 2-[2-(2,4
After adding 200 μl of ethyl acetate (difluorophenylamino)-5-fluoro-6-medoxynicotinoyl, the mixture was allowed to react under heating under reflux for 1.5 hours. The reaction solution is added to a mixture of 8-8-ethyl acetate and 8--water, and the organic layer is separated, washed with 5 d of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and 1 rnl of diethyl ether is added to the obtained crystalline substance to obtain crystals, which yields 1-(2,4-difluorophenyl 1-
6-Fluoro-1-94-dihydro-7-medoxy 4
-Oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 170rn9 (IfS18 Z8%) is obtained. The physical properties of this compound were consistent with those obtained in Example 3 (1).

(2) In place of the (N,N-dimethylformamide dimethyl sulfate) complex in (1) above, the (N-formylpyrrolidine-dimethyl sulfate) complex was used and the reaction was carried out in the same manner as in (1). -4 result is obtained.

Table 4 FF Example 5 Add 335 ml of (N,N-dimethylformamide-dimethyl sulfate) complex compound to 6 ml of methylene chloride, and heat at 0°C.
After adding 65mg1 of sodium methoxide, 0 to 1
React at 0°C for 1 hour. Then, 2-[2-(2,4
-difluorophenylamino)-5-fluoro-6-(
300 ~ 2,4,6-)limethylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester and 115 μm of acetic anhydride were added, and after reacting at room temperature for 2 hours, 2N
- Add 0.31 Fnl of hydrochloric acid and 3rnl of ethanol, and react for 1.5 hours at room temperature. The reaction solution is added to a mixed solution of 5 rnl of methylene chloride and 5 rul of water, and the organic layer is separated, washed with 6N saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 21 t of diisopropyl ether was added to the obtained crystalline substance to obtain crystals.1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4- Oxo-7
-(2,4,6-)limethylbenzenesulfonyloxy l-1,8-katchirisin-3-carboxylic acid ethyl ester 245! ng (yield 80.2%).

The physical properties of this compound were consistent with those obtained in Example 3 (1).

Example 6 2-(:6-(3-amino-1-pyrrolidinyl)-2-
(2,4-difluorophenylamino)-5-fluoronicotinoyl] ethyl acetate (200~) was suspended in 4rnl of toluene, N,N-dimethylformamide dimethyl acetal (1701119) was added, and the mixture was reacted under heating under reflux for 7 hours. let

Then, the solvent was distilled off under reduced pressure, and diethyl ether 1- was added to the resulting residue to form crystals, which had a melting point of 13.
1-(2,4-difluorophenyll-7-(3-(N,N-dimethylaminomethyleneimino)-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4- exhibiting a temperature of 6 to 138°C 195 μm of oxo-1,8-su7tyridine-3-carboxylic acid ethyl ester (yield: 84.5%) was obtained.

If this is recrystallized with ethanol, the melting point is 137-139.
Obtain crystals showing ℃.

IR(KBrlcrrl-';'c = 0 173
0.169ONMR (CDCl, lδ value; 1.38 (3H,t, J-7Hz l, 1.6
5-2. ．． 15 (2H, ml, '2..85 (6
H,! 1.3.10~3.95 (5H, m),
4.34 (2H, q, J-7Hz), 6.75
~7.70 (4H, m), 7.92 (LH, d
, J-13Hzl.

8.30 (IH,s) Example 7 Add (N,N-dimethylformamide-dimethyl sulfate) complex compound 2451n9 to toluene 4-, add 66μ of sodium methoxide under water cooling, and react for 30 minutes at room temperature. let Then, 200 μl of 2-[:6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester was added, and the mixture was heated under reflux for 50 μl. Allow time to react. Reaction solution: 20 d of dichloroform and 20 r of water
The organic layer was separated, washed with 20 d of saturated brine, and 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: chloroform:ethanol = 50:1 (if purified with a volume ratio of 1'1, the melting point was 184-186 2-(:6-(3
-acetylamino-1-pyrrolidinyl)-2-(2,4
-difluorophenylamino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylic acid ethyl ester 190 da (yield: 84.9 da) was obtained.

IR (KBrl side-': l/(-01680,16
35 (sh) NMR (CDCI,) δ value 8 191 (6H, sl, 3.25-4.70 (7
H, m), 6.45-7.10+2H, ml, 7°38 (1) L d, J-14Hz), 7.53
(IH,s).

8.10-8.65 (IH, ml, 11.62
(IH,bB) Example 8 2-(6-(3-acetylamino-1-virolisi=k)
-2-(2,4-difluorophenylamino-5-fluoronicotinoyl)-3-(N.

N-dimethylamino)acrylic acid ethyl ester 200
Suspend m9 in 4 doors of ethanol and add 0.4 IN-hydrochloric acid.
After adding m1i, react for 5 minutes at room temperature.

Next, 10 d of chloroform and 10 d of water were added to the reaction solution, the organic layer was separated, and 10 d of water and 10 d of saturated saline were added.
After sequentially washing with d and then drying with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and 4N diethyl ether is added to the resulting crystalline material to obtain a crystalline product, 7-(3
-acetylamino-1-pyrrolidinyl)-1-(2,4
-difluorophenyl)-6-fluoro-1+ 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 180rn9 (yield 98.6%
Get +.

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

Example 9 7-(3-acetylamino-1-pyrrolidinyl)-1-
(2,4-difluorophenyl)-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyrisin-3
-carboxylic acid ethyl ester 500η 6N-hydrochloric acid 5M
and react under heating and reflux for 4 hours. Then,
Count the precipitated crystals and use 1rn water! If washed with
7-(3-amino-1-
pyrrolidinyl)-1-(2,4-difluorophenyl)
-6-fluoro-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic acid hydrochloride 390 mI
? (yield: 84.0 h). If this is recrystallized with a mixed solvent of concentrated hydrochloric acid and ethanol (volume ratio 1:3), the melting point is 24.
Crystals exhibiting a temperature of 7-250°C (decomposition) are obtained.

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

6.95-7.90 (3H, m), 8.22 (
LH, d, J-11Hz).

9.18 (IH,s) Similarly, the following compound is obtained.

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°C (decomposition) (reconsolidation solvent; concentrated hydrochloric acid: methanol = 1:2 (volume ratio)) N kite (TFA
-d, ) δ value 8 3.33 to 3.92 (4H, m), 3.92 to 4
．． 50 (4H, m), 6.90~7.90 (
3H, ml, 8.30 (IH, d, J-12Hz
J, 9.18(IH,3) Example 10 1-(2,4-difluorophenyl)-7-C3-(N
, N-dimethylaminomethyleneimino)-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 100 ■ suspended in 1 ml of 16N-hydrochloric acid The mixture was allowed to react under heating and reflux for 2 hours. Then, the solvent is distilled off under reduced pressure, and 1 ml of ethanol is added to the obtained crystalline substance to collect crystals ftP, which yields 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl). )-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride 85~ (yield 94.0
h).

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

Example 11 2-(6-(3-acetylamino-1-pyrrolidinyl)
-2-(2,4-difluorophenylami/1-5-
Fluoronic f/yl)-3-(N.

N-dimethylamino)acrylic acid ethyl ester 200
Suspend rn9 in 4M ethanol and add 4ml of 6N-hydrochloric acid.
After adding, the mixture is reacted for 3.5 hours under heating and reflux. Then, the solvent is distilled off under reduced pressure, and 2N ethanol is added to the obtained crystalline substance to form crystals. -6-fluoro-1,4-dihydro-4-okine-1,8-su7tyridine-3-carboxylic acid hydrochloride 1
45 cm (yield: 85.4 cm) was obtained.

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

Reference Example 1 23.0 P of 2-(N-(2,4-difluorophenyl)-amidino)acetic acid methyl ester hydrochloride was added to 92 m of water.
1 and methylene chloride 92d, 2N
-Adjust the pH to 13.0 with aqueous sodium hydroxide solution.

Separate the organic layer and add 50M water and 50vL of saturated saline.
After successively washing with water, drying with anhydrous magnesium sulfate. To this solution was added 27.154 sodium salt of ethyl hydroxymethylene fluoroacetate at room temperature, and the mixture was reacted under heating under reflux for 4 hours, and then the solvent was distilled off under reduced pressure. 92 M of water and 46 m of ethyl acetate were added to the resulting residue.
1 of water to separate the precipitated crystals and suspend them in 184 ml of water. After adjusting the pH to 1.0 with 6N-hydrochloric acid, the precipitated crystals were separated and mixed with 46 d of water and 4 d of isopropyl alcohol.
2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid methyl ester exhibiting a melting point of 222-223°C when washed with 6ml of 15.
05' (yield 57.9%) is obtained. If this is recrystallized from ethyl acetate, crystals having a melting point of 222-223°C are obtained.

IR(KBr)crIM-'; v, 2-0 170
ONMR (TFA-d, ) δ value; 4.06 (3H, sl, 6.71-7.65 (
3H, ml, 8.12 (IH, d.

J-11Hz) In the same way, a compound with 2 is obtained.

02-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid ethyl ester Melting point: 177-178°C (reconsolidation solvent: ethyl acetate) IR(KBr)crn''''c -017QQNMR
(TFA-d, ) δ value 1 1.52 (3H, t, J-7Hz), 4.50
(2H, q, J -7Hz l.

6.80-7.65 (3H, ml, 8.15 (I
H, d, J -11Hz)05-Fluoro-2-(
4-fluorophenylamino)-6-hydroxynicotinic acid methyl ester Melting point: 227-228°C (reconsolidation solvent: ethyl acetate) IR (KBr) cm-';'exo 169ON
MR (TFA-d, )δ value; 4.05 (3I(,a), 6.89-7.53 (
4H, m), 8.11 (LH.

d, J-11Hz) Reference Example 2 2-(2,4-difluorophenylamino r-5-fluoro-6-hydroxynicotinic acid methyl ester 3.0
01i” & suspended in 30ml of methanol and diluted with 2N at room temperature.
- After adding taiml of sodium hydroxide aqueous solution, react under heating and reflux for 4 hours. Then, the reaction solution was added to a mixed solution of 60 ml of ethyl acetate and 60 ml of water, and the aqueous layer was separated. After adjusting the aqueous layer to pH 1.0 with 6N-hydrochloric acid,
If the precipitated crystals are separated and washed sequentially with 15 M water and 15 ml of isopropyl alcohol, 2-(2,4-difluorophenylamino)-5-, which has a melting point of 213-216°C, is obtained.
Fluoro-6-hydroxynicotinic acid Z687 (yield 93.7%) is obtained. If this is recrystallized with acetone-ethanol (volume ratio 1:1) mixed solvent, the melting point is 215-2.
Crystals exhibiting a temperature of 16°C are obtained.

IR(KBrlcnt-';'c, 0170ONM
R(DMSO-d,) δ value.

6.65-7.58 (2H, m), 7.86 (L
H, d, J-11Hz), 8.12~8.68 (
IH, ml, 10.49 (The following compound is obtained in the same manner as IH, bsl.

O5-fluoro-2-(4-fluorophenylamino)
-6-Hydroxynicotinic acid melting point; 216-217°C (reconsolidation solvent; acetone:methanol = 1:1 (volume ratio)) IR (KBr) crri-': v 1685 (
ah)4O NMR (DMSO-d,) δ value: 6.84-7.94 (5H, ml, 10.33 (
IH, bs) Reference Example 3 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid methyl ester 200
Dissolve In9 in N,N-dimethylformamide 5 rILt, add 110 ml of potassium carbonate and 1 g of methyl iodide at room temperature, and react at the same temperature for 1 hour. Add 20 ml of water and 20 ml of ethyl acetate to the reaction solution. was added, the organic # was separated, and mixed with 10 ml of water and saturated saline
After sequentially washing with rnl, it is dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 5d of isopropyl alcohol was added to the obtained crystalline substance to form crystals. -6-Medoxynicotinic acid methyl ester 190 (yield 'lf-90,7
%). If this is recrystallized from ethyl acetate, the melting point is 1.
Crystals exhibiting a temperature of 60.5-161.5°C are obtained.

IR(KBr)cln-': V(2-0169ON
MR<CDC1,) δ value; 3.89 (3H,s l, 3.98 (3H,s
), 6.57-7.08 (2H, ml.

7.81 (iH, ci, J=11Hz), 8.1
0-8.97 (IH, ml.

10.24 (IH, bs) Reference Example 4 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid methyl ester 9.5
? , phosphorus pentachloride 26.59- and phosphorus oxychloride 46-
．． 99- is reacted at 70-80°C for 4 hours.

Then, the reaction solution was gradually added to 285 ml of water to remove all the precipitated crystals, and then washed with 57 ml of water. The obtained crystals were subjected to column chromatography [Wako Silica Gel C-20
0, elution solvent: toluene], the melting point is 137~
1396C f6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid methyl ester 3.5? (yield 34.7%). If this is recrystallized from diisopropyl ether, the melting point is 139.
5-140.5°C to obtain crystals showing gold.

IR(KBrlrW1″″Inijic,,,Q 1695
NMR (CDCI,) δ value; 3.93 (3H,s), 6.61-7.06 (
2H, ml, 7.94 (IH, d.

J-9Hz), 8.15-8.57 (IH, m
l, 10.13 (IH, bs 1 Reference Example 5 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid methyl ester 500
Suspend (2) in 10rfLl of methylene chloride,
- After adding 440 μg of trimethylbenzenesulfonyl chloride and 220 rng of triethylamine,
Allow time to react. 15 m/ml of water is added to the reaction solution, and the organic layer is separated, washed with 15 m/ml of water, and then dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, and 15 ml of diethyl ether is added to the resulting crystalline substance to collect the crystals, resulting in 2-(2,4-difluorophenylamino)-5 having a melting point of 153-155°C. -Fluoro-6-(2,4,67 trimethylbenzenesulfonyloxy)nicotinic acid methyl ester 660 μm (yield 81.9%) is obtained. If this is recrystallized from ethyl acetate, crystals having a melting point of 155-156°C are obtained.

IR(KBr)crll-'Bνc,,0 170ON
MR (CDCl,) δ value; λ33 (3H, s), 2.59 (6H, s),
3.92 (3H, sl, 6.32-6.84
(2H, ml, 6.92 (2H, sl, 7.35~
7.94 (IH, ml.

B, 05 (IH, d, J-9Hz), 10.1
7 (IH,b8) The following compound is obtained in the same manner.

02- (2,4-difluorophenyl 7mi/)-5-
Fluoro-6-(2,4,6-)lyisopropylbenzenesulfonyloxy)nicotinic acid ethyl ester Melting point: 147-148°C (reconsolidation solvent: ethyl acetate) IR(KBr)crrl-”; 17QONMR(C
DCl, ) δ value; 1.21 (12H, d, J-7Hz), 1.2
8 (6) I, d, J-7Hz +.

1.40 (3H,t, J-7Hz l, 2.5
5-3.30 (IH, ml.

Reference Example 6 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinic acid methyl ester 3.899-
, dissolved in N-dimethylformamide 39-, thiophenol 1.34 P and triethylamine 1.2
After adding 31i', the reaction is allowed to proceed at room temperature for 5 hours. Then, 120 ml of ethyl acetate and 120 d of water were added to the reaction solution, and the pH was adjusted to 2.0 with 2N hydrochloric acid. The organic layer is separated, sequentially washed with 80 d of water and 3 Qrnl of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and n-hexane 2 was added to the resulting crystalline material.
If you add 0ml and calculate the number of crystals, the melting point will be 126-128
℃e indicated f2- I 2.4-difluorophenylamine/
)-5-Fluoro-6-phenylthionicotinic acid methyl ester λ85? (yield 90.2%). If this is recrystallized from diisopropyl ether, the melting point is 128.
Crystals are obtained showing a temperature of ~128.5°C.

IR(KBr)crn-'; W. -81685 listens (
CDC1,) δ value.

10.25 (IH, bs) Similarly, the following compound is obtained.

02-(2,4-difluorophenylamino)-6-ethylthio-5-fluoronicotinic acid methyl ester melting point; 113.5-114°C (reconsolidation solvent; diisopropyl ether) IR(KBr)m-'; νcaxQ 168O
NMR (CDCI, ) δ value; 1.29 (3H, t, J-7Hz), 3.07
(2H, q, J -7Hz l.

3.90 (3H,s), 6.50-7.20 (
2H, ml, 7.66 (LH, d.

J-10Hz l, 7.80~8.50 (IH, m
), 10.00 (IH, bs) Reference Example 7 2-(2,4-difluorophenylamino)-5-7 fluoro-6-methoxynicotinic acid methyl ester 2.00
f was dissolved in tetrahydro-72-60d and IN at room temperature.
- Hydroxide) After adding 25.5 - of IJium aqueous solution,
The reaction is allowed to proceed under heating under reflux for 7 hours. Then, the solvent is distilled off under reduced pressure, and 100 ml of ethyl acetate and 100 ml of water are added to the resulting residue, and the pH is adjusted to 2.0 with 2N hydrochloric acid. The organic layer is separated, sequentially washed with 50 m of water and 50 m of saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, and 10 rnl of diethyl ether is added to the obtained crystalline substance to form a crystal, the melting point is 2.
1.40 f of 2-(2,4-difluorophenylamine)-5-fluoro I:1-6-medoxynicotinic acid (yield 73.3%) exhibiting a temperature of 37 to 240°C is obtained. If this is recrystallized with acetone, crystals having a melting point of 239 to 240°C are obtained.

IR(KBr)crn-1; ν. =81665NMR(
DMSO-d, ) δ value; 3.98 (3H, s), 6.76 = 7.48 (2H, t
n), 7.86 (IH, d, J=11Hz), 8.
10-8.60 (IH, m).

10.51 (IH, bs) Similarly, the following compound is obtained.

06-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid Melting point: 226-228°C
(Recrystallization solvent; benzene) IR (KBr), -1; ν. -o168ONMR (acetone-do) δ value; 6.60-7.41 (2H, m).

10.30 (IH, bs), 1.0.64 (IH, bs
)0 2-(2,4-difluorophenylamine)-5
-Fluoro-6-(2,4,6-)rimetherbenzenesulfonyloxy)-nicotinic acid Melting point: 179-180
°C (recrystallization solvent; benzene) IR (KBr), 7";l', .1665NM
R (acetone-d6) δ value; 2.32 (31 (,S), 2.55 (6H,S).

bs) 0 2-(2,4-difluorophenylamine)-5-
Fluoro-6-(2,4,6-triimprobylbenzenesulfonyloxy)nicotinic acid Melting point: 163.5-164.5°C (reconsolidation taste: benzene) I Ft (KB r ), -1; -o1675
NMR (CDC13 DMSQ-d6) δ value; 1.22 (12H, d, J = 7H2), 1.30 (6H
,d.

J=7Hz), 2.55=3.30(IH, m), 3.
70=4.40 (2H, m)! bS) , 10.57 (I Ht b s ) 0 2
-(2,4-difluorophenylamino)-6-ethylthio-5-fluoronicotinic acid Melting point: 209-210°C
(Recrystallization solvent; benzene) IR(KBr) −' Niji. ,, o1665fi NMR (acetone-d,) δ value: 1.30 (3H,t, J=7Hz), 3.14
(2H, q.

J=7H2), 6.70-7.50 (2H, m)tbs
), 10.27(IH, bs) 0 2-(2,4-difluorophenylamino)-5-
Fluoro-6-phenylthionicotinic acid melting point; 264~
265°C (reconsolidation solvent; ethyl acetate: ethanol = 1 = 1
(Capacity ratio)) IR(KBr)c, -t; ν. -016
6ONMR (DMSO-d, ) δ value; 6.00-7.73 (8H, m), 7.85 (IH, d
, J=10 Hz) s 10.58 (I H,b
S) Reference Example 8 120 μm of 3-aminopyrrolidine dihydrochloride was added to N.

The suspension was suspended in 30 N-dimethylformamide, 250 μm of triethylamine was added, and the mixture was allowed to react at room temperature for 5 minutes.

Then, 2-(2,4-difluorophenylamino)-
5-fluoro-6-(2,4゜6-)'Jmethylbenzenesulfonyloxy)nicotinic acid methyl ester 30
Add 0.0 cm and react at room temperature for 1.5 hours. Chloroform (10) and water (10) are added to the reaction solution, and the organic layer is separated, washed successively with 10 (10) of water and 10 ml of saturated brine, and then dried over anhydrous magnesium sulfate. Then, 100 μl of 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. If you add diethyl ether 5 to the obtained crystalline substance to form a crystal, the melting point will be 197 ~
6-(3-acetylamino-1-pyrrolidinyl)-2-(2°4-difluorophenylamino) showing 201°C
-5-fluoronicotinic acid methyl ester 210 μm (yield: 82.4 μm) was obtained. If this is recrystallized from ethyl acetate, crystals having a melting point of 202 to 203°C are obtained.

I R(KB r ), -1: sic=o1675D
C13 NMR' DMSO-d, ) δ value: m), 7.62 (IH, d, J=14Hz), 7.
83-8.60 (2H, m), 10.30 (LH, bs
) Reference Example 9 6-(3-acetylamino-1-pyrrolidinyl)-2-
(2,4-Difluorophenylamino)=5-fluoronicotinic acid methyl ester 9801!9 was suspended in a mixture of 3Qml of tetrahydro7ran, 10ml of methanol and 4ml of water, and IN-sodium hydroxide-aqueous solution 5. 3
- is added, and then reacted at 65°C for 3 hours. Then, the reaction solution was mixed with 50m7 of ethyl acetate! The mixture was added to a mixed solution of 5Qml of water and the aqueous layer was separated, and the pH was adjusted to 2.0 with IN-hydrochloric acid. Separate the precipitated crystals and add 2-2 parts of water and 2-2 parts of ethanol.
- If washed sequentially with -, 6-
(3-acetylamino-1-pyrrolidinyl)-2-(2
, 4-difluorophenylamino)-5-fluoronicotinic acid (yield 93.Q%). If this is recrystallized with a mixed solvent of acetone and methanol (volume ratio 1:1), crystals having a melting point of 233.5 to 236°C are obtained.

IR(KBr)-1; ν. ,, o1645Q curvature NMR (TFA-dl) δ value; m), 6.82-7.80 (3H, m), 8.27 (I
H,d.

J=13Hz) Reference Example 10 The reaction was carried out in the same manner as in Reference Examples 8 and 9 to obtain the compound of .

06-(4-acetel-1-piperazinyl)-2-(2
, 4-') Fluorophenyl 7mi/)-5-fluoronicotinic acid Melting point: 243-244°C (Reconsolidation solvent: Ethyl acetate:equol = 1:1 (volume ratio)) IR (KBr)-1
; ν,. 1670.1635 (Sh) aπ NMR (TFA-ctl) δ value; 2-48 (3H, s) t 3.47-4.40
(8Ht m) +6.83~7.82 (3H, m),
8.47 (LH, d, J = 13 Hz) Reference Example 11 2.341 of 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid was suspended in 94 mL of anhydrous tetrahydrofuran and cooled with water. N below,
After adding 2.002 ml of N'-carbonyldiimidazole, the mixture is allowed to react at room temperature for 2 hours.

Then, 3.5% of magnesium salt of ethoxycarbonylacetic acid was added at room temperature, and the reaction was carried out under heating and reflux for 1.5 hours.
- and adjust the pH to 2.0 with 6N hydrochloric acid. The organic layer is separated and washed sequentially with 80ml of IJium aqueous solution and 80ml of water, and then 80ml of water is added and the pH is adjusted to 2.0 with 6N hydrochloric acid. The organic layer is separated, washed successively with 80 ml of water and 80 ml of saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

When diethyl ether 8- is added to the obtained crystalline substance and the crystal is made into a vocal range, it shows a melting point of 161-162''C f2- [
1.93 t (yield: 66.2 t) of 2-(2,4-')fluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetic acid ethyl ester are obtained. If this is recrystallized with benzene, crystals having a melting point of 161.5 to 162°C are obtained.

IR(KBr), -, +; ν(=Q 1725,16
65NMR (CDCl5) 15 value; 1.29 (3H, t, J = 7Hz) + 3.74 (2H,
s).

4.20 (2H, Q, J=7Hz), 6.57-7.6
9(4F(.

m) = 10.17 (IH, bs), 11.52 (IH,
bs) The following compound is obtained in the same manner.

0 2-(s-fluoro-2-(4-fluorophenylamino)-6-hydroxynicotinoyl]acetic acid ethyl ester melting point; 185°C (decomposition) (reconsolidation solvent; ethyl acetate) IR(KBr)-1; ν .=o1715,1685Qπ NMR (CDCl3) δ value; 1.30 (3H,t, J=7Hz), 3.75 (2H
,s).

4.25 (2H, q, J=7Hz), 7.08~7
．． 34 (4H, m), 7.48 (IH, d, J = 11H
z).

11.68 (IH, bs) Reference Example 12 2-(2,4-difluorophenyl 7mi/)-5-fluoro-6-medoxynicotine M 5. OOf methylene chloride 150 dK @ turbid, thionyl chloride 5.98 F
and after adding 3 drops of N,N-dimethylformamide,
React for 2 hours under heating and reflux.

The solvent and excess thionyl chloride were distilled off under reduced pressure, and 710 ml of n-hexane was added to the resulting crystalline material to form the crystals, which showed a melting point of 153-1.54°C and f2-(2,
4-difluorophenylamino)-5-fluoro-6-
Medoxynicotinic acid chloride 4.87f (yield 91.7
%). If this is recrystallized from methylene chloride, crystals having a melting point of 154 to 155°C are obtained.

IR(KBr)-1 Niji. = o1680fi NMR (CDCl3) δ value; 3.98 (3H, s), 6.60-7.10 (2H, m
).

bs) Reference Example 13 200 mg of 2-(2,4-')fluorophenylamino)-5-fluoro-6-medoxynicotinic acid chloride was dissolved in anhydrous tetrahydro 7-ran 7-, and -20 to -1
Imidazole 45■ and triethylamine 65 at 0°C
After dropping 1 g of anhydrous tetrahydrofuran solution containing the cape, the mixture was allowed to react at room temperature for 30 minutes. Next, magnesium salt of ethoxycarbonylacetic acid 150'19 was added at room temperature, and the reaction was carried out under heating and reflux for 30 minutes.The reaction solution was added to a mixture of ethyl acetate 10 and water 10, and the pH was adjusted to 2 with 2N hydrochloric acid. , adjust to 0. Separate the organic layer, add 5 d of water, and adjust the stiffness to 7.5 with a saturated aqueous solution of hydrogen carbonate.After separating the organic layer and washing sequentially with water 5- and saturated brine 5-, Dry with anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, and 1 ytl of diimpropyl ether is added to the obtained crystalline substance to form a crystal.
2-(2-(2,4-difluorophenylamino)-5-fluoro-6-medoxynicotinoyl]acetic acid ethyl ester 1901H! (yield 81.7%) having a melting point of 148-149°C is obtained. If you recrystallize with benzene,
Crystals with a melting point of 149-150°C are obtained.

IR (KBr)-1; c-o1745aπ NMR (CD01g) δ value; 1.30 (3H, t, J=7Hz), 3.90 (2H,
5) t4.02 (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) Reference Example 14 The reaction was carried out in the same manner as in Reference Examples 12 and 13 to obtain the compounds shown in Table 5.

Table-5 Reference Example 15 2-(2-(2,4-difluorophenylamino)-5
-Fluoro-6-hydroxynicotinoyl]acetic acid ethyl ester (400 μ) was dissolved in methylene chloride (0 μ) and cooled with water (2,4,6-) IJ methylbenzenesulfonyl chloride (3001 μ) and triethylamine (150 μ).
After adding, react at room temperature for 2 hours. 4 ml of methylene chloride and 4 ml of water were added to the reaction solution, the organic layer was separated, and washed sequentially with 4 ml of water and 4 ml of saturated saline.
Dry over anhydrous magnesium sulfate and remove the solvent under reduced pressure.

2 ml of diethyl ether is added to the obtained crystalline substance and the crystals are separated to form 2-(2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-
)! J methylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester 520XIF (yield: 85.8%) was obtained.

The physical properties of this compound were consistent with those obtained in Reference Example 14.

Similarly, the following compound is obtained.

02-(2-(2,4-difluorophenylamino)-
5-Fluoro-6-(2,4,6-triimprobylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester The physical properties of this compound were consistent with those obtained in Reference Example 14.

02~(2-(2,4-difluorophenylamine)-
5-Fluoro-6-methanesulfonyloxynicotinoyl]acetic acid ethyl ester melting point; 98-99°C (reconsolidation solvent: benzene) IR (KBr) crn″″l; c=0
173ONMR (CDCl5) δ value; 1.27 (3H, t, J=7Hz), 3.28 (3H,
s).

3.93 (2H, S), 4.23 (2H, q, J=7H
z).

6.63-7.43 (2H, m).

bs) Reference Example 16 50 μ of 3-aminopyrrolidine dihydrochloride was suspended in 1.5-chloroform, 110 μ of triethylamine was added, and after reacting at room temperature for 10 minutes, 2-(2-(2,4 −
difluorophenylamino)-5-fluoro-6-(2
, 4,6-Trimethylbenzenesulfonyloxy)nicotinoyl]acetic acid ethyl ester (150 μl) was added, and the mixture was allowed to react at room temperature for 1.5 hours. Next, 5 ml of chloroform and 5 ml of water were added to the reaction solution, the organic layer was separated, and 5 ml of water was added.
After sequentially washing with saturated saline and saturated saline, it is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and diimpropyl ether 2 is added to the obtained crystalline substance to obtain 2-(6
-(3-amino-1-pyglysilyl)-2-(2,4
-difluorophenylamino)-5-fluoronicotinoyl]acetic acid methyl ester 110■ (yield 93o2%)
get.

IR (KBr), -1; c-o173ONMR (D
MSO-d, ) δ value; 1, 22 (3H, t s J = 7 Hz) +
1.50~2-30 (2H.

m), 3.30-4.40 (9H, rn),
6.80-7.60 (2H, m), 7.81 (IH,
d, J=14Hz), 8.00~s, 70 (I H
+ rn ) * L 1-45 (L H+ b S
) Reference Example 17 2-[:2-(2,4-difluorophenylamino)-
5-Fluoro-6-hydroxynicotinoyl]ethyl acetate 1.0 Of was dissolved in 10 m of anhydrous acetonitrile/
After adding triethylamine 390~ and diethyl phosphoric acid chloride 6707η while cooling with water, the mixture is reacted at room temperature for 1.5 hours. Add 50% methylene chloride to this reaction solution.
ml and 50ml of water, separate the organic layer, and add 5oml of water.
After washing with Me 4 times each time, it is dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was
- When adding hexane 15- and counting the precipitated crystals, 2-[6-dinitoxyphosphinyloxy-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetic acid shows a melting point of 127 to 1300. Ethyl ester 1
．． 26F (yield 91.0%) was obtained. If this is recrystallized with benzene, crystals having a melting point of 131.5 to 133°C are obtained.

IR(KBr)crn-1; c-, 174ONM
R (CDCI!) δ value; 1.30 (3H, t, J-7Hz) + 1.33 (3H,
t+J=7Hz), 1.35(3H,t,J=
7Hz), 3.95(2H,S), 4.15(2
H, q, J = 7Hz), 4.25 (2H, q, J = 7H
z), 4.30 (2H, q, J=7Hz), 6.65=
7.35 (2H, m), 7.96 (LH, d.

J=9H2), 8.15-8.75 (IHlm), 11
．． 05 (IH, bs) The following compound is obtained in the same manner.

0 2-(2-(2,4-difluorophenylamino)
-6-diphethoxyphosphinyloxy-5-fluoronicotinoyl]acetic acid ethyl ester melting point: 85-86°C (reconsolidation solvent: diethyl ether) IR (KBr), -'; cic,,, o174ON
MR (CDCI3) δ value; 1.25 (3H, t, J=7Hz), 3.
90 (2H, s).

4.20 (2H, Q, J=7Hz) + (2H,
rn) s 11.07 (L H, b s ) Reference Example 18 2-(2-(2,4-difluorophenylamino)-5
-Fluoro-6-hydroxynicotinoyl]acetic acid ethyl ester 1.05F was suspended in anhydrous acetonitrile loml, and under water cooling, triethylamine 450mg and diphenylphosphoric azide 1.22? 4 at room temperature after adding
Allow time to react. Ethyl acetate (50) and water (50) are added to this reaction solution, and organic J- is separated and 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-
If purified with benzene], the melting point is 13.
2-[6-azido-2-(2,4-
550 μm of ethyl difluorophenylamino-5-fluoronicotinoyl acetate (yield 48.9%) was obtained. If this is recrystallized with benzene, the melting point is 130.5
Crystals exhibiting a temperature of ~131.5°C are obtained.

IR (KBr), -1; νN32130, c-01
75ONM R (CDC13) δ value: 1.29 (3H, t, J=7Hz), 3.92 (2H+
3) +4.25 (2H, q, J=7Hz), 6.60~
8.45 (4H.

”), 10.94 (IH, bs) Reference Example 19 2-(2-(2,4-difluorophenylamino)-5
-Fluoro-6-phenylthionicotino.

yl]ethyl acetate 2. O? methylene chloride 20
After dissolving dK and adding rn-chloroperbenzoic acid (purity: 80%) at 1.01 F under ice cooling, the mixture was reacted at the same temperature for 5 hours. Next, after removing the precipitate from house to house, add 20 l of water to the F solution.
nt and add saturated hydrogen carbonate) pH with IJum aqueous solution
Adjust to 7.5. The organic layer is separated, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako Silica Gel C-2O0. If purified with solvent: benzene: ethyl acetate = 50:1 (volume ratio)],
f2-[:6-benzenesulfinyl-2-(2,4-'jfluorophenylamino)-5-fluoronicotinoyl, 1 vinegar 1! E ethyl ester 1.39F (yield 67.1%) is obtained. If this is recrystallized with diimpropyl ether, the melting point is 107.
Crystals exhibiting a temperature of ~107.5°C are obtained.

IR (KBr)-1; c = 01730C gastric NMR (CDCl3) δ 1 direct; 1.2 s (
3n, t, J=7H2), 3.97(2H,S).

4.21 (2H, C1, J==7Hz), 6.60-8
．． 00 (8H.

m), 8.30-8.85 (IH, m), 10.90 (
IH.

bs) Similarly, the following compound is obtained.

0 2-C2-(2,4-difluorophenylamino)
-6-ethanesulfinyl-5-fluoronisfnoyl]acetic acid ethyl ester melting point; 115-116°C (reconsolidation solvent; diimpropyl ether) IR (KBrL-' t 'C-01735NMR (C
DCl3) δ value; 1.29 (3H, t, J=7H2), 1.31 (3H,
t.

J=7Hz), 3.08 (2H,q, J=7Hz).

4.03 (2H, s), 4.23 (2H, q, J=7H
z).

6.65-7.15 (2H, m), 7.97 (LH, d
, J=9 Hz), 8.40~9.00 (IH
, tn) t 10.88 (IH, bs) Reference Example 20 2-(2-(2,4-difluorophenylamino)-6
-Ethylthio-5-fluoronicotinoyl]acetic acid ethyl ester 1.4Of was dissolved in methylene chloride 14- and m-chloroperbenzoic acid (purity: 80%) 1.
After adding 59F, react at room temperature for 3 hours. After removing the precipitate from each house, 10% of water was added to the furnace solution, and the solution was adjusted to [7.5] with a saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed successively with 10ml of water and 10ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10'd of diethyl ether was added to the resulting residue to collect the precipitated crystals, which yielded 2-C2-(2,4-difluorophenyl amino)
-6-nitanesulfonyl-5-fluoronicotinoyl)
Vinegar ffi ethyl ester 1.28F (yield 84°6%)
get. If this is recrystallized from diimpropyl ether, crystals having a melting point of 114 to 115°C are obtained.

IR (KBr)-1; c-017400π NMR (CDCl5) δ value; 1.24 (3H, t, J=7Hz), 1.27 (3H,
, t, J=7H2), 3.27(2H,q, J=7Hz
), 4.00 (2H, s), 4.18 (2H, (1, J
=7Hz), 6.5510.60 (LH, bs) Similarly, the following compound is obtained. 2-116-penzenesulfonyl-2-(2゜4-
difluorophenylamino)-5-fluoronicotinoyl]acetic acid ethyl ester melting point; 140-141°C (reconsolidation solvent; ethyl acetate) IR (KBr), -1;
D013) δ value; 1.27 (3H, t, J=7Hz), 4.01 (2H,
S).

4.21 (2H, Q, J=7Hz), 6.40-7.0
O(2H.

(I H * b s ) Reference Example 21 1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-7-hydro, roxy-4-okine-1
,8-naphthyridine-3-carboxylic acid ethyl ester 3
．． 0OS' was suspended in 30-methylene chloride, and 1.09 F of triethylamine and 3.0 Or of 2,4,6-triimprobylbenzenesulfonyl chloride were added under water cooling, and the suspension was suspended at the same temperature for 30 minutes, then at room temperature for 6 Allow time to react.

Next, 20 tons of methylene chloride and 20 m of water were added to the stone plate.
The organic layer was separated, washed sequentially with 20 ml of water and 20 rnl of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystalline material was mixed with 6 ml of ethyl acetate and 12 ml of diethyl ether.
If we add a mixture of / and count the number of crystals, we get 1-(2,4-
(difluorophenyl)-6-fluoro-1,4-dihydro-4-okyne-7-(2゜4,6-)ly(propylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylic acid ethyl ester4. 50r (yield 86.6%) is obtained.

The physical properties of this compound were consistent with those obtained in Example 3 α).

Reference Example 22 1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-7-medoxy-4-oxo-1,8
-Naphthyridine-3-carboxylic acid ethyl ester 500
(2) is suspended in 2.5 ml of phosphorus oxychloride and reacted under heating and reflux for 1.5 hours.

Then, the solvent was distilled off under reduced pressure, and the resulting crystalline material was washed with 10 ml of diethyl ether to obtain 7-chloro-
1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 430F (yield 85.
0%).

The physical properties of this compound were consistent with those obtained in Example 3 (1).

Reference Example 23 150 μm of 3-aminopyrrolidine dihydrochloride is suspended in 5 μm of ethanol, and 310 μm of triethylamine is added and dissolved. Then, 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-okine-7
-(2,4,6-triinfurobylbenzenesulfonyloxy)-1.

8-+7 thylJ gin-3-carboxylic acid ethyl ester 5
Add ooH1 and react at room temperature for 2 hours. Add 6 g of water to the reaction solution, separate the precipitated crystals, and wash with 5 ml of water to obtain 7-(3-amino-1) with a melting point of 200-202°C.
-pyrrolidinyl)-1-(2゜+-difluorophenyl)-6-fluoro-1゜4-dihydro-4-oxo-1
,8-naphthyridine-3-carboxylic acid ethyl ester 3
30■ (yield 96.3%) was obtained. This is ethyl acetate.
If recrystallized with ethanol (volume ratio 1:1) mixed solvent,
Crystals with a melting point of 206-209°C are obtained.

NMR (TFA-dt) δ value; 1, 48 (3H, t s J = 7 Hz) +
2-19 to 2.86 (2H.

rn), 3.33=4.90 (7H, m), 6.89~
7.85 (3H, rr+), 8.18 (I Hw
d + J = 11 Hz) *9.04 (IH,
s) Reference Example 24 64 μm of 3-aminopyrrolidine dihydrochloride was mixed with 2 μm of ethanol.
ml, add 130 ml of triethylamine and dissolve. Then, 200 μl of 1(2?4-difluorophenyl)-7-diphenoxyphosphinyloxy-6-fluoro-1,4-dihydro-4-oxine-1,8-naphthyridine-3-carboxylic acid ethyl ester and react at room temperature for 1 hour. Add water to the reaction solution to separate the precipitated crystals, and then wash with 3 ml of water to obtain 7
-(3-amino-1-pyrrolidinyl)-1-(2,4-
110η (ill 175.9%) of ethyl difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is obtained.

The physical properties of this compound were consistent with those obtained in Reference Example 23.

Reference Example 25 400~ of anhydrous piperazine was mixed with 4.5 parts of ethanol and N
, 7-azido-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-
After processing 450 μl of 1,8-naphthyridine-3-carboxylic acid ethyl ester and reacting at 80° C. for 1 hour, the solvent was distilled off under reduced pressure. Ethyl acetate 30# is added to the resulting residue.
1/1 and water were added sequentially, and the pH was adjusted to 1 with 2N hydrochloric acid.
Adjust to 0 and separate the aqueous layer. Add 15 mg of chloroform, adjust the pH to 8.5 with IN-sodium hydroxide aqueous solution, and separate the organic layer. The organic layer is washed successively with 10 parts of water and 10 parts of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and diethyl ether 5#I/ is added to the resulting residue to precipitate crystals, which give 1-(2,4-difluorophenyl)-6- with a melting point of 208-213°C. Fluoro-1,4-dihydro-
420 μl of 4-okine-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (yield: 84.0%) was obtained. This was mixed with acetone-methanol (
If recrystallized with a mixed solvent (volume ratio 1:1), the melting point will be 220~
Crystals exhibiting a temperature of 223°C are obtained.

NMR (TFA-dx) δ value; 1.50 (3H, t, J=7Hz), 3.39-3.9
3 (4H.

m), 3-93 to 4-44 (4H* m) +
466 (2H* qtJ=7Hz), 6.89~7
．． 82 (3H, m), 8.32 (IH.

d, J=12H2), 9.14 (IH9S) Reference Example 26 1-(2,4-difluorophenyl)-6-fluoro-
1,4-dihydro-4-oxo-7-phenylthio-1
,8-su7tyridine-3-carboxylic acid ethyl ester 4
00■ and 380d of anhydrous piperazine were suspended in 12 bottles of N,N-dimethylformamide and heated at 95 to 100°C for 6 hours.
Allow time to react. Then, the solvent was distilled off under reduced pressure, and 10 m of ethyl acetate and 30 m of water were sequentially added to the resulting residue, and the pH was adjusted to 0.5 with 6N hydrochloric acid. Separate the aqueous layer, add 30 ml of ethyl acetate, adjust the pH to 9.0 with a 10% aqueous potassium carbonate solution, and separate the organic layer.

Furthermore, the aqueous layer is extracted twice with 20 parts of ethyl acetate, combined with the organic layer, washed with 20 m of saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure, and 5Int of diethyl ether is added to the obtained crystalline material to form a crystal.
,4-difluorophenyl)-6-fluoro-1,4-
Dihydro-4-oxo-7-(1-piperazinyl)-1
,8-naphthyridine-3-carboxylic acid ethyl ester 2
30■ (yield 6o, 7%) is obtained.

The physical properties of this compound were consistent with those obtained in Reference Example 25.

Reference Example 27 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-1,+-dihydro-4-okyne-1,
8-Catchyridine-3-carboxylic acid ethyl ester 1.
00? was dissolved in 15 g of methylene chloride, and m-
After adding 1.06 F of chloroperbenzoic acid (purity 80%), the mixture is reacted at the same temperature for 30 minutes and at room temperature for 4 hours. After removing the precipitate, add water IQm/ to solution F, adjust the pH to 7.5 with a saturated aqueous sodium bicarbonate solution, and separate the organic layer. The organic product was washed with 10 parts of water and 10 parts of saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 10 rnt of diethyl ether was added to the resulting residue to collect the precipitated crystals.
1-(2,4-difluorophenyl)-7-ethanesulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 0.94 f! (yield 87.2%).

The physical properties of this compound were consistent with those obtained in Example 3 (1).

Reference Example 28 ω 3-7 120 ml of minopyrrolidine dihydrochloride is suspended in ethanol, and 250 μl of triethylamine is added and dissolved. Then, 300 μ of 7-penzenesulfinyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was added. React for 3 hours at room temperature. Add 10 diethyl ether to the reaction solution.
After adding m1 and separating the crystals, washing with water 12- gives 7-(3-amino-1-pyrrolidinyl)-x-(2,
4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 230w9 (yield 83.8%) is obtained.

The physical properties of this compound were consistent with those obtained in Reference Example 23.

■ 7-penzenesulfinyl-1-(2,4
-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ester O instead of 1-(2,4-difluorophenyl)-7-ethanesulfinyl 7-(3-amino- 1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-okyne-1゜8-naphthyridine-3-carboxylic acid ethyl ester 230cm (yield 83.6%) ).

The physical properties of this compound were consistent with those obtained in Reference Example 23.

Reference Example 29 (1) 120 W of 3-aminopyrrolidine dihydrochloride was suspended in 3 ml of ethanol, and 250 μl of triethylamine was suspended in 3 ml of ethanol.
Add and dissolve. Then, 30011v of 7-penzenesulfonyl-1-(2,4-1fluorophenyl)-5-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was added. , and react at 45-50°C for 4 hours. Add 10 d/ml of diethyl ether to the reaction solution, remove the crystals, and then add 12 d/ml of water.
7-(3-amino-1-hyrolysinyl)
-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 2301119 (yield 86.6%) is obtained.

The physical properties of this compound were consistent with those obtained in Reference Example 23.

■ 7-benzenesulfonyl-1-(2゜4-
1-(2,4-difluorophenyl)-7-ethanesulfonyl instead of ethyl ester of difluorophenyl)-6-fluoro-1゜4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. -6-Fluoro-
Using 270 μl of 1,4,-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (
If the reaction is carried out under the same conditions as in 1), 7-(3-amino-1-pyrrolidinyl)-1-(2゜4-difluorophel)-6-fluoro-1゜4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid ethyl ester 225 (yield 84.9%) is obtained.

The physical properties of this compound were consistent with those obtained in Reference Example 23.

Reference example 30 7-(3-amino-1-pyrrolidinyl)-1-(2,4
-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naph f I) ') no 3
-carboxylic acid ethyl ester 1.002 to 6N-hydrochloric acid 6
d and reacted under heating and reflux for 2 hours. Next, 6 ml of water was added to the reaction solution to collect the crystals, and then 2 ml of water was added.
If washed with Carboxylic acid hydrochloride 920cm (yield 90.2
h).

The physical properties of this compound were consistent with those obtained in Example 9. Similarly, the following compound is obtained.

01-(2,4-difluorophenyl)-6-fluoro-x,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-su7teridine-3-carboxylic acid hydrochloride of this compound The physical properties were consistent with those obtained in Example 9.

Reference Example 31 The following compound was obtained by reacting in the same manner as in Reference Examples 21, 23 and 30.

07-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride melting point; 210-217°C (decomposition) NMR (TFA-dl) δ value; 2.20-2.85 (2H, m), 3.48-4.98
(5H.

tn), 7.07-7.78 (4H, m), 8.18f
lH,d.

J=11Hz), 9.18flH,s) or more

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1^a has a carboxyl protecting group; R^2 has a halogen atom, hydroxyl group, azide group, or substituent Alkoxy, alkylthio, arylthio, alkanesulfinyl, arenesulfinyl, alkanesulfonyl, arenesulfonyl, alkanesulfonyloxy, arenesulfonyloxy, dialkoxyphosphinyloxy or diaryloxyphosphinyloxy groups, amino groups are protected Moyoi 3-
An amino-1-pyrrolidinyl group or a 1-pepyrazinyl group whose imino group may be protected; and X represents a hydrogen atom or a fluorine atom. ] 2-(5-fluoronicotinoyl)acetic acid derivative or its salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^3 and R^4 are the same or different, and are alkyl or represents a cycloalkyl group, or R^
3 and R^4 may be an alkylene group combining to form a ring, R^5 and R^6 are the same or different and represent an alkyl group, or R^5 and R^6
may be bonded together with adjacent nitrogen atoms to form a heterocyclic group. ▲ There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2 and X have the same meanings as above, and R^
1 represents a hydrogen atom or a carboxyl protecting group] A method for producing a 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.