JP2000229946A - Production of quinolonecarboxylic acid and its intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially produce the subject compound by reacting an aniline derivative with a cyclopropane derivative, reducing the reaction product, subsequently reacting the product with the dialkyl ester of an alkoxymalonic acid and bringing the reaction product to a ring opening reaction and hydrolysis. SOLUTION: The objective compound expressed by formula IV R1 and R2 are each H, a halogen, a (substituted) alkyl or the likes; and Cy is a group expressed by formula II [D is a 5 or 6 membered heterocycle or a carbon ring; R3 and R4 are each H, a halogen, a (substituted) alkyl or the likes]} is obtained by reacting a 3-substituted aniline derivative expressed by formula I with a compound expressed by formula III (R5 is a halogen or the like; and R6 is an alkyl) to obtain an N-(1-alkoxy)cyclopropyl-3-substituted aniline derivative, which is brought to a reduction reaction, subsequently reacting the obtained compound with the dialkyl ester of an alkoxymalonic acid of the formula: R8OCH=C(COOR7)2 (R7 and R8 are each an alkyl) to obtain the dialkyl ester of an (N-cyclopropyl-3-substituted anilino)methylmalonic acid, which is subjected to a ring opening reaction and subsequently to hydrolysis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound represented by the general formula [1b] useful as an antibacterial agent:

Embedded image During the "formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl which may be substituted, an alkoxy or alkylthio group or a protected or unprotected hydroxyl group; R ²
Is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group, an optionally protected hydroxyl or amino group or a nitro group; Cy is

Embedded image (Wherein D is a 5- or 6-membered heterocyclic or hydrocarbon ring; R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group) , Nitro group,
At least one group selected from a cyano group, an acyl group, an optionally protected hydroxyl group, an optionally protected or substituted amino group; R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted A good alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio group, an optionally protected hydroxyl group, an optionally protected or substituted amino group, a cycloalkane ring together with the carbon atom to which R ⁴ is attached. One or more groups selected from the groups to be formed are shown. ) Group,
Or an optionally substituted carbocycle or an optionally substituted heterocycle, respectively. And a process for producing the quinolone carboxylic acid or a salt thereof represented by the formula:

[0002]

2. Description of the Related Art A method for producing a compound of the general formula [1b] is described in WO9.
6/05192, WO97 / 29102, PCT / JP98 / 03529, PCT / JP98 / 0485
4 and Japanese Patent Application No. 10-110146 are known.

[0003]

The compound represented by the general formula [1b] is an excellent compound as an antibacterial agent, and development of these industrial production methods is required.

[0004]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted intensive studies and as a result, the following general formula [4]

Embedded image During the "formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl which may be substituted, an alkoxy or alkylthio group or a protected or unprotected hydroxyl group; R ²
Is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group, an optionally protected hydroxyl or amino group or a nitro group; R ⁹ is a hydrogen atom or —OR ⁶ (R ⁶ is , Represents an alkyl group.); Cy represents

Embedded image (Wherein D is a 5- or 6-membered heterocyclic or hydrocarbon ring; R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group) , Nitro group,
At least one group selected from a cyano group, an acyl group, an optionally protected hydroxyl group, an optionally protected or substituted amino group; R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted A good alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio group, an optionally protected hydroxyl group, an optionally protected or substituted amino group, a cycloalkane ring together with the carbon atom to which R ⁴ is attached. One or more groups selected from the groups to be formed are shown. ) Group,
Or an optionally substituted carbocycle or an optionally substituted heterocycle, respectively. N-
The present inventors have found that a method using a cyclopropyl-3-substituted aniline derivative or a salt thereof as an intermediate is useful as an industrial production method of a quinolonecarboxylic acid represented by the general formula [1b] or a salt thereof, and the present invention Was completed.

Hereinafter, the present invention will be described in detail. Unless otherwise specified herein, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, hexyl, a linear or branched C _1-10 alkyl groups such as heptyl, and octyl; Lower alkyl groups such as methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl A linear or branched C _1-5 alkyl group such as sec-butyl, tert-butyl and pentyl; a cycloalkyl group is, for example, C _3-6 such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. An alkenyl group means a linear or branched C such as vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl;
_2-10 alkenyl groups;

The alkoxy group includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
A linear or branched C _1-10 alkoxy group such as isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy; a lower alkoxy group is, for example, methoxy, ethoxy; , N-propoxy, isopropoxy, n-butoxy,
A straight or branched C _1-5 alkoxy group such as isobutoxy, sec-butoxy, tert-butoxy and pentyloxy; a lower alkoxycarbonyl group includes, for example,
Linear or branched C _1- such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl. ₅ alkoxy group -CO- group; trialkylsilyloxy group includes, for example, trimethylsilyloxy group and 1-dimethyl-t-butylsilyloxy group;

An alkylthio group is, for example, methylthio
E, ethylthio, n-propylthio, isopropylthio,
n-butylthio, isobutylthio, sec-butylthio, tert
-Butylthio, pentylthio, hexylthio, heptyl
Linear or branched C such as thio and octylthio;
_1-10An alkylthio group; for example, a lower alkylthio group
For example, methylthio, ethylthio, n-propylthio, isop
Ropirthio, n-butylthio, isobutylthio, sec-butyl
Such as luthio, tert-butylthio and pentylthio
Chain or branched C_1-5Alkylthio group; alkyl
Sulfonyl groups include, for example, methylsulfonyl, ethyl
Sulfonyl, n-propyl sulfonyl, isopropyl sulf
Fonyl, n-butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl, pen
Tylsulfonyl, hexylsulfonyl, heptylsulfo
Linear or branched, such as nyl and octylsulfonyl
Chain C _1-10Alkylsulfonyl group; lower alkylsulfur
A honyl group is, for example, methylsulfonyl, ethylsulfonyl
Honyl, n-propylsulfonyl, isopropylsulfonyl
, N-butylsulfonyl, isobutylsulfonyl, sec-
Butylsulfonyl, tert-butylsulfonyl and pen
Linear or branched C such as tylsulfonyl_1-5Al
An acyl group is, for example, formyl
Groups, such as acetyl and ethylcarbonyl,
Is a branched C_2-5Alkanoyl groups and benzoyl and
And an aroyl group such as naphthylcarbonyl; an aryl group
Is, for example, phenyl, naphthyl, indanyl, ind
Benzyl and tetrahydronaphthyl groups;
A phonyl group is, for example, phenylsulfonyl and naph
An aralkyl group is, for example, a benzylsulfonyl group;
Benzyl, phenethyl, benzhydryl and trityl
Which group; cycloalkane ring means cyclopropane, cyclopropane
Clobutane, cyclopentane and cyclohexane, etc.
C_3-6A cycloalkane ring means each.

The amino-protecting group includes all groups that can be used as ordinary amino-protecting groups, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, ter
t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl,
2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl,
Isopropoxycarbonyl, phthaloyl, succinyl,
Acyl groups such as alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and pivaloyl; al-lower alkyl groups such as benzyl, diphenylmethyl and trityl; 2-nitrophenylthio and 2,4-dinitrophenylthio Aryl-thio groups such as methanesulfonyl and p-toluenesulfonyl;
Di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; al-lower alkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene; 3-hydroxy-4
Nitrogen-containing heterocyclic alkylidene groups such as -pyridylmethylene; cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3
Cycloalkylidene groups such as -dimethyl-5-oxycyclohexylidene; diaryl- or dial lower alkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; 5-methyl-2-oxo-2H
Oxygen-containing heterocyclic alkyl groups such as -1,3-dioxol-4-yl-methyl; and substituted silyl groups such as trimethylsilyl.

The carboxyl-protecting group includes all groups which can be used as ordinary carboxyl-protecting groups and includes, for example, lower groups such as methyl, ethyl, propyl, isopropyl, 1,1 dimethylpropyl, butyl and tert-butyl. Alkyl groups; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl,
p-nitrobenzyl, p-methoxybenzyl and bis (p-
Ar-lower alkyl groups such as methoxyphenyl) methyl;
Acyl lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; Halogeno lower alkyl groups such as 2,2,2-trichloroethyl; lower alkylsilyl lower alkyl groups such as 2- (trimethylsilyl) ethyl; acyloxy lower alkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; phthalimide Nitrogen-containing heterocyclic-lower alkyl groups such as methyl and succinimidomethyl; cycloalkyl groups such as cyclohexyl; lower alkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; A lower alkoxyalkyl group such as benzyloxymethyl; a lower alkylthio lower alkyl group such as methylthiomethyl and 2-methylthioethyl; an arylthio lower alkyl group such as phenylthiomethyl; 1,1-dimethyl-2- Lower alkenyl groups such as propenyl, 3-methyl-3-butenyl and allyl; and trimethylsilyl, triethylsilyl, triisopropylsilyl,
Substituted silyl groups such as diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

The hydroxyl-protecting group includes all groups that can be used as ordinary hydroxyl-protecting groups, for example, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyl Oxycarbonyl, 3,4-
Dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2
-(Phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy- 1
Acyl groups such as naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; methyl, ethyl and tert-butyl A lower alkyl group such as 2,2,2-trichloroethyl; a lower alkyl silyl lower alkyl group such as 2-trimethylsilylethyl; a lower alkenyl group such as allyl;
ar-lower alkyl groups such as p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; oxygen- and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; methoxymethyl, methylthio Methyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,
Lower arzaxy- and lower alkylthio-lower alkyl groups such as 2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1-methyl-1-methoxyethyl; lower alkylsulfonyl groups such as methanesulfonyl; p Arylsulfonyl groups such as -toluenesulfonyl; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl Etc.

The carbocycle of Cy includes cyclopropane,
Examples thereof include a 3- to 6-membered saturated carbon ring such as cyclohexane and benzene. As a heterocyclic ring of Cy, furan,
5- to 6-membered heterocycles such as thiophene, imidazole, pyrrole, piperidine, pyridine, pyrimidine and thiazole.

D represents a 5- or 6-membered heterocyclic ring or a hydrocarbon ring, and is preferably a 5- or 6-membered heterocyclic ring. The heteroatom forming the ring means one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Examples of preferred heterocycles include triazine, pyridazine, pyrimidine, pyrazine, and the like. 5- or 6-membered aromatic heterocycle such as pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyran, furazane; tetrahydro-2
H-pyran, tetrahydro-2H-thiopyran, piperidine, dioxane, oxathiane, morpholine, thiomorpholine, dithiane, piperazine, pyrrolidine, tetrahydrothiophene, tetrahydrofuran, pyrazolidine, imidazolidine, tetrahydroisothiazole,
1,3-thiazolan, tetrahydroisoxazole,
1,3-oxazolan, dithiolan, oxathiolan,
Examples thereof include a 5- or 6-membered aliphatic heterocycle such as dioxolan.

Examples of the 5- or 6-membered hydrocarbon ring in D include 5- or 6-membered unsaturated hydrocarbon rings such as benzene, cyclohexene and cyclopentene; and saturated hydrocarbon rings such as cyclohexane and cyclopentane.

[0014] alkyl in R ^1, alkoxy and alkylthio groups; alkyl in R ^2, alkoxy and alkylthio groups; alkyl in R ^3, alkenyl, cycloalkyl, aryl, alkoxy and alkylthio groups; alkyl in R ^4, alkenyl, cycloalkyl, Aralkyl, aryl, alkoxy and alkylthio groups; examples of the substituent of a carbocyclic or heterocyclic ring of Cy include a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an unprotected hydroxyl group; And an optionally substituted lower alkylamino group, an alkyl group, an alkoxy group, an alkylthio group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, and an alkyl group substituted with a halogen atom. Is, they may be a plurality of substituents.

Further, those substituents are further selected from halogen atoms, lower alkyl groups, cycloalkyl groups, aralkyl groups, aryl groups, lower alkoxy groups, lower alkylthio groups, acyl groups, hydroxyl groups and amino groups. It may be substituted with one or more groups.

Typical compounds represented by the general formula [4] include, for example, the following. N1-cyclopropyl-2-methyl-3-phenylanilineN1-cyclopropyl-2-methyl-3- (2-naphthyl) anilineN1-cyclopropyl-3- [6- (acetyloxy)-
2-Naphthyl] -2-methylaniline N1-cyclopropyl-3- [6-[(dimethylamino)
Methyl] -2-naphthyl] -2-methylanilineN1-cyclopropyl-3- (2,3-dihydro-1H
-5-indenyl) -2-methylanilineN1-cyclopropyl-3- (2,6-dimethyl-4-
Pyridyl) -2-methylanilineN1-cyclopropyl-3- [6- (acetylamino)-
3-pyridyl] -2-methylanilineN1-cyclopropyl-3- (5,6-dimethyl-3-
Pyridyl) -2-methylanilineN1-cyclopropyl-3- (6-methoxy-3-pyridyl) -2-methylanilineN1-cyclopropyl-3- [6- (acetylamino)-
5-methyl-3-pyridyl] -2-methylanilineN1-cyclopropyl-3- [6- [acetyl (methyl)
Amino] -5-methyl-3-pyridyl] -2-methylanilineN1-cyclopropyl-3- [6- (dimethylamino)-
5-methyl-3-pyridyl] -2-methylanilineN1-cyclopropyl-3- [6- [acetyl (methyl)
Amino] -3-pyridyl] -2-methylaniline N1-cyclopropyl-3- [6- (dimethylamino)-
3-pyridyl] -2-methylaniline

N 1 -cyclopropyl-2-methyl-3
-(4-pyridyl) anilineN1-cyclopropyl-2,5-dimethyl-3- (2,6
-Dimethyl-4-pyridyl) anilineN1-cyclopropyl-2-methyl-3- (3-pyridyl) anilineN1-cyclopropyl-3- [6- (1,2-diacetyl-2-methylhydrazino) -3-pyridyl] -2-methylaniline N1-cyclopropyl-2-methyl-3- (6-methyl-3-pyridyl) aniline N1-cyclopropyl-2-methyl-3- (5-methyl-3 -Pyridyl) anilineN1-cyclopropyl-3- [5- (hydroxymethyl)
-3-Pyridyl] -2-methylaniline N1-cyclopropyl-3- [5,6-di (acetylamino) -3-pyridyl] -2-methylaniline N1-cyclopropyl-3- [6- ( (Acetylamino)-
5-methyl-3-pyridyl] -2-difluoromethoxyanilineN1-cyclopropyl-3- [6- (acetylamino)-
5-methyl-3-pyridyl] -2-methoxyaniline

N1-cyclopropyl-2-difluoromethoxy-3- (2,6-dimethyl-4-pyridyl) anilineN1-cyclopropyl-2-methyl-3- (4,5,6-
Trimethyl-3-pyridyl) anilineN1-cyclopropyl-3- (4,6-dimethyl-3-
Pyridyl) -2-methylanilineN1-cyclopropyl-3- (2,6-dimethyl-4-
Pyridyl) -2-methylaniline-N (Py) -oxideN1-cyclopropyl-3- [2- (hydroxymethyl)
-6-methyl-4-pyridyl] -2-methylanilineN1-cyclopropyl-3- [6- (hydroxymethyl)
-5-methyl-3-pyridyl] -2-methylaniline

N 1 -cyclopropyl-2-methyl-3
-[1-methyl-2- (p-toluenesulfonyl) -2,
3-dihydro-1H-5-isoindolyl] aniline N1-cyclopropyl-2-difluoromethoxy-3
-[1-methyl-2- (p-toluenesulfonyl) -2,
3-dihydro-1H-5-isoindolyl] aniline N1-cyclopropyl-2-methyl-3- (1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl) aniline N1-cyclopropyl -2-difluoromethoxy-3
-(1-methyl-2-tritol-2,3-dihydro-1
H-5-isoindolyl) aniline N1-cyclopropyl-3- [2- (2,2-dimethylpropanoyl) -1-methyl-2,3-dihydro-1H
-5-isoindolyl] -2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-[2- (2,2-dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-5-isoindolyl] aniline N1-cyclopropyl-3- (2-benzyloxycarbonyl-1-methyl- 2,3-dihydro-1H-5-
Isoindolyl) -2-methylaniline N1-cyclopropyl-3- (2-benzyloxycarbonyl-1-methyl-2,3-dihydro-1H-5-
Isoindolyl) -2-difluoromethoxyaniline N1-cyclopropyl-3- [7-fluoro-2- (p
-Toluenesulfonyl) -2,3-dihydro-1H-5
-Isoindolyl] -2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-[7-Fluoro-2- (p-toluenesulfonyl)-
2,3-dihydro-1H-5-isoindolyl] aniline N1-cyclopropyl-3- (7-fluoro-2-trityl-2,3-dihydro-1H-5-isoindolyl) -2-methylaniline N1- Cyclopropyl-2-difluoromethoxy-3
-(7-Fluoro-2-trityl-2,3-dihydro-
1H-5-isoindolyl) aniline N1-cyclopropyl-3- [2- (2,2-dimethylpropanoyl) -7-fluoro-2,3-dihydro-1
H-5-isoindolyl] -2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-[2- (2,2-dimethylpropanoyl) -7-fluoro-2,3-dihydro-1H-5-isoindolyl] aniline N1-cyclopropyl-3- (2-benzyloxycarbonyl-7-fluoro- 2,3-dihydro-1H-5
-Isoindolyl) -2-methylaniline N1-cyclopropyl-3- (2-benzyloxycarbonyl-7-fluoro-2,3-dihydro-1H-5
-Isoindolyl) -2-difluoromethoxyaniline N1-cyclopropyl-3- [7-chloro-2- (p-
Toluenesulfonyl) -2,3-dihydro-1H-5-
Isoindolyl] -2-methylaniline N1-cyclopropyl-3- [7-chloro-2- (p-
Toluenesulfonyl) -2,3-dihydro-1H-5-
Isoindolyl]-2-difluoromethoxyaniline N1-cyclopropyl-3- (7-chloro-2-trityl-2,3-dihydro-1H-5-isoindolyl)
-2-Methylaniline N1-cyclopropyl-3- (7-chloro-2-trityl-2,3-dihydro-1H-5-isoindolyl)
-2-difluoromethoxyanilineN1-cyclopropyl-3- [7-chloro-2- (2,
2-dimethylpropanoyl) -2,3-dihydro-1H
-5-isoindolyl] -2-methylaniline N1-cyclopropyl-3- [7-chloro-2- (2,
2-dimethylpropanoyl) -2,3-dihydro-1H
-5-isoindolyl] -2-difluoromethoxyaniline N1-cyclopropyl-3- (2-benzyloxycarbonyl-7-chloro-2,3-dihydro-1H-5-
Isoindolyl) -2-methylaniline N1-cyclopropyl-3- (2-benzyloxycarbonyl-7-chloro-2,3-dihydro-1H-5-
Isoindolyl) -2-difluoromethoxyaniline N1-cyclopropyl-3- (7-chloro-2-methyl-2,3-dihydro-1H-5-isoindolyl)-
2-methylaniline N1-cyclopropyl-3- (7-chloro-2-methyl-2,3-dihydro-1H-5-isoindolyl)-
2-difluoromethoxyaniline N1-cyclopropyl-2-difluoromethoxy-3
-(1,3-dihydro-5-isobenzofuranyl) aniline N1-cyclopropyl-3- (1,3-dihydro-5-
Isobenzofuranyl) -2-methylaniline N1-cyclopropyl-3- (1,3-benzodioxol-5-yl) -2-methylaniline N1-cyclopropyl-3- (1,3- Benzodioxol-5-yl) -2-difluoromethoxyaniline N1-cyclopropyl-3- (1,4-benzodioxan-6-yl) -2-methylaniline N1-cyclopropyl-3- (1 , 4-benzodioxan-6-yl) -2-difluoromethoxyaniline N1-cyclopropyl-3- (3,4-dihydro-2H
-1,4-benzoxazin-7-yl) -2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-(3,4-dihydro-2H-1,4-benzoxazine-
7-yl) aniline N1-cyclopropyl-2-methyl-3- (6-quinolyl) aniline N1-cyclopropyl-2-difluoromethoxy-3
-(6-quinolyl) aniline N1-cyclopropyl-3- (8-fluoro-6-quinolyl) -2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-(8-Fluoro-6-quinolyl) aniline N1-cyclopropyl-3- (8-chloro-6-quinolyl) -2-methylaniline N1-cyclopropyl-3- (8-chloro-6-quinolyl) -2-Difluoromethoxyaniline N1-cyclopropyl-3- [2- (acetylamino)
-6-quinolyl] -2-methylaniline N1-cyclopropyl-3- [2- (acetylamino)
-6-quinolyl] -2-difluoromethoxyaniline N1-cyclopropyl-3- [2- (acetylamino)
-8-Fluoro-6-quinolyl] -2-methylaniline N1-cyclopropyl-3- [2- (acetylamino)
-8-fluoro-6-quinolyl] -2-difluoromethoxyaniline N1-cyclopropyl-3- (6-isoquinolyl)-
2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-(6-isoquinolyl) aniline N1-cyclopropyl-3- (1,3-dimethyl-6-
Isoquinolyl) -2-methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-(1,3-dimethyl-6-isoquinolyl) aniline N1-cyclopropyl-2-methyl-3- (6-quinazolinyl) aniline N1-cyclopropyl-2-difluoromethoxy-3
-(6-quinazolinyl) aniline N1-cyclopropyl-3- (benzo [b] thiophene-
5-yl) -2-methylaniline N1-cyclopropyl-3- (benzo [b] thiophene-
5-yl) -2-difluoromethoxyaniline N1-cyclopropyl-3- (5-indolyl) -2
-Methylaniline N1-cyclopropyl-2-difluoromethoxy-3
-(5-Indolyl) aniline Next, the production method of the present invention will be described.

[Manufacturing method]

(Equation 1)

Wherein R ¹ , R ² and Cy have the same meaning as described above. R ⁵ is a halogen atom or a trialkylsilyloxy group; R ⁶ , R ⁷ and R ⁸ are an alkyl group Each of which is represented by the general formulas: [1a], [1b], [2], [4a], [4b] and
The compound of [6] may be in the form of a salt, and examples of such a salt include salts of a known basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.

Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; tartaric acid,
Salts with organic carboxylic acids such as formic acid, lactic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Salts, also in the acidic group, include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine,
Pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine,
Examples thereof include salts with nitrogen-containing organic bases such as N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine.

Hereinafter, the manufacturing method will be described in detail. (1) Preparation of a compound of the general formula [4a] or a salt thereof In the presence of a base, a compound of the general formula [2] or a salt thereof is added
A compound of the general formula [3] or a salt thereof in which R ⁵ is a halogen atom, or a compound of the general formula [2] or a salt thereof in the presence of an acid, wherein R ⁵ is a trialkylsilyloxy group By reacting the compound of the formula [3] or a salt thereof, the compound of the general formula [4a] or a salt thereof can be produced.

The solvents used in these reactions include:
There is no particular limitation as long as it does not adversely affect the reaction. When R ⁵ is a halogen atom, for example, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aliphatic hydrocarbons such as pentane and hexane When R ⁵ is a trialkylsilyloxy group, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-hexanol and cyclopropanol No. Examples of the base used in this reaction include trialkylamines such as triethylamine. Examples of the acid used for this reaction include organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, toluic acid, phthalic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; hydrochloric acid, sulfuric acid, And inorganic acids such as phosphoric acid.

The amount of the base used may be at least equimolar to the compound of the general formula [2] or a salt thereof, and is preferably 1 to 5 moles. The amount of the acid to be used is 0.005 to 50-fold, preferably 0.1 to 20-fold the molar amount of the compound of the general formula [2] or a salt thereof. The amount of the compound of general formula [3] to be used is 1.0 to 1.0 with respect to the compound of general formula [2] or a salt thereof
It is 2.0 times mol, preferably 1.0 to 1.3 times mol. These reactions are usually carried out under an inert gas (eg, argon, nitrogen) atmosphere at −20 to 100 ° C., preferably 20 to 90 ° C.
Then, it may be carried out for 0.5 to 24 hours. In addition, the general formula [4a]
Can be used for the next reaction without isolation.

Compounds of the general formula [3] are described in Organic Synthesis, Vol. 63, No. 14,
7, 1985] and the Journal of the Chemical Society, Chemical Communications (J. Chem.
Soc., Chem. Commun) [page 897, 1987] and the like or a method analogous thereto.

(2) Production of a compound of the general formula [4b] or a salt thereof by subjecting a compound of the general formula [4a] or a salt thereof to a reduction reaction to produce a compound of the general formula [4b] or a salt thereof. Can be.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, tetrahydrofuran, diethyl ether,
Ethers such as dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and tetraethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; and alcohols such as methanol, ethanol and isopropanol And these solvents may be used as a mixture. Examples of the reducing agent used in this reaction include sodium borohydride in the presence of boron trifluoride such as a boron trifluoride ether complex and boron trifluoride tetrahydrofuran complex; sodium borohydride in the presence of a metal halide; Sodium borohydride; aluminum hydride complex compounds such as lithium aluminum hydride; Aluminum halide, iron (III) chloride, zinc chloride, cobalt (II) chloride, platinum chloride may be used as a metal halide if necessary in the reduction reaction.
(II), ruthenium (II) chloride, rhodium (II) chloride, palladium (II) chloride, zirconium (IV) chloride, calcium chloride, lithium chloride, and the like, and the amount of the compound represented by the general formula [4a] Or 0.1 to 0.1
It is 1 mole, preferably 0.3 to 0.7 mole. Also,
As the reduction reaction, catalytic reduction using metal palladium such as palladium-activated carbon may be performed.

The amount of the reducing agent varies depending on the type of the reducing agent. For example, in the case of sodium borohydride, the general formula
It is at least equimolar, preferably 1.0 to 2.5 moles, per mole of the compound [4a] or a salt thereof. The amount of the boron trifluoride ether complex and the boron trifluoride tetrahydrofuran complex to be used is at least equimolar, preferably 1.3 to 3.3 times, the molar amount of the compound of the general formula [4a] or a salt thereof.
The reaction is usually carried out at -20 to 100 ° C, preferably at -5 to 80 ° C.
C. for 2 to 10 hours.

(3) Preparation of the compound of the general formula [6] or a salt thereof The compound of the general formula [6] or a salt thereof is converted into a compound of the general formula [4b] or a salt thereof in the presence or absence of a solvent. By reacting a compound of the general formula [5].

The solvent used in this reaction, if desired, is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran Ethers such as, anisole, diethylene glycol diethyl ether and dimethyl cellosolve;
Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. May be used.

The amount of the compound represented by the general formula [5]
It may be at least equimolar to the compound of [4b] or a salt thereof, and preferably 1 to 10 moles. This reaction is preferably performed at 50 to 150 ° C. for 20 minutes to 50 hours. Further, the compound of the general formula [6] or a salt thereof can be used for the next reaction without isolation.

(4) Preparation of the compound of the general formula [1a] or a salt thereof (4i) The compound of the general formula [1a] or the salt thereof may be prepared by adding the compound of the general formula [6] in the presence or absence of a solvent. Can be obtained by heating.

The solvent used in this reaction, if desired, is not particularly limited as long as it does not adversely affect the reaction. For example, a solvent having a high boiling point such as biphenyl, diphenyl ether, o-dichlorobenzene and dibutyl phthalate is used. Active solvents are mentioned, and these may be used as a mixture. The reaction is usually carried out at 50-260 ° C. for 1 minute to 50
It may be carried out for 10 minutes to 3 hours at a temperature of preferably 100 to 260 ° C. (4ii) The compound of the general formula [1a] or a salt thereof can be obtained by heating the compound of the general formula [6] or a salt thereof in the presence or absence of a solvent in the presence of a ring-closing agent.

Examples of the ring closing agent used in this reaction include polyphosphoric acid, polyphosphate ester, phosphorus pentoxide,
Ring closing agents such as concentrated sulfuric acid, methanesulfonic acid and Eaton's reagent (a solution of phosphorus pentoxide in methanesulfonic acid) can be used. The amount of the ring-closing agent is at least equimolar to the compound of the general formula [6] or a salt thereof. Preferably, it is 1 to 10 moles. Solvents used as desired in this reaction include:
Although not particularly limited as long as it does not adversely affect the reaction, in addition to the solvent exemplified in the above (4i), when using polyphosphoric acid, polyphosphate ester or phosphorus pentoxide as a ring-closing agent, for example, Examples thereof include benzene, dioxane, and dimethylformamide. When concentrated sulfuric acid or the like is used as the ring-closing agent, for example, acetic anhydride, acetic acid, or the like can be used. These solvents may be used as a mixture. The reaction is usually carried out at 50-260 ° C. for 1 minute to 50
It may be carried out for a time, preferably at 50 to 140 ° C., for 10 minutes to 3 hours. In this reaction, the hydrolysis of the ester group also proceeds simultaneously, and the compound of the general formula [1b] can be directly obtained.

(5) Preparation of compound of general formula [1b] or salt thereof Compound of general formula [1b] or salt thereof is prepared by subjecting compound of general formula [1a] or salt thereof to hydrolysis reaction. can do. This reaction is performed, for example, by using Protective Groups Organic Synthesis (PROTECT
IVE GROUPS IN ORGANIC SYNTHESIS, 2nd. Edition),
[Theodra W. Green]
(1981), John Wiley & Sons, Inc. (John Wiley & Sons. Inc.)] or a method analogous thereto.

Next, a method for producing the compound of the general formula [2] as a raw material will be described. The compound of the general formula [2] can be produced, for example, by the production route of the following production method A.

[Production Method A]

(Equation 2)

Wherein R ¹ , R ² and Cy have the same meaning as described above. R ¹⁰ and R ¹¹ are alkyl groups or a boron atom formed by R ¹⁰ and R ¹¹ together. the ring;. X is a halogen atom, methylsulfonyloxy, an alkylsulfonyloxy group and p- fluorophenyl sulfonyl arylsulfonyloxy groups such as oxy, such as trifluoromethylsulfonyloxy, respectively "R ¹⁰ and R ¹¹ Examples of the ring containing a boron atom formed together include a 5- to 8-membered ring containing at least one heteroatom atom selected from an oxygen atom and a nitrogen atom as a heteroatom atom forming the ring, or a ring thereof. Condensed ring of, for example, 1,
3,2-dioxaborolane, 1,3,2-dioxaborinane, 1,
3,5,2-dioxaazaboranane, 1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocan, 1,3,6,2-dioxaazaborocan And the like. General formula [7] and
The compound of the formula [9] may be in the form of a salt, and examples of the salt include the same salts as those of the compound of the general formula [2].

(A-1) Preparation of the compound of the general formula [9] or a salt thereof The compound of the general formula [9] or a salt thereof is a compound of the general formula [7] or a salt thereof with a compound of the general formula [8] Or its salt,
It can be obtained by subjecting to a coupling reaction using a palladium catalyst in the presence or absence of a base.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include water; alcohols such as methanol, ethanol and propanol; and aromatic compounds such as benzene, toluene and xylene. Group hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; dioxane, tetrahydrofuran, anisole,
Ethers such as 1,2-dimethoxyethane, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide; And amides such as N-dimethylacetamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethylsulfoxide. These solvents may be used as a mixture.

The base optionally used in this reaction includes, for example, sodium hydrogen carbonate, sodium carbonate,
Potassium carbonate, tripotassium phosphate, cesium carbonate, cesium fluoride, potassium fluoride, sodium fluoride, triethylamine and the like can be mentioned. Examples of the palladium catalyst used in this reaction include palladium-activated carbon, metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; and tetrakis (triphenylphosphine) palladium (0 ), Bis (triphenylphosphine) palladium (II) chloride, bis (tricyclohexylphosphine) palladium (II) chloride and 1,1′-bis
Organic palladium complexes such as (diphenylphosphino) ferrocene palladium (II) chloride are exemplified.

The amount of the base used may be at least equimolar to the compound of the general formula [7] or a salt thereof, and is preferably 2 to 5 moles. The amount of the palladium catalyst to be used may be 0.00001 mol or more, and preferably 0.001 to 0.005 mol, per mol of the compound of the general formula [7] or a salt thereof. The amount of the compound of the general formula [8] or a salt thereof to be used may be at least equimolar to the compound of the general formula [7] or a salt thereof, and is preferably 1.0 to 1.5 moles. This coupling reaction may be usually performed in an inert gas (eg, argon, nitrogen) atmosphere at 50 to 170 ° C. for 1 minute to 24 hours.

The compound of the general formula [8] or a salt thereof can be produced by subjecting a halogeno carbocycle or a halogeno heterocycle to a boration reaction. This reaction is described, for example, in the fourth edition of Experimental Chemistry, Vol. 24, pp. 61-91, 1992.
Year] and Journal of Organic Chemistry (J. Org. Chem), [58, 2201-2208, 1993].
And the like or a method similar thereto.

(A-2) Production of the compound of the general formula [2] or a salt thereof The compound of the general formula [2] or a salt thereof is produced by subjecting the compound of the general formula [9] or a salt thereof to a reduction reaction. can do. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include alcohols such as methanol, ethanol, and isopropanol; tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether. Ethers; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide; and water. These solvents may be used as a mixture. Examples of the reducing agent used in this reaction include metals such as zinc, aluminum, iron and tin and metal salts thereof; sodium borohydride, lithium borohydride, potassium borohydride and calcium borohydride. Borohydride complex compounds and the like. When iron is used as the reducing agent, ammonium chloride can be used as the reaction accelerator. Further, as the reduction reaction, catalytic reduction using metal palladium such as palladium-activated carbon may be performed.

The amount of the reducing agent to be used varies depending on the type of the reducing agent, but it is at least equimolar, preferably 1 to 5 times, the molar amount of the compound of the general formula [9] or a salt thereof. The reaction accelerator may be used in an amount of 0.1 to 3 moles per mole of the compound of the general formula [9] or a salt thereof. This reaction is usually
It may be carried out at −20 to 150 ° C., preferably at 0 to 100 ° C., for 10 minutes to 24 hours. Alternatively, the compound of general formula [2]
It can be produced by the production route of the following production method B.

[Production Method B]

(Equation 3)

Wherein R ¹ , R ² , Cy, R ¹⁰ , R ¹¹ and X have the same meaning as described above. The compounds of the general formulas [10] and [8] may be salts. The salts thereof include the same salts as the salts of the above-mentioned compound of the general formula [2]. The compound of the general formula [2] or a salt thereof is obtained by reacting a compound of the general formula [10] or a salt thereof with a compound of the general formula [8] or a salt thereof in the presence or absence of a base using a palladium catalyst or a nickel catalyst. And subjecting it to a coupling reaction.

The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include water; alcohols such as methanol, ethanol and propanol; and aromatic compounds such as benzene, toluene and xylene. Group hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as dioxane, tetrahydrofuran, anisole and diethylene glycol diethyl ether; esters such as ethyl acetate and butyl acetate; ketones such as acetone and methyl ethyl ketone Nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; and dimethylsulfoxide and the like. Sulfoxide such, and the like, may be used those solvents mixed. The base optionally used in this reaction includes, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, tripotassium phosphate, cesium carbonate, cesium fluoride, potassium fluoride, sodium fluoride, triethylamine and the like.

The palladium catalyst used in this reaction includes, for example, organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium
(0), bis (tricyclohexylphosphine) palladium
Organic palladium complexes such as (II) chloride and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride. As the nickel catalyst used in this reaction, for example, bis (diphenylphosphino) ethane nickel (II) chloride, bis (diphenylphosphino) propane nickel (II) chloride, bis (diphenylphosphino) butane nickel (II) chloride And organic nickel complexes such as bis (triphenylphosphine) nickel (II) chloride and 1,1′-bis (diphenylphosphino) ferrocenenickel (II) chloride.

The amount of the base used may be at least equimolar to the compound of the formula [10] or a salt thereof, and is preferably 2 to 5 moles. The amount of the palladium catalyst or nickel catalyst to be used may be 0.00001 times or more, and preferably 0.001 to 0.05 times, based on the compound of the general formula [10] or a salt thereof, respectively. General formula
The amount of the compound [8] or a salt thereof to be used may be at least equimolar to the compound of the general formula [10] or a salt thereof, and is preferably 1.0 to 1.5 times mol. This coupling reaction may be usually performed in an atmosphere of an inert gas (eg, argon or nitrogen) at 50 to 170 ° C. for 1 minute to 24 hours.

The general formula [1a] in the above-mentioned production method,
Compounds of [1b], [2], [4a], [4b] and [6] or salts thereof; Compounds of general formulas [7], [8] and [9] in Production Method A or salts thereof; In the compound of the general formula [10] or a salt thereof in Production Method B, isomers (eg, optical isomers, geometric isomers, tautomers, etc.)
When these are present, these isomers can be used, and solvates, hydrates and various forms of crystals can be used. In addition, the general formulas [1a], [2], [4]
In the compounds of [a], [4b], [6], [7], [8], [9] and [10] or salts thereof, compounds having an amino group, a hydroxyl group or a carboxyl group are previously prepared from these compounds. The group is protected with a normal protecting group, and after the reaction,
These protecting groups can be eliminated by a method known per se. In addition, the general formulas [1a], [1b], [2], [4a], [4b],
The compounds of [6], [7], [8], [9] and [10] or salts thereof can be isolated and purified by ordinary methods such as extraction, crystallization, distillation and column chromatography.

[0053]

EXAMPLES Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited to these. REFERENCE EXAMPLE 1 4.0 g of 5-bromo-2-methylpyridine was dissolved in 30 mL of diethyl ether, and 16.0 mL of an n-hexane solution of n-butyllithium (1.53 mol solution) at -70 ° C. was taken at −70 ° C. for 15 minutes. And drop it. After stirring at the same temperature for 1 hour, trimethyl borate
A solution of 2.54 g in 10 mL of diethyl ether is added dropwise over 15 minutes. After dropping, raise the temperature to room temperature.
After stirring for 2 hours, 1.86 g of 1,3-propanediol is added at 5 ° C., and the mixture is stirred at the same temperature for 1 hour. To the reaction mixture is added 2.35 g of methanesulfonic acid at 5 ° C., and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is cooled to room temperature, the insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. 80 mL of benzene is added to the obtained residue, the insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by distillation under reduced pressure to obtain 2.51 g of 5- (1,3,2-dioxaborinan-2-yl) -2-methylpyridine. IR (KBr) cm ^-1 : 1315 NMR (CDCl ₃ ) δ value: 1.8-2.2 (2H, m), 2.55 (3H, s), 4.16 (4H,
t, J = 5.5Hz), 7.11 (1H, d, J = 7.7Hz), 7.89 (1H, dd, J = 7.7Hz,
(1.8Hz), 8.79 (1H, d, J = 1.8Hz) Boiling point: 107 ℃ (2mmHg)

REFERENCE EXAMPLE 2 2.50 g of 2-bromo-6-nitrotoluene was suspended in a mixed solvent of 10 mL of water and 12.5 mL of 1,2-dimethoxyethane.
To this is added 5- (1,3,2-dioxaborinan-2-yl)-
2.46 g of 2-methylpyridine, 2.58 g of sodium carbonate and bis (triphenylphosphine) palladium (II) chloride
After adding 81 mg, the mixture is refluxed for 2 hours under a nitrogen atmosphere. The reaction mixture is added to a mixed solvent of methylene chloride (30 mL) and water (30 mL), and the organic layer is separated. The obtained organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. N-Hexane was added to the obtained residue and the mixture was collected by filtration to give colorless crystals of 2-methyl-5- (2-methyl-
2.51 g of 3-nitrophenyl) pyridine are obtained. IR (KBr) cm ^-1 : 1519,1340 NMR (CDCl ₃ ) δ value: 2.36 (3H, s), 2.64 (3H, s), 7.0-7.6 (4H,
m), 7.7-8.0 (1H, m), 8.45 (1H, d, J = 2.1Hz)

Reference Example 3 2.5 g of 2-methyl-5- (2-methyl-3-nitrophenyl) pyridine was suspended in a mixed solvent of 12.5 mL of water and 25 mL of ethanol, and 0.32 g of ammonium chloride and 3.06 g of iron powder were added. After refluxing for 20 minutes. The reaction mixture is cooled to room temperature, the insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. A mixed solvent of 25 mL of water and 25 mL of chloroform is added to the obtained residue, and the mixture is adjusted to pH 9 with a 1 mol / L aqueous sodium hydroxide solution, and then the organic layer is separated. The obtained organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. N-Hexane is added to the obtained residue, and the mixture is collected by filtration to obtain 2.05 g of 2-methyl-3- (6-methyl-3-pyridyl) aniline as pale yellow crystals. IR (KBr) cm ^-1 : 3325 NMR (CDCl ₃ ) δ value: 2.05 (3H, s), 2.60 (3H, s), 3.2-4.0 (2H, b
rs), 6.6-6.9 (2H, m), 7.04 (1H, d, J = 7.8Hz), 7.1-7.3 (1H,
m), 7.52 (1H, dd, J = 7.8Hz, 2.1Hz), 8.45 (1H, d, J = 2.1Hz)

Reference Example 4 0.20 g of 3-chloro-2-methylaniline was added to 1-methyl-
Dissolved in 3-mL 2-pyrrolidone, 0.28 g of 5- (1,3,2-dioxaborinan-2-yl) -2-methylpyridine, 0.43 g of cesium fluoride and 52 mg of bis (tricyclohexylphosphine) palladium (II) chloride. After the addition, the mixture is stirred at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture is added to a mixed solvent of 10 mL of water and 10 mL of ethyl acetate, and the organic layer is separated. The obtained organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. N-Hexane was added to the obtained residue and the mixture was collected by filtration to obtain 0.16 g of 2-methyl-3- (6-methyl-3-pyridyl) aniline as pale yellow crystals. Physical properties of this compound were consistent with those of the compound obtained in Reference Example 3.

REFERENCE EXAMPLE 5 9.28 g of 2-chloro-6-nitrophenol was dissolved in 57 mL of acetic acid, and 5.73 g of acetic anhydride and 1.86 g of 5% palladium carbon were dissolved.
After stirring, the mixture is stirred at room temperature and normal pressure in a hydrogen stream for 12 hours. The reaction mixture is filtered and the solvent is distilled off under reduced pressure. A mixed solvent of 100 mL of water and 100 mL of ethyl acetate is added to the obtained residue, and the mixture is adjusted to pH 6.5 with a 1 mol / L aqueous sodium hydroxide solution, and then the organic layer is separated. The obtained organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to obtain 6.22 g of N- (3-chloro-2-hydroxyphenyl) acetamide as colorless crystals. IR (KBr) cm ^-1 : 3345,1652 NMR (CDCl ₃ ) δ value: 2.22 (3H, s), 6.78 (1H, dd, J = 8.1 Hz, 8.1H)
z), 7.14 (1H, dd, J = 8.1Hz, 1.4Hz), 7.49 (1H, dd, J = 8.1Hz, 1.
4Hz), 7.7-8.6 (2H, brs)

Reference Example 6 N- (3-chloro-2-hydroxyphenyl) acetamide (5.42 g) was dissolved in N, N-dimethylformamide (16.3 mL), and sodium chlorodifluoroacetate (6.68 g), sodium carbonate (4.64 g) and sodium iodide (3.07 g) were dissolved. After adding g,
Stir at 120 ° C. for 4 hours. The reaction mixture is added to a mixed solvent of 100 mL of water and 100 mL of ethyl acetate, adjusted to pH 1.5 with hydrochloric acid, and then the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to give N- [3-chloro-2- (difluoromethoxy) phenyl] acetamide as colorless crystals.
2.97 g are obtained. IR (KBr) cm ^-1 : 3298,1672 NMR (CDCl ₃ ) δ value: 2.23 (3H, s), 6.54 (1H, t, J = 74.3 Hz), 7.0
-7.4 (2H, m), 7.5-8.0 (1H, brs), 8.2-8.5 (1H, m)

Reference Example 7 N- [3-chloro-2- (difluoromethoxy) phenyl] acetamide (2.95 g) was dissolved in ethanol (18 mL), concentrated hydrochloric acid (5 mL) was added, and the mixture was refluxed for 1 hour. After the reaction mixture was concentrated under reduced pressure, 50 mL of water and 50 mL of ethyl acetate were added to the obtained residue.
Add 1 mL / L of a mixed solvent and add 1 mol / L aqueous sodium hydroxide solution.
After adjusting to pH 8.0, the organic layer is separated. The obtained organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3-
2.42 g of chloro-2- (difluoromethoxy) aniline are obtained. IR (neat) cm ^-1 : 3490,3403 NMR (CDCl ₃ ) δ value: 3.7-4.3 (2H, brs), 6.49 (1H, t, J = 75.0H)
z), 6.5-7.1 (3H, m)

Reference Example 8 (1R) -5-bromo-2- (2,2-dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-5-
Dissolve 20.0 g of isoindoline in 100 mL of tetrahydrofuran, add 25.4 g of triisopropyl borate, and then add
With n-butyllithium n-hexane solution (1.50 molar solution) 9
0.0 mL is added dropwise over 1 hour. After stirring at the same temperature for 1 hour, 200 mL of water is added, the temperature is raised to 10 ° C., and adjusted to pH 2 with 6 mol / L hydrochloric acid. After stirring at the same temperature for 1 hour, the crystallized crystals were collected by filtration to obtain colorless crystals of (1R) -2- (2,2-dimethylpropanoyl) -1-methyl-2,3-dihydro-1H.
This gives 10.5 g of -5-isoindolylboronic acid. IR (KBr) cm ^-1 : 3471,1594 NMR (d ₆ -DMSO) δ value: 1.25 (9H, s), 1.35 (3H, d, J = 6.3Hz), 4.
7-5.4 (3H, m), 7.27 (1H, d, J = 8.1Hz), 7.6-8.2 (2H, m)

Reference Example 9 3-chloro-2- (difluoromethoxy) aniline 2.42
g in a mixed solvent of 4.8 mL of water and 24.2 mL of dioxane to give (1R) -2- (2,2-dimethylpropanoyl)
4.46 g of -1-methyl-2,3-dihydro-1H-5-isoindolylboronic acid, 7.96 g of tripotassium phosphate and bis (tricyclohexylphosphine) palladium (II)
After adding 0.19 g of chloride, the mixture is refluxed for 3 hours under a nitrogen atmosphere. The reaction mixture is added to a mixed solvent of 30 mL of water and 20 mL of ethyl acetate, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; n-hexane: ethyl acetate = 3: 1] to give 2-difluoromethoxy-3-[(1R) -2- (2,2) as a colorless oil. -Dimethylpropanoyl) -1-methyl-2,3-dihydro-1H
4.45 g of [-5-isoindolyl] aniline are obtained. IR (neat) cm ^-1 : 3490, 3350, 1618 NMR (CDCl ₃ ) δ value: 1.35 (9H, s), 1.51 (3H, d, J = 6.3 Hz), 3.9-
4.2 (2H, brs), 4.8-5.2 (2H, m), 5.48 (1H, q, J = 6.4Hz), 5.97
(1H, t, J = 75.4Hz), 6.6-6.9 (2H, m), 7.0-7.5 (4H, m)

Example 1 2-methyl-3- (6-methyl-3-pyridyl) aniline
Dissolve 2.40 g in 16.8 mL of methanol, and add 2.91 g of acetic acid and 1
-Ethoxy-1-trimethylsilyloxycyclopropane
After adding 2.64 g, the mixture is refluxed for 4 hours under a nitrogen atmosphere. The reaction solution is concentrated under reduced pressure to obtain 3.25 g of N1- (1-methoxycyclopropyl) -2-methyl-3- (6-methyl-3-pyridyl) aniline.

Example 2 0.55 g of sodium borohydride was added to 15 m of tetrahydrofuran.
Suspended in L and boron trifluoride diethyl ether complex at 5 ℃
A solution of 2.06 g in 5 mL of tetrahydrofuran is added dropwise over 10 minutes. After stirring at the same temperature for another 1 hour,
(1-methoxycyclopropyl) -2-methyl-3- (6
A solution of -methyl-3-pyridyl) aniline in 13 mL of tetrahydrofuran is added dropwise over 10 minutes. After refluxing for 3 hours, 30 mL of 2 mol / L hydrochloric acid is added dropwise at 5 ° C., and the mixture is further refluxed for 30 minutes. Cool the reaction mixture to room temperature and add 40 mL of ethyl acetate. After adjusting the pH to 9 with a 5 mol / L aqueous sodium hydroxide solution, the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. N-Hexane was added to the obtained residue and the mixture was collected by filtration to obtain 2.24 g of N1-cyclopropyl-2-methyl-3- (6-methyl-3-pyridyl) aniline as colorless crystals. IR (KBr) cm ^-1 : 3292 NMR (CDCl ₃ ) δ value: 0.4-1.0 (4H, m), 1.97 (3H, s), 2.4-2.8 (4
H, m), 4.0-4.3 (1H, brs), 6.65 (1H, dd, J = 6.4Hz, 2.3Hz), 7.0
-7.4 (3H, m), 7.51 (1H, dd, J = 7.8Hz, 1.8Hz), 8.45 (1H, d, 1.8
Hz)

Example 3 N1-cyclopropyl-2-methyl-3- (6-methyl-
2.2 g of 3-pyridyl) aniline are suspended in 3.2 g of diethyl ethoxymethylenemalonate and stirred at 130 ° C. for 4 hours. After distilling off the ethanol produced, add 9.36 g of polyphosphoric acid and add 100
Stir at 30 ° C for 30 minutes. Cool the reaction mixture to room temperature and add water
Add 40 mL and 40 mL of ethyl acetate. By filtering the precipitate, 1-cyclopropyl-8-methyl-7 as pale yellow crystals was obtained.
-(6-methyl-3-pyridyl) -4-oxo-1,4-
Dihydro-3-quinolinecarboxylic acid ethyl ester 1.96
get g. IR (KBr) cm ^-1 : 1719 NMR (CDCl ₃ ) δ value: 0.8-1.6 (7H, m), 2.62 (3H, s), 2.65 (3H,
s), 3.9-4.1 (1H, m), 4.40 (2H, q, J = 7.1Hz), 7.1-7.4 (2H, m),
7.62 (1H, dd, J = 7.8Hz, 2.2Hz), 8.36 (1H, d, J = 8.1Hz), 8.53
(1H, d, J = 2.2Hz), 8.73 (1H, s)

Example 4 1-Cyclopropyl-8-methyl-7- (6-methyl-
3-pyridyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester 2.20 g in ethanol 22m
Dissolve in L, add 1 mL / L aqueous sodium hydroxide solution (22 mL), and stir at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the crystals were collected by filtration to give pale yellow crystals of 1-cyclopropyl-8-methyl-7- (6-methyl-3-pyridyl) -4-oxo-1,4. 1.89 g of dihydro-3-quinolinecarboxylic acid are obtained. IR (KBr) cm ^-1 : 1726,1612 NMR (CDCl ₃ ) δ value: 1.0-1.5 (4H, m), 2.67 (3H, s), 2.71 (3H,
s), 4.0-4.3 (1H, m), 7.3-7.5 (2H, m), 7.65 (1H, dd, J = 8.2Hz,
2.2Hz), 8.39 (1H, d, J = 8.2Hz), 8.55 (1H, d, J = 2.2Hz), 9.00
(1H, s), 14.5-14.7 (1H, brs)

Example 5 3.0 g of 2-methyl-3-phenylaniline was added to 21 m of methanol.
Dissolve in L, add 3.93 g of acetic acid and 3.57 g of 1-ethoxy-1-trimethylsilyloxycyclopropane, and reflux under a nitrogen atmosphere for 4 hours. The reaction was concentrated under reduced pressure,
N1- (1-methoxycyclopropyl) -2-methyl-3
4.15 g of phenylaniline are obtained.

Example 6 0.74 g of sodium borohydride was added to 20 m of tetrahydrofuran.
Suspended in L and boron trifluoride diethyl ether complex at 5 ℃
A solution of 2.79 g in 5 mL of tetrahydrofuran is added dropwise over 10 minutes. After stirring at the same temperature for another 1 hour,
1- (1-methoxycyclopropyl) -2-methyl-3-
Tetrahydrofuran solution 1 containing 4.15 g of phenylaniline
5 mL is added dropwise over 10 minutes. After refluxing for 3 hours, the reaction mixture is added to a mixed solvent of 80 mL of water and 40 mL of ethyl acetate, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. N-Hexane was added to the obtained residue and the mixture was collected by filtration to obtain 2.98 g of N1-cyclopropyl-2-methyl-3-phenylaniline as colorless crystals. IR (KBr) cm ^-1 : 3432 NMR (CDCl ₃ ) δ value: 0.4-0.9 (4H, m), 1.97 (3H, s), 2.3-2.6 (1
H, m), 3.9-4.3 (1H, brs), 6.69 (1H, dd, J = 6.8Hz, 2.0Hz), 6.9
-7.6 (7H, m)

Example 7 N-cyclopropyl-2-methyl-3-phenylaniline (2.64 g) was suspended in diethyl ethoxymethylenemalonate (2.81 g) and stirred at 130 ° C. for 4 hours. After the generated ethanol is distilled off, 12.0 g of polyphosphoric acid is added and the mixture is stirred at 80 ° C. for 30 minutes. The reaction mixture is cooled to room temperature and 40 mL of water and 40 mL of ethyl acetate are added. The precipitate is filtered to obtain 3.01 g of ethyl 1-cyclopropyl-8-methyl-4-oxo-7-phenyl-1,4-dihydro-3-quinolinecarboxylate as pale yellow crystals. IR (KBr) cm ^-1 : 1734 NMR (CDCl ₃ ) δ value: 0.8-1.6 (7H, m), 2.61 (3H, s), 3.8-4.1 (1
H, m), 4.41 (2H, q, J = 7.1Hz), 7.0-7.5 (6H, m), 8.34 (1H, d, J =
8.2Hz), 8.73 (1H, s)

Example 8 2-Difluoromethoxy-3-[(1R) -2- (2,2
-Dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-5-isoindolyl] aniline (4.42 g) dissolved in 27 mL of methanol, 2.83 g of acetic acid and 1-ethoxy-
After adding 1.68 g of 1-trimethylsilyloxycyclopropane, the mixture is refluxed for 7 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and N1- (1-methoxycyclopropyl) -2
-Difluoromethoxy-3-[(1R) -2- (2,2-
4.50 g of dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-5-isoindolyl] aniline are obtained.

Example 9 N1- (1-methoxycyclopropyl) -2-difluoromethoxy-3-[(1R) -2- (2,2-dimethylpropanoyl) -1-methyl-2,3-dihydro- 1H-
4.50 g of 5-isoindolyl] aniline in isopropanol
Dissolve in 53 mL, add 4.46 g of sodium borohydride, and reflux for 68 hours. After cooling the reaction mixture to room temperature, 35 mL of acetone is added dropwise over 30 minutes. After stirring at the same temperature for 1 hour, the mixture is added to a mixed solvent of 100 mL of water and 50 mL of ethyl acetate, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; n-hexane: ethyl acetate = 5: 1] to give a colorless oil, N1-cyclopropyl-2-difluoromethoxy-3-[(1R)-
2- (2,2-dimethylpropanoyl) -1-methyl-
2,3-dihydro-1H-5-isoindolyl] aniline
0.59 g is obtained. [α] _D 13 (22 ° C., c = 1.0, MeOH) IR (CHCl ₃ ) cm ⁻¹ : 3448,1609 NMR (CDCl ₃ ) δ value: 0.4-1.1 (4H, m), 1.35 (9H, s) , 1.50 (3H,
d, J = 6.4Hz), 2.3-2.6 (1H, m), 4.7-4.9 (1H, brs), 4.9-5.1 (2
H, m), 5.47 (1H, q, J = 6.3Hz), 5.89 (1H, t, J = 66.7Hz), 6.69 (1
(H, dd, J = 6.6Hz, 2.7Hz), 6.9-7.7 (5H, m)

Example 10 N 1 -cyclopropyl-2-difluoromethoxy-3-
[(1R) -2- (2,2-dimethylpropanoyl) -1
-Methyl-2,3-dihydro-1H-5-isoindolyl] aniline in 0.59 g of diethyl ethoxymethylenemalonate
Dissolve in 0.34 g and stir at 130 ° C for 22 hours. After the generated ethanol is distilled off, 6.0 g of Eaton reagent (phosphorus pentoxide 10% w / w methanesulfonic acid solution) is added, and the mixture is stirred at 60 ° C. for 2 hours. The reaction mixture is cooled to room temperature, added to a mixed solvent of 20 mL of water and 20 mL of ethyl acetate, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
The obtained residue is subjected to column chromatography [eluent;
n-hexane: ethyl acetate = 1: 2] to give colorless crystals of 1-cyclopropyl-8-difluoromethoxy-.
7-[(1R) -2- (2,2-dimethylpropanoyl)
-1-Methyl-2,3-dihydro-1H-5-isoindolyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester 0.16 g is obtained. IR (KBr) cm ^-1 : 1730,1610 NMR (CDCl ₃ ) δ value: 0.9-1.7 (19H, m), 4.0-4.6 (3H, m), 4.9-
5.2 (2H, m), 5.3-5.7 (1H, m), 5.92 (1H, t, J = 76.0Hz), 7.0-7.
6 (4H, m), 8.44 (1H, d, J = 8.3Hz), 8.69 (1H, s)

Example 11 1-Cyclopropyl-8-difluoromethoxy-7-
[(1R) -2- (2,2-dimethylpropanoyl) -1
-Methyl-2,3-dihydro-1H-5-isoindolyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester (1.0 g) is suspended in concentrated hydrochloric acid (2 mL) and heated under reflux for 3 hours. After cooling the reaction mixture to room temperature, it is concentrated under reduced pressure. Ethanol is added to the obtained residue, and the precipitate is collected by filtration. The obtained 1-cyclopropyl-8-difluoromethoxy-7-[(1R) -1-methyl-2,3-
Dihydro-1H-5-isoindolyl] -4-oxo-
1,4-Dihydro-3-quinolinecarboxylic acid hydrochloride is suspended in 2 mL of water, and adjusted to pH 7.5 with a 2 mol / L aqueous sodium hydroxide solution under ice-cooling. The obtained precipitated crystals are collected by filtration to give 1-cyclopropyl-8-difluoromethoxy-7.
-[(1R) -1-methyl-2,3-dihydro-1H-5
-Isoindolyl] -4-oxo-1,4-dihydro-3
0.75 g of quinolinecarboxylic acid are obtained. [α] _D -5.2 (29 ° C., c = 0.5, 0.1N NaOH) IR (KBr) cm ⁻¹ : 1630 NMR (d ₁ -TFA) δ value: 1.2-2.1 (7H, m), 4.6-5.2 ( 3H, m), 5.2-
5.6 (1H, m), 6.20 (1H, t, J = 73.0Hz), 7.6-8.0 (3H, m), 8.12 (1
(H, d, J = 8.5Hz), 8.80 (1H, d, J = 8.5Hz), 9.65 (1H, s)

[0073]

The method of using the N-cyclopropyl-3-substituted aniline derivative represented by the general formula [4] of the present invention or a salt thereof as an intermediate is based on the quinolone carboxylic acid represented by the general formula [1b]. It is useful as an industrial method for producing an acid or a salt thereof.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 401/04 C07D 401/04

Claims (2)

[Claims] 1. A compound of the general formula"Where R¹Is a hydrogen atom, a halogen atom,
Optionally alkyl, alkoxy or alkylthio
A group or an optionally protected hydroxyl group;²
Represents a hydrogen atom, a halogen atom, an optionally substituted
Alkyl, alkoxy or alkylthio groups, protected
An optionally substituted hydroxyl or amino group or nitro
Cy is represented by the following formula:(Wherein D is a 5- or 6-membered heterocyclic ring or hydrocarbon)
A ring; R^ThreeIs a hydrogen atom, a halogen atom,
Alkyl, alkenyl, cycloalkyl, a
Reel, alkoxy or alkylthio group, nitro group,
Cyano group, acyl group, hydroxy which may be protected
Selected from amino groups which may be protected or substituted.
One or more groups represented by^FourIs a hydrogen atom, a halogen atom
, Optionally substituted alkyl, alkenyl, cycloalkyl
Loalkyl, aralkyl, aryl, alkoxy or
Is an alkylthio group, an optionally protected hydroxyl
A group, an amino group which may be protected or substituted, R^FourBut
Groups that form a cycloalkane ring with the carbon atom to which they are attached
And represents one or more groups selected from ) Group,
Or an optionally substituted carbocycle or substituted
The optional heterocycle is shown below. 3-
The substituted aniline derivative or a salt thereof has the following general formula:"R⁵Is a halogen atom or a trialkylsilyloxy
A group; R⁶Represents an alkyl group. "
1-alkoxy-1-substituted cyclopropane represented by
The conductor is reacted to obtain the following general formula:"Where R¹, R², R⁶And Cy are the same as above.
Show meaning. N- (1-alkoxy) cyclo represented by
Obtaining a propyl-3-substituted aniline derivative or a salt thereof;
Then, it is subjected to a reduction reaction to obtain the following general formula:"Where R¹, R²And Cy have the same meaning as described above.
Show. N-cyclopropyl-3-substituted ani represented by
A phosphorus derivative or a salt thereof is obtained, and then the following general formula:⁸OCH = C (COOR⁷)₂  "Where R⁷And R⁸Are the same or different
Represents a hydroxyl group. The alkoxymalonic acid dialki represented by
And the following general formula:"Where R⁷Represents an alkyl group;¹, R²and
Cy has the same meaning as described above. (N-
Cyclopropyl-3-substituted alinino) methylenemalonic acid
To obtain a dialkyl ester or a salt thereof,
And then subjecting it to a hydrolysis reaction.
The following general formula:"Where R¹, R²And Cy have the same meaning as described above.
Show. Represented by the quinolone carboxylic acid or a salt thereof
Manufacturing method. 2. A compound of the general formula During the "formula, R ¹ represents a hydrogen atom, a halogen atom, an alkyl which may be substituted, an alkoxy or alkylthio group or a protected or unprotected hydroxyl group; R ²
Is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group, an optionally protected hydroxyl or amino group or a nitro group; R ⁹ is a hydrogen atom or —OR ⁶ (R ⁶ is , Represents an alkyl group.); Cy represents: (Wherein D is a 5- or 6-membered heterocyclic or hydrocarbon ring; R ³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group) , Nitro group,
At least one group selected from a cyano group, an acyl group, an optionally protected hydroxyl group, an optionally protected or substituted amino group; R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted A good alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio group, an optionally protected hydroxyl group, an optionally protected or substituted amino group, a cycloalkane ring together with the carbon atom to which R ⁴ is attached. One or more groups selected from the groups to be formed are shown. ) Group,
Or an optionally substituted carbocycle or an optionally substituted heterocycle, respectively. N-
A cyclopropyl-3-substituted aniline derivative or a salt thereof.