JP2000143631A - Production 7-bromo-quinolonecarboxylic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and advantageously obtain the subject compound useful as an intermediate for producing a quinolone carboxylic acid being an antimicrobial agent by reacting a specific dibromohydroxybenzoic ester with a specific halide and subjecting a carboxyl-protecting group to an elimination reaction, etc. SOLUTION: A compound of formula I (R1a is a carboxyl-protecting group) (e.g. 2,4-dibromo-3-hydroxybenzoic ester, etc.), is reacted with a compound of the formula R2-X [R2 is a (substituted) alkyl; X is a halogen] to give a compound of formula II. Then the carboxyl-protecting group is subjected to an elimination reaction to give a compound, which is subjected to a keto esterification reaction to give a compound of formula III (R1b is a carboxyl- protecting group), which is reacted with an orthoester or an acetal and then with a compound of the formula R3-NH2 [R3 is a (substituted) alkyl or the like] to give a compound of formula IV, which is subjected to a ring closure reaction to give the objective compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

Embedded image Wherein R ¹ is a hydrogen atom or an alkyl group;
² represents an optionally substituted alkyl group; R ³ represents an optionally substituted alkyl, cycloalkyl, aryl or heterocyclic group; R ⁴ represents a hydrogen atom, a halogen atom, One or more selected from an alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group, a nitro group, a cyano group, an acyl group, an optionally protected hydroxyl group, and an optionally protected or substituted amino group R ⁵ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl,
An alkoxy or alkylthio group, a nitro group, a cyano group, an acyl group, an optionally protected hydroxyl group,
D is one or more groups selected from an amino group which may be protected or substituted, a group forming a cycloalkane ring together with a carbon atom to which R ⁵ is bonded; D is a 5- or 6-membered heterocyclic ring or hydrocarbon The rings are respectively shown. And a method for producing a useful intermediate for producing the quinolonecarboxylic acid or a salt thereof represented by the formula:

[0002]

2. Description of the Related Art As a method for producing a compound of the general formula [1],
The method described in WO 97/29102 is known.

[0003]

Among the compounds of the general formula [1], (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H
-5-isoindolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is a particularly excellent compound as an antibacterial agent, and is useful for producing a compound of the general formula [1]. The following general formula [2] which is a useful intermediate

Embedded image Wherein R ^1b is a carboxyl protecting group; R ² is an optionally substituted alkyl group; R ³ is an optionally substituted alkyl, cycloalkyl, aryl or heterocyclic group; The development of an industrially useful method for producing a 7-bromo-quinolone carboxylic acid derivative represented by the formula:

[0004]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies. As a result, the following intermediates using 2,4-dibromo-3-hydroxybenzoic acid ester as a raw material were obtained. The method of passing is represented by 7 in the general formula [2].
The present inventors have found that this is an excellent method as an industrial production method of a -bromo-quinolonecarboxylic acid derivative, and have completed the present invention.

Hereinafter, the present invention will be described in detail. In the present specification, unless otherwise specified, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; an alkyl group means, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, te
a linear or branched C _1-10 alkyl group such as rt-butyl, pentyl, hexyl, heptyl and octyl; an alkenyl group is, for example, vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl And branched C such as octenyl and
_2-10 alkenyl group; the cycloalkyl group, for example, cyclopropyl, cyclobutyl, _{C 3-6} cycloalkyl groups such as cyclopentyl and cyclohexyl;

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; an alkoxycarbonyl group is, for example, methoxycarbonyl, An alkoxy-CO- group such as ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl; an alkylamino group is, for example, , Methylamino, ethylamino,
Linear or branched C such as propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and dipentylamino;
An amino group substituted with a _1-10 alkyl group;

The alkylthio group includes, for example, methylthio, ethylthio, n-propylthio, isopropylthio,
n-butylthio, isobutylthio, sec-butylthio, tert
Linear or branched C such as -butylthio, pentylthio, hexylthio, heptylthio and octylthio;
_An acyl group includes, for example, a linear or branched C _2-5 alkanoyl group such as formyl group, acetyl and ethylcarbonyl and an aroyl group such as benzoyl and naphthylcarbonyl; an aryl group; Is, for example, a phenyl and naphthyl group;
Aralkyl groups include, for example, benzyl, phenethyl,
A diphenylmethyl and triphenylmethyl group; a heterocyclic group is an oxygen atom as a hetero atom forming the ring,
A 4-, 5- or 6-membered ring containing one or more heteroatoms selected from a nitrogen atom and a sulfur atom or a fused ring thereof, for example, oxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, Imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl and morpholinyl groups are respectively meant. As the cycloalkane ring for R ⁵ , for example, a cycloalkane ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc., and as a 5-membered or 6-membered heterocyclic ring for D, as a heteroatom forming the ring A heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, for example, triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, 5- or 6-membered aromatic heterocycle such as isothiazole, pyrazole, pyran, furazane; tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, piperidine, dioxane, oxathiane, morpholine, thiomorpholine, dithiane, piperazine, Pi 5- or 6-membered aliphatic heterocycle such as loridine, tetrahydrothiophene, tetrahydrofuran, pyrazolidine, imidazolidine, tetrahydroisothiazole, 1,3-thiazolan, tetrahydroisoxazole, 1,3-oxazolan, dithiolan, oxathiolan, dioxolan, etc. Is mentioned. As the 5- or 6-membered hydrocarbon ring for D, benzene, cyclohexene,
5- or 6-membered unsaturated hydrocarbon rings such as cyclopentene; and saturated hydrocarbon rings such as cyclohexane and cyclopentane. In addition, in this specification, lower means C1-5. However, lower in the lower alkenyl group means having 2 to 5 carbon atoms.

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

The carboxyl protecting group includes all groups that can be used as a usual carboxyl protecting group, and includes, for example, methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl and tert-butyl. Alkyl groups; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl, p-
Aralkyl groups such as nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; acyl- groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl Lower alkyl group; 2
Oxygen-containing heterocyclic groups such as 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; nitrogen-containing heterocyclic-lower alkyl groups such as phthalimidomethyl and succinimidomethyl; cycloalkyl groups such as cyclohexyl; methoxymethyl, methoxyethoxymethyl And lower alkoxy-lower alkyl groups such as 2- (trimethylsilyl) ethoxymethyl;
Al-lower alkoxy-lower alkyl groups such as benzyloxymethyl; lower alkylthio-lower alkyl groups such as methylthiomethyl and 2-methylthioethyl; arylthio-lower alkyl groups such as phenylthiomethyl;
1,1-dimethyl-2-propenyl, 3-methyl-3-
Lower alkenyl groups such as butenyl and allyl; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl And the like.

The hydroxyl-protecting group includes all groups that can be used as ordinary hydroxyl-protecting groups, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-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-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,
Acyl groups such as dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; lower alkyl groups such as methyl, ethyl and tert-butyl; 2,2,
2-trichloroethyl, 2-trimethylsilylethyl,
Substitution such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1-methyl-1-methoxyethyl Lower alkyl groups; lower alkenyl groups such as allyl; benzyl, p-methoxybenzyl,
Aralkyl groups such as 3,4-dimethoxybenzyl, diphenylmethyl and trityl; tetrahydrofuryl,
Oxygen- and sulfur-containing heterocyclic groups such as tetrahydropyranyl and tetrahydrothiopyranyl; lower alkyl- and aryl-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropyl Substituted silyl groups such as silyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl, and the like.

R ² alkyl group; R ³ alkyl group, cycloalkyl group, aryl group or heterocyclic group; R ⁴ alkyl group, alkenyl group, cycloalkyl group, aryl group, alkoxy group, alkylthio group or amino group Group;
An alkyl group, an alkenyl group, a cycloalkyl group for R ⁵ ,
An aralkyl group, an aryl group, an alkoxy group, an alkylthio group or an amino group is a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group,
One or more of a lower alkylamino group which may be protected, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, and a lower alkyl group substituted with a halogen atom. May be substituted with a group. Next, the manufacturing method of the present invention will be described.

[0012]

(Equation 1)

Wherein R ^1a , R ^1b , R ² , R ³ and X have the same meaning as described above. General formulas [2], [3], [4], [5], [6],
The compounds of [7], [8] and [9] can also be in the form of salts, which are usually known as basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups. Salts may be mentioned.
Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; tartaric acid, formic acid, lactic acid,
Salts with organic carboxylic acids such as citric acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid; Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine,
N, N-dimethylaniline, N-methylpiperidine, N
-Methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and salts with nitrogen-containing organic bases such as N, N′-dibenzylethylenediamine, and the like. .

(1) Method for producing a compound of the general formula [5] or a salt thereof A compound of the general formula [4] is reacted with a compound of the general formula [3] or a salt thereof in the presence or absence of a base. Thus, the compound of the general formula [5] or a salt thereof can be produced. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, for example, n-
Aliphatic hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane; methylene chloride, chloroform and dichloroethane Halogenated hydrocarbons; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide; and water. You may use it. When water is used as the reaction solvent, it is effective to use a generally known phase transfer catalyst. Examples of the phase transfer catalyst to be used include quaternary ammonium salts such as tetramethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride and tetrabutylammonium hydrogensulfate. When the phase transfer catalyst is used, the amount of the phase transfer catalyst is determined by the general formula [3]
The amount may be 0.1 mole or more, and preferably 0.3 to 1.0 mole, based on the compound or a salt thereof. Bases used as desired include, for example, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amounts of the base and the compound of the general formula [4] to be used may be at least equimolar to the compound of the general formula [3] or a salt thereof, preferably 1 to 10 times. . This reaction is usually 0-
It may be carried out at 180 ° C. for 5 minutes to 30 hours. The obtained compound of the general formula [5] or a salt thereof may be used for the next reaction without isolation.

(2) Preparation of the compound of the general formula [6] or a salt thereof The compound of the general formula [5] or a salt thereof is subjected to an ordinary elimination reaction of a carboxyl protecting group to give a compound of the general formula [6]
Or a salt thereof.

(3) Method for preparing compound of general formula [7] or a salt thereof The compound of general formula [7] or a salt thereof is generally known from the compound of the general formula [6] or a salt thereof. It can be obtained by subjecting to a ketoesterification reaction. (A) Angew. Chem. Int.
Ed. Engl.) Vol. 18, p. 72 (1979), activating the carboxyl group of the compound of the general formula [6] or a salt thereof, for example, N, N'-carbonyldiene. After derivatization to an active acid amide or the like with imidazole, it is reacted with a magnesium salt of malonic acid monoester to give a compound of the general formula [7]
Or a salt thereof. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and diethyl ether. Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; and N, N
Amides such as -dimethylformamide and N, N-dimethylacetamide, and these solvents may be used as a mixture. The amount of the magnesium salt of malonic acid monoester to be used may be at least equimolar to the compound of the general formula [6] or a salt thereof, and preferably 1 to 2 moles. This reaction is usually 0
It may be carried out at 〜100 ° C., preferably 10-80 ° C., for 5 minutes to 30 hours. (B) Alternatively, for example, a carboxyl group of a compound of the general formula [6] or a salt thereof is converted to an acid halide with a halogenating agent such as thionyl chloride, and then a metal salt such as sodium or ethoxymagnesium malonate diester is used. And partially subjecting the carboxyl-protecting group to elimination and decarboxylation using p-toluenesulfonic acid or trifluoroacetic acid in an aqueous solvent to obtain a compound of the general formula [7] or a salt thereof. be able to. The solvent used in the reaction with the acid halide and the metal salt of malonic acid diester is not particularly limited as long as it does not adversely affect the reaction, and specifically, the same as (3) (a) described above. Solvents. The amount of the metal salt of malonic acid diester used may be at least equimolar to the compound of the general formula [6] or a salt thereof, and preferably 1 to 3 moles. This reaction is usually carried out at -50
It may be carried out at 〜100 ° C. for 5 minutes to 30 hours.

(4) Method for producing the compound of the general formula [9] or a salt thereof (a) The compound of the general formula [9] or the salt thereof can be added to the compound of the general formula [7] or a salt thereof in orthoacetic acid in acetic anhydride. It can be obtained by reacting an orthoester such as methyl acid or ethyl orthoformate and then reacting the compound of the general formula [8] or a salt thereof. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, for example, benzene,
Aromatic hydrocarbons such as toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol, ethanol and propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These solvents may be used as a mixture. The amount of the orthoester used may be at least equimolar to the compound of the general formula [7] or a salt thereof, and is preferably 1 to 10
What is necessary is just a double mole. These reactions are usually 0-150
C., preferably at 50 to 150.degree. C. for 20 minutes to 50 hours. Then, in order to react the compound of the general formula [8] or a salt thereof, the compound of the general formula [8] or the salt thereof is used in an amount of at least equimolar to the compound of the general formula [7] or the salt thereof. It may be carried out usually at 0 to 100 ° C., preferably at 10 to 60 ° C. for 20 minutes to 30 hours. (B) Alternatively, a compound of the general formula [7] or a salt thereof may be added to an N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide in the presence or absence of an acid anhydride such as acetic anhydride. After reacting an acetal such as diethyl acetal, the compound of the general formula [8] or a salt thereof can be reacted to obtain a compound of the general formula [9] or a salt thereof. When an acid anhydride is used, the amount of the acid anhydride to be used may be at least equimolar to the compound of the general formula [7] or a salt thereof, and preferably 1 to 5 times. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include the same solvents as in the above (4) (a). The amount of the acetal used may be at least equimolar to the compound of the general formula [7] or a salt thereof, and preferably about 1 to 5 moles. These reactions are usually carried out at 0 to 100 ° C., preferably at 20 ° C.
It may be carried out at ~ 85 ° C for 20 minutes to 50 hours. Next, in order to react the compound of the general formula [8] or a salt thereof, the compound of the general formula [8] or the salt thereof is used in an equimolar amount or more with respect to the compound of the general formula [7] or the salt thereof. Normally, it is usually 0 to 100 ° C., preferably 10 to 60 ° C. for 20 minutes to
It should be carried out for 30 hours. (C) Alternatively, the carboxyl group of the compound of the general formula [6] or a salt thereof is converted to an acid halide with a halogenating agent such as thionyl chloride, and then ethyl 3-dimethylaminoacrylate and 3-cyclopropylamino A 3-amino-acrylic acid derivative such as acrylic acid ethyl ester may be reacted, and in some cases, a compound of the general formula [8] or a salt thereof may be reacted to obtain a compound of the general formula [9] or a salt thereof. it can. The solvent used in the reaction with the acid halide and the 3-amino-acrylic acid derivative is not particularly limited as long as it does not adversely affect the reaction.Specifically, the same as (3) (a) described above. Solvents. The amount of the 3-aminoacrylic acid to be used may be at least equimolar to the compound of the general formula [6] or a salt thereof, preferably 1 to 3 times. These reactions are usually performed at 0 to 150 ° C, preferably at 50 to 110 ° C.
Then, it may be carried out for 30 minutes to 50 hours. Then, in order to react the compound of the general formula [8] or the salt thereof, the compound of the general formula [8] or the salt thereof may be used in an equimolar amount or more with respect to the compound of the general formula [6] or the salt thereof. The reaction may be carried out usually at 0 to 100 ° C., preferably at 10 to 60 ° C. for 20 minutes to 30 hours.

(5) Preparation of the compound of the general formula [2] or a salt thereof The compound of the general formula [2] or a salt thereof is prepared by converting the compound of the general formula [9] or a salt thereof in the presence of a fluoride salt or a base. Alternatively, it can be obtained by subjecting to a ring closure reaction in the absence. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction,
Examples include amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and dimethyl cellosolve; sulfoxides such as dimethyl sulfoxide; and water. The solvents may be used as a mixture. As the fluoride salt used as desired in this reaction, for example, sodium fluoride, potassium fluoride and the like can be mentioned. Examples of the base optionally used in this reaction include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amounts of the fluoride salt and the base used may be each equimolar or more with respect to the compound of the general formula [9] or a salt thereof.
Preferably, it may be 1.0 to 3.0 moles. This reaction may be usually performed at 0 to 180 ° C. for 5 minutes to 30 hours.
The obtained compound of the general formula [2] or a salt thereof may be used for the next reaction without isolation.

The thus-obtained compound of the general formula [2] or a salt thereof is subjected to, for example, a protection reaction and / or a deprotection reaction to give another compound of the general formula [2] or a salt thereof. Can be guided.

The general formulas [2] to
In the compound of [9] or a salt thereof, isomers (eg, optical isomers, geometric isomers, tautomers, and the like)
When these are present, these isomers can be used, and solvates, hydrates and various forms of crystals can be used. In the compounds of the general formulas [3] to [9] or salts thereof, the compound having an amino group, a hydroxyl group or a carboxyl group may be protected with a conventional protecting group in advance, and after the reaction, These protecting groups can be eliminated by a method known per se.

Next, a method for producing the compound of the general formula [1] or the salt thereof from the compound of the general formula [2] or the salt thereof will be described. The compound of general formula [1] or a salt thereof can be produced, for example, as shown in formula 2.

[0022]

(Equation 2)

[Wherein R ¹ , R ^1b , R ² , R ³ ,
R ⁴ , R ⁵ and D have the same meaning as described above, and R ⁶ and R ⁷ represent a hydrogen atom or a lower alkyl group or a ring formed together. As the ring formed by R ⁶ and R ⁷ together,
A 5- to 8-membered ring containing one or more hetero atoms selected from an oxygen atom and a nitrogen atom as a hetero atom forming the ring, or a fused ring thereof, for example, 1,3,2-dioxaborolan, 3,2-dioxaborinane, 1,3,5,2-dioxaazaborinane, 1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocan and 1,3, 6,
2-dioxaazaborocan and the like.

The compound of the general formula [1] or a salt thereof can be prepared by using a palladium catalyst in the presence or absence of a base.
It can be obtained by subjecting a compound of the general formula [10] or a salt thereof and a compound of the general formula [2] or a salt thereof 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 hydrocarbons such as benzene, toluene and xylene. Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as dioxane, tetrahydrofuran, anisole, 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 N, N-
Examples thereof include amides such as dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These solvents may be used as a mixture. Bases used as desired in this reaction include, for example, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, and the like. Examples of the palladium catalyst used in this reaction include palladium-active carbon and metal palladium such as palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; tetrakis (triphenylphosphine) palladium (0) And organic palladium complexes such as bis (triphenylphosphine) palladium (II) chloride and 1,1'-bis (diphenylphosphino) ferrocenepalladium (II) chloride. The amount of the palladium catalyst used may be 0.01% mol or more based on the compound of the general formula [2] or a salt thereof, and is preferably
It may be 0.1 to 1.0% mol. The amount of the compound of the general formula [10] or a salt thereof to be used is equimolar or more, preferably 1.0 to 1.5 times, with respect to the compound of the general formula [2] or a salt thereof. This coupling reaction is usually performed under an inert gas (eg, argon, nitrogen) atmosphere at 50 to 170 ° C.
Then, it may be performed for 1 minute to 24 hours. Examples of the salt of the compound of the general formula [1] include salts similar to the salts of the compounds of the general formulas [2] to [9]. The compound of the general formula [10] or a salt thereof can be produced, for example, by the method described in WO 97/29102. Examples of the salt of the compound of the general formula [10] include salts similar to the salts of the compounds of the general formulas [2] to [9].

[0025]

EXAMPLES Next, the present invention will be described with reference to Reference Examples, Examples and Production Examples, but the present invention is not limited to these.

The mixing ratios in the eluents were all dose ratios, and silica gel, 100-270 mesh (manufactured by Fuji Silysia) was used as the carrier in the column chromatography.

Reference Example 1 A mixture of 193.3 g of bromine and 600 ml of methylene chloride was subjected to -20 ° C.
Then, 176.1 g of tert-butylamine is added dropwise over 1 hour. After stirring at the same temperature for 1 hour, 100.0 g of m-hydroxybenzoic acid ethyl ester is added in 5 portions, and the mixture is stirred at the same temperature for 2 hours, at 0 ° C for 1 hour, and further at room temperature for 10 hours. The precipitated crystals are collected by filtration, and 500 ml of ethyl acetate and 300 ml of 6 mol / L hydrochloric acid are added to the obtained mixture, and the organic layer is separated. The obtained organic layer is washed with brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by distillation under reduced pressure (135-142 ° C / 0.5 mmHg) to obtain 121.0 g of 2,4-dibromo-3-hydroxybenzoic acid ethyl ester as a colorless oil. IR (KBr) cm ^-1 : ν _{c = o} 1722 NMR (CDCl ₃ ) δ value: 1.40 (3H, t, J = 7.1 Hz), 4.40 (2H, q, J = 7.
1Hz), 6.39 (1H, brs), 7.26 (1H, d, J = 8.3Hz), 7.52 (1H, d, J =
(8.3Hz)

Example 1 2,4-Dibromo-3 was added to a mixture of 400 ml of 35% aqueous sodium hydroxide solution and 49.8 g of tetrabutylammonium bromide.
-Hydroxybenzoic acid ethyl ester 100.0 g of toluene
After adding 400 ml of the mixed solution, 53.4 g of chlorodifluoromethane is blown in at room temperature over 1 hour. 400 ml of water is added to the reaction mixture, and the organic layer is separated. The obtained organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
The solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography [eluent; n-hexane: ethyl acetate = 1]
0: 1], colorless crystals of 2,4-dibromo-3-
110.8 g of ethyl difluoromethoxybenzoate are obtained. IR (KBr) cm ^-1 : v _{c = o} 1727 NMR (CDCl ₃ ) δ value: 1.41 (3H, t, J = 7.1 Hz), 4.41 (2H, q, J = 7.
1Hz), 6.65 (1H, t, J = 74.0Hz), 7.48 (1H, d, J = 8.3Hz), 7.66 (1
(H, d, J = 8.3Hz)

Example 2 10.0 g of ethyl 2,4-dibromo-3-hydroxybenzoate was dissolved in 10 ml of N, N-dimethylformamide, and 4.5 g of potassium carbonate was added thereto, followed by N, N-dimethyl of chlorodifluoromethane. 100 ml of a formamide solution (10 molar solution) is added and stirred in a sealed tube at 120-130 ° C. for 3 hours. The reaction mixture is added to a mixed solvent of 100 ml of ethyl acetate and 100 ml of water, adjusted to pH 2 with 6 mol / L hydrochloric acid, and then the organic layer is separated. The obtained organic layer is washed with brine, 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 = 4: 1] to obtain 10.8 g of 2,4-dibromo-3-difluoromethoxybenzoic acid ethyl ester as colorless crystals. The ester is hydrolyzed according to a conventional method to give 2,4-dibromo-3-difluoromethoxybenzoic acid. IR (KBr) cm ^-1 : ν _{c = o} 1717 NMR (CDCl ₃ ) δ value: 6.68 (1H, t, J = 74.0 Hz), 7.60-7.90 (2H,
m), 8.83 (1H, brs)

Example 3 2,4-Dibromo-3-difluoromethoxybenzoic acid 10
Dissolve 0.0 g in methylene chloride 600 ml, imidazole 21.6 g
After addition of 96.5 g of triethylamine and 37.8 g of thionyl chloride under ice-cooling, the mixture is stirred at the same temperature for 30 minutes and further at room temperature for 1 hour. Then, 27.5 g of magnesium chloride,
29.3 g of triethylamine, 98.4 g of malonic acid monoethyl ester potassium salt and N, N-dimethylformamide 10
0 ml is added in sequence, and the mixture is refluxed for 6 hours. Water 6 to the reaction mixture
After adding 00 ml and adjusting the pH to 1 with 6 mol / L hydrochloric acid, the organic layer is separated. The obtained organic layer is washed successively with a saturated aqueous solution of sodium hydrogencarbonate 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 = 20: 1] to give colorless crystals of 2,2.
108.2 g of ethyl 4-dibromo-3-difluoromethoxybenzoylacetate are obtained. IR (KBr) cm ^-1 : ν _{c = o} 1670 NMR (CDCl ₃ ) δ value: 1.25 (1.8 H, t, J = 7.1 Hz), 1.34 (1.2 H, t,
J = 7.1Hz), 3.98 (1.2H, s), 4.19 (1.2H, q, J = 7.1Hz), 4.29 (0.
8H, q, J = 7.1Hz), 5.40 (0.4H, s), 6.65 (1H, t, J = 73.7Hz), 7.2
5 (1H, d, J = 8.3Hz), 7.65 (0.6H, d, J = 8.3Hz), 7.69 (0.4H, d, J
= 8.3Hz), 12.41 (0.4H, s)

Example 4 100.0 g of ethyl 2,4-dibromo-3-difluoromethoxybenzoylacetate was dissolved in 600 ml of methylene chloride, 31.9 g of acetic anhydride and 37.2 g of N, N-dimethylformamide dimethyl acetal were added, and the mixture was added at room temperature. Stir for 1 hour and evaporate the solvent under reduced pressure. The obtained residue was dissolved in 500 ml of isopropanol, and 14.8 g of cyclopropylamine was dissolved.
And stirred at room temperature for 1 hour, and the precipitated crystals are collected by filtration to obtain 95.2 g of colorless crystals of ethyl 2- (2,4-dibromo-3-difluoromethoxybenzoyl) -3-cyclopropylaminoacrylate. . IR (KBr) cm ^-1 : ν _{c = o} 1675, 1621 NMR (CDCl ₃ ) δ value: 0.60-1.20 (7H, m), 2.80-3.20 (1H, m),
3.96 (2H, q, J = 7.1Hz), 6.61 (1H, t, J = 74.0Hz), 6.92 (1H, d, J
= 8.3Hz), 7.58 (1H, d, J = 8.3Hz), 8.28 (0.8H, d, J = 13.9Hz),
8.37 (0.2H, d, J = 13.9Hz), 9.60-9.90 (0.2H, m), 10.80-11.3
0 (0.8H, m)

Example 5 100.0 g of ethyl 2- (2,4-dibromo-3-difluoromethoxybenzoyl) -3-cyclopropylaminoacrylate was dissolved in 400 ml of dimethyl sulfoxide, 34.3 g of potassium carbonate was added, and 90 ° C. And stir for 2 hours. The reaction mixture was cooled to room temperature, added to 800 ml of water, and the precipitated crystals were collected by filtration to give colorless crystals of 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3. -Carboxylic acid ethyl ester
78.3 g are obtained. IR (KBr) cm ^-1 : ν _{c = o} 1687, 1640 NMR (CDCl ₃ ) δ value: 0.70-1.70 (7H, m), 3.70-4.70 (3H, m),
6.52 (1H, t, J = 74.5Hz), 7.58 (1H, d, J = 8.5Hz), 8.24 (1H, d, J
= 8.5Hz), 8.59 (1H, s)

Example 6 2,4-Dibromo-3-difluoromethoxybenzoic acid 10.
0 g is dissolved in 30 ml of toluene, 0.2 g of N, N-dimethylformamide is added, then 4.13 g of thionyl chloride is added under ice cooling, and the mixture is heated under reflux for 2 hours. Then, after cooling to room temperature, 10.2 g of triethylamine and 4.14 g of ethyl 3-dimethylaminoacrylate are sequentially added at room temperature, and the mixture is heated at 60 ° C. for 5 hours. After cooling to room temperature, cyclopropylamine 1.65 g
And stirred at room temperature for 30 minutes. 20 ml of water is added to the reaction mixture, and the organic layer is separated. The solvent was distilled off from the obtained organic layer under reduced pressure, 35 ml of isopropyl alcohol was added to the obtained crystal, and the mixture was recrystallized by heating to give colorless crystals of 2- (2,4-dibromo-3-difluoromethoxybenzoyl) -3. 7.93 g of ethyl cyclopropylaminoacrylate are obtained.

Production Example 1 (R) -2- (2,2-dimethylpropanoyl) -1-
Methyl-5- (4,4,5,5-tetramethyl-1,3,2
-Dioxaborolan-2-yl) isoindoline (2.5 g) was dissolved in ethanol (15 ml), and ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate was added thereto. 2.8 g of ester and 1.1 g of sodium carbonate are added. Then
After adding 150 mg of 10% palladium-activated carbon under a nitrogen atmosphere, the mixture is stirred and refluxed for 3 hours under the same atmosphere. After cooling the reaction mixture, the reaction mixture was added to a mixed solvent of 15 ml of water and 30 ml of acetone, and the obtained precipitate was collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7- [2- (2, 2-dimethylpropanoyl) -1-methyl-2,3-dihydro-
1H-5-isoindolyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester 3.6 g is obtained.

Production Example 2 (R) -1-cyclopropyl-8-difluoromethoxy-7- [2- (2,2-dimethylpropanoyl) -1-
Methyl-2,3-dihydro-1H-5-isoindolyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester (34 g) was suspended in concentrated hydrochloric acid (68 ml).
After stirring and refluxing for an hour, 340 ml of water was added, and the solvent 170 was added under normal pressure.
The ml is distilled off in 3 hours. After cooling the reaction solution, 17 ml of ethanol was added, and the resulting precipitated crystals were collected by filtration. The obtained (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro-3-
The quinoline carboxylic acid / hydrochloride was suspended in 340 ml of water, adjusted to pH 7.5 with 2 mol / L sodium hydroxide under ice-cooling, and the obtained precipitated crystals were collected by filtration to obtain (R) -1-cyclopropyl- 8
-Difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-
1,4-dihydro-3-quinolinecarboxylic acid monohydrate 2
5.55 g are obtained.

Production Example 3 (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl) -4-oxo-1,4-dihydro- 3-
Quinolinecarboxylic acid monohydrate 24g 50% ethanol 192m
l, warmed to 40 ° C, methanesulfonic acid 5.7
Add 1 g to make a homogeneous solution. Then add 2.4 g of activated carbon,
After stirring at the same temperature for 10 minutes, the insoluble matter is removed by filtration. The filtrate is concentrated, and the resulting precipitate is collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-5-isoindolyl).
26.64 g of methanesulfonate monohydrate of -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid are obtained.

[0037]

Industrial Applicability The production method of the present invention is useful as a method for industrially producing a compound of the general formula [2] or a salt thereof, which is an intermediate of the compound of the general formula [1] useful as an antibacterial agent. .

Claims (1)

[Claims] 1. A compound of the general formula In the formula, R ^1a represents a carboxyl-protecting group. A 2,4-dibromo-3-hydroxybenzoic acid ester represented by the general formula R ² -X wherein R ² is substituted An alkyl group which may be
X represents a halogen atom. With a compound represented by the general formula: In the formula, R ^1a and R ² have the same meaning as described above, to give a 3-alkoxy-2,4-dibromobenzoate ester, which is then subjected to a elimination reaction of a carboxyl protecting group. , The general formula A 3-alkoxy-2,4-dibromobenzoic acid represented by "wherein R ² has the same meaning as described above" is obtained, and then subjected to a ketoesterification reaction to obtain a compound of the general formula Wherein R ^1b represents a carboxyl protecting group;
² has the same meaning as above. Give represented 3-alkoxy-2,4-dibromo-benzoyl acetic ester ", then after reacting the ortho ester or acetal of the general formula R ³ -NH _2" wherein, ^{R 3} is substituted Represents an alkyl, cycloalkyl, aryl or heterocyclic group which may be represented by the general formula: Wherein R ^1b , R ² and R ³ have the same meanings as described above.
A dibromobenzoyl) -3-substituted aminoacrylate is obtained and then subjected to a ring closure reaction. A method for producing a 7-bromo-quinolone carboxylic acid derivative represented by the formula: wherein R ^1b , R ² and R ³ have the same meanings as described above.