JP2000026460A - Production of 7-isoindoline-quinolonecarboxylic acid derivative and production of isoindoline-5-boronic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject derivative useful as an antibacterial agent by reacting each specific isoindolineboronic acid derivative with a quinolonecarboxylic acid (salt) derivative in the presence of a metallic palladium, etc., in a good efficiency, in a high purity and in a high yield. SOLUTION: This 7-isoindoline-quinolonecarboxylic acid derivative of formula III is obtained by reacting an isoindoline-5-boronic acid derivative (salt) of formula I [R3 is H, a halogen (substituted) alkyl or the like; R4 is H, an aryl or the like; R5 is H, a (substituted) alkyl or the like; R7, R8 are each H, a lower alkyl and form a ring by bonding together] with a 7-eliminable group- substituted quinolonecarboxylic acid (salt) of formula II [R1 is H or a carboxy protecting group; R2 is a (substituted) alkyl or the like; R6 is H, a halogen or the like; A is CH or the like; X2 is an eliminable group] in the presence of a palladium (salt). Further, it is preferable to obtain a compound of formula VI by reacting a compound of formula IV (X1 is a halogen) with a dialkoxyborane of formula V (Z is an alkylene) or the like, and to react with a compound of formula II without isolating the compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the following general formula [1] useful as an antibacterial agent:

Embedded image Wherein R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is an optionally substituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group;
³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group, a nitro group, a cyano group,
R ⁴ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, an at least one group selected from an acyl group, an optionally protected hydroxyl group, an optionally protected or substituted amino group; Alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio group, optionally protected hydroxyl or imino group, optionally protected or substituted amino group, alkylidene group, oxo group, carbon atom to which R ⁴ is bonded R ⁵ represents a hydrogen atom, an optionally substituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R ^{6 represents} one or more groups selected from a group forming a cycloalkane ring together with R ^6. Is a hydrogen atom, a halogen atom, an optionally substituted alkyl,
An alkoxy or alkylthio group, an optionally protected hydroxyl or amino group or a nitro group;
A represents CH or CY (Y represents a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group or an optionally protected hydroxyl group), respectively. The present invention relates to a method for producing 7-isoindoline-quinolonecarboxylic acid or a salt thereof represented by the general formula (1) and a method for producing an intermediate thereof.

[0002]

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

Embedded image Wherein, in the formula, R ³ , R ⁴ and R ⁵ have the same meaning as described above; X ¹ represents a halogen atom. The lithiated or Grignard 5-halogenoisoindoline derivative represented by the formula: After being subjected to the reaction, it is reacted with a trialkyl borate to give the following general formula [4b]

Embedded image Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above; and R ⁹ represents a hydrogen atom or an alkyl group. Or a salt thereof. Then, the following general formula [5a]

Embedded image Wherein, R ¹ , R ² , R ⁶ and A have the same meaning as described above; and X ³ represents a halogen atom.
The compound of the general formula [1] or a salt thereof is reacted with a halogenoquinolone carboxylic acid in the presence of a palladium complex such as bis (triphenylphosphine) palladium (II) chloride and tetrakis (triphenylphosphine) palladium (0). It states that it can be manufactured.

[0003]

Among the compounds of the general formula [1], the following compound named T-3811:
It is a compound which is particularly excellent as an antibacterial agent, and development of an industrial production method for this compound has been demanded.

Embedded image

[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 In the formula, R ³ , R ⁴ and R ⁵ have the same meaning as described above; R ⁷ and R ^{8 each} represent a hydrogen atom or a lower alkyl group or a ring formed together. Isoindoline-5-boronic acid derivative or a salt thereof, and the following general formula [5]

Embedded image In the formula, R ¹ , R ² , R ⁶ , A and X ² have the same meanings as described above. It has been found that it can be easily performed in the presence of metal palladium or a palladium salt.

The following general formula [4a]

Embedded image Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above; Z represents an alkylene group. The isoindolin-5-boronic acid derivative or its salt represented by the general formula Instead of boration via a chlorination or Grignard reaction, in the presence of a palladium catalyst, the following general formula [2]

Embedded image "R ^3, R ^4, R ⁵ and X ¹ are the a the same meaning as described." The 5-halogeno-isoindoline derivatives or salts thereof represented by easily reacting a dialkoxy borane or alkoxy diborane The compound of the general formula [4a] or a salt thereof is not isolated, but is reacted with the compound of the general formula [5] or a salt thereof to obtain a compound represented by the general formula [1]. It has been found that a so-called one-pot reaction for producing an isoindoline-quinolonecarboxylic acid derivative or a salt thereof can be performed. And
The present invention has been completed because they are useful methods as industrial production methods.

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;
The lower alkyl group is, for example, a linear or branched C _1-5 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. An alkenyl group is, for example, a linear or branched C _2-10 alkenyl group such as vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl; a lower alkenyl group is, for example, A straight-chain or branched C _2-5 alkenyl group such as vinyl and allyl; an alkylidene group is a straight-chain or branched group such as methylene, ethylidene, propylidene, isopropylidene, butylidene, hexylidene and octylidene; Chain C
_A lower alkylidene group;
For example, a linear or branched C _1-5 alkylidene group such as methylene, ethylidene, propylidene and isopropylidene; a cycloalkyl group is, for example, a C _3-6 such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A cycloalkyl group; a cycloalkane ring is, for example, a carbon atom such as cyclopropane, cyclobutane, cyclopentane and cyclohexane;
_An alkylene group, for example, ethylene, trimethylene, tetramethylene, 1,2
-Dimethylethylene, 1,3-dimethyltrimethylene,
A linear or branched _{C 1 -10} alkylene group such as 1,1,2,2-tetramethyl ethylene;

[0007] Alkoxy groups include, for example, methoxy,
Toxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, pliers
Ruoxy, hexyloxy, heptyloxy and octane
Linear or branched C such as tyloxy_1-10Al
A lower alkoxy group, for example, methoxy
Si, ethoxy, n-propoxy, isopropoxy, n-but
Xy, isobutoxy, sec-butoxy, tert-butoxy and
Or branched C such as and pentyloxy
_1-5An alkoxy group; a lower alkoxycarbonyl group;
Is, for example, methoxycarbonyl, ethoxycarbonyl
, N-propoxycarbonyl, isopropoxycarbonyl
, N-butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl and
And lower alkoxy such as pentyloxycarbonyl
CO-group (lower alkoxy is a straight-chain or branched
Branched C_{1- 5}Shows an alkoxy group. ); Lower alk
A ruamino group is, for example, methylamino, ethylamido.
No, propylamino, butylamino, pentylamino,
Hexylamino, dimethylamino, diethylamino,
Tylethylamino, dipropylamino, dibutylamino
And branched C such as dipentylamino
_{1 -5}An amino group substituted with an 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;
_A lower alkylthio group;
For example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-
A linear or branched C _1-5 alkylthio group such as butylthio, tert-butylthio and pentylthio; an alkylsulfonyl group is, for example, methylsulfonyl,
Linear or branched such as ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl and octylsulfonyl C _1-10 alkylsulfonyl group a; and the lower alkylsulfonyl group, for example, methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n- butylsulfonyl, iso-butylsulfonyl, sec- butylsulfonyl, tert- butylsulfonyl and A linear or branched C _1-5 alkylsulfonyl group such as pentylsulfonyl;
For example, a formyl group, a linear or branched C _2-5 alkanoyl group such as acetyl and ethylcarbonyl and an aroyl group such as benzoyl and naphthylcarbonyl; an aryl group includes, for example, a phenyl and naphthyl group; Sulfonyl groups include, for example, phenylsulfonyl and naphthylsulfonyl groups; aralkyl groups include, for example, benzyl and phenethyl groups;
The heterocyclic group is a 4-, 5- or 6-membered ring containing at least one heteroatom atom selected from an oxygen atom, a nitrogen atom and a sulfur atom as a heteroatom atom forming the ring, 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, respectively.

The amino, lower alkylamino and imino group-protecting groups include all groups which can be used as ordinary amino group-protecting groups, for example, 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, diphenylmethoxycarbonyl, 1.1 −
Dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,
Acyl groups such as 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and pivaloyl; al-lower alkyl groups such as benzyl, diphenylmethyl and trityl; arylthio groups such as 2-nitrophenylthio and 2,4-dinitrophenylthio Alkyl- or aryl-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene; benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5- Chlorobenzylidene and 2
Al-lower alkylidene groups such as -hydroxy-1-naphthylmethylene; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene; cyclohexylidene, 2-ethoxycarbonylcyclohexylidene;
2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-
Cycloalkylidene groups such as oxycyclohexylidene; diaryl- or dial-lower alkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl; And a substituted silyl group such as trimethylsilyl.

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

The hydroxyl group-protecting group includes all groups which can be used as ordinary hydroxyl group-protecting groups, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, Methoxybenzyloxycarbonyl,
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-adamantyloxy Carbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-
Acyl groups such as ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; methyl, tert- Lower alkyl groups such as butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl; lower alkenyl groups such as allyl; alkenyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl. Lower alkyl groups; oxygen- and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl;
Methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1-methyl-1-
Lower alkoxy- and lower alkylthio-lower alkyl groups such as methoxyethyl; methanesulfonyl and p-
Lower alkyl- and aryl-sulfonyl groups such as toluenesulfonyl; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert
And substituted silyl groups such as -butylmethoxyphenylsilyl.

[0012] alkyl in ^{R 2,} alkenyl, cycloalkyl, aryl or heterocyclic group; alkyl in ^{R 3,} alkenyl, cycloalkyl, aryl, alkoxy, alkylthio or amino group; the alkyl in ^{R 4,} alkenyl, cycloalkyl, Al alkyl, aryl, alkoxy, alkylthio or amino group; the alkyl in R ^5, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; alkyl in R ^6, an alkoxy or alkylthio group; and the alkyl in Y, an alkoxy or alkylthio group Examples of the substituent include a halogen atom, a cyano group, a carboxyl group which may be protected, a hydroxyl group which may be protected, an amino group which may be protected and Lower alkylamino group, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, aryl group, cycloalkyl group, lower alkenyl group, lower alkyl group substituted with a halogen atom which may be Alternatively, it may be substituted with two or more kinds of groups.

The ring formed by R ⁷ and R ⁸ together includes one or more hetero atoms selected from an oxygen atom and a nitrogen atom as the hetero atoms forming the ring.
Membered to 8-membered ring or a fused ring thereof, for example, 1,3,2-
Dioxaborolane, 1,3,2-dioxaborinane, 1,
3,5,2-dioxaazaborinane, 1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocan,
1,3,6,2-dioxaazaborocan and the like. Examples of the leaving group for X ² include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; methylsulfonyloxy;
An alkylsulfonyloxy group which may be substituted with a halogen atom such as trifluoromethylsulfonyloxy; and an arylsulfonyloxy group which may be substituted with a halogen atom such as p-fluorophenylsulfonyloxy. Next, the manufacturing method of the present invention will be described.

[0014]

(Equation 1)

[0015]

(Equation 2)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , A and Z have the same meaning as described above. General formulas [1], [2], [4], [4a] and [5]
May be salts, and examples of such salts include salts of commonly known basic groups such as amino groups or acidic groups such as hydroxyl or carboxyl groups. Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, lactic acid, 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; and as the salt in the acidic group, for example, 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,
Examples thereof include salts with a nitrogen-containing organic base such as 1-ephenamine and N, N'-dibenzylethylenediamine.

Production method 1 (1) A method for producing a compound of the general formula [1] or a salt thereof. The compound of the general formula [1] or a salt thereof is prepared by coupling the compound of the general formula [4] or the salt thereof with the compound of the general formula [5] or the salt thereof using metal palladium in the presence or absence of a base. It can be produced by subjecting to a ring 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;
Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used as a mixture. Bases used in this reaction as desired include, for example, potassium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine and the like. The amount of use is 1 mole or more, preferably 1 to 3 moles, per mole of the compound of the general formula [5] or a salt thereof. The metal palladium used in this reaction includes, for example, palladium-activated carbon, palladium black, and the like. As the palladium salt, for example, inorganic palladium salts such as palladium chloride,
Organic palladium salts such as palladium acetate are exemplified.
The amount of use thereof may be at least 0.00001 times mol, preferably 0.001 to 0.05 times mol, of the compound of the general formula [5] or a salt thereof. The amount of the compound of the general formula [4] or a salt thereof to be used is 1 mol or more, preferably 1.0 to 1.5 times, the mol of the compound of the general formula [5] 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. The general formula [5]
Or a salt thereof is described, for example, in WO 97/2910
2 can be produced.

Production method 2 (2.1) A method for producing a compound of the general formula [4a] or a salt thereof.
The compound of the general formula [4a] or a salt thereof can be prepared by adding a dialkoxyborane of the general formula [3a] or a salt of the general formula [3a] to a compound of the general formula [2] or a salt thereof using a palladium catalyst in the presence or absence of a base. It can be produced by reacting the alkoxydiborane of [3b]. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, for example, benzene, toluene,
Aromatic hydrocarbons such as xylene; aliphatic hydrocarbons such as n-hexane and cyclohexane; methylene chloride;
Halogenated hydrocarbons such as 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 And amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These solvents may be used as a mixture. Examples of the base optionally used in this reaction include, for example, potassium acetate, potassium tert-butoxide, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.
0] -7-undecene, tributylamine and triethylamine. The amount of use is 1 mole or more, preferably 1 to 3 moles, per mole of the compound of the general formula [2] or a salt thereof.

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, tetrakis (triphenylphosphine) palladium (0), organic palladium complexes such as bis (triphenylphosphine) palladium (II) chloride and 1,1′-bis (diphenylphosphino) ferrocene palladium (II) chloride. The amount of use thereof may be at least 0.00001 times mol, preferably 0.001 to 0.05 times mol, of the compound of the general formula [5] or a salt thereof. As the dialkoxyborane used in this reaction, for example,
4,4,5,5-tetramethyl-1,3,2-dioxaborolane, catecholborane and the like, and examples of alkoxydiborane include 4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl-4 ', 4',
5 ′, 5′-tetramethyl-1 ′, 3 ′, 2′-dioxaborolane and the like. The amount of use is at least equimolar to the compound of the general formula [2] or a salt thereof, preferably 1.0 to 1.0.
It is about 1.5 times mol. This reaction may be carried out usually at 0 to 150 ° C., preferably 80 to 110 ° C. for 1 to 24 hours under an inert gas (eg, argon, nitrogen) atmosphere.

(2.2) A method for producing a compound of the general formula [1] or a salt thereof. The compound of the general formula [1] or a salt thereof may be prepared by isolating the compound of the general formula [4a] or a salt thereof produced in the above (2.1) without isolation, if necessary. And an inert gas (eg, argon, nitrogen) in the presence or absence of a base, with the addition of a palladium catalyst
Under an atmosphere, a compound of the general formula [5] or a salt thereof is added,
It can be produced by further reacting.

The general formula [2] in the above-mentioned production method,
When isomers (for example, optical isomers, geometric isomers, tautomers, and the like) exist in the compounds of [4], [4a] and [5] or salts thereof, these isomers are used. And solvates, hydrates and various forms of crystals can be used. In addition, the amino group in the compounds of the general formulas [2], [4], [4a] and [5] or their salts is protected with a usual protecting group in advance, and after the reaction, these amino groups are obtained by a method known per se. Can also be removed. The compound of the general formula [1] or a salt thereof thus produced is extracted,
It can be isolated and purified according to one or more conventional methods such as crystallization and column chromatography.

In the compound of the general formula [1] produced by the method of the present invention, R ² is a cycloalkyl group which may be substituted; R ³ is a hydrogen atom, a halogen atom or an alkyl group. R ⁴ is a hydrogen atom or an alkyl group; R ⁵ is a hydrogen atom or an alkyl group; A is CH or CY (Y is a halogen atom, lower alkyl or lower alkoxy which may be substituted with a halogen atom; Represents a group.), And typical compounds include, for example, the following compounds.

1-cyclopropyl-7- (isoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8-chloro-1-cyclopropyl-7- (isoindoline -5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-fluoro-7- (isoindoline-5-yl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (isoindoline-5-yl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7 -(Isoindoline-5-yl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-difluoromethoxy-7-
(Isoindoline-5-yl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (isoindoline-5-yl) -8-trifluoromethyl-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid

7- (7-chloroisoindoline-5
Yl) -1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (7-fluoroisoindoline-5-yl) -1,4 -Dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (7-fluoroisoindolin-5-yl) -8-methyl-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (7-fluoroisoindolin-5-yl) -8-methoxy-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-difluoromethoxy-7-
(7-fluoroisoindoline-5-yl) -1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (7-fluoroisoindoline-5-yl) -8-trifluoromethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-methoxy-7- (7-methylisoindoline-5-yl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (2-methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-8-methyl-7-
(2-methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-methoxy-7- (2-methylisoindoline-5-yl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-difluoromethoxy-7-
(2-methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (2-methylisoindoline-5-yl) -8-tri Fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(±) -1-cyclopropyl-7- (1
-Methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (±) -1-cyclopropyl-8-methyl-7- (1
-Methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (+)-1-cyclopropyl-8-methyl-7- (1
-Methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (-)-1-cyclopropyl-8-methyl-7- (1
-Methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (±) -1-cyclopropyl-8-methoxy-7-
(1-methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (+)-1-cyclopropyl-8-methoxy-7-
(1-Methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (-)-1-cyclopropyl-8-methoxy-7-
(1-methylisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (±) -1-cyclopropyl-8-difluoromethoxy-7- (1-methylisoindoline -5-yl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (+)-1-cyclopropyl-8-difluoromethoxy-7- (1-methylisoindoline-5-yl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid (-)-1-cyclopropyl-8-difluoromethoxy-7- (1-methylisoindoline-5-yl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-7- (4-fluoroisoindolin-5-yl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4-fluoroisoindolin-5-yl) -8-methyl-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4-fluoroisoindoline-5-yl) -8-methoxy-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-difluoromethoxy-7-
(4-fluoroisoindoline-5-yl) -1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4-fluoroisoindoline-5-yl) -8-trifluoromethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (6-fluoroisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclo Propyl-7- (6-fluoroisoindolin-5-yl) -8-methyl-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (6-fluoroisoindolin-5-yl) -8-methoxy-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8-difluoromethoxy-7-
(6-fluoroisoindoline-5-yl) -1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (6-fluoroisoindoline-5-yl) -8-trifluoromethyl-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid

1-cyclopropyl-7- (4,7-difluoroisoindoline-5-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4 , 7-Difluoroisoindoline-5-yl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-difluoroisoindoline-5- Yl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-difluoroisoindoline-5-yl) -8-difluoromethoxy-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-7- (4,7-difluoroisoindolin-5-yl) -8-trifluoromethyl-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid

In the compound of the general formula [4a] produced by the method of the present invention, a preferred compound is R
³ is a hydrogen atom, a halogen atom or an alkyl group; R ⁴
Is a hydrogen atom or an alkyl group; R ⁵ is a hydrogen atom or an alkyl group; and Z is 1,1,2,2-tetramethylethylene, and typical compounds include, for example, The compound of.

5- (4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl) isoindoline7-chloro-5- (4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl) isoindoline7-fluoro-5- (4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl) isoindoline 7-methyl-5- (4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl) isoindoline2-methyl-5- (4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl) isoindoline 1-methyl-5- (4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl) isoindoline (±) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindoline (+)-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindoline (-)-1-methyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindoline 4-fluoro-5- (4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl) isoindoline 6-fluoro-5- (4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl) isoindoline4,7-difluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoindoline

[0031]

EXAMPLES Next, the present invention will be described specifically with reference to examples and reference examples, but the present invention is not limited to these examples. The mixing ratios in the eluents are all volume ratios, and the carrier in column chromatography is
Silica gel 60, 70-230 mesh (Merck) was used.

Example 1 500 mg of (R) -5-bromo-2- (2,2-dimethylpropanoyl) -1-methyl-isoindoline was added to toluene 5
and 510 mg of triethylamine, bis (triphenylphosphine) palladium (II) chloride
After successively adding 35 mg and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane 330 mg, 5
Heat to reflux for hours. Then, 7-bromo-1-
After adding 480 mg of ethyl ethyl ester of cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 360 mg of sodium carbonate and 35 mg of bis (triphenylphosphine) palladium (II) chloride, a nitrogen atmosphere was added. Heat under reflux for 3 hours. The reaction solution is added to a mixed solvent of 20 ml of ethyl acetate and 10 ml of water, and the organic layer is separated. The separated organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 2) to give (R) -1-cyclopropyl-8-difluoromethoxy. -7- [2- (2,2-dimethylpropanoyl)-
470 mg of ethyl 1-methyl-2,3-dihydro-1H-isoindoline-5-yl] -4-oxo-1,4-dihydro-3-quinolinecarboxylate are obtained. IR (KBr) cm ^-1 : 1730,1610 NMR (CDCl ₃ ) δ value: 0.85 to 1.45 (4H, m), 1.37 (9H, s), 1.40
(3H, d, J = 6.0Hz), 1.50 (3H, t, J = 7.0Hz), 4.12 (1H, m), 4.41
(2H, q, J = 7.0Hz), 4.95 (1H, d, J = 12.0Hz), 5.08 (1H, d, J = 12.
0Hz), 5.50 (1H, q, J = 6.0Hz), 5.90 (1H, t, J = 76.0Hz), 7.39 (1
H, d, J = 8.0Hz), 7.41 (1H, d, J = 8.0Hz), 7.49 (1H, s), 7.54 (1
(H, d, J = 8.0Hz), 8.45 (1H, d, J = 8.0Hz), 8.69 (1H, s)

Example 2 1 g of (R) -5-bromo-2- (2,2-dimethylpropanoyl) -1-methyl-isoindoline was added to dioxane 10
and dissolved in 1.02 g of triethylamine, 1,1 ′.
-Bis (diphenylphosphino) ferrocene palladium (II) chloride and 4,4,5,5-tetramethyl-1,
After sequentially adding 650 mg of 3,2-dioxaborolane, the mixture is refluxed for 2 hours under a nitrogen atmosphere. 30 ml of ethyl acetate
The mixture is adjusted to pH 2 with 2 mol / L hydrochloric acid, and the organic layer is separated. The separated organic layer is washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate =
Purification by 5: 1) yields (R) -2- (2,2-dimethylpropanoyl) -1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) 400 mg of isoindoline are obtained. IR (KBr) cm ^-1 : 1740,1620,1360,1145 NMR (CDCl ₃ ) δ value: 1.33 (9H, s), 1.35 (12H, s), 1.46 (3H, d,
J = 6.0Hz), 4.93 (1H, d, J = 12.0Hz), 5.00 (1H, d, J = 12.0Hz),
5.46 (1H, q, J = 6.0Hz), 7.25 (1H, d, J = 7.0Hz), 7.71 (1H, s),
7.75 (1H, d, J = 7.0Hz)

Example 3 (R) -5-bromo-2- (2,2-dimethylpropanoyl) -1-methyl-isoindoline (200 mg) was dissolved in dimethyl sulfoxide (3 ml).
g, bis (triphenylphosphine) palladium (II)
14 mg of chloride and 4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl-4 ', 4', 5 ', 5'
-Tetramethyl-1 ', 3', 2'-dioxaborolane 170mg
Are successively added, and the mixture is refluxed for 5 hours under a nitrogen atmosphere.
The reaction solution is added to a mixed solvent of 10 ml of ethyl acetate and 10 ml of water, adjusted to pH 2 with 2 mol / L hydrochloric acid, and then the organic layer is separated. The separated organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give
(R) -2- (2,2-dimethylpropanoyl) -1-
Methyl-5- (4,4,5,5-tetramethyl-1,3,2
-Dioxaborolan-2-yl) isoindoline 140mg
Get.

Example 4 (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 and filtering the reaction mixture, the mixture was added to a mixed solvent of 15 ml of water and 30 ml of acetone.
The resulting precipitated crystals were collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7- [2- (2,2-
Dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-isoindoline-5-yl] -4-oxo-
3.6 g of 1,4-dihydro-3-quinolinecarboxylic acid ethyl ester are obtained.

Example 5 (R) -2- (2,2-dimethylpropanoyl) -1-
Methyl-5- (4,4,5,5-tetramethyl-1,3,2
-Dioxaborolan-2-yl) isoindoline 0.39 g
Was dissolved in a mixed solvent of 10 ml of acetone and 10 ml of water, and 0.5 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate and carbonic acid were added thereto. 0.26g potassium
Add. Then, under a nitrogen atmosphere, 1 mg of palladium acetate
, And refluxed with stirring for 2 hours under the same atmosphere. After cooling, the reaction mixture is added to a mixed solvent of 50 ml of ethyl acetate and 50 ml of water, 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 was dissolved in acetone (5 ml), water (5 ml) was added, the mixture was stirred for 30 minutes, water (30 ml) was further added, the mixture was stirred for 30 minutes, and the precipitated crystals were 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 0.52 g is obtained.

Reference Example 1 1-Cyclopropyl-8-difluoromethoxy-7-
[2- (2,2-Dimethylpropanoyl) -1-methyl-2,3-dihydro-1H-isoindoline-5-yl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester After suspending 34 g of concentrated hydrochloric acid in 68 ml and stirring and refluxing for 3 hours, 340 ml of water was added, and the solvent was 170 ml under normal pressure.
For 3 hours. After cooling the reaction solution, ethanol 1
7 ml is added, and the resulting precipitated crystals are collected by filtration. The obtained (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-isoindoline-5-yl) -4-oxo-1,4-dihydro- The 3-quinolinecarboxylic 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 give (R) -1-cyclohexane. Propyl-8-difluoromethoxy-7- (1-methyl-2,
3-dihydro-1H-isoindoline-5-yl) -4
-Oxo-1,4-dihydro-3-quinolinecarboxylic acid monohydrate 25.55 g is obtained.

Reference Example 2 (R) -1-cyclopropyl-8-difluoromethoxy-7- (1-methyl-2,3-dihydro-1H-isoindoline-5-yl) -4-oxo-1,4 -24 g of dihydro-3-quinolinecarboxylic acid monohydrate is suspended in 192 ml of 50% ethanol, heated to 40 ° C, and 5.71 g of methanesulfonic acid is added to make a homogeneous solution. Then, 2.4 g of activated carbon was added, and the mixture was stirred at the same temperature for 10 minutes, followed by filtration. The filtrate was concentrated, and the obtained precipitate was collected by filtration to give (R) -1-cyclopropyl-8-difluoromethoxy-7-. 26.64 g of methanesulfonate monohydrate of (1-methyl-2,3-dihydro-1H-isoindoline-5-yl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid is obtained. .

[0039]

Industrial Applicability The production method of the present invention provides industrial production of 7-isoindoline-quinolone carboxylic acid derivatives useful as antibacterial agents, particularly, T-3811 and its intermediate, isoindoline-5-boronic acid derivative. Useful as a law.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07F 5/02 C07F 5/02 C

Claims (2)

[Claims] 1. A compound represented by the following general formula [1] Wherein R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is an optionally substituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group;
³ is a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group, a nitro group, a cyano group,
R ⁴ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, an at least one group selected from an acyl group, an optionally protected hydroxyl group, an optionally protected or substituted amino group; Alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio group, optionally protected hydroxyl or imino group, optionally protected or substituted amino group, alkylidene group, oxo group, carbon atom to which R ⁴ is bonded R ⁵ represents a hydrogen atom, an optionally substituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R ^{6 represents} one or more groups selected from a group forming a cycloalkane ring together with R ^6. Is a hydrogen atom, a halogen atom, an optionally substituted alkyl,
An alkoxy or alkylthio group, an optionally protected hydroxyl or amino group or a nitro group;
A represents CH or CY (Y represents a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group or an optionally protected hydroxyl group), respectively. The method for producing the compound represented by the formula (1) is any one of the following or one of the following: In the presence of metal palladium or a palladium salt, the following general formula [4] In the formula, R ³ , R ⁴ and R ⁵ have the same meaning as described above; R ⁷ and R ^{8 each} represent a hydrogen atom or a lower alkyl group or a ring formed together. Isoindoline-5-boronic acid derivative or a salt thereof, and the following general formula [5]: In the formula, R ¹ , R ² , R ⁶ and A have the same meaning as described above; X ² represents a leaving group. A method comprising reacting a salt. In the presence of a palladium catalyst selected from palladium metal, palladium salt or palladium complex, the following general formula [2] A 5-halogenoisoindoline derivative or a salt thereof represented by the formula: wherein R ³ , R ⁴ and R ⁵ have the same meaning as described above; X ¹ represents a halogen atom. Wherein Z represents an alkylene group, or a dialkoxyborane represented by the formula: Wherein Z has the same meaning as described above, and is reacted with an alkoxydiborane represented by the following general formula [4a]. In the formula, R ³ , R ⁴ , R ⁵ and Z have the same meanings as described above. After forming an isoindoline-5-boronic acid derivative or a salt thereof, they are not isolated, The following general formula [5] Reacting a 7-leaving group-substituted-quinolonecarboxylic acid or a salt thereof represented by the formula: wherein R ¹ , R ² , R ⁶ , A and X ² have the same meanings as described above. Features method. 2. In the presence of a palladium catalyst selected from metal palladium, a palladium salt or a palladium complex, the following general formula [2]: Wherein R ³ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio group, a 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 represents a hydrogen atom, a halogen atom, an optionally substituted A good alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio group, an optionally protected hydroxyl or imino group, an optionally protected or substituted amino group, an alkylidene group, an oxo group, and R ⁴ R ⁵ represents a hydrogen atom, an optionally substituted alkyl, cycloalkyl, alkylsulfonyl,
X ^{1 represents} an arylsulfonyl, acyl or aryl group;
Represents a halogen atom. With a 5-halogenoisoindoline derivative or a salt thereof represented by the following formula: Wherein Z represents an alkylene group, or a dialkoxyborane represented by the formula: Wherein the compound is reacted with an alkoxydiborane represented by the following general formula [4a]: A method for producing an isoindoline-5-boronic acid derivative or a salt thereof represented by the formula: wherein R ³ , R ⁴ , R ⁵ and Z have the same meanings as described above.