JP3200203B2 - Quinolinecarboxylic acid derivatives and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate for producing an antibacterial compound and a method for producing the intermediate.

[0002]

2. Description of the Related Art Conventionally, formula (IV),

[0003]

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(Where R ¹Is defined as follows.
One. ) Quinolonecarboxylic acid-based synthetic antibacterial
Agent (hereinafter, referred to as compound (IV)) is 2,4,5-tri
The production was carried out using fluorobenzoic acid as a raw material.

[0005]

DISCLOSURE OF THE INVENTION The present inventors diligently studied a process for producing compound (IV) using less expensive 4-chloro-2,5-difluorobenzoic acid as a raw material.

[0006]

As a result, 4-chloro-
It has been found that 2,5-difluorobenzoic acid is converted into a compound of the formula (I) or (II) which is a boron chelate compound, and the object can be achieved by using the compound as a production intermediate, thereby completing the present invention. .

[0007]

The present invention provides a compound of the formula (I):

[0008]

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Wherein X ¹ and X ² each independently represent a halogen atom, and R represents a halogen atom or an alkoxyl group.

Further, the present invention provides a compound of the formula (II):

[0011]

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(Where X is¹Represents a halogen atom, R
Represents a halogen atom or an alkoxyl group;
¹Is the base

[0013]

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(Wherein R ² and R ³ each independently represent an alkyl group or a phenyl group), or a saturated heterocyclic substituent, and the saturated heterocyclic substituent Has a size of a four-membered ring to eight-membered ring, contains one or two nitrogen atoms as a component of the ring structure, and may further contain an oxygen atom or a sulfur atom as a component of the ring structure. The saturated heterocyclic substituent includes an amino group, a mono- or dialkylamino group containing an alkyl group having 1 to 6 carbon atoms, an alkylcarbonylamino group having 2 to 7 carbon atoms, and an alkyloxycarbonylamino group having 2 to 7 carbon atoms. Group, halogenoalkylcarbonyl group having 2 to 7 carbon atoms, halogenoalkyloxycarbonylamino group having 2 to 7 carbon atoms, phenylalkyloxycarbonylamino group (phenyl group may have a nitro group or a halogen atom), carbon number An alkyl group having 1 to 6 carbon atoms, an alkylene group having 2 to 5 carbon atoms (which forms a spiro ring system or a bicyclo ring system by combining with atoms forming a ring structure of a heterocyclic substituent), a halogen atom, or a carbon atom having 1 to 6 carbon atoms It may have one or more substituents selected from the group of substituents consisting of 1 to 6 alkoxyl groups. )).

Further, the present invention provides a compound of the formula (I)

[0016]

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The compound represented by the formula (III):

[0018]

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(Wherein R ¹Is as described above. )
Compound (hereinafter, referred to as compound (III)) or a salt thereof
(II) characterized by reacting

[0020]

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(Hereinafter referred to as compound (II)).

The compound (I) according to the present invention is a compound in which the carboxylic acid moiety is substituted and borated, and is considered to form a chelate with a carbonyl group as shown in the formula. The 1,4-dihydro-4-oxoquinoline compound having such a partial structure (—CO ₂ BR ₂ ) is referred to herein as a boron chelate or a chelate compound.

The substituents X ¹ of the compound (I) chloride, means a halogen atom such as fluorine, typically fluorine being preferred. The substituent X ² also means a halogen atom, and usually chlorine or fluorine is preferred.

The two substituents R bonded to boron represent a halogen atom or an alkoxyl group, and the two Rs may be the same or different. As the halogen atom, usually, a fluorine atom may be used. The alkoxyl group may have 1 to 6 carbon atoms.

Compound (I) can be produced, for example, by the method shown in Chemical formula 15.

[0026]

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That is, 4-chloro-2,5-difluorobenzoic acid is treated with thionyl chloride to give 4-chloro-2,5-difluorobenzoic acid.
5-Difluorobenzoyl chloride is reacted with a reagent synthesized from magnesium alkoxide and malonic diester to give 4-chloro-2,5-difluorobenzoylmalonic diester.

This is subjected to a decarboxylation reaction in the presence of a catalytic amount of an acid, and the resulting 4-chloro-2,5-difluorobenzoyl acetic acid ester is reacted with orthoformate to give 3
To obtain -alkoxy-2- (4-chloro-2,5-difluorobenzoyl) acrylate.

This is reacted with cis-1-amino-2-fluorocyclopropane to give 3- (cis-2-fluorocyclopropyl) amino-2- (4-chloro-
The 2,5-fluorobenzoyl) acrylate is treated under basic conditions to give 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline- A 3-carboxylic acid ester is obtained.

This is hydrolyzed to obtain 1- (cis-
2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is reacted with borofluoric acid to give 1- (cis-2
-Fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate can be obtained.

In the reaction for obtaining the chelate compound, 1-
(Cis-2-fluorocyclopropyl) -7-chloro-
6-Fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid may be reacted with boron trifluoride, a tetrahydrofuran complex or a diethyl ether complex of boron trifluoride, in addition to boron trifluoride. Incidentally, borofluoric acid is usually used as an aqueous solution.

The amount of boron trifluoride, boron trifluoride complex or borofluoric acid to be used is usually 1 to 50 mol per 1 mol of compound (I), but is preferably used. , In the range of 1 to 5 moles.

The solvent may or may not be used, but when used, ketones such as acetone and methyl ethyl ketone, diethyl ether, tetrahydrofuran,
Ether compounds such as 1,2-dimethoxyethane and dioxane, hydrocarbon compounds such as benzene, toluene and hexane, chloroform, methylene chloride, 1,2-
Various compounds such as halogenated hydrocarbons such as dichloroethane, acetonitrile, acetic acid, and acetic anhydride can be used, and a boron trifluoride complex or borofluoric acid may also be used as a solvent.

The amount of the solvent to be used may be about 2 to 50 times (volume / weight ratio) the compound (I), but usually about 2 to 5 times.

The reaction temperature may be generally in the range of 0 to 150 ° C., but is preferably in the range of 10 to 30 ° C.

The resulting compound (I) usually precipitates as a powdery or crystalline solid, and can be easily isolated by filtration.

Compound (II) or compound according to the present invention
Substituent R of (III) ¹Of which the heterocyclic substituent is
Represents That is, the heterocyclic substituent is a so-called cyclic
It means an amino group. Are cyclic amino groups cyclic amines?
Derived substituents, but cyclic amines are alicyclic compounds
The carbon atoms that make up the cyclic structure of the product
It is a compound having a structure that occurs instead. Compound (I
Size of cyclic amino group in I) or compound (III)
Is preferably a 4- to 8-membered ring, particularly a 5- to 5-membered ring.
Or a 6-membered ring is preferred. Oxazolidine, morpholy
, Thiazolidine, thiomorpholine, imidazolidine,
Acids as ring constituent atoms such as pyrazolidine and piperazine
May contain elemental, sulfur or multiple nitrogen atoms
No. Cyclic amino groups include pyrrolidines and pipera
Gins are particularly preferred.

The cyclic amino group may have a substituent. Examples of the substituent include an amino group which may have a substituent, an aminoalkyl group which may have a substituent,
A polar group such as a 5-substituted-2-oxo-1,3-dioxol-4-ylmethyl group or a hydroxyl group; a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms; Alkylene group. In the case of a polar group, it may be bonded to a cyclic amino group via an alkyl chain having 1 to 6 carbon atoms. Here, examples of the substituent of the amino group include an alkyl group, an acyl group, and an alkyloxycarbonyl group. When the cyclic amino group has a substituent, the cyclic amino group is a cyclic amino group having a plurality of steric structures having a stereoisomer relationship. Examples of the polar group include an unsubstituted amino group, an aminomethyl group,
A 1-aminoethyl group and a hydroxyl group are particularly preferred.

Examples of the alkyl group include a methyl group, an ethyl group and a propyl group, and these may have a bonding mode such as a gem-dimethyl group and a gem-diethyl group. Further, it is also preferable that an alkylene group having 2 to 5 carbon atoms is bonded to a carbon atom of the cyclic amino group to form a cyclic amino group which is a spiro ring system. A 4- to 8-membered cyclic amine may be crosslinked to form a bicyclo ring.

Examples of these cyclic amino groups, particularly those substituted with an amino group, or those having a second nitrogen atom include those having the following structural formulas.

[0041]

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(Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ¹³ and R ¹⁴ are mutually bonded to form As the alkylene group of 5, a ring having a size of three to six members may be formed. )

Specific examples of these substituents include a 3-aminopyrrolidinyl group, a 3-methylaminopyrrolidinyl group, a 3-dimethylaminopyrrolidinyl group, a 3-ethylaminopyrrolidinyl group, Propylaminopyrrolidinyl, 3-isopropylaminopyrrolidinyl, 3-amino-4-methylpyrrolidinyl, 4-amino-2-methylpyrrolidinyl, 4-amino-2,3-dimethylpyrrolidinyl Dinyl group, 3-methylamino-4-methylpyrrolidinyl group, 4-methylamino-2-methylpyrrolidinyl group,
4-methylamino-2,3-dimethylpyrrolidinyl group,
3-dimethylamino-4-methylpyrrolidinyl group, 4-
Dimethylamino-2-methylpyrrolidinyl group, 4-dimethylamino-2,3-dimethylpyrrolidinyl group, 3-methylpiperazinyl group, 4-methylpiperazinyl group, 3,
4-dimethylpiperazinyl group, 3,5-dimethylpiperazinyl group, 3,4,5-trimethylpiperazinyl group, 4
-Ethyl-3,5-dimethylpiperazinyl group, 4-isopropyl-3,5-dimethylpiperazinyl group, 3-aminomethylpyrrolidinyl group, 3-methylaminomethylpyrrolidinyl group, 3- (1 -Amino) ethylpyrrolidinyl group, 3- (1-methylamino) ethylpyrrolidinyl group,
3- (1-ethylamino) ethylpyrrolidinyl group, 3-
(1-amino) propylpyrrolidinyl group, 3- (1-methylamino) propylpyrrolidinyl group, 3-aminopyrrolidinyl group, 4-amino-3,3-dimethylpyrrolidinyl group, 7-amino -5-azaspiro [2.4] heptane-5-yl group, 8-amino-6-azaspiro [3.4]
Octan-6-yl group, 1,4-diazabicyclo [3.
2.1] Octan-4-yl group, 3,8-diazabicyclo [3.2.1] octan-3-yl group, 8-methyl-
3,8-diazabicyclo [3.2.1] octane-3-
Yl group, 8-ethyl-3,8-diazabicyclo [3.
2.1] octane-3-yl group and the like.

The reaction of reacting compound (I) with compound (III) to obtain compound (II) will be described below. In this reaction, compound (III) may be reacted with compound (III) in an amount of 1 to several times the amount of compound (I) without a solvent or in a solvent in the presence of a deoxidizing agent.

This reaction is preferably carried out in the presence of a deoxidizing agent, which is used for removing hydrogen halide and boron chelate decomposition products formed. Specific examples thereof include organic tertiary amines such as triethylamine and tributylamine or heterocyclic compounds such as pyridine, DMAP, N-alkylmorpholine, N-alkylpiperidine, N-alkylpyrrolidine, and lithium.
Inorganic bases such as carbonates or bicarbonates of alkali metals such as sodium and potassium or alkaline earth metals such as calcium can be mentioned. On the other hand, the compound (III) may be added in excess to have an effect as a deoxidizing agent.

The amount of the deoxidizing agent may be usually 1 to 4 mol per 1 mol of the compound (I).

Solvents used in this reaction include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide and dimethylacetamide, ketone solvents such as acetone and methyl ethyl ketone, ether solvents such as diethyl ether and dioxane, and ethyl acetate. Or an alcoholic solvent such as methanol or ethanol.

The amount of the solvent used may be in the range of 2 to 30 times (volume / weight ratio) the compound (I).

The reaction may be carried out at a temperature in the range of room temperature to 200 ° C. for about 2 to 20 hours.

The compound (II) usually precipitates as a solid by cooling the reaction solution or adding a solvent in which the compound (II) is hardly soluble, such as water, to the reaction solution. Can be easily isolated.

As described above, according to the method of the present invention,
The compound (II), which is an intermediate for producing a medically useful antibacterial agent, can be obtained with high yield and efficiency, and the present invention is an industrially advantageous production method.

In the reaction, depending on the type of solvent, the amount of deoxidizing agent used, the reaction temperature and the reaction time, the reaction does not stop at the stage of the substitution reaction of compound (III), and the boron chelate is decomposed, May be acid.

[0053]

Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Reference Example 1: 4-chloro-2,5-difluoro
Synthesis of diethyl lobenzoylmalonate 63.2 g of 4-chloro-2,5-difluorobenzoic acid and 72 ml of thionyl chloride were added to 190 ml of toluene and refluxed for 5 hours. After distilling off the solvent, the operation of adding toluene and distilling off excess thionyl chloride by azeotropic distillation was performed twice to obtain 4-chloro-
It was 2,5-difluorobenzoyl chloride. on the other hand,
Magnesium ethoxide 39.8 g, diethyl malonate 53.
A suspension composed of 0 g and 200 ml of toluene was stirred for 2 hours, and after cooling the suspension, the suspension of 4-chloro-2,5-difluorobenzoyl chloride obtained above was stirred while stirring the suspension. 125 ml of the solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction, dilute hydrochloric acid was added to make the mixture acidic, the contents were dissolved and the aqueous layer and the organic layer were separated.
Was extracted further. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (111.8 g) as an oil. As a result of ¹ H-NMR spectrum analysis in deuterated chloroform, this compound was found to be a mixture of a keto form and an enol form. This was used as a mixture for the next reaction.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.28 (6H, t, J =
7.2 Hz), 4.31 (4H, q, J = 7.2 Hz), 5.13 (2/3 × 1H, d,
J = 2.6 Hz, keto), 7.31 (1H, dd, J = 5.9 Hz, 10.5
Hz), 7.83 (1H, dd, J = 6.2 Hz, 9.0 Hz), 13.95 (1/3 ×
(1H, S, enol form).

Reference Example 2: 4-chloro-2,5-difluoro
Synthesis of ethyl lobenzoylacetate To 111 g of diethyl 4-chloro-2,5-difluorobenzoylmalonate, 280 ml of water was added to emulsify, and 0.7 g of paratoluenesulfonic acid was added.
Heated to reflux for an hour. After cooling, the reaction solution was extracted with 500 ml of toluene, the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The crystalline residue was recrystallized from n-hexane to obtain 49 g of the title compound.
As a result of ¹ H-NMR spectrum analysis in deuterated chloroform, this compound was found to be a mixture of a keto form and an enol form. This was used as a mixture for the next reaction.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.28 (1/6 × 3H, t,
J = 7.2 Hz), 1.34 (5/6 × 3H, t, J = 7.2 Hz), 3.96 (1/6
× 2H, d, J = 3.3 Hz, keto), 4.24 (1/6 × 2H, q, J =
7.2 Hz), 4.30 (5/6 × 2H, q, J = 7.2 Hz), 5.88 (5/6 × 1
H, s, enol form), 7.25 (1H, dd, J = 5.9 Hz, 10.5 H
z), 7.73 (1H, dd, J = 6.4 Hz, 10.0 Hz), 12.70 (5/6 × 1
(H, s, enol form).

Reference Example 3: 3- (cis-2-fluorocyclic)
Lopropyl) amino-2- (4-chloro-2,5-diph
Synthesis of ethyl chlorobenzoyl) -acrylate Ethyl 4-chloro-2,5-difluorobenzoylacetate
47.7 g and 75.2 ml of ethyl orthoformate were treated with acetic anhydride 51.
The solution dissolved in 4 ml was heated at 110 to 120 ° C., and reacted for 6 hours while distilling off low boiling point substances at normal pressure. After the reaction, the solvent was distilled off, and the residue was sufficiently dried under reduced pressure.
-Ethoxy-2- (4-chloro-2,5-difluorobenzoyl) -acrylic acid ethyl ester was obtained. This was dissolved in 715 ml of toluene, para-toluenesulfonate of cis-1-amino-2-fluorocyclopropane was added, and 22.0 g of triethylamine was added under ice-cooling, followed by stirring at room temperature for 1 hour. After the reaction, the reaction solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (64.2 g) as a residue. This compound is ¹ H-NM in deuterated chloroform
As a result of analysis of the R spectrum, it was found that the mixture was a mixture of Z form and E form. Parentheses indicate either Z-form or E-form.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.08 (1.04) (3H, t,
J = 7.2 Hz), 1.2 to 1.5 (2H, m), 2.8 to 3.1 (1H, m), 4.0
8 (4.04) (2H, q, J = 7.2 Hz), 4.72 (1H, dm, J = 64 H
z), 7.04-7.40 (2H, m), 8.28 (8.21) (1H, d, J = 14.1 H
z), 10.65-11.16 (9.22 to 9.62) (1H, m).

Reference Example 4: 1- (cis-2-fluorocyclic)
Propyl) -7-chloro-6-fluoro-1,4-di
Ethyl hydro-4-oxoquinoline-3-carboxylate
Synthesis of stel 3- (cis-2-fluorocyclopropyl) amino-2
64.2 g of-(4-chloro-2,5-difluorobenzoyl) acrylic acid ethyl ester was dissolved in 317 ml of toluene, 317 ml of a 3N aqueous sodium hydroxide solution and 3.17 g of tetra-n-butylammonium bromide were added, and the mixture was stirred at room temperature for 3 hours. . After the reaction, 317 ml of water was added to the reaction solution, and 82 ml of concentrated hydrochloric acid was added under ice cooling. The precipitated crystals are collected by filtration and water 130
Washed with 0 ml. The washed crystals were dissolved in chloroform, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 54.3 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.40 (3H, t, J = 7
Hz), 1.5 to 1.9 (2H, m), 3.2 to 3.7 (1H, m), 4.42 (2H, q,
J = 7 Hz), 5.12 (1H, dm, J = 61 Hz), 7.90 (1H, d, J =
5.7 Hz), 8.26 (1H, d, J = 9.3 Hz), 8.62 (1H, s).

Reference Example 5: 1- (cis-2-fluorocyclic)
Propyl) -7-chloro-6-fluoro-1,4-di
Synthesis of Hydro-4-oxoquinoline-3-carboxylic acid 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 10.0 g was dissolved in 100 ml of a mixture of acetic acid and concentrated hydrochloric acid (1: 1).
Heat at 0 ° C. for 3 hours. After the reaction, the reaction solution was ice-cooled, and the precipitated crystals were collected by filtration, washed with ethanol and ether, and dried to obtain 9.0 g of the title compound.

¹ H-NMR (d ₆ -DMSO) δ (ppm): 1.68 to 2.10 (2H,
m), 3.78 to 4.04 (1H, m), 5.37 (1H, dm, J = 65.6 Hz), 8.2
4 (1H, d, J = 9.3 Hz), 8.53 (1H, d, J = 5.9 Hz), 8.94
(1H, s), 14.45 (1H, br, s).

Example 1 1- (cis-2-fluorocyclic)
Propyl) -7-chloro-6-fluoro-1,4-di
Hydro-4-oxoquinoline-3-carboxylic acid difluoride
Synthesis of boron chelate 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 0.99 g, boron trifluoride tetrahydrofuran complex 1.07 g and acetic anhydride
1.97 ml of the mixture was heated at 110-120 ° C for 2 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration, washed with dichloroethane, and washed with 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-. 0.96 g of 3-carboxylic acid boron difluoride chelate was obtained.

¹ H-NMR (d ₆ -DMSO) δ (ppm): 1.76 to 2.20 (2H,
m), 4.08 to 4.40 (1H, m), 5.48 (1H, dm, J = 65.6 Hz), 8.5
8 (1H, d, J = 9.0 Hz), 8.96 (1H, d, J = 5.9 Hz), 9.44
(1H, s).

Example 2 1- (cis-2-fluorocyclic)
Propyl) -7-chloro-6-fluoro-1,4-di
Hydro-4-oxoquinoline-3-carboxylic acid difluoride
Synthesis of boron chelate 0.9-ethyl ethyl 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 42% borofluoric acid A mixture of 0.75 g of the aqueous solution and 1.97 ml of acetic anhydride was heated at 110 to 120 ° C. for 6 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration, washed with methanol,
1.04 g of 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate was obtained. ^{The 1} H-NMR spectrum was the same as the compound obtained in Example 1.

Example 3 1- (cis-2-fluorocyclyl)
Propyl) -7-chloro-6-fluoro-1,4-di
Hydro-4-oxoquinoline-3-carboxylic acid difluoride
Synthesis of boron chelate 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.3 g, boron trifluoride tetrahydrofuran complex 0.6 g And a mixture of 1.5 ml of toluene
Heated at 00 ° C. for 11 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration and washed with toluene to obtain the title compound. ^{The 1} H-NMR spectrum was the same as the compound obtained in Example 1.

Example 4: 7- (7- (S) -tert-butene
Xycarbonylamino-5-azaspiro [2.4] hep
Tan-5-yl) -6-fluoro-1- (cis-2-f
(Fluorocyclopropyl) -1,4-dihydro-4-oxo
Synthesis of soquinoline-3-carboxylic acid 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate 0.14 g,
7- (S)-(tert-butoxycarbonylamino) -5
0.17 ml of triethylamine in a solution of 0.1 g of azaspiro [2.4] heptane and 0.7 ml of dimethylsulfoxide
Was added. After stirring at room temperature for 10 hours, 1 ml of cold water was added, and the crystals were collected by filtration. This is washed with water, dried at 90 ° C. for 5 hours,
7- (7-tert-butoxycarbonylamino-5-azaspiro [2.4] heptan-5-yl) -6-fluoro-1- (cis-2-fluorocyclopropyl) -1,4
0.19 g of -dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate was obtained. 0.19 g of the above compound,
Triethylamine 37mg and 95% aqueous methanol
1.9 ml of the mixture was heated to reflux for 10 hours. The reaction solution was neutralized with triethylamine and adjusted to pH 7. After the reaction solution was cooled on ice, the precipitated crystals were collected by filtration and washed with water. After drying at 90 ° C. under reduced pressure for 5 hours, 7- (7-tert-butoxycarbonylamino-5-azaspiro [2.4] heptane-5-yl) is obtained.
-6-Fluoro-1- (cis-2-fluorocyclopropyl) -1,4-dihydro-4-oxoquinoline-3-
0.16 g of carboxylic acid was obtained. Its ¹ H-NMR spectrum was consistent with that previously reported.

Example 5: 7- (7- (S) -tert-butene
Xycarbonylamino-5-azaspiro [2.4] hep
Tan-5-yl) -6-fluoro-1- (cis-2-f
(Fluorocyclopropyl) -1,4-dihydro-4-oxo
Synthesis of soquinoline-3-carboxylic acid 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate 0.29 g,
7- (S)-(tert-butoxycarbonylamino) -5
0.14 ml of triethylamine in a solution of 0.21 g of azaspiro [2.4] heptane and 1.4 ml of dimethylacetamide
Was added. After stirring at room temperature for 8 hours, 2 ml of cold water was added, and the crystals were collected by filtration, washed with water, dried at 90 ° C. for 5 hours, and treated with 7- (7-
Tertiary butoxycarbonylamino-5-azaspiro [2.4] heptan-5-yl) -6-fluoro-1-
0.43 g of (cis-2-fluorocyclopropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate was obtained. 0.43 g of the above compound, 83 mg of triethylamine and 4.3 ml of 95% aqueous methanol
Was refluxed for 10 hours. The reaction solution was neutralized with triethylamine and adjusted to pH 7. After cooling the reaction solution with ice, the crystals were collected by filtration and washed with water. Dry under reduced pressure at 90 ° C for 5 hours.
(7-tert-butoxycarbonylamino-5-azaspiro [2.4] heptan-5-yl) -6-fluoro-1
0.37 g of-(cis-2-fluorocyclopropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained. Its ¹ H-NMR spectrum was consistent with that previously reported.

Example 6: 7- (7- (S) -tert-butene
Xycarbonylamino-5-azaspiro [2.4] hep
Tan-5-yl) -6-fluoro-1- (cis-2-f
(Fluorocyclopropyl) -1,4-dihydro-4-oxo
Synthesis of Soquinoline-3-carboxylic acid 0.29 g of 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate,
7- (S)-(tert-butoxycarbonylamino) -5
0.14 ml of triethylamine in a solution of 0.21 g of azaspiro [2.4] heptane and 1.4 ml of dimethylacetamide
Was added. This was stirred at room temperature for 8 hours. Next, 5 ml of a 5% aqueous sodium hydroxide solution was added, and the mixture was heated at 100 ° C. for 2 hours. Acetic acid was added to the reaction solution to adjust the pH to 7, and the precipitated crystals were collected by filtration and washed with water. After drying at 90 ° C. under reduced pressure for 5 hours, 7- (7-tert-butoxycarbonylamino-5
-Azaspiro [2.4] heptane-5-yl) -6-fluoro-1- (cis-2-fluorocyclopropyl)-
0.35 g of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained. Its ¹ H-NMR spectrum was consistent with that previously reported.

Continuation of the front page (56) References JP-A-2-231475 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07F 5/02 C07F 5/04 CA (STN) REGISTRY ( STN)

Claims (6)

(57) [Claims] (1) Formula (I) (Wherein, X ¹ and X ² each independently represent a halogen atom, and R represents a halogen atom or an alkoxyl group). 2. The compound according to claim 1, wherein X ¹ is a fluorine atom and X ² is a chlorine atom. 3. A compound of the formula (II)(Where X¹Represents a halogen atom, and R represents a halogen atom
And an alkoxyl group. ¹Is the group(Where R^TwoAnd R^ThreeAre each independently an alkyl group or
Represents a phenyl group. ) Means or saturated
And the saturated heterocyclic substituent is 4
It has a size from a membered ring to an eight-membered ring, and contains 1
Or two nitrogen atoms, and the constituents of the ring structure
And may further contain an oxygen atom or a sulfur atom.
The saturated heterocyclic substituent may be an amino group, a mono- or dial-containing alkyl group having 1 to 6 carbon atoms.
Alkylamino group having 2 to 7 carbon atoms, alkyloxycarbonylamino group having 2 to 7 carbon atoms, halogenoalkylcarbonyl group having 2 to 7 carbon atoms, halogenoalkyloxycarbonyl group having 2 to 7 carbon atoms
Amino group, phenylalkyloxycarbonylamino group (phenyl
The group may have a nitro group or a halogen atom.
An alkyl group having 1 to 6 carbon atoms, an alkylene group having 2 to 5 carbon atoms (the ring structure of the heterocyclic substituent)
Spiro ring system or bicyclo ring
Form a system. ), A halogen atom or an alkoxyl group having 1 to 6 carbon atoms
Having one or more substituents selected from the group of substituents consisting of
May be. ). 4. The compound according to claim 3, wherein X ¹ is a fluorine atom. 5. A compound of the formula (I)(Where X¹ And X²Each independently represents a halogen atom
R represents a halogen atom or an alkoxyl group
I do. And a compound represented by the formula (III):(Where R ¹Is the group(Where R^TwoAnd R^ThreeAre each independently an alkyl group or
Represents a phenyl group. ) Means or saturated
And the saturated heterocyclic substituent is 4
It has a size from a membered ring to an eight-membered ring, and contains 1
Or two nitrogen atoms, and the constituents of the ring structure
And may further contain an oxygen atom or a sulfur atom.
The saturated heterocyclic substituent may be an amino group, a mono- or dial-containing alkyl group having 1 to 6 carbon atoms.
Alkylamino group having 2 to 7 carbon atoms, alkyloxycarbonylamino group having 2 to 7 carbon atoms, halogenoalkylcarbonyl group having 2 to 7 carbon atoms, halogenoalkyloxycarbonyl group having 2 to 7 carbon atoms
Amino group, phenylalkyloxycarbonylamino group (phenyl
The group may have a nitro group or a halogen atom.
An alkyl group having 1 to 6 carbon atoms, an alkylene group having 2 to 5 carbon atoms (the ring structure of the heterocyclic substituent)
Spiro ring system or bicyclo ring
Form a system. ), A halogen atom or an alkoxyl group having 1 to 6 carbon atoms
Having one or more substituents selected from the group of substituents consisting of
May be. ) Or a salt thereof
Formula (II) characterized by the following:(Where X¹, R and R ¹Is the same as above. )
Method of producing a compound. 6. The method according to claim 5, wherein X ¹ is a fluorine atom and X ² is a chlorine atom.