JPH08208617A - Intermediate for producing quinoline carboxylic acid derivative - Google Patents

Abstract

PURPOSE: To obtain the new intermediate useful for producing a fluoroquinoline carboxylic acid derivative having a methoxy group at the 8-position expressing an excellent antimicrobial activity. CONSTITUTION: A compound of formula I (R8 is alkyl), e.g. 3,4-difluoro-N-(2- fluoroethyl)-2-methoxyaniline, a compound of formula II, e.g. 6,7-difluoro-1-(2- fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, a compound of formula III (R7a is alkyl), e.g. 6,7-difluoro-8-methoxy-1-methyl-1,4-dihydro-4- oxoquinoline-3-carboxylic acid ethyl ester, etc. For example, the compound of formula I is obtained by reacting a compound of formula IV with 1-10 times moles of trifluoroacetic acid anhydride in a solvent such as N,N- dimethylformamide, reacting the obtained compound with a lower alkyl halide, etc., and subsequently hydrolyzing the reaction product.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an intermediate for producing 8-methoxyquinolinecarboxylic acid derivative having excellent antibacterial activity, and a starting material thereof.

[0002]

2. Description of the Related Art Among so-called fluoroquinolinecarboxylic acids having a fluorine atom at the 6-position, a compound having a methoxy group at the 8-position has not been known.

[0003]

The present inventors have found that a fluoroquinolinecarboxylic acid derivative having a methoxy group at the 8-position exhibits excellent antibacterial activity, studied its production method, and found a useful intermediate thereof. The present invention was completed by finding out.

[0004]

Means for Solving the Problems 3,4-Difluoro-2-methoxyaniline in the present application is the following compound (IX)
Say 1st invention of this application WHEREIN: General formula (XIII)

[0005]

[Chemical 6]

The present invention relates to a compound represented by the formula (wherein R ₈ represents a lower alkyl group or a halogeno lower alkyl group) [hereinafter referred to as compound (XIII)], and the second invention is represented by the general formula (II _a )

[0007]

[Chemical 7]

(Wherein R ₈ has the same meaning as described above)
The present invention relates to a compound represented by the formula [hereinafter referred to as compound (II _a )], and the third invention relates to a compound represented by the general formula (IV _a )

[0009]

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(In the formula, R _7a represents a lower alkyl group,
₈ is related compounds [hereinafter compound (referred to as IV _a)] represented by have) the same as defined above, the fourth invention, the general formula (XV)

[0011]

[Chemical 9]

(Wherein R _7a has the same meaning as described above)
A compound represented by [hereinafter compound referred to as (XV)] relates to a fifth aspect of the present invention, the general formula (II _b)

[0013]

[Chemical 10]

The present invention relates to a compound represented by the formula (wherein R ₉ represents a lower alkyl group) [hereinafter referred to as compound (II _b )].

In the present invention, compounds (IV _a ), (X
R _7a in V) and R ₉ in compound (II _b )
Represents a lower alkyl group. Examples of the lower alkyl group include linear or branched carbon number such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, or t-butyl group. There may be mentioned 1 to 4 lower alkyl groups, preferably a methyl group and an ethyl group.

In the present invention, the compounds (XIII), (I
R ₈ in I _a ) and (IV _a ) represents a lower alkyl group or a halogeno lower alkyl group.

The lower alkyl group represented by R ₈ includes, for example, methyl group, ethyl group, propyl group, isopropyl group,
Examples thereof include a linear or branched lower alkyl group having 1 to 4 carbon atoms such as a butyl group, an isobutyl group, an s-butyl group, or a t-butyl group, and preferably a methyl group or an ethyl group. , A propyl group, and an isopropyl group. R
_As the halogeno lower alkyl group shown by ₈ , for example, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 3-fluoropropyl group, 4- Examples thereof include a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a halogen atom such as a fluorobutyl group, preferably a difluoromethyl group, a trifluoromethyl group, and 2-fluoroethyl. And a 2-chloroethyl group.

Compounds (IX), (IV _a ) and (II
_a ) is a compound (XI) according to the following reaction route [C].
II) can be produced by the reaction route [D], and the compounds (XV) and (II _b ) can be produced by the reaction route [E]. The compound (IV _a ) can also be produced by the reaction route [D].

[0019]

[Chemical 11]

[0020]

[Chemical 12]

[0021]

[Chemical 13]

(In the formula, X represents a halogen atom such as chlorine, bromine and iodine, and R _7a , R ₈ and R ₉ have the same meanings as described above.) Reaction paths [C] [D] and [E] Each process (process 1
14) will be described in detail below.

First to fifth steps (reaction path [C])
Is a method for obtaining compounds (IX), (IV _a ) and (II _a ).

First step : This step comprises the known compound (VI
This is a step of reacting I) with methyl halide in the presence of a base in a solvent to obtain compound (VIII).

Examples of the solvent used in this reaction include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; ketones such as acetone and methylethylketone. Examples thereof include esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile.

Examples of the base used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; metal hydrogen such as sodium hydride. Compounds; metal alkoxides such as sodium methylate, sodium ethylate, potassium tert-butoxide or triethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] -7-undecene, 1 , 5-diazabicyclo [4.3.0] -7-
Mention may be made of tertiary amines such as nonene. The amount used is preferably equimolar to 5 times the molar amount of the compound (VII).

The methyl halide used in this reaction may be, for example, methyl chloride, methyl bromide or methyl iodide. The amount used is preferably equimolar to 10-fold the molar amount of compound (VII).

This reaction proceeds even at room temperature, but it is usually carried out by heating in the range of room temperature to 150 ° C., and in some cases, it may also be carried out under pressure in an autoclave.

Second step : In this step, the nitro group of compound (VIII) obtained in the first step is reduced to give compound (I
X) is obtained.

This reaction is carried out under acidic conditions, for example using stannous chloride, tin, zinc or iron, preferably stannous chloride or tin, or by a method using zinc under neutral or alkaline conditions. Be seen.

The solvent used at that time is, for example,
Alcohols such as methanol, ethanol and propanol
Examples thereof include alcohols, acetonitrile, acetic acid and water, and alcohols, acetic acid and water are preferable. You may mix and use these. As the acid used,
Examples thereof include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid or ammonium salts thereof, and organic acids such as acetic acid and propionic acid, with hydrochloric acid, sulfuric acid, acetic acid and ammonium chloride being preferred. Examples of the alkali include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The reaction temperature is, for example, 0 to 200 ° C, preferably 0 to 150 ° C. The reaction time is, for example, 30 minutes
72 hours, preferably 1 to 24 hours.

Further, this reaction is carried out in a solvent in the presence of a catalyst.
It can also be carried out with hydrogen gas.

The solvent used is not particularly limited as long as it is inert to this reaction, and for example, methanol is used.
Alcohols such as alcohol, ethanol, propanol, isopropanol and butanol; ethers such as diethyl ether, tetrahydrofuran and dioxane;
Water; acetic acid can be mentioned, and the above-mentioned alcohols are preferable.

Examples of the catalyst used include noble metal catalysts such as platinum oxide, palladium-carbon and platinum-carbon. Platinum oxide and palladium-carbon are preferred. The amount of the catalyst used may be, for example, the compound (VI
The amount can be 0.01 to 50 wt% with respect to II), preferably 0.1 to 50 wt%. Hydrogen gas may be passed through the reaction solution at normal pressure, or at 100 K
The reaction may be carried out in an autoclave under pressure up to g / cm ² . It is preferably normal pressure to 50 kg / cm ² .

The reaction temperature is, for example, 0 to 200 ° C, preferably 0 to 150 ° C. The reaction time varies depending on the other conditions described above, but is, for example, 10 minutes to 24 hours, preferably 15 minutes to 12 hours.

Third step : In this step, the compound (IX) obtained in the second step is reacted with ethoxymethylenemalonic acid dialkyl ester to give (3,4-difluoro-2-methoxy) anis as an intermediate. It consists of a step in which the linomethylene malonic acid dialkyl ester (XIV ′) is formed, and a step in which the compound (X) is obtained by thermal reduction without isolation to obtain the compound (X).

[0038]

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(In the formula, R _7a has the same meaning as described above) In the reaction in the first step, compound (IX) and 0.5 to 5 moles of ethoxymethylenemalonic acid dialkyl ester were added in the presence or absence of a solvent. It is carried out by reacting in the presence.

The solvent used is, for example, methanol, ethanol, propanol, isopropanol,
Alcohols such as butanol; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether
Ethers such as ter, tetrahydrofuran, dioxane; Esters such as methyl acetate and ethyl acetate; Halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; Ketones such as acetone and methyl ethyl ketone; Although it is possible to use such nitriles, it is preferable to carry out without solvent in order to carry out the subsequent reaction as it is without isolating the product (XIV ′).

The reaction temperature is, for example, room temperature to 200 ° C., and the reaction time is, for example, 1 hour to 15 hours.

After the reaction of the first stage is completed, the solvent is distilled off when the solvent is used, and the reaction of the second stage is carried out by heating the reaction mixture to 200 ° C. or higher. This reaction proceeds even without solvent, but it is preferable to use a high boiling point solvent such as diphenyl ether, nitrobenzene or sulfolane.

[0043] Step 4: In this step, the compound obtained in Step 3 (X), a lower alkyl halide or a halogenated lower alkyl halides (R ₈ -X) are reacted with a compound of (IV _a) The reaction is carried out in the same manner as described in the first step.

Step 5 : This step is a step of hydrolyzing the ester portion of the compound (IV _a ) obtained in the fourth step to obtain the compound (II _a ).

This hydrolysis reaction proceeds under both acidic and alkaline conditions, and is carried out by appropriately selecting the hydrolysis method used in ordinary organic chemical reactions.

Steps 6 to 10 (reaction pathway [D]) are alternative methods for obtaining the compound (IV _a ).

Sixth Step : This step is a step of trifluoroacetylating the amino group of the compound (IX) obtained in the second step with trifluoroacetic anhydride to obtain the compound (XI).

This reaction is carried out by reacting compound (IX) with 1 to 10-fold molar amount of trifluoroacetic anhydride in the presence or absence of a solvent.

The solvent used is, for example, N, N
Amides such as dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide;
Ketones such as acetone and methyl ethyl ketone; Esters such as methyl acetate and ethyl acetate; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; Diethyl ether, tetrahydrofuran,
Examples thereof include ethers such as dioxane.

The reaction temperature is usually 0 to 150 ° C.

Step 7 : In this step, compound (XI) obtained in Step 6 is reacted with lower alkyl halide or halogenated lower alkyl halide (R ₈ -X) to obtain compound (XII). Step, and the reaction is performed in the same manner as described in the first step.

Eighth step : This step is a step of removing the trifluoroacetyl group of the compound (XII) obtained in the seventh step by hydrolysis to obtain the compound (XIII). It is performed in the same manner as described above.

Ninth step : This step is a step of reacting the compound (XIII) obtained in the eighth step with ethoxymethylenemalonic acid dialkyl ester to obtain a compound (XIV). The reaction is the third step. The process is performed in the same manner as described in the previous stage of the process.

The target compound (XIV) of this step is
It can usually be used in the 10th step without purification.

Step 10 : In this step, compound (I) is obtained by cyclizing compound (XIV) obtained in step 9.
This is the step of obtaining V _a ). This reaction can be carried out in the same manner as described in the latter part of the third step, but in order to accelerate the reaction, for example, dehydration or de-alcohol agent such as polyphosphoric acid, sulfuric acid, acetic anhydride, or their The mixture may be added.

Steps 11 to 14 (reaction pathway [E]) are methods for obtaining compounds (XV) and (II _b ).

Step 11 : In this step, the nitrogen atom at the 1-position of compound (X) obtained in step 3 is aminated with O- (2.4-dinitrophenyl) hydroxylamine to give compound (XV). The step of obtaining M. P. Wen
tlland et al. Med. Chem. , 1984, 2
7 , 1103 to 1108.

Step 12 : This step is a step for obtaining the compound (XVI) in which the amino group at the 1-position of the compound (XV) obtained in the 11th step is protected by a formyl group, and is the same as the 11th step. For example, M. P. Wentland
Et al., J. Med. Chem. , 1984, 27 , 110
It can be performed according to the method described in 3 to 1108.

[0059] Thirteenth Step: This step is a lower alkyl halide to the compound obtained in the 12th step (XVI) (R ₉ -
X) is reacted to obtain compound (XVII), and the reaction is performed in the same manner as described in the first step.

Step 14 : This step is a step in which the formyl group of the compound (XVII) obtained in the 13th step is removed by hydrolysis to obtain the compound (II _b ), and the reaction is described in the 5th step. The same is done.

Each compound produced as described above can be obtained from a mixture of each reaction by a usual treatment such as filtration, concentration, extraction, distillation and the like, and if necessary, a recrystallization method, a column chromatography method. It is purified by a conventional purification means such as.

[0062]

The compound (II _a ) obtained by the present invention
And (II _b ) are directly or after forming the boron fluoride chelate compound (V), and the compound (IV _a ) is the free carboxylic acid compound (II) or the boron fluoride chelate compound (V). Then, the quinolinecarboxylic acid compound (I) is derived by a reaction (method A or method B) with the diamine compound (III). This quinolinecarboxylic acid compound (I) exhibits excellent antibacterial activity.

[0063]

[Chemical 15]

[0064]

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[Wherein R ₁ represents a lower alkyl group, a halogeno lower alkyl group or a lower alkylamino group, and R 1
₇ represents a hydrogen atom or a lower alkyl group such as methyl and ethyl, and Y represents a general formula (XVIII).

[0066]

[Chemical 17]

(Wherein R ₂ and R ₃ are the same or different and each represents a hydrogen atom or a lower alkyl group, n is 2 or 3, and m is 1 or 2) or the general formula (XIX). )

[0068]

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(In the formula, R ₄ , R ₅ and R ₆ are the same or different and each represents a hydrogen atom or a lower alkyl group,
n'represents 0 or 1. ). The compound (I) is obtained by reacting the compound (II) or its boron fluoride chelate compound (V) with 1 to several molar times of the diamine compound (III) in the presence or absence of a deoxidizing agent. It is manufactured by reacting in the presence or absence of.

The solvent used in this reaction is
Aprotic polar solvents such as dimethylsulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, N, N-dimethylacetamide are suitable, but other ketones such as acetone and methyl ethyl ketone; diethyl ether, Ethers such as tetrahydrofuran and dioxane; esters such as methyl acetate and ethyl acetate; methanol, ethanol, propanol,
Alcohols such as isopropanol and butanol;
Nitriles such as acetonitrile can also be used.

Examples of the deoxidizing agent include tertiary amines such as triethylamine, tributylamine, pyridine, picoline, lutidine and collidine, and inorganic bases such as sodium carbonate and potassium carbonate. The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (II), but in the case of the amines, they can be used in a large excess as a solvent. In addition, excess diamine compound (II
Since I) acts as a deoxidizing agent, the reaction proceeds smoothly even if no other deoxidizing agent is added. The reaction temperature is room temperature to 200 ° C.

After completion of the reaction, the target compound of this reaction can be obtained by treating the reaction mixture according to a conventional method, and if necessary, further purified by a conventional purification means such as recrystallization method or column chromatography. You can

When the method B is applied, first the target
The compound (VI) is obtained, which can be converted to an (I) .BF ₃ adduct or (I) by treating with a hydrous alcohol or a basic hydrous alcohol, respectively. The (I) · BF ₃ adduct is easily induced to (I) by the base treatment.

The base used in this treatment operation includes alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, or triethylamine, and 3 such as 4-dimethylaminopyridine. Mention may be made of primary amines.

The (I) or (I) .BF ₃ adduct thus obtained is, if necessary, converted into a desired salt by a conventional method.

The conversion reaction of the compound (II) or (IV) into the boron fluoride chelate compound (V) is carried out by reacting borofluoric acid according to the method described in JP-A-59-67290. Can be done.

The compound having the above general formula (I) thus produced may have optical isomers based on the asymmetric carbon atom of the Y moiety in the structure.
In such a case, if desired, the above-mentioned reaction is carried out using the optically resolved raw material compound Y-H (III) to obtain the corresponding optical isomer of the target compound (I) or the compound (I). Each optical isomer can be obtained by treating the optical isomer mixture of I) according to a conventional optical resolution method.

[0078]

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1 3,4-difluoro-2-me
Synthesis of toxaniline (IX) 2,3-difluoro-6-nitrophenol (VII)
(Known compound) 20.0 g (0.114 mol) was dissolved in 700 ml of acetone, and 18.9 g (0.1
37 mol) and 34.1 g (0.24 mol) of methyl iodide were added, and the mixture was heated under reflux for 20 hours with stirring. Then, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, the ethyl acetate layer was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain 3,4-difluoro-2-methoxynitrobenzene (VIII) 23.
0 g was obtained as a yellow oil. MS spectrum: m / e 189 (M ⁺ ), 159 (M
⁺ -CH ₂ O).

23.0 g of 3,4-difluoro-2-methoxynitrobenzene (VIII) obtained as described above
(0.114 mol) was dissolved in 1 liter of 80% methanol aqueous solution, 22.6 g (0.422 mol) of ammonium chloride and 38.2 g of reduced iron were added, and the mixture was heated under reflux for 4 hours with stirring.

Then, the reaction solution was filtered, the filtrate was concentrated under reduced pressure,
The residue was extracted with toluene. The toluene layer was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain 10.4 g of 3,4-difluoro-2-methoxyaniline (IX) as a reddish brown oily substance. MS spectrum: m / e 159 (M ⁺ ), 144 (M
⁺ -CH _3).

Example 2 6,7-Difluoro-8-
Methoxy-1-methyl-1,4-dihydro-4-oxo
Quinoline-3-carboxylic acid ethyl ester (IV _a , R
_7a : Ethyl; R ₈ : Methyl) 3,4-difluoro-2-methoxyaniline (IX)
1.84 g (0.011 mol) of diethyl ethoxymethylene malonate (2.84 g, 0.013 mol) was added,
It stirred at 140-150 degreeC for 3 hours. Then 20 ml of diphenyl ether was added to the reaction mixture, and 240-250
The mixture was stirred at 0 ° C for 1 hour. After allowing to cool to room temperature, 100 ml of n-hexane was added, and the precipitated crystals were collected by filtration to give 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3.
-1.60 g of carboxylic acid ethyl ester (X) was obtained as a colorless powder. MS spectrum: m / e 283 (M ⁺ ), 237 (M
⁺ -C ₂ H ₅ OH).

1.60 g (0.0057 mol) of 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylic acid ethyl ester (X) obtained as described above was dissolved in 20 ml of dimethylformamide, 60-65 by adding 1.20 g (0.0085 mol) of potassium carbonate and 2.40 g (0.0017 mol) of methyl iodide.
The mixture was stirred at C for 17 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane, the dichloromethane layer was washed with water, dried and then distilled under reduced pressure to obtain 6,7-difluoro-8-methoxy-1-methyl-1,4-dihydro-4-. oxoquinoline-3-carboxylic acid ethyl ester (IV _a, R _7a:
1.60 g of ethyl; R ₈ : methyl) was obtained as a light brown powder. MS spectrum: m / e 297 (M ⁺ ), 225 (M
^{_{+ -CH 2 = CH 2 -CO 2}} ).

Example 3 6,7-Difluoro-1-
(2-Fluoroethyl) -8-methoxy-1,4-dihi
Doro-4-oxoquinoline-3-carboxylic acid (II _a ,
Synthesis of R ₈ : 2-fluoroethyl) 3,4-difluoro-2-methoxyaniline (IX) 1
0.2 g (0.064 mol) was dissolved in 100 ml of toluene, and 16.2 g (0.07) of trifluoroacetic anhydride was cooled under ice cooling.
7 mol) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain 3,4-difluoro-2-methoxy-N- (trifluoroacetyl) aniline (XI) 1.
3.5 g was obtained as light brown needle crystals. MS spectrum: m / e 255 (M ⁺ ), 186
_{^{(M + -CF 3), 158}} (M + -COCF 3).

3.00 g (0.012 mol) of 3,4-difluoro-2-methoxy-N- (trifluoroacetyl) aniline (XI) obtained as described above was added to N, N-dimethylformamide (hereinafter referred to as DMF). Dissolved in 50 ml, potassium carbonate 2.44 g (0.018 mol), catalytic amounts of potassium iodide and 2-fluoroethyl bromide 1.80 g (0.014 mol) were added, and the mixture was stirred at 65 ° C. for 5 hours. did. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and subjected to silica gel column chromatography (solvent: toluene) to give 3,4-difluoro-N- (2
- fluoroethyl) -2-methoxy -N- (trifluoroacetyl) aniline (XII, R _8: to give 2-fluoroethyl) 0.69 g as a colorless oil. MS spectrum: m / e 301 (M ⁺ ), 268
_{^{(M + -CH 2 F),}} 232 (M + -CF 3).

Then, 3,4 obtained as described above
-Difluoro-N- (2-fluoroethyl) -2-methoxy-N- (trifluoroacetyl) aniline (XI
80% containing 0.69 g of I, R ₈ : 2-fluoroethyl) and 0.25 g (0.0046 mol) of potassium hydroxide.
After dissolving in an aqueous solution of methanol and leaving at room temperature for 5 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with toluene to give 3,4-difluoro-N- (2-fluoroethyl) -2-methoxyaniline (XIII, R ₈ : 2-fluoroethyl) 0.4
5 g was obtained as a light brown oil. MS spectrum: m / e 205 (M ⁺ ), 190
_{^{(M + -CH 3), 172}} (M + -CH 2 F).

Next, the 3,4-difluoro-N obtained here was obtained.
-(2-Fluoroethyl) -2-methoxyaniline (X
III, R _8: 2- fluoroethyl) 0.45 g (0.
A mixture of 0.57 g (0.0026 mol) of diethyl ethoxymethylene malonate and 140-
After heating at 150 ° C for 6 hours and allowing to cool to room temperature, acetic anhydride (2 ml) and concentrated sulfuric acid (1 ml) were sequentially added, and the mixture was allowed to stand at room temperature for 1 hour. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration,
6,7-Difluoro-1- (2-fluoroethyl) -8
-Methoxy-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid ethyl ester was obtained 0.18g as a colorless powder (IV _a, R _7a; 2- fluoroethyl, ethyl, R _8). MS spectrum: m / e 329 (M ⁺ ), 284
^{_{(M + -OC 2 H 5)}} , 257 (M + -CH 2 = CH 2
-CO _2).

The above 6,7-difluoro-1- (2-fluoroethyl) -8-methoxy-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid ethyl ester (I
V _a, R _7a; ethyl, R _8; 2-fluoroethyl) 0.
18 g (0.0005 mol) was dissolved in 15 ml of methanol, and 5 ml of a 4% (W / V) casey-sodium aqueous solution was added, and the mixture was allowed to stand at room temperature for 5 hours. The crystals that were made acidic with concentrated hydrochloric acid were collected by filtration, and 6,7-difluoro-1- (2-fluoroethyl) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (II 0.11 g of _a , R ₈ ; 2-fluoroethyl) was obtained as a colorless powder. MS spectrum: m / e 301 (M ⁺ ), 257
(M ⁺ -CO _2).

Example 4 6,7-Difluoro-1-E
Tyl-8-methoxy-1,4-dihydro-4-oxoki
Norrin-3-carboxylic acid ethyl ester (IV _a ,
R _7a ; ethyl, R ₈ ; ethyl) 3,4-difluoro-2-methoxy-N- (trifluoroacetyl) aniline (XI) obtained in Example 3 7.
0 g (0.027 mol) was dissolved in 130 ml of DMF, 5.66 g (0.041 mol) of potassium carbonate and 6.39 g (0.041 mol) of ethyl iodide were added, and the mixture was stirred at 70 ° C for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and silica gel column chromatography was carried out.
(Solvent: toluene) gives 3,4-difluoro-N-
Ethyl-2-methoxy-N- (trifluoroacetyl)
Aniline (XII, R _8: Ethyl) The 7.6g was obtained as a red-brown oil. MS spectrum: m / e 283 (M ⁺ ), 214
(M ⁺ -CF _3).

Then, 3.4 g of potassium hydroxide was added.
(0.060 mol) in 80% methanol aqueous solution, left at room temperature for 5 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with toluene to give 3,4-difluoro-N-ethyl-.
2- methoxyaniline (XIII, R _8; ethyl) 5.
5 g was obtained as a reddish brown oil. MS spectrum: m / e 187 (M ⁺ ), 172
(M ⁺ -CH _3).

Next, 4.0 g (0.021 mol) of this compound and 5.54 g of diethyl ethoxymethylenemalonate.
(0.026 mol) was heated at 150 to 160 ° C. for 9 hours and allowed to cool to room temperature, then 42 ml of acetic anhydride and concentrated sulfuric acid 18
ml was added sequentially and left at room temperature for 1 hour. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration to give 6,7-difluoro-1-ethyl-8-methoxy-1,4-dihydro-4.
-Oxoquinoline-3-carboxylic acid ethyl ester (I
V _a, R _7a; ethyl, R _8; ethyl) 2.09 g as a colorless powder. MS spectrum: m / e 311 (M ⁺ ), 239 (M
^{_{+ -CH 2 = CH 2 -CO 2}} ).

Example 5 6,7-Difluoro-8-me
Toxy-1-methylamino-1,4-dihydro-4-o
Xoxoquinoline-3-carboxylic acid (II _b , R ₉ : methyl
Synthesis of 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylic acid ethyl ester (X) 1.13
g (0.004 mol) was dissolved in 20 ml of DMF, 1.10 g (0.008 mol) of potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours. Next, 0.81 g (0.0041 mol) of O- (2,4-dinitrophenyl) hydroxylamine was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was washed with water and ethanol in this order.
The obtained solid substance was extracted with chloroform, the chloroform was distilled off under reduced pressure, and 1-amino-6,7-difluoro-8-
Methoxy-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid ethyl ester (XV, R _7a ; ethyl)
0.62 g was obtained as an ocher powder. MS spectrum: m / e 298 (M ⁺ ) IR spectrum (KBr, ν _max , cm ^-1 ): 338
0,3200,1720 NMR spectrum _{(CDCl 3, δ): 1.38} (3H, t, -OCH 2 CH 3) 4.23 (3H, d, -OCH 3) 4.32 (2H, q, -O _{CH 2 CH 3) 6.01 (2H} , s, -N NH 2) 7.88 (1H, d.d, 5 -position H) 8.48 (1H, s, 2 -position H).

To 3.8 ml (0.04 mol) of acetic anhydride,
1.5 ml (0.04 mol) of formic acid was added dropwise under ice cooling, the mixture was stirred for 15 minutes, and further stirred at 50 ° C. for 15 minutes. 1-Amino-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (XV, R _7a ; ethyl) 0 obtained as above in this solution 4.6 g (0.002 mol) of formic acid 4.2 ml
The (0.11 mol) solution was added dropwise under ice cooling and stirred at room temperature for 9 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was washed with water and then with ether, and 6,7-difluoro-1- (formylamino) -8-methoxy-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid ethyl ester (XV
I, R _7a ; ethyl) (0.6 g) was obtained as a pale yellow powder. IR spectrum (KBr, ν _max , cm ^-1 ): 1700
～1725,1614 NMR Spectrum _{(DMSO-d 6 -CDCl 3,} δ) 1.39 (3H, t, -COOCH 2 CH 3) 3.98 (3H, s, -O CH 3) 4.35 (2H, _{q, -COO CH 2 CH 3)} 7.97 (1H, d.d, 5 -position H) 8.38 (1H, bs, -NH CH O) 9.41 (2H, bs, - NH CHO + 2 -position H) .

6,7-Difluoro-1- (formylamino) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (XVI, R _7a ; Ethyl) 0.6 g (0.001
8 mol) dissolved in 8 ml DMF, 0.51 potassium carbonate
g (0.0037 mol) and methyl iodide 0.78 g
(0.0052 mol) was added, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, the chloroform layer was washed with water, dried and then distilled under reduced pressure.
6,7-Difluoro-1- (N-formylmethylamino) -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (XVII, R
0.5 g of _7a : ethyl, R ₉ : methyl) was obtained as a colorless powder. MS spectrum: m / e 340 (M ⁺ ), 268 (M
^{_{+ -CH 2 = CH 2 -CO 2}} ).

6,7-Difluoro-1- (N-formylmethylamino) -8-methoxy-obtained as described above
1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (XVII, R _7a: ethyl, R _9: methyl) ethanol and 0.5 g (0.0015 mol) - le 10
Dissolved in ml, 1N-caseiso-da aqueous solution 4.5 ml
(0.0045 mol) was added and stirred at room temperature for 2 hours. After completion of the reaction, the crystals precipitated by acidification with acetic acid were collected by filtration, and 6,7-difluoro-8-methoxy-1- (methylamino) -1,4-dihydro-4-oxoquinoline-3 was collected.
- carboxylic acid (II _b, R _9: methyl) was obtained 0.35g of a colorless powder. MS spectrum: m / e 284 (M ⁺ ), 240 (M
⁺ -CO ₂₎ NMR spectrum _{(CDCl 3, δ): 2.90} (3H, d, -NH CH 3) 4.30 (3H, d, -OC H 3) 6.69 (1H, q, - NH _{CH 3) 8.10 (1H, d.d} , 5 -position H) 8.83 (1H, s, 2 -position H) 14.33 (1H, s, -COOH).

Reference Example 1 6-Fluoro-1- (2-phenylene )
Luoroethyl) -8-methoxy-7- (4-methyl-1)
-Piperazinyl) -1,4-dihydro-4-oxoquino
Phosphorus-3-carboxylic acid / hydrochloride

[0097]

[Chemical 19]

6,7-Difluoro-obtained in Example 3
1- (2-fluoroethyl) -8-methoxy-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 0.1
1 g (0.0004 mol) and N-methylpiperazine 0.
20 g (0.002 mol) of dimethyl sulfoxide 3 m
It was dissolved in 1 and stirred at 70 ° C. for 6 hours. After the reaction, the solvent and excess N-methylpiperazine were distilled off under reduced pressure at the same temperature, and the residue was washed with ethyl acetate to obtain a pale yellow powder. This was suspended in a mixed solution of 20 ml of ethanol and 1 ml of concentrated hydrochloric acid and concentrated under reduced pressure, 20 ml of water was added to the residue, insoluble materials were filtered off, the filtrate was concentrated under reduced pressure, and the obtained crystals were concentrated with ethanol. After washing, the desired 6-fluoro-1- (2-fluoroethyl) -8-methoxy-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-
30 mg of 3-carboxylic acid / hydrochloride was obtained as a colorless powder. Melting point: 270 to 272 ° C (decomposition) MS spectrum: m / e 381 (M ⁺ ), 337 (M
⁺ -CO ₂₎ NMR spectrum _{(DMSO-d 6, δ)} : 2.85 (3H, s, N + -CH 3) 4.65~5.10 (4H, m, N-CH 2 CH 2 -
F) 7.90 (1H, d, H at the 5th position) 8.90 (1H, s, H at the 2nd position) Elemental analysis: C ₁₈ H ₂₁ F ₂ N ₃ O ₄ · HCl · 2H ₂ O CHN theory Value 47.63 5.77 9.26% Measured value 47.95 5.26 9.28%.

Reference Example 2 1-Ethyl-6-fluoro-
8-methoxy-7- (4-methyl-1-piperazinyl)
-1,4-dihydro-4-oxoquinoline-3-carbo
Boron trifluoride adduct

[0100]

Embedded image

6,7-Difluoro-obtained in Example 4
1-Ethyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 0.40
g (0.0013 mol) 42% borofluoric acid 8m
After suspending in 1 l and stirring at 100 to 110 ° C. for 3 hours, crystals of the chelate compound (V) which were precipitated by pouring into water were collected by filtration and washed with water. After drying this thoroughly, dimethyl sulfoxide 4
Dissolved in ml, 0.7 g of N-methylpiperazine (0.00
7 mol) was added and left at room temperature overnight. The reaction mixture was poured into 150 ml of diethyl ether, and the precipitate was precipitated.
The yellow crystals of compound (VI) were collected by filtration, suspended in 100 ml of 80% aqueous methanol solution, and heated under reflux for 4 hours with stirring. The reaction solution was filtered while hot, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the crystals obtained were washed with ethanol to obtain the desired 1-ethyl-6-fluoro-8-methoxy-7- (4
-Methyl-1-piperazinyl) -1,4-dihydro-4
50 mg of -oxoquinoline-3-carboxylic acid boron trifluoride adduct was obtained as a colorless powder. Melting point: 186-192 ° C (decomposition) MS spectrum: m / e 363 (M ⁺ ), 319 (M
⁺ -CO ₂₎ NMR spectrum _{(DMSO-d 6, δ)} : 1.34 (3H, t, N-CH 2 CH 3) 2.80 (3H, s, N-CH 3) 3.85 (3H, _{s, -OCH 3) 4.69 (2H} , q, N- CH 2 CH 3) 7.86 (1H, d, 5 -position H) 8.90 (1H, s, 2 -position H) elemental analysis: C ₁₈ C H N theoretical value as H ₂₂ FN ₃ O ₄ · BF ₃ 50.14 5.14 9.75% measured value 49.84 5.44 9.60%.

Reference Example 3 1-Ethyl-6-fluoro-
8-methoxy-7- (4-methyl-1-piperazinyl)
-1,4-dihydro-4-oxoquinoline-3-carbo
Acid 1-ethyl-6-fluoro-8-methoxy-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3 obtained by the method described in Reference Example 2
-Carboxylic acid boron trifluoride adduct 130 mg (0.0
(003 mol) is dissolved in 30 ml of water, 0.36 ml of a 1N-caseiso-da water solution is added, and the crystals obtained by concentrating the reaction solution under reduced pressure are washed with ethanol and then with cold water to obtain the objective 1
70 mg of -ethyl-6-fluoro-8-methoxy-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid were obtained as a light brown powder. Melting point: 207 to 209 ° C (decomposition) MS spectrum: m / e 363 (M ⁺ ), 319 (M
⁺ -CO ₂₎ NMR spectrum (DMSO-d ₆ -CDCl _3,
δ): 1.34 (3H, t , N-CH 2 CH 3) 2.47 (3H, s, N-CH 3) 3.85 (3H, s, O-CH 3) 4.69 (2H, _{q, N- CH 2 CH 3)} 7.86 (1H, d, 5 -position H) 8.86 (1H, s, 2 -position H) elemental _{analysis: C 18 H 22 FN 3 O} 4 · 3H 2 O as a C H N theoretical 51.79 6.76 10.07% found 51.89 6.58 9.93%.

Reference Example 4 1-Ethyl-6-fluoro-
8-methoxy-7- (4-methyl-1-piperazinyl)
-1,4-dihydro-4-oxoquinoline-3-carbo
Obtained in phosphate Reference Example 2 1-ethyl-6-fluoro-8-methoxy-7- (4-methyl-1-piperazinyl) -1,
4-Dihydro-4-oxoquinoline-3-carboxylic acid chelate compound (VI) (yellow crystals) 200 mg (0.
(00064 mol) was suspended in 50 ml of 80% aqueous methanol solution containing 0.5 ml of triethylamine, and the mixture was heated under reflux with stirring for 6 hours. The reaction solution is filtered while hot to remove insoluble matter,
The crystals obtained by concentrating the filtrate under reduced pressure were washed with ethanol,
Targeted 1-ethyl-6-fluoro-8-methoxy-
90 mg of 7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as a light brown powder. This compound had a melting point, MS spectrum, NMR spectrum and elemental analysis of Reference Example 3
It was confirmed to be the same as the compound obtained in.

[Reference Examples 5 to 26] The compounds shown in Table 1 were synthesized by the methods of Reference Examples 1, 2, 3 and 4.

[0105]

[Table 1]

[0106]

[Table 2]

[0107]

[Table 3]

[0108]

[Table 4]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI technical display location (C07D 401/04 207: 14 215: 56) (72) Inventor Yoshimi Fujiwara Ube City Ogushi 1978 Address 5 Ube Kosan Co., Ltd. Ube Laboratory (72) Inventor Tetsuji Katsube Ube City, Yamaguchi Prefecture Kogushi 5 1978 Address 5 Ube Kosan Co., Ltd. Ube Laboratory

Claims (5)

[Claims] 1. A compound represented by the general formula (XIII): (In the formula, R ₈ represents a lower alkyl group or a halogeno lower alkyl group). 2. A compound represented by the general formula (II _a ): (In the formula, R ₈ has the same meaning as described above). 3. A compound represented by the general formula (IV _a ): (In the formula, R _7a represents a lower alkyl group, and R ₈ has the same meaning as described above). 4. A compound represented by the general formula (XV): (In the formula, R _7a has the same meaning as described above). 5. A compound represented by the general formula (II _b ): (In the formula, R ₉ represents a lower alkyl group).