JP2589007B2 - Production intermediate of quinolone carboxylic acid derivative - 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 a quinolonecarboxylic acid derivative having an 8-fluorine-substituted methoxy group, which exhibits excellent antibacterial activity.

[0002]

BACKGROUND ART Various quinolone carboxylic acid derivatives having a substituent at the 8-position are known, but quinolone carboxylic acid derivatives having a fluorine-substituted methoxy group at the 8-position are not known.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have found that a quinolone carboxylic acid derivative having a fluorine-substituted methoxy group at the 8-position shows excellent antibacterial activity, studied a method for producing the derivative, and found a useful intermediate thereof. The present invention has been completed.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by the formula:

[0005]

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Is a compound having

In the formula, R ¹ represents a fluorine-substituted methoxy group,
X represents a halogen atom, R _a ¹⁰ represents a lower alkyl group.

The fluorine-substituted methoxy group for R ¹ includes monofluoromethoxy, difluoromethoxy and trifluoromethoxy.

As the halogen atom for X, fluorine, chlorine,
Bromine or iodine atoms are mentioned.

[0010] As the lower alkyl group R _a ¹⁰ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and s- butyl or t- butyl and the like.

[0011] Suitable R ^1, monofluoromethoxy, difluoromethoxy and trifluoromethoxy, and the like, suitable X, fluorine, chlorine and bromine atoms. Examples of R _a ¹⁰ is exemplified methyl and ethyl Can be

The compound (VII) is produced according to the reaction formulas (D) and (E).

Reaction formula (D)

[0014]

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In the above formula, R ¹ represents a mono or difluoromethoxy group, X has the same meaning as described above, and R ¹³ represents a lower alkoxy group or an amino group.

Reaction formula (E)

[0017]

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In the above formula, R ¹ represents a trifluoromethoxy group, X and R ¹³ have the same meanings as described above,
Xa represents ^a halogen atom.

The lower alkoxy group for R ¹³ includes methoxy, ethoxy, propoxy or butoxy.

Examples of the halogen atom for X ^a include a chlorine, bromine or iodine atom.

First step: This step is a step of esterifying or amidating compound (XIV) to obtain compound (XV).

When R ¹³ is a lower alkoxy group: The compound is subjected to a usual esterification reaction by a method of subjecting the corresponding alcohol (R ¹³ H) to dehydration condensation with compound (XIV) in the presence of an acid (eg, hydrogen chloride or sulfuric acid). (XV) is obtained.

When R ¹³ is an amino group: Compound (XIV) is reacted with thionyl chloride (equimolar or more) in an inert solvent (eg, benzene, toluene, chloroform, dichloromethane or diethyl ether) or without a solvent to give acid chloride. After that, excess thionyl chloride is distilled off, and the compound (XV) is obtained by dropping the residue into aqueous ammonia at room temperature or with cooling.

Second step: This step is a step of obtaining compound (XVI) by reacting compound (XV) with a fluoromethane halide in a solvent in the presence of a base.

The solvent used in this reaction is N, N-
Examples include dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetone, methylethylketone or acetonitrile.

The base used in this reaction includes alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkali carbonates such as sodium carbonate and potassium carbonate; metal hydrides such as sodium hydride; sodium methylate; Metal alkoxides such as sodium ethylate, potassium tert-butoxide or triethylamine,
4-dimethylaminopyridine, 1,8-diazabicyclo
[5.4.0] -7-undecene, 1,5-diazabicyclo
[4.3.0] Tertiary amines such as -5-nonene. The use amount thereof is preferably from equimolar to 5 times the molar amount of the compound (XV).

The halogenated fluoromethane used in this reaction includes chlorofluoromethane, bromofluoromethane, chlorodifluoromethane and bromodifluoromethane. The amount of the compound to be used is generally equimolar to 10-fold molar amount relative to compound (XV).

This reaction proceeds at room temperature, but is usually 50
It is carried out by heating in the range of up to 150 ° C., and in some cases also under pressure in an autoclave.

Third step: This step is a step of reacting compound (XIV) with halogenated fluoromethane in the presence of a base to obtain compound (VII). This reaction is carried out in the same manner as the above-described reaction in the second step. However, the amount of the base used in this reaction is 2 to 10-fold the molar amount of the compound (XIV).

Fourth step: This step is carried out using compound (XVI) or
In this step, compound (VII) is obtained by hydrolyzing (XVIII) with an acid or alkali according to a conventional method. The compound (XV
In the case of a compound in which R ^{13 of} (I) or (XVIII) is an amino group, the compound (I) or (XVIII) is also hydrolyzed with sulfuric acid-sodium nitrite (New Experimental Chemistry Course 14 II 943 (Maruzen Co., Ltd.)) to give the compound ( VII) is obtained.

Fifth step: This step is carried out using compound (XV) or (X
IV) is reacted with difluoromethane halide in a solvent in the presence of a base to obtain compound (XVII) or (XIX). The solvent and base used in this reaction are the same as those in the above-mentioned second step. Examples of the halogenated difluoromethane used in this reaction include dichlorodifluoromethane, dibromodifluoromethane, and bromochlorodifluoromethane. The reaction conditions are as described in the second section above.
It is similar to that of the process.

However, the base used in the reaction for obtaining compound (XIX) from compound (XIV) is 2 to 10 moles.

Step 6: This step comprises the step of reacting compound (XVII) or
(XIX) is treated with a fluorinating agent in a solvent to give compound (XVII)
This is the step of obtaining (I) or (VII).

The solvent used in this reaction is N, N-
Aprotic polar solvents such as dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and hexamethylphosphoric triamide; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; halogens such as chloroform, dichloromethane and carbon tetrachloride Carbonized compounds; aromatic hydrocarbons such as benzene and toluene; esters such as methyl acetate and ethyl acetate; and ethers such as diethyl ether, tetrahydrofuran and dioxane.

The fluorinating agent used in the present reaction includes hydrogen fluoride, silver borofluoride (AgBF ₄ ) or mercury fluoride.

This reaction is carried out under heating, and it is preferable to heat the mixture to near the boiling point of the solvent used. Reaction time is 5-20
Time.

Compounds (IV), (II) and (V) are prepared according to reaction formula (C).

Reaction formula (C)

[0039]

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[0040] In the formula, R ^1, R _a ¹⁰ and X are the same meanings as described above, R ¹¹ and R ¹² are the same or different nitrogen atom to which an alkyl group or R ^11, R ¹² are attached And a cyclic amino group formed together with an oxygen or sulfur atom or a sulfinyl group or a sulfonyl group in some cases.

Step 7: This step comprises reacting compound (VII) with thionyl chloride in a solvent or without solvent to give compound (VIII).
This is the step of obtaining

The solvent used in this reaction includes benzene, toluene, chloroform, dichloromethane or diethyl ether.

The amount of thionyl chloride used in this reaction is at least equimolar to compound (VII).

In this reaction, a catalytic amount of pyridine or N, N
Dimethylformamide may be used.

The reaction temperature is freely selected from room temperature to the boiling point of the solvent used. The reaction is continued until the generation of hydrogen chloride gas stops, and after completion of the reaction, the solvent and excess thionyl chloride are distilled off, and the residue may be used as it is in the next reaction, or may be used after purification by distillation under reduced pressure. You may.

Eighth step: In this step, the compound (VIII) is reacted with malonic diester (CH ₂ (CO ₂ R _a ¹⁰ ) ₂ ) to give the compound
This is the step of obtaining (IX).

First, malonic diester is reacted with magnesium ethoxide to obtain ethoxymagnesium malonic diester. This reaction is usually diethyl ether,
The reaction is carried out by stirring equimolar malonic acid diester and magnesium ethoxide for 1 to 10 hours under reflux with heating using an ether such as tetrahydrofuran or dioxane as a solvent. After the reaction, the reaction mixture is a suspension of magnesium ethoxymalonic acid diester, and an equimolar amount of acid chloride (VIII) is added dropwise thereto under cooling or at room temperature and stirred to obtain compound (IX). The reaction is completed within 5 hours.

Ninth step: This step is a step of obtaining compound (X) by hydrolyzing and decarboxylating compound (IX).

The compound (IX) is obtained by heating and refluxing for 3 to 20 hours using tetrahydrofuran or dioxane as a solvent in the presence of a catalytic amount or equimolar amount of p-toluenesulfonic acid monohydrate.

Step 10: This step is a step of obtaining compound (XI) by reacting compound (X) with ethyl orthoformate.

The compound (X) is obtained by heating under reflux with no solvent in excess of acetic anhydride and ethyl orthoformate. The reaction is completed in 1 to 5 hours. After the reaction, excess acetic anhydride and ethyl orthoformate are distilled off under reduced pressure, and the obtained residue may be directly used for the next reaction, or may be purified by silica gel column chromatography.

Eleventh step: This step is the reaction of compound (XI) or compound (XII) with cyclopropylamine to give compound (X
III).

The compound (XI) or (XII) is equimolar to 2 times the molar amount of cyclopropylamine is converted to benzene, toluene, diethyl ether, tetrahydrofuran, chloroform,
Compound (XIII) is obtained by reacting in an inert solvent such as dichloromethane or carbon tetrachloride with cooling or at room temperature. This reaction is usually completed in 1 to 3 hours.

[0054] Twelfth Step: This step is a step of obtaining compound (VIII) The reaction of a compound of di-substituted amino acrylic acid ^{(R 11 R 12 NCH = CHCO} 2 R a 10) a (XII).

The compound (VIII) is reacted with an equimolar amount of the 3-disubstituted aminoacrylate in an inert solvent such as tetrahydrofuran, diethyl ether, dioxane, benzene, toluene, chloroform or dichloromethane for 1 to 15 hours at room temperature or under heating. To form a compound (X
II) is obtained.

Step 13: In this step, the compound (XIII) is subjected to a ring-closure reaction in a solvent in the presence of a base to give a compound.
This is the step of obtaining (IV).

As the solvent used in this reaction, N, N-
Aprotic polar solvents such as dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and hexamethylphosphoric acid triamide; ethers such as diethyl ether, tetrahydrofuran and dioxane; and nitriles such as acetonitrile.

Examples of the base used in this reaction include sodium hydride, potassium fluoride, sodium carbonate, potassium carbonate, and potassium tert-butoxide.

The compound (IV) can be obtained by reacting at room temperature to the boiling point of the solvent used in the presence of a base in an equimolar amount to 2 times the molar amount of the compound (XIII). The reaction time is usually 1 to 10 hours.

Fourteenth step: This step is a step of obtaining compound (II) by hydrolyzing compound (IV).

This step can be performed in the same manner as in the first step. However, it is preferable to carry out the reaction under acidic conditions in order to avoid side reactions.

Fifteenth step: This step is a step of obtaining a boron complex (V) from compound (II) or compound (IV).

The conversion of compound (II) or compound (IV) to compound (V) can be carried out, for example, by reacting borofluoric acid or boron trifluoride according to the method described in JP-A-59-67290. Can be.

Each compound produced as described above is
It is obtained from the mixture of each reaction by ordinary treatments such as filtration, concentration, extraction and distillation, and further purified by ordinary purification means such as recrystallization method and column chromatography as needed.

In Reaction Formulas D and E, 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) used as a starting material is converted to a known compound, 4-hydroxy-benzoic acid, as shown in the following reaction formula. 3,5,6-trifluorophthalic acid (XX)
By heating and decarboxylation in water or an aqueous solvent.

Reaction formula (F)

[0067]

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[0068]

The reaction of the compounds (II) and (V) obtained according to the present invention with the piperazine derivative (III) (reaction formula A,
The quinolone carboxylic acid derivatives (I) obtained according to (A) and (B) show excellent antibacterial activity.

Reaction formula (A)

[0070]

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Reaction formula (B)

[0072]

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In the above formula, R ¹ has the same meaning as described above, and YH represents a piperazine derivative.

The method for obtaining compound (I) by Method A or B is described in JP-A-2-124873.

Next, the present invention will be described more specifically with reference to examples and reference examples.

[0076]

【Example】

(Example 1) Synthesis of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VII)-Method via ester 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) 2
Dissolve 0.0 g (0.104 mol) in 500 ml of ethanol.
The mixture was heated under reflux for 4 hours, and then ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure.
5 - trifluorobenzoic acid ethyl ester (XV: R ¹³ = OE
t) 16.9 g was obtained as a colorless powder.

MS spectrum (CI): m / e 221 (M ⁺ +1), 175 (M ⁺ -OC ₂ H ₅ ) 3-hydroxy-2,4,5-trifluorobenzoic acid obtained as above 8.83 g of acid ethyl ester (XV: R ¹³ = OEt) (0.
(0.4 mol) was dissolved in 40 ml of dimethylformamide, and 1.76 g (0.044 mol) of 60% sodium hydride was added little by little under ice-cooling and stirring. After the addition was completed, the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was transferred to a 200 ml stainless steel autoclave, and 28.0 g (0.32 mol) of chlorodifluoromethane was added thereto.
And 100 ml of dimethylformamide containing
The mixture was stirred at 5-100 ° C for 5 hours. After completion of the reaction, dimethylformamide was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene) to give ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate. 4.85 g of the ester (XVI: R ¹³ = OEt) were obtained as a colorless liquid.

MS spectrum (CI): m / e 271 (M ⁺ +1), 225 (M ⁺ -OC ₂ H ₅ ) 3-difluoromethoxy-2,4,5 obtained by the above method
- trifluorobenzoic acid ethyl ester (XVI: R ¹³ = OE
t) Dissolve 5.79 g (0.021 mol) in 40 ml of ethanol, 6%
20 ml of aqueous sodium hydroxide solution was added and the mixture was left overnight at room temperature. The reaction mixture was acidified by adding 3.5 ml of concentrated hydrochloric acid,
After concentration under reduced pressure, extraction with ethyl acetate, washing the ethyl acetate layer with water,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VII) 5.2
2 g were obtained as a colorless powder.

Melting point 68-70 ° C MS spectrum (CI): m / e 243 (M ⁺ +1), 225 (M ⁺ -OH), 223 (M ⁺ -
F), 192 (M ⁺ -CF ₂ ), 175 (M ⁺ -CF ₂ -OH) NMR spectrum (CDCl ₃ , δ): 6.67 (1H, t, J = 72 Hz, -OCH
_{F 2), 7.83 (1H,} m, aromH), 10.74 (1H, br, COOH) ( Example 2) 3-difluoromethoxy-2,4,5 - Synthesis of trifluoroacetic acid (VII) - amide via Method 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) 1
00.0 g (0.52 mol) was dissolved in 400 ml of benzene, 300 ml of thionyl chloride was added, and the mixture was heated under reflux for 3 hours. The solvent and excess thionyl chloride were distilled off under reduced pressure to give 3-hydroxy-2,4,5-trifluoro. Benzoic acid chloride was obtained. This was dropped into 1500 ml of 28% aqueous ammonia under ice-cooling and stirring.
After stirring for 2 hours, the mixture was left at room temperature overnight, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 3-Hydroxy-2,4,5-trifluorobenzoic acid amide (XV: R ¹³ = NH ₂ )
88.2 g were obtained as a colorless powder.

MS spectrum (CI): m / e 192 (M ⁺ +1), 175 (M ⁺ -NH ₂ ) Melting point 153-155 ° C 3-hydroxy-2,4,5- obtained as described above. 5.00 g (0.026 mol) of trifluorobenzoic acid amide (XV: R ¹³ = NH ₂ ) was dissolved in 130 ml of dimethylformamide, 4.70 g (0.034 mol) of potassium carbonate and chlorodifluoromethane 6.
8 g (0.079 mol) was added, and the mixture was stirred at 100 ° C. for 3 hours in an autoclave. After completion of the reaction, 500 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 1: 1 mixture) to give 3 -Difluoromethoxy-2,4,5-trifluorobenzoic acid amide (XVI: R ¹³ =
The NH ₂₎ 5.08 g was obtained as colorless needle crystals.

Melting point 102-104 ° C MS spectrum (CI): m / e 242 (M ⁺ +1), 225 (M ⁺ -NH ₂ ) 3-difluoromethoxy-2,4,5 obtained as above
-Trifluorobenzoic acid amide (XVI: R ¹³ = NH ₂ ) 15.53 g
(0.064 mol) was suspended in 20 ml of concentrated sulfuric acid, and 30 ml of an aqueous solution of 6.60 g (0.096 mol) of sodium nitrite was gradually added dropwise with stirring under ice-cooling, followed by heating and refluxing for 30 minutes. After cooling to room temperature, 50 ml of water was added, extracted with chloroform, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3-difluoromethoxy-2,4,5-trifluorobenzoic acid ( VII) 15.59 g was obtained as a colorless powder. This was confirmed by melting point, MS spectrum and NMR spectrum to be the same as that obtained by the above-described method via ester.

Example 3 3-Difluoromethoxy-2,
Synthesis of 4,5-trifluorobenzoic acid (VII)-Direct method 5 ml of water was added to 2.18 g (0.052 mol) of sodium hydroxide and dissolved. 4.97 g of fluorobenzoic acid (XIV) (0.026
Mol) was added little by little under ice-cooling. After completion of addition, cool under ice
Stirred for 0 minutes. The reaction mixture was transferred to a 200 ml stainless steel autoclave, and 100 ml of dimethylformamide containing 24.0 g (0.277 mol) of chlorodifluoromethane was added thereto.
and stirred under pressure at 100-110 ° C for 5 hours. After completion of the reaction, the reaction mixture was added to water and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate-ethanol 9: 1 mixture).
2.00 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VII) was obtained as a colorless powder.

From the melting point, MS spectrum and NMR spectrum, it was confirmed that the product was the same as that obtained by the above-mentioned method via ester and via amide.

Example 4 2,4,5-Trifluoro-3-
Synthesis of trifluoromethoxybenzoic acid (VII) 5.0 g (0.023 mol) of 3-hydroxy-2,4,5-trifluorobenzoic acid ethyl ester (XV: R ¹³ = OEt) was dissolved in dimethylformamide (20 ml) and stirred under ice-cooling. 1.0 g (0.025 mol) of 60% sodium hydride was added little by little, and after the addition was completed, the mixture was stirred for 30 minutes under ice cooling. Then dimethylformamide containing 28.0 g (0.13 mol) of difluorodibromomethane
130 ml was added and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction mixture was poured into 300 ml of water, extracted with toluene,
The toluene layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent: toluene) to give 3-difluorobromomethoxy-2,4,5-trifluorobenzoic acid ethyl ester (X
VII: R ¹³ = OEt, X ^a = Br) 5.60 g was obtained as a colorless liquid.

MS spectrum (CI): m / e 351 (M ⁺ +3), 349 (M ⁺ +1) Then, this 3-difluorobromomethoxy-2,4,5-trifluorobenzoic acid ethyl ester (XVII: R ¹³ = OEt, X
^a = Br) 1.50 g (0.0043 mol) was dissolved in 10 ml of toluene,
Add 2.50 g (0.013 mol) of silver borofluoride (AgBF ₄ ),
The mixture was heated under reflux for 8 hours with stirring. The reaction solution was filtered, the filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (solvent:
Toluene) to give 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid ethyl ester (XVIII: R ¹³
= OEt) 1.12 g was obtained as a colorless liquid.

MS spectrum (CI): m / e 289 (M ⁺ +1), 269 (M ⁺ -F) 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid obtained as above Ethyl ester (XVIII: R ¹³
= OEt) 5.05g (0.0175mol) was dissolved in ethanol 100ml, 1
19.3 ml (0.0193 mol) of N caustic soda was added and left at room temperature for 2 hours. After adding 19.3 ml of 1N hydrochloric acid, the mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure.
5-trifluoro-3-trifluoromethoxybenzoic acid
(VII) 3.98 g was obtained as a colorless powder.

MS spectrum (CI): m / e 261 (M ⁺ +1), 243 (M ⁺ -OH) NMR spectrum (CDCl ₃ , δ): 7.88 (1H, m, aromH) (Example 5) 1 -Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (IV: R ¹
= OCHF ₂ , _Ra ¹⁰ = Et) Synthesis of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VII: X = F, R ¹ = OCHF ₂ ) 5.22 g (0.0216 mol) in benzene 300 ml , 15 ml of thionyl chloride was added, and the mixture was heated under reflux for 3 hours. After the reaction, benzene and excess thionyl chloride were distilled off under reduced pressure to give 3-difluoromethoxy-2,4,5.
Trifluorobenzoic acid chloride (VIII: X = F, R ¹ =
OCHF ₂ ) was obtained.

On the other hand, 2.80 g (0.02 g) of magnesium ethoxide
38 mol) and 3.81 g (0.0238 mol) of malonic acid diethyl ester were heated to reflux in 60 ml of anhydrous diethyl ether with stirring for 1 hour to obtain a diethyl ether suspension of ethoxymagnesium malonic acid diethyl ester. Under stirring at room temperature, a solution prepared by dissolving the above acid chloride in 50 ml of anhydrous diethyl ether was added dropwise, and the mixture was further stirred at room temperature for 2 hours. 35 mL of 1N hydrochloric acid was added to the reaction mixture, and the mixture was vigorously stirred, followed by separation. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
7.07 g of 2,4,5-trifluorobenzoylmalonic acid diethyl ester (IX: X = F, R ₁ = OCHF ₂ , _Ra ¹⁰ = Et) was obtained as a brown liquid.

MS spectrum (CI): m / e 385 (M ⁺ +1), 339 (M ⁺ -OC ₂ H ₅ ) Then, this was dissolved in 200 ml of dioxane, and 4.52 g of p-toluenesulfonic acid monohydrate was obtained. (0.0238 mol), and the mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 100 ml of water.
And 2.52 g (0.03 mol) of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-difluoromethoxy-.
5.66 g of 2,4,5-trifluorobenzoylacetic acid ethyl ester (X: X = F, R ₁ = OCHF ₂ , _Ra ¹⁰ = Et) was obtained as a reddish brown liquid.

[0090] Next, 20 ml of acetic anhydride and 6 ml of ethyl orthoformate were added thereto, and the mixture was heated under reflux for 2 hours, and then excess acetic anhydride and ethyl orthoformate were distilled off under reduced pressure. Residue is dichloromethane dichloromethane 200m
l, cyclopropylamine 1.25 g (0.02
2 mol) was added dropwise, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (toluene: ethyl acetate = 9: 1 mixture) to give 3-
Cyclopropylamino-2- (3-difluoromethoxy-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester (XIII: X = F, R ¹ = OCHF ₂ , _Ra ¹⁰ = Et)
3.29 g were obtained as a candy liquid.

MS spectrum (CI): m / e 380 (M ⁺ +1) Then, this was dissolved in 150 ml of anhydrous diethyl ether.
0.39 g (0.0098 mol) of sodium hydride was added little by little at room temperature with stirring. After the addition was completed, the mixture was further stirred at room temperature for 1 hour, and 1N hydrochloric acid was added with vigorous stirring to make the whole reaction solution acidic. The reaction mixture was filtered, washed with water, then with diethyl ether, and 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-.
Oxoquinoline-3-carboxylic acid ethyl ester (IV:
(R ¹ = OCHF ₂ , _Ra ¹⁰ = Et) 1.44 g were obtained as colorless needle crystals.

Melting point: 224 to 226 ° C. MS spectrum (CI): m / e 360 (M ⁺ +1) (Example 6) 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro Synthesis of 4-oxoquinoline-3-carboxylic acid (II: R ¹ ＝ OCHF ₂ ) 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid ethyl ester (IV: R ¹ = OCHF ₂ ,
^{_{R a 10 = Et) 1.40g (}} 0.0039 mol) in acetic acid 9 ml, concentrated sulfuric acid 1.
2 ml and 7 ml of water were added, and the mixture was heated under reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, washed with water and then with diethyl ether, and 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1, 4-dihydro-4-oxoquinoline-3-
1.09 g of carboxylic acid (II: R ¹ = OCHF ₂ ) was obtained as colorless needle crystals.

Melting point 202-207 ° C. MS spectrum (CI): m / e 332 (M ⁺⁺ 1) Elemental analysis value (%): as C ₁₄ H ₉ F ₄ NO ₄ (Example 7) 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.BF ₂ chelate (V: R
¹ = 1- cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester ^{_{OCHF 2) (IV: R 1}} = OCHF 2,
^{_{R a 10 = Et) 9.50g (}} 0.0265 mol) dissolved in methyl isobutyl ketone 150ml of boron trifluoride - ether complex 5.
63 g was added and the mixture was heated under reflux for 6 hours. The reaction solution was cooled on ice and the precipitated crystals were collected by filtration, washed with diethyl ether and then with chloroform, and washed with 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3. -Sulfonic acid / BF ₂ chelate (V: R
¹ = OCHF ₂ ) 6.15 g was obtained as a colorless powder.

Melting point: 225-233 ° C. MS spectrum (CI): m / e 380 (M ⁺ +1) Elemental analysis value (%): As C ₁₄ H ₈ BF ₆ NO ₄ .1 / 2H ₂ O Example 8 1-Cyclopropyl-6,7-difluoro-8-trifluoromethoxy-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid ethyl ester (IV:
Synthesis of R ¹ = OCF ₃ , _Ra ¹⁰ = Et) Using 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid (VII: X = F, R ¹ = OCF ₃ ) as a starting material, 1-cyclopropyl-6,7
-Difluoro-8-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (IV: R ¹ = OCF ₃ , _Ra ¹⁰ = Et) was obtained as colorless needle crystals.

Melting point: 160-161 ° C. MS spectrum (CI): m / e 378 (M ⁺ +1) (Example 9) 1-cyclopropyl-6,7-difluoro-8-trifluoromethoxy-1,4- Dihydro-4-
Oxoquinoline-3-carboxylic acid / BF ₂ chelate (V:
Synthesis of R ¹ = OCF ₃ ) ¹ from the compound obtained in Example 8 in the same manner as in Example 7.
-Cyclopropyl-6,7-difluoro-8-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.BF ₂ chelate (V: R ¹ = OCF ₃ ) was obtained as a colorless powder. .

Melting point 266-271 ° C. MS spectrum (CI): m / e 398 (M ⁺ +1) Elemental analysis value (%): as C ₁₄ H ₇ BF ₇ NO ₄ .1 / 2H ₂ O (Example 10) Synthesis of 3-fluoromethoxy-2,4,5-trifluorobenzoic acid (VII)-Via ester method The same method as in Example 1 except that bromofluoromethane was used instead of chlorodifluoromethane. Thereby 3
-Fluoromethoxy-2,4,5-trifluorobenzoic acid (VII: R ¹ = OCF ₃ , X = F) was obtained as a colorless powder.

Melting point 84-86 ° C MS spectrum (CI): m / e 225 (M ⁺ +1), 207 (M ⁺ -OH) (Example 11) 1-cyclopropyl-6,7-difluoro-8- Synthesis of fluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 3-fluoromethoxy-2,4,5-trifluorobenzoic acid (VII: X = F, R ¹ = OCH ₂ F ) As a starting material, in the same manner as in Example 5, 1-cyclopropyl-6,7-
Difluoro-8-fluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (IV: R ¹ = OCH ₂ F, _Ra ¹⁰ = Et) was obtained as a colorless powder.

Melting point 181-183 ° C. MS spectrum (CI): m / e 342 (M ⁺ +1) (Example 12) 1-cyclopropyl-6,7-difluoro-8-fluoromethoxy-1,4-dihydro Synthesis of 4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-6,7-difluoro-8-fluoromethoxy-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid ethyl ester (IV: R ¹ OOCH ₂ F, R
_a ¹⁰ = Et) in the same manner as in Example 6 from 7.48 g 1-cyclopropyl-6,7-difluoro-8-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 6.36g of colorless Obtained as a powder.

Melting point 203-204 ° C MS spectrum (CI): m / e 314 (M ⁺ +1) (Reference Example 1) Synthesis of 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) 4- Hydroxy-3,5,6-trifluorophthalic acid (XX) 27
00 g and 6 liters of water were placed in an autoclave, replaced with nitrogen, and heated at 140 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to precipitate crystals. The crystals were filtered, washed with chloroform and dried. 3-Hydroxy-2,4,5-trifluorobenzoic acid as a colorless powder
(XIV) 1623 g was obtained.

Melting point 144-146 ° C MS spectrum (CI): m / e 192 (M ⁺ ) NMR spectrum (CD ₃ OD, δ): 4.94 (1H, bs, -OH), 7.25 (1
(H, m, aromH) (Reference Example 2) 1-cyclopropyl-8-difluoromethoxy-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-
Synthesis of carboxylic acid

[0101]

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2.58 g of 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid / BF ₂ chelate (0.
0068 mol) in 20 ml of dimethyl sulfoxide,
1.63 g (0.016 mol) of methylpiperazine was added, and the mixture was left overnight at room temperature. The reaction mixture was poured into 100 ml of water, and the precipitated yellow crystals were collected by filtration and washed with water. The crystals were dissolved in 500 ml of 80% methanol containing 15 ml of triethylamine, and 3
After heating under reflux for one hour, the solvent was distilled off under reduced pressure, and the residue was washed with ethanol to obtain 2.30 g of a pale yellow powder. This was dissolved in 50 ml of water, the insoluble material was removed by filtration, and the filtrate was diluted with 1N sodium hydroxide solution to pH 7.50.
The precipitated crystals were collected by filtration, washed with water, and then washed with ethanol to give 1.74 g of the desired compound as fine yellow fine needle-like crystals.

Melting point 223-225 ° C. MS spectrum (CI): m / e 412 (M ⁺⁺ 1) Elemental analysis value (%): As C ₁₉ H ₂₀ F ₃ N ₃ O ₄ .H ₂ O (Reference Example 3) 1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-[(3S) -methyl-1-piperazinyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / hydrochloric acid Synthesis of salt 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.82 g (0.0055 mol) and (2S) -methylpiperazine 1.20 g ( 0.012 mol) was dissolved in 30 ml of pyridine, and the mixture was stirred at 105-110 ° C for 3 hours.
The powder (free form) obtained by washing the residue with water was dissolved in 400 ml of a 1: 1 mixture of chloroform and methanol.
The residue was washed with a 1: 1 mixture of chloroform and methanol to obtain 1.84 g of the title compound as a pale yellow powder.

Melting point 283-286 ° C. (decomposition) MS spectrum (CI): m / e 412 (M ⁺ +1) Elemental analysis value (%): As C ₁₉ H ₂₁ ClF ₃ N ₃ O ₄ The 2-methylpiperazine used in this reaction was disclosed in
It can be obtained by the method described in -124873.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Teruhiko Inoue 1978 Kogushi, Oji, Ube City, Yamaguchi Prefecture Inside Ube Research Laboratories in Ube Industries, Ltd. (72) Inventor Yoshimi Fujiwara 1978 Kogushi Ogushi, Ube City, Yamaguchi Prefecture 5 Ube Industries, Ltd. Ube Research Institute (72) Inventor Tetsuji Katsue 1978 Kogushi, Ube City, Ube City, Yamaguchi Prefecture 5 Ube Industries, Ltd. Ube Research Institute

Claims (4)

(57) [Claims] (1) Formula (1) A compound having the formula: In the formula, R ¹ represents a fluorine-substituted methoxy group, and X represents a halogen atom. 2. The formula: A compound having the formula: Wherein, R ¹ represents a fluorine-substituted methoxy group, R _a ¹⁰ represents a lower alkyl group. 3. The formula: A compound having the formula: In the formula, R ¹ represents a fluorine-substituted methoxy group. 4. The formula: A compound having the formula: In the formula, R ¹ represents a fluorine-substituted methoxy group.