JP2939280B2 - Fluorine-substituted methoxyquinolone carboxylic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Objects of the Invention The present inventors have completed the present invention in which a quinolone carboxylic acid derivative having a fluorine-substituted methoxy group has been found to exhibit excellent antibacterial activity.

Structure of the invention Formula formula A compound (1), (2) or (3) having the formula:
Esters and their intermediates (20 ') or (8), salts thereof.

In the formula, R ¹ has at ^{least one} of a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a lower alkylamino group, or a lower alkyl group, a hydroxyl group, a lower alkoxy group or a halogen atom as a substituent. indicates also phenyl group, R ² represents a hydrogen atom or an amino group, R 2 ^'represents a hydrogen atom, an amino group or a nitro group, R ³ represents a fluorine-substituted methoxy group, R ⁴ is a lower alkyl group , A halogeno lower alkyl group, a cycloalkyl group,
Or a lower alkyl group, a hydroxyl group, a lower alkoxy group or a phenyl group optionally having at least one of halogen atoms as a substituent, R ¹³ represents a lower alkyl group, and X represents (Wherein, R ⁵ is a hydrogen atom, a hydroxyl group, an amino group, an aralkyl group, a lower aliphatic acyl group or a hydroxyl group as a substituent, a lower alkoxy group, a lower aliphatic acyloxy group, a lower aliphatic acyl group, a carboxy group, a lower alkoxy group. carbonyl group, a sulfo group, an amino group, a lower aliphatic acylamino group, a mono-lower alkylamino group or di-lower alkylamino group substituted lower alkyl group optionally having, R ⁶
Represents a hydrogen atom or a hydroxyl group as a substituent, a lower alkoxy group or a lower alkyl group which may have a halogen atom, A is an ethylene group, a trimethylene group, or a group of the formula -COCH ₂ - represents a group, m is 1 or 2 Is shown. ), ((Where (Wherein, R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group, and n ′ represents 0 or 1), a hydroxyl group or a lower alkoxy group, and R ⁷ represents a hydrogen atom , A hydroxyl group, a hydroxyl group as a substituent, a lower alkoxy group or a lower alkyl group which may have a halogen atom or a lower alkoxy group which may have a fluorine atom in an alkyl portion, B is a methylene group, an ethylene group , A trimethylene group or a tetramethylene group, and n represents 1 or 2. )), (In the formula, R ¹⁰ represents a hydrogen atom or a lower alkyl group.) (Wherein, Q represents an oxygen atom or a sulfur atom), Y represents an alkylene chain having 1 to 5 carbon atoms which may be substituted with a lower alkyl group or a halogen-substituted lower alkyl group, The chains may contain unsaturation in the chains.

Z represents an oxygen atom or a sulfur atom.

The lower alkyl group for R ¹ , R ⁴ and R ¹³ includes, for example, methyl, ethyl, propyl or isopropyl.

The halogeno lower alkyl group for R ¹ and R ⁴ is, for example, difluoromethyl, trifluoromethyl, fluoroethyl or chloroethyl.

The lower alkenyl group for R ¹ is, for example, vinyl, anil or isopropenyl.

The lower alkylamino group for R ¹ is, for example, methylamino, ethylamino, propylamino or isopropylamino.

Of the substituents of the phenyl group having a substituent of R ¹ and R ⁴ ,
Examples of the alkyl group in the alkyl portion of the alkyl group and the alkoxy group include methyl, ethyl, propyl and isopropyl.

Examples of the halogen atom of the substituent of the phenyl group having the substituents of R ¹ and R ⁴ include a fluorine or chlorine atom.

Examples of the fluorine-substituted methoxy group for R ³ include monofluoromethoxy, difluoromethoxy and trifluoromethoxy.

The cycloalkyl group for R ⁴ is, for example, cyclopropyl,
Cyclobutyl, cyclopentyl or cyclohexyl.

Examples of the alkyl group of the alkyl group which may have a substituent of R ⁵ include, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

Alkyl moiety of the lower alkoxy group of the substituent for the alkyl group having a substituent of R ^5, the alkyl moiety of the lower aliphatic acyloxy group, the alkyl moiety of the lower aliphatic acyl group, the alkyl moiety of the lower alkoxycarbonyl group, a lower aliphatic acylamino The alkyl group of the alkyl portion of the group, the alkyl portion of the monoalkylamino group and the alkyl group of the alkyl portion of the dialkylamino group may be, for example,
Isopropyl, butyl or isobutyl can be mentioned.

The aralkyl group of R ⁵ , R ⁸ and R ⁹ is, for example, benzyl,
4-methoxybenzyl, 4-aminobenzyl, 4-methylaminobenzyl or dimethylaminobenzyl.

The lower aliphatic acyl group for R ⁵ includes, for example, formylacetyl, propionyl, butyryl or isobutyryl.

Examples of the alkyl group of the alkyl group which may have a substituent for R ⁶ include, for example, methyl, ethyl, propyl and isopropyl.

The alkoxy group of the lower alkoxy-substituted alkyl group for R ⁶ is, for example, methoxy, ethoxy, propoxy or isopropoxy.

Examples of the halogen atom of the alkyl group having a halogen atom of R ⁶ include a fluorine or chlorine atom.

Examples of the alkyl group of R ⁸ , R ⁹ and R ¹⁰ include, for example, methyl, ethyl, propyl and isopropyl.

The alkoxy group for W is, for example, methoxy, ethoxy,
Propoxy or isopropoxy.

Examples of the alkyl group of the alkyl group of the hydroxyl group, the lower alkoxy group or the alkyl group optionally having a halogen atom and the alkoxy group optionally having a fluorine atom of R ⁷ include methyl, ethyl, propyl and isopropyl.

The alkoxy group of the alkyl group substituted with the lower alkoxy of R ^{7 has} the same meaning as the alkoxy group of W described above, and the halogen atom of the alkyl group having a halogen atom of R ⁷ is, for example, a fluorine or chlorine atom. Can be

Alkylene chain which may contain an unsaturated bond of Y is, for example _{-CH 2 -, - (CH 2} ) 2 -, - CH = CH -, - CH (C
_{H 3) -, - CH (} CH 3) CH 2 - or -C (CH ₃₎ = CH- and the like.

Suitable R ¹ includes methyl, ethyl, propyl, isopropyl, fluoroethyl, vinyl, isopropenyl, methylamino, phenyl, fluorophenyl, difluorophenyl, methoxyphenyl or hydroxyphenyl.

Preferred R ² is a hydrogen atom or amino.

Suitable R ^{2 ′} is a hydrogen atom, amino or nitro.

Suitable R ³ includes monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

Suitable R ⁴ includes methyl, ethyl, propyl, isopropyl, fluoroethyl, phenyl, fluorophenyl, difluorophenyl, or cyclopropyl.

Suitable R ¹³ includes methyl, ethyl, propyl or isopropyl.

A preferred X is Preferred R ⁵ is a hydrogen atom, a hydroxyl group, an amino group, methyl,
Ethyl, hydroxyethyl, methoxyethyl, acetoxyethyl, formylmethyl, formylethyl, acetylmethyl, acetylethyl, ethoxycarbonylmethyl,
Sulfomethyl, aminoethyl, dimethylaminoethyl, aminobenzyl, formyl or acetyl.

Preferred R ⁶ is a hydrogen atom, methyl, ethyl, propyl, isopropyl, hydroxymethyl, fluoromethyl or methoxymethyl.

Suitable A include ethylene, trimethylene, tetramethylene or -COCH ₂ - and the like.

 Preferred m is 1 or 2.

Preferred W is hydroxyl, methoxy, ethoxy, amino,
Methylamino, ethylamino, dimethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl.

Preferred B includes methylene, ethylene, trimethine and tetramethylene.

Preferred R ⁷ is a hydrogen atom, a hydroxyl group, methoxy, ethoxy,
2,2,2-trifluoroethoxy, methyl, ethyl, methoxymethyl.

 Preferred n is 1 or 2.

Preferred R ¹⁰ is a hydrogen atom or methyl.

 Preferred Q is an oxygen or sulfur atom.

Preferred Y is _{-CH (CH 3) -, -} CH = CH- or -C (C
H ₃₎ = CH-, and the like.

 Preferred Z is an oxygen or sulfur atom.

The compound having the formula (1), (2), or (3) is
It can be converted to a salt or ester as required.

The compound having the formula (20 ') or (8) can be converted to a salt thereof, if necessary.

Such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,
Acid addition of organic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate Salts or metal salts of carboxylic acids such as sodium, potassium, calcium, magnesium, manganese, iron, aluminum salts. Further, as a group forming an ester,
Lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, aralkyl groups such as benzyl, lower aliphatic acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl, 1- ( Ethoxycarbonyloxy) ethyl, 1-
Lower alkoxycarbonyloxyalkyl groups such as (isopropoxycarbonyloxy) ethyl, N, N-disubstituted aminocarbonylalkyl groups such as N, N-dimethylaminocarbonylmethyl group, phthalidyl group or (5-
Methyl-2-oxo-1,3-dioxolen-4-yl)
Examples include groups that can be easily converted into carboxy groups in vivo such as methyl groups. The compound (1) of the present invention,
(2) and (3) can also exist as hydrates.

Suitable compounds having the above general formula (1), (2) or (3) of the present invention include the compounds exemplified in the following table, and pharmacologically acceptable salts and esters thereof.

The novel compound having the formula (1), (2) or (3) of the present invention can be produced according to the following reaction formula [A].

In the above formula, R ¹ , R ² , R ³ , R ⁴ , X, Y and Z have the same meanings as described above.

The compounds (1), (2) and (3) of the present invention can be prepared by converting the compound (4), (5) and (6) with the amine compound (7) one to several times by mole in the presence of a deoxidizing agent or It is produced by reacting in the absence or presence of a solvent.

As the solvent used in this reaction, aprotic polar solvents such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and dimethylacetamide are preferable, but also ketones such as acetone and methyl ethyl ketone, diethyl ether, and tetrahydrofuran. And ethers such as dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, propanol, isopropanol and butanol, and nitriles such as acetonitrile. Examples of the deoxidizing agent include 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5-nonene,
Use amines such as triethylamine, tributylamine, pyridine, picoline, lutidine, collidine, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium-t-butoxide, or inorganic bases such as sodium carbonate and potassium carbonate. be able to. The amount of the deoxidizing agent to be used is preferably from equimolar to 5 times the molar amount of the compound (4), (5) or (6). In the case of the amines, a large excess can be used as a solvent. The reaction proceeds smoothly without adding other deoxidizing agents. The reaction is performed at a temperature ranging from 0 ° C 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 can be further purified by a usual purification means such as a recrystallization method and column chromatography, if necessary.

The general formulas (1) and (2) thus produced
Alternatively, the compound having (3) may have an optical isomer or a geometric (cis, trans) isomer based on the asymmetric carbon atom of the X portion in the structure. In such a case, if desired, the above reaction is carried out using the optically resolved or separated raw material compound XH (7), whereby the corresponding optical isomer of the target compound (1), (2) or (3) is obtained. To obtain the isomers or geometric isomers, or to obtain the respective stereoisomers from the optical isomers or the mixture of geometric isomers of the compound (1), (2) or (3) according to a usual optical resolution or separation method Can be.

Compounds (4), (5) and (6) are synthesized according to reaction formulas [B], [C] and [D].

Reaction Formula [B-1] For the synthesis of compound (4) in which R ¹ is a lower alkyl group, a halogeno lower alkyl group or a phenyl group which may have a substituent, wherein R ³ is the same as described above. R ¹³ represents ^a hydrogen atom or a nitro group, R ¹³ has the same meaning as described above, R ¹⁴ and R ¹⁵ may be the same or different alkyl groups such as methyl and ethyl, or R ¹⁴ and R ¹⁵ Together represent ethylene, trimethylene or tetramethylene, and these alkylene chains may have an oxygen or sulfur atom interposed.

Compound (8) is synthesized according to reaction formula [E].

Compounds (9), (10), (11) (12), (14), (1
The synthesis of 5) is a method described in JP-A-60-169475.

From compound (9) to (13), (14) and compound (17)
To (18) can be carried out according to the method described in JP-A-63-316757, and reduction of compounds (13), (14) and (15) can be carried out according to a conventional method. The hydrolysis of compounds (15) and (16) can be performed according to a conventional method.

Reaction formula [B-2] Regarding the synthesis of compound (4) wherein R ¹ is a lower alkenyl group: In the formula, R ² , R ³ and R ¹³ have the same meaning as described above, and R ⁶ is other than a fluorine atom Represents an alkyl group substituted with a halogen atom.

Compound (19) is obtained by reacting (15) or (1) in Reaction Formula [B-1].
6) corresponds to a compound in which R ¹ is a halogenoalkyl group.

Compound (20) can be constructed according to the method described in JP-A-50-108276, and hydrolysis of compound (20) can be carried out according to a conventional method.

Reaction formula [B-3] Compound (4) when R ¹ is a lower alkylamino group
Wherein R ³ , R ^a R ¹³ , R ¹⁴ and R ¹⁵ are as defined above, R ^c is an alkyl group such as methyl, ethyl, propyl, isopropyl, and L is Indicates a halogen atom such as chlorine, bromine or iodine.

The synthesis of compounds (21), (23) and (24) is described in
The alkylation of the compounds (23) and (24) can be carried out according to the methods described in JP-A-63-169475 and JP-A-63-316757. Compounds (13), (21)
The reduction reaction of (25) and (25) can be performed according to a conventional method, and the hydrolysis of compounds (25) and (26) can be performed according to a conventional method.

Reaction formula [C-1] In the formula, R ³ and Y have the same meanings as described above.

Compound (27) is a known compound and is disclosed in JP-A-63-1328.
No. 91) and the synthesis of compound (29) are described in JP-A-59-222426.
Compound (31) can be prepared according to the method described in Japanese Unexamined Patent Publication No. 14 (III), 1506 (Maruzen Publishing).
Compounds (32) to (35) can be synthesized according to the method described in
Can be synthesized according to the method described in JP-A-58-103393. Compounds (28), (30), (36) and (37) can be synthesized according to a conventional method, and compound (35) can be synthesized. ) And compound (37) can be hydrolyzed according to a conventional method.

Compound (29) is synthesized according to Reaction Formula [C-2]. In the formula, L and L 'represent the same or different halogen atoms other than a fluorine atom.

The synthesis of compounds (29a) and (29b) is described in JP-A-59-22.
Compound (38) can be synthesized according to the method described in JP-A-58-128374, and compound (29c) can be synthesized according to the method described in New Experimental Chemistry 1
4 (I) It can be performed according to the method described in 321 (Maruzen Publishing).

Reaction formula [D] In the formula, R ³ , R ⁴ , R ^a , and R ¹³ have the same meanings as described above.

Compounds (39), (40), (41), (42), (43),
The compounds (6a) and (6b) can be synthesized according to the method described in JP-A-62-187472, and the reduction of the nitro group of the compounds (42) and (43) can be carried out according to a conventional method. .

Reaction formula [E]: Synthesis method of compound (8) [E-1] In the formula, L represents the same meaning as described above, and R ¹⁶ represents an alkoxy group such as methoxy or ethoxy or an amino group.

Compound (45) is a known compound (JP-A-63-2644).
No. 40) It can be obtained by decarboxylating 4-hydroxy-3,5,6-trifluorophthalic acid according to a conventional method. Esterification and amidation of compound (45) and hydrolysis of compound (47) can be carried out according to a conventional method. Fluoroalkylation of compounds (45) and (46) is described in
It can be carried out according to the method described in JP-A-59-222426.

[E-2] In the formula, R ¹⁶ , L and L ′ have the same meanings as described above.

The esterification and amidation of the compound (45) and the hydrolysis of the compound (49) can be carried out according to a conventional method, and the synthesis of the compounds (50) and (48) is described in JP-A-58-12.
JP 8374 can be performed according to the method described, fluorination of compound (50) and (48), Shin Jikken Kagaku Koza 14
(I) It can be carried out according to the method described in 321 (Maruzen Publishing).

[E-3] In the formula, R ³ has the same meaning as described above.

 The nitration of compound (8a) can be performed according to a conventional method.

Effects of the Invention The target compound of the present invention having the general formulas (1), (2) and (3) and a salt thereof exhibit excellent antibacterial activity.

Accordingly, the compounds of the present invention are useful as antibacterial agents for treating bacterial infections caused by pathogenic bacteria. Dosage forms for that purpose include, for example, tablets, capsules, granules,
Oral administration by powders, syrups and the like or parenteral administration by intravenous injections, intramuscular injections, suppositories and the like can be mentioned. The dose varies depending on age, body weight, symptoms, administration form and number of administrations, but usually about 100 to 1000 mg per day is orally administered to an adult once or several times a day.

Next, the present invention will be described more specifically with reference to Reference Examples and Examples. Reference Examples 9 to 21 are the embodiments of claims 2 to 3 of the present invention.

[Reference Example 1] 2,4,5-trifluoro-3-difluoromethoxybenzoic acid 2,4,5-trifluoro-3-hydroxybenzoic acid 20.0 g
(0.104 mol) was dissolved in 500 ml of ethanol and 5 ml of concentrated sulfuric acid
After heating under reflux for 4 hours, ethanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium bicarbonate and then with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 2,4,5-trifluoro-
16.9 g of ethyl 3-hydroxybenzoate was obtained as a colorless powder.

MS spectrum (CI): m / e 221 (M + +1), 175 (M + -OC 2 H
₅ ) Ethyl ester of 2,4,5-trifluoro-3-hydroxybenzoic acid 8.83 g (0.04 mol) obtained as above was dissolved in 40 ml of dimethylformamide, and 1.76 g of 60% sodium hydride was stirred under ice-cooling and stirring. 0.044 mol) was added little by little, and after the addition was completed, the mixture was stirred for 30 minutes under ice cooling. The reaction mixture is
The mixture was transferred to a 0 ml stainless steel autoclave, 100 ml of dimethylformamide containing 28.0 g (0.32 mol) of chlorodifluoromethane was added thereto, and the mixture was stirred under pressure at 95-100 ° 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 2,4,5-trifluoro-3-difluoromethoxybenzoate. 4.85 g of the ester were obtained as a colorless liquid.

MS spectrum (CI): m / e 271 (M + +1), 225 (M + -OC 2 H
₅ ) 2.79 g (0.021 g) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid ethyl ester obtained by the above method
Mol) was dissolved in 40 ml of ethanol, 20 ml of a 6% aqueous sodium hydroxide solution was added, and the mixture was left overnight at room temperature. The reaction mixture was acidified by adding concentrated hydrochloric acid (3.5 ml), concentrated under reduced pressure, extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 2,4,5-trifluoro-3. -5.22 g of difluoromethoxybenzoic acid was obtained as a colorless powder.

Melting point: 68-70 ° C MS spectrum (CI): m / e243 (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 (1 H, br, COOH) [Reference Example 2] 2,4,5-trifluoro-3-fluoromethoxybenzoic acid Instead of chlorodifluoromethane, bromofluoromethane Was used to obtain 2,4,5-trifluoro-3-fluoromethoxybenzoic acid as a colorless powder in the same manner as in [Reference Example 1].

Melting point: 84-86 ° C MS spectrum (CI): m / e225 (M ⁺ +1), 207 (M ⁺ -OH) [Reference Example 3] 2,4,5-trifluoro-3-difluoromethoxybenzoic acid 2, 4,5-trifluoro-3-hydroxybenzoic acid 100.0
g (0.52 mol) dissolved in 400 ml of benzene, thionyl chloride 30
After addition of 0 ml and heating under reflux for 3 hours, the solvent and excess thionyl chloride were distilled off under reduced pressure to give 2,4,5-trifluoro-
3-Hydroxybenzoic acid chloride was obtained. This was added dropwise to 150 ml of 28% aqueous ammonia under ice-cooling and stirring, and after continuing stirring for 2 hours, the mixture was allowed to stand at room temperature overnight, acidified with diluted 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 to give 2,4,5-trifluoro-3.
-88.2 g of hydroxybenzoic acid amide was obtained as a colorless powder.

MS spectrum (CI): m / e192 ( M + +1), 175 (M + -NH 2) mp: 153-155 ° C. obtained above 2,4,5-trifluoro-3-hydroxybenzoic acid 5.00 g (0.026 mol) of amide was dissolved in 130 ml of dimethylformamide, and 4.70 g (0.034 mol) of potassium carbonate was dissolved.
Mol) and 6.8 g (0.079 mol) of chlorodifluoromethane, and the mixture was stirred at 100 ° C. for 3 hours in an autoclave. After the completion of the reaction, add 500 ml of water, extract with ethyl acetate,
After washing the organic layer with water, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (solvent: toluene-ethyl acetate).
(1: 1 mixture) to give 5.08 g of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid amide as colorless needle crystals.

Melting point: 102-104 ° C MS spectrum (CI): m / e242 (M ⁺ +1), 225 (M ⁺ -NH ₂ ) 2,4,5-Trifluoro-3-difluoromethoxybenzoic acid obtained as above 15.53 g (0.064 mol) of acid amide
Was suspended in 20 ml of concentrated sulfuric acid, and sodium nitrite 6.60 was stirred under ice-cooling.
30 ml of an aqueous solution of g (0.096 mol) was gradually added dropwise, and then the mixture was heated and refluxed for 30 minutes. After allowing to cool to room temperature, add 50 ml, extract with chloroform, wash the organic layer with water, dry over anhydrous sodium sulfate, depressurize the solvent, and remove 15.59 g of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid in colorless form Obtained as a powder. This was confirmed by melting point, MS spectrum and NMR spectrum to be the same as described above.

Reference Example 4 To 2.18 g (0.052 mol) of sodium hydroxide of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid was added 5 ml of water and dissolved, and then 20 ml of dimethylformamide was added thereto. 4.97 g (0.026 mol) of fluoro-3-hydroxybenzoic acid was added little by little under ice cooling. After completion of the addition, the mixture was stirred for 30 minutes under ice cooling. The reaction mixture was transferred to a 200 ml stainless steel autoclave, and chlorodifluoromethane 2 was added thereto.
100 ml of dimethylformamide containing 4.0 g (0.277 mol) was added, and the mixture was stirred under pressure at 100 to 110 ° C. for 5 hours. After completion of the reaction, the reaction mixture was added to water and extracted with chloroform. After washing the chloroform layer with water and drying over anhydrous sodium sulfate, the solvent was distilled off.
The residue was subjected to silica gel column chromatography (solvent: ethyl acetate-ethanol 9: 1 mixture) to obtain 2.00 g of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid as a colorless powder.

This was confirmed by melting point, MS spectrum and NMR spectrum to be the same as described above.

Reference Example 5 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid 2,4,5-trifluoro-3-hydroxybenzoic acid ethyl ester 5.0 g (0.023 mol) was added to dimethylformamide 2
Dissolve in 0 ml, and add 1.0 g (0.0%
25 mol) was added little by little, and after completion of the addition, the mixture was stirred for 30 minutes under ice cooling. Then 28.0 g of difluorodibromomethane (0.1
(3 mol) was added and the mixture was stirred at room temperature for 23 hours. After the reaction is completed, the reaction mixture is
l, 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 5.60 g of ethyl 3-difluorobromomethoxy-2,4,5-trifluorobenzoate as a colorless liquid.

MS spectrum (CI): m / e351 (M ⁺⁺ 3), 349 (M ⁺⁺ 1) Then, the 3-difluorobromomethoxy-2,4,5-
1.50 g (0.0043 mol) of trifluorobenzoic acid ethyl ester was dissolved in 10 ml of toluene, and 2.50 g (0.013 g) of silver borofluoride was dissolved.
Mol), and the mixture was heated and refluxed for 8 hours under stirring and light shielding. The reaction solution was passed, the solution was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (solvent: toluene) to give 2,4,5-
1.12 g of trifluoro-3-trifluoromethoxybenzoic acid ethyl ester was obtained as a colorless liquid.

MS spectrum (CI): m / e 289 (M ⁺ +1), 269 (M ⁺ -F) 2,5,5-trifluoro-3-trifluoromethoxybenzoic acid ethyl ester 5.05 g obtained as described above ( 0.0
715 mol) in 100 ml of ethanol, 1N sodium hydroxide 1
9.3 ml (0.0193 mol) 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, 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 to give 2,4,5-trifluoro-. 3.98 g of 3-trifluoromethoxybenzoic acid was obtained as a colorless powder.

MS spectrum (CI): m / e261 ( M + +1), 243 (M + -OH) NMR spectrum _{(CDCl 3, δ): 7.88} (1H, m, aromH) Reference Example 6] 2,4,5 Trifluoro-3-difluoromethoxy-6-
Nitrobenzoic acid Dissolve 15.0 g (0.062 mol) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid in 40 ml of concentrated sulfuric acid, add dropwise 20 ml of concentrated nitric acid (d = 1.42) under ice-cooling and stirring, and add 60 ° C. For 7 hours. The reaction solution was allowed to cool to room temperature, poured into ice water, and extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
16.6 g of 4,5-trifluoro-3-difluoromethoxy-6-nitrobenzoic acid was obtained as a yellow powder.

Mp: 77-80 ° C. MS ^{spectrum: m / e287 (M +)} , 243 (M + -CO 2) Reference Example 7] 2,4,5-trifluoro-3-difluoromethoxy-6-
Nitrobenzoic acid 30 ml of concentrated nitric acid (d = 1.42) is cooled in an ice-water bath, and concentrated sulfuric acid 60
ml was carefully added. 2,4, with vigorous stirring under ice cooling
25 g of 5-trifluoro-3-fluoromethoxybenzoic acid was slowly added. After the addition, the mixture was stirred at the same temperature for 3 hours. The reaction solution was poured into ice water and extracted with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 20,66 g of 2,4,5-trifluoro-3-fluoromethoxy-6-nitrobenzoic acid as a yellow powder.

Mp: 80-83 ° C. MS ^{spectrum: m / e269 (M +)} , 225 (M + -CO 2) Reference Example 8] 2,4,5-trifluoro-3-hydroxy-benzoic acid 3,5,6 2,700 g of trifluoro-4-hydroxyphthalic acid
And water 6 into the autoclave,
Heated at C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to precipitate crystals. The crystals were collected, washed with chloroform, and dried. 2,4,5 as colorless powder
1623 g of -trifluoro-3-hydroxybenzoic acid were obtained.

Melting point: 144-146 ° C MS spectrum: m / e192 (M ⁺ ) NMR spectrum: (CD ₃ D, δ): 4.94 (1H, bs, —OH), 7.25
(1H, m, aromH) [Reference Example 9] 6,7-difluoro-8-difluoromethoxy-1- (4
-Fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid In 30 g (0.124 mol) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acid, 90 ml of benzene and 40 ml of thionyl salt were added.
Was added and the mixture was heated under reflux for 2 hours. After the reaction, benzene and excess thionyl chloride were distilled off under reduced pressure to obtain 2,4,5-trifluoro-3-difluoromethoxybenzoic acid chloride.

17.6 g of 3-dimethylaminoacrylic acid ethyl ester
(0.13 mol) was dissolved in 60 ml of anhydrous acetonitrile, 13.83 g (0.137 mol) of triethylamine was added, and a solution prepared by dissolving the above acid chloride in 30 ml of acetonitrile was gradually added dropwise at room temperature. After the dropwise addition, the mixture was heated under reflux for 1 hour. The reaction mixture was filtered, the liquid was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: 1: 1 mixture of ethyl acetate-toluene) to give 2- (2,4,5-trifluoro-3-difluoromethoxy). 44.25 g of benzoyl) -3-dimethylaminoacrylic acid ethyl ester was obtained as a red liquid.

MS spectrum (CI): m / e368 (M ⁺ +1) 2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl) -3-dimethylaminoacrylic acid ethyl ester 12.4 g (0.034 mol) in acetonitrile 100 ml And 4-fluoroaniline was slowly added dropwise with stirring at room temperature, followed by stirring at room temperature for 1 hour. After heating under reflux for 4 hours, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene) to give 2- (2,4,5).
-Trifluoro-3-difluoromethoxybenzoyl)
10.8 g of ethyl 3- (4-fluoroanilino) acrylate was obtained as a slightly yellow solid.

MS spectrum (CI): m / e434 (M ⁺⁺ 1) 2- (2,4,5-trifluoro-
10.8 g (0.025) of ethyl 3-difluoromethoxybenzoyl) -3- (4-fluoroanilino) acrylate
Mol) was dissolved in 100 ml of anhydrous diethyl ether,
1.5 g (0.038 mol) of sodium hydroxide
The mixture was stirred at the same temperature for 30 minutes. 37.4 ml of IN hydrochloric acid was added to the reaction mixture, and the mixture was vigorously stirred to make the entire reaction solution acidic, and the precipitated crystals were washed with water and then with diethyl ether to give 6,6.
7-difluoro-8-difluoromethoxy-1- (4-
7.65 g of (fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained as a colorless powder.

MS spectrum (CI): m / e414 (M ⁺⁺ 1) Then, 7.65 g (0.0185 mol) of this ester compound was treated with 45 m of acetic acid.
l, 31.5 ml of water and 5.6 ml of concentrated sulfuric acid were suspended in a mixture and heated under reflux for 2 hours with stirring. After cooling, add water to remove insolubles,
The mass was washed with water, then with diethyl ether,
6.68 g of -difluoro-8-difluoromethoxy-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as a colorless powder.

Melting point: 211-216 ° C MS spectrum (CI): m / e386 (M ⁺⁺ 1) The following compound was synthesized in the same manner as in [Reference Example 9].

[Reference Example 16] 5-amino-1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2,4,5-trifluoro-3- Difluoromethoxy-6
-Nitrobenzoic acid (15.97 g, 0.056 mol) in benzene (50 ml)
, 40 ml of thionyl chloride was added, and the mixture was heated under reflux for 2 hours. After the reaction, benzene and excess thionyl chloride were distilled off under reduced pressure to give 2,4,5-trifluoro-3-difluoromethoxy-.
6-Nitrobenzoic chloride was obtained.

On the other hand, 6.82 g (0.058 mol) of magnesium ethoxide and 9.35 g (0.058 mol) of malonic acid diethyl ester were heated under reflux in 150 ml of anhydrous diethyl ether with stirring for 2 hours to obtain a suspension of diethyl ethoxymagnesium malonate in diethyl ether. A liquid was obtained. Under stirring at room temperature, the above acid chloride was added to anhydrous diethyl ether 150 ml.
Was added dropwise, and the mixture was further stirred at room temperature for 2 hours.

100 ml of IN 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 to give 2,4,5-trifluoro-3-difluoromethoxy-. 31.2 g of 6-nitrobenzoylmalonic acid diethyl ester was obtained as a red liquid.

MS spectrum (CI): m / e430 (M ⁺⁺ 1), 384 (M ⁺ -OE
t), 270 [M ⁺ -CH (CO ₂ Et) ₂ ] Then, this was dissolved in 300 ml of dioxane, and 10.6 g (0.056 mol) of P-toluenesulfonic acid monohydrate was added.
Heated to reflux for an hour. The reaction solution was distilled off under reduced pressure, and the residue was
l and 4.7 g (0.056 mol) of sodium hydrogen carbonate were added, and extracted with toluene. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 2,4,5-trifluoro-3.
19.4 g of -difluoromethoxy-6-nitrobenzoylacetic acid ethyl ester were obtained as a red liquid.

MS spectrum (CI): m / e358 (M ⁺⁺ 1), 312 (M ⁺ -OE
t), 270 (M ⁺ -CH ₂ COOEt) Then, 38 ml of acetic anhydride and 11 ml of ethyl orthoformate were added thereto, and the mixture was heated under reflux for 3 hours.
Ethyl orthoformate is distilled off, and 2- (2,4,5-trifluoro-3-difluoromethoxy-6-nitrobenzoyl)
20.6 g of ethyl 3-ethoxyacrylate was obtained as a red liquid.

MS spectrum (CI): m / e414 (M ⁺⁺ 1) 3.89 g (0.047 mol) of ethylamine hydrochloride and ethanol
50 ml of the solution was added to a solution of sodium methylate under ice-cooling and stirring.
2.58 g (0.047 mol) were added. This solution is 2- (2,4,
A solution of 16.4 g of 5-trifluoro-3-difluoromethoxy-6-nitrobenzoyl) -3-ethoxyacrylic acid ethyl ester in 30 ml of ethanol was added under ice-cooling. After stirring for 1 hour under ice cooling and further for 1 hour at room temperature, the insolubles were removed and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 4: 1 mixture to give 3-ethylamino-2- (2,
15.24 g of 4,5-trifluoro-3-difluoromethoxy-6-nitrobenzoyl) acrylic acid ethyl ester was obtained as yellow crystals.

MS spectrum (CI): m / e413 (M ⁺⁺ 1) 3-ethylamino-2- (2,4,
15.24 g (0.03 g of 5-trifluoro-3-difluoromethoxy-6-nitrobenzoyl) acrylic acid ethyl ester
(7 mol) was dissolved in 150 ml of ethanol, 3.0 g of 5% palladium carbon was added, and hydrogen gas was passed for 50 minutes while stirring at room temperature. The reaction mixture was filtered, the solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 4: 1 mixture) to give 2- (6-amino-2,
8.5 g of 4,5-trifluoro-3-difluoromethoxybenzoyl) -3-ethylaminoacrylic acid ethyl ester
Was obtained as a slightly yellow powder.

MS spectrum (CI): m / e383 (M ⁺⁺ 1) 2- (6-amino-2,4,5-trifluoro-3-difluoromethoxybenzoyl) -3 obtained as above
-Ethyl aminoacrylic acid ethyl ester 7.08 g (0.018
5 mol) in 100 ml of tetrahydrofuran, 60% under ice-cooling
0.96 g (0.024 mol) of sodium hydride was gradually added, followed by stirring at the same temperature for 30 minutes. 24 ml of IN hydrochloric acid was added to the reaction mixture, and the mixture was vigorously stirred to make the whole reaction solution acidic, and the precipitated crystals were washed with water and then with ethyl ether, and then washed with 5-amino-1-ethyl-6,7-difluoro-8-. 5.99 g of ethyl difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained as a colorless powder.

MS spectrum (CI): m / e363 (M ⁺⁺ 1) Then, 5.99 g (0.0165 mol) of this ester was treated with acetic acid 38.
Suspended in a mixture of 1 ml, 27.9 ml of water and 5.0 ml of concentrated sulfuric acid.
Heated to reflux for an hour. After cooling, water was added to remove insolubles, and the collected product was washed with water and then with diethyl ether.
5.3 g of 5-amino-1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as pale yellow crystals.

Melting point: 281-283 ° C MS spectrum (CI): m / e335 (M ⁺⁺ 1) The following compound was synthesized in the same manner as in [Reference Example 16].

[Reference Example 19] 6,7-Difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid 1- (2 -Bromoethyl) -6,7-difluoro-8-difluoromethoxy-
1.00 g (0.0023 mol) of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was dissolved in 50 ml of dimethylformamide, and potassium carbonate 0.49 g (0.0035 mol)
Was added and the mixture was stirred at 95 to 100 ° C for 4 hours, and the solvent was distilled off under reduced pressure. The residue was washed with water and then with diethyl ether,
0.70 g of -difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid ethyl ester was obtained as a slightly brown powder.

MS spectrum (CI): m / e345 ( M +), 300 (M + -OC 2 H 5), 2
^{_{73 (M + -OC 2 H 5}} -CH = CH 2) which is then in acetic acid 12 ml, water 8ml and concentrated sulfuric acid 0.8ml was added, the reaction mixture is heated until a solution state, and stirred.
Water was added to the resulting solution, and the precipitated precipitate was collected, washed with water, and washed with ethyl acetate to obtain the title compound (0.27 g) as a colorless powder.

Melting point: 165-166 ° C MS spectrum (CI): m / e 317 (M ⁺ ), 273 (M ⁺ -CH = CH ₂ ) [Reference Example 20] 5-amino-6,7-difluoro-8-difluoromethoxy- 1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid 2- (2,4,5) obtained as an intermediate in Reference Example 16
-Trifluoro-3-difluoromethoxy-6-nitrobenzoyl) -3-ethoxyacrylic acid ethyl ester
Dissolve 18.81 g (0.046 mol) in 250 ml of ethanol, and add 9.33 g (0.0046 mol) of 2-bromoethylamine hydrobromide.
And 4.60 g (0.046 mol) of triethylamine were added, and the mixture was stirred at room temperature for 10 hours and concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The obtained oil was crystallized by adding n-hexane. The crystals were collected, washed with n-hexane, and ethyl 3- (2-bromoethylamino) -2- (2,4,5-trifluoro-3-difluoromethoxy-6-nitrobenzoyl) acrylate 19.72 g was obtained as a pale yellow powder.

MS spectrum (CI): m / e493 (M ⁺⁺ 3), 491 (M ⁺⁺ 1) Then, 9.82 g (0.02 mol) of this was dissolved in 250 ml of tetrahydrofuran, and 1.76 g of 60% sodium hydride at room temperature.
(0.044 mol) was added in portions, and the mixture was heated under reflux for 1 hour. Under ice-cooling and stirring, water was added to the reaction mixture to decompose excess sodium hydride.
When 0 ml was added, a precipitate precipitated. Collect this, wash with water,
After further washing with diethyl ether, 1- (2-bromoethyl) -6,7-difluoro-8-difluoromethoxy-
1,4-dihydro-5-nitro-4-oxoquinoline-3
-7.50 g of carboxylic acid ethyl ester were obtained as a light brown powder.

MS spectrum (CI): m / e473 (M ⁺⁺ 3), 471 (M ⁺⁺ 1) Then, this was suspended in 600 ml of methanol, and 3.7 g of 20% palladium on carbon (50% water-containing substance) was added. Under stirring, hydrogen gas was passed in for 50 minutes. The reaction mixture was heated while heating, the liquid was concentrated under reduced pressure, and the residue was washed with diethyl ether to give 5-amino-1- (2-bromoethyl) -6,7-difluoro-8-difluoromethoxy-1,4-dihydro-.
4-oxoquinoline-3-carboxylic acid ethyl ester 4.
70 g was obtained as a colorless powder.

MS spectrum (CI): m / e443 (M ⁺⁺ 3), 441 (M ⁺⁺ 1) Then, this was dissolved in 250 ml of dimethylformamide, and 3.31 g (0.024 mol) of potassium carbonate was added.
Stir and pass for 5 hours. The liquid was concentrated under reduced pressure, and the resulting solid was washed with water, acetone-insoluble material was removed, and acetone was distilled off under reduced pressure to obtain a solid. This was washed with ethanol and then with diethyl ether to give 3.79 g of 5-amino-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1-vinylquinoline-3-carboxylic acid ethyl ester. Obtained as a brown powder.

MS spectrum (CI): m / e360 (M ⁺ ), 309 (M ⁺ -CHF ₂ ) Then, this was suspended in a mixed solution of 60 ml of acetic acid, 40 ml of water and 4 ml of concentrated sulfuric acid, and stirred for 2.5 hours under reflux with heating. After cooling to room temperature, 100 ml of water was added, and the precipitated crystals were washed with water and washed to give 3.18 g of the title compound as an off-white powder.

Melting point: 255-260 ° C (decomposition) MS spectrum: m / e332 (M ⁺ ) [Reference Example 21] 6.7-difluoro-8-difluoromethoxy-1,4-dihydro-1-methylamino-4-oxoquinoline-3 -Carboxylic acid (R ³ = OCHF ₂ ) 3-ethoxy-2- (2,4,5-triene obtained from 2,4,5-trifluoro-3-difluoromethoxybenzoic acid according to the method of Reference Example 16 27.67 g (0.07 g of fluoro-3-difluoromethoxybenzoyl) acrylic acid ethyl ester
51 mol), methylene chloride (100 ml) was added, and benzoylhydrazine (14.15 g, 0.1040 mol) was added under ice water cooling and stirring.
Stir at room temperature for 3 hours, then leave overnight. The reaction solution was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: a 9: 1 mixture of toluene-ethyl acetate).
20.76 g of ethyl 3- (2-benzoyl) hydrazino-2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl) acrylate was obtained as pale-colored crystals.
12.32 g (0.0269 mol) of the obtained crystal was dissolved in 150 ml of tetrahydrofuran, and 1.61 g (0.0402 mol) of 60% sodium hydride was dissolved.
Mol) at room temperature, followed by stirring and then heating under reflux for 2 hours. After cooling, add IN hydrochloric acid (20 ml), water (100 ml) and ethyl acetate (150 m)
Extracted twice with l. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography (solvent: a mixture of toluene and ethyl acetate at a ratio of 9: 1 to 2: 3) to give 1-benzoylamino-6,7-difluoro-8-difluoromethoxy-1,4.
-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 2.76 g was obtained as colorless crystals.

Melting point: 98-99 ° C. (ethanol reconstitution) MS spectrum (CI): m / e439 (M ⁺⁺ 1) 1.89 g (0.0136 mol) of finely ground potassium carbonate were added into 20 ml of dimethylformamide, and then 1 −
Benzoylamino-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-
After adding 3.0 g (0.0068 mol) of carboxylic acid ethyl ester and stirring at room temperature for 60 minutes, methyl iodide 1.27 ml (0.02 mol) was added.
04 mol), and the mixture was further stirred for 4 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with 50 ml of water and 150 ml of chloroform. The organic layer was dried over anhydrous sodium sulfate and then distilled off under reduced pressure to give 1- (N-benzoylmethylamino) -6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-. 3.1 g of 3-carboxylic acid ethyl ester was obtained as pale yellow crystals.

MS spectrum (CI): m / e453 (M ⁺⁺ 1) 1.26 g (0.0027 mol) of the obtained crystal was mixed with 20 ml of ethanol.
Was added and 10 ml (0.010 mol) of IN sodium hydroxide was added with stirring to carry out a reaction for 2 hours. Then, the mixture was neutralized with IN hydrochloric acid, and 100 ml of water was further added, whereby a precipitate was formed. This was removed to give 0.62 g of 6,7-difluoro-8-difluoromethoxy-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a colorless powder.

MS spectrum (CI): m / e320 ( M +), 276 (M + -CO 2) Reference Example 22] 7,8-Difluoro-9-difluoromethoxy-5-oxo -5H- thiazolo [3.2-a] Quinoline-4-carboxylic acid 2-amino-5,6-difluorophenol 54.1 g (0.37
3 mol) and dissolved in 30 ml of acetic acid, then 38.1 g of acetic anhydride at room temperature
(0.373 mol) was added slowly. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and recrystallized from water to obtain 2-acetylamino-5,6-difluorophenol (40.9 g) as yellow-colored crystals.

Melting point: 123-125 ° C. 20.0 g (0.107 mol) of 2-acetylamino-5,6-difluorophenol obtained as above is dissolved in 120 ml of dimethylformamide, 19.2 g (0.139 mol) of potassium carbonate and 27.8 g of chlorodifluoromethane. g (0.139 mol)
Was added and stirred in an autoclave at 100 ° C. for 5 hours. After completion of the reaction, the mixture was poured into water 1 and extracted with ethyl acetate. The organic 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: ethyl acetate-toluene 1: 3 mixed solution),
24.6 g of 3,4-difluoro-2-difluoromethoxyacetanilide was obtained as brown crystals.

29.3 g (0.124 mol) of 3,4-difluoro-2-difluoromethoxyacetanilide was dissolved in 170 ml of ethyl alcohol, 45 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, ethyl alcohol and concentrated hydrochloric acid were distilled off under reduced pressure. 200 ml of water was added to the residue, the mixture was made alkaline with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography (solvent: chloroform) to give 20,4-63 g of 3,4-difluoro-2-difluoromethoxyaniline as a red liquid.

MS spectrum (CI): m / e196 (M ⁺⁺ 1) 3,4-difluoro-2-difluoromethoxyaniline 4
6.0 g (0.236 mol) was dissolved in 450 ml of anhydrous benzene, 9.05 g (0.0787 mol) of thiophosgene was added, and the mixture was heated under reflux for 1 hour with vigorous stirring. After cooling the mixture, insolubles were separated and the solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent: n-hexane) to give 3,4-
13.84 g of difluoro-2-difluoromethoxyphenyl isothiocyanate was obtained as a colorless liquid.

123 ml of dioxane and finely ground potassium hydroxide 3.8
While stirring 6 g (0.0585 mol) of the mixture, dioxane
Malonic acid diethyl ester dissolved in 10 ml 11.0 g (0.068
7 mol) was added slowly. After the addition, 13.84 kg (0.0584 mol) of 3,4-difluoro-2-difluoromethoxyphenyl isothiocyanate dissolved in 10 ml of dioxane was added dropwise. The mixture was further stirred at room temperature for 10 hours. The reaction solution was ice-cooled, and 5.4 g (0.0671 mol) of chloromethyl methyl ether was gradually added dropwise. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water 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.
-Difluoro-2-difluoromethoxyanilino) -1
30.42 g of-(methoxymethylthio) methylenemalonic acid diethyl ester was obtained as a yellow liquid.

MS spectrum (CI): m / e442 ( M + +1), 364 (M + -SCH 2 O
CH ₃ ) After dissolving 7.6 g (0.017 mol) of 1- (3,4-difluoro-2-difluoromethoxyanilino) -1- (methoxymethylthio) methylenemalonic acid diethyl ester obtained above in 22.8 g of diphenyl ether, Heated at ° C. for 5 minutes. The reaction solution was allowed to cool and poured into 130 ml of n-hexane.
After separating the precipitated crystals, the collected product was washed with n-hexane and treated with 6,7-difluoro-8-difluoromethoxy-4-.
3.72 g of hydroxy-2-methoxymethylthioquinoline-3-carboxylic acid ethyl ester was obtained as pale yellow crystals.

MS spectrum (CI): m / e396 (M ⁺⁺ 1) 14.88 g (0.038 mol) of ethyl 6,7-difluoro-8-difluoromethoxy-4-hydroxy-2-methoxymethylthioquinoline-3-carboxylate obtained above )
Was dissolved in 500 g of a 30% hydrogen bromide acetic acid solution, and left at room temperature for 24 hours. The reaction solution was poured into ice water, and the precipitated crystals were separated. The collected matter is washed with water and then dried by ventilation to give 6,7-difluoro-8.
11.4 g of -difluoromethoxy-4-hydroxy-2-mercaptoquinoline-3-carboxylic acid ethyl ester was obtained as a yellow powder.

MS spectrum (CI): m / e352 (M ⁺⁺ 1) 9.0 g (0.0256 mol) of 6,7-difluoro-8-difluoromethoxy-4-hydroxy-2-mercaptoquinoline-3-carboxylic acid ethyl ester obtained above Was dissolved in 50 ml of dimethylformamide, and 7.06 g of potassium carbonate (0.051
Mol) and bromoacetaldehyde diethyl acetal 7.
57 g (0.0384 mol) was added, and the mixture was heated and stirred at 80 ° C. for 9 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 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. The residue was subjected to silica gel column chromatography (solvent: ethyl acetate-toluene 1: 1 mixture) to give 6,7-difluoro-8-difluoromethoxy-4-hydroxy-2- (2,2-diethoxyethylthio). 6.) 6.95 g of quinoline-3-carboxylic acid ethyl ester were obtained as a colorless powder. To 6.48 g of the obtained colorless powder, concentrated sulfuric acid 2
8.6 g was added, and the mixture was heated and stirred at 90 ° C. for 20 minutes. The reaction solution was poured into ice water, and the precipitate was separated by filtration. After washing with water and drying, 7,8-difluoro-9-difluoromethoxy-5-oxo-5H-
5.08 g of thiazolo [3.2-a] quinoline-4-carboxylic acid ethyl ester was obtained as a colorless powder.

MS spectrum (CI): m / e376 ( M + +1), 303 (M + -CO 2 E
t) 7,8-Difluoro-9-difluoromethoxy-5-oxo-5H-thiazolo [3.2-a] obtained as described above
Quinoline-4-carboxylic acid ethyl ester 3.58 g (0.009
(5 mol) was added 35.8 g of concentrated sulfuric acid, and the mixture was heated with stirring at 80 ° C. for 10 hours. The reaction solution was poured into ice water to separate a precipitate. The collected product was subjected to silica gel column chromatography (solvent: chloroform-methanol 7: 3 mixture) to give 7,8-difluoro-9-difluoromethoxy-5-oxo-5H-thiazolo [3.2-a] quinoline- 2.92 g of 4-carboxylic acid was obtained as a pale yellow powder.

MS spectrum (CI): m / e348 (M ⁺⁺ 1), melting point: 225-228 ° C [Reference Example 23] 9-cyclopropyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9- Tetrahydroisothiazolo (5,4
-B] Quinoline-3,4-dione 2,4,5-dione obtained from 2,4,5-trifluoro-3-difluoromethoxybenzoic acid according to the method of [Reference Example 16]
12.69 g (0.0406 mol) of trifluoro-3-difluoromethoxybenzoylacetic acid ethyl ester and 5.23 g (0.0528 mol) of cyclopropylisothiocyanate were added to 80 ml of tetrahydrofuran. This solution is cooled with ice water,
% Sodium hydride 1.95 g (0.0487 mol) were added in portions. Stirring at room temperature for 2 hours resulted in a reddish brown transparent liquid. After standing in a refrigerator for 60 hours, 4.62 g (0.0325 mol) of methyl iodide was added dropwise at room temperature, and the mixture was stirred for 9 hours. Some of the solvent was distilled off under reduced pressure, diluted with 200 ml of water, and extracted three times with 100 ml of ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give an oil. The oily product was subjected to silica gel column chromatography (solvent: toluene and then a 9: 1 mixture of toluene-ethyl acetate) to give 3-cyclopropylamine-3-methylthio-2- (2,4,5-trifluoro- 6.88 g of ethyl 3- (difluoromethoxybenzoyl) acrylate was obtained as a brown oil.

MS spectrum (CI): m / e426 (M ⁺⁺ 1) To 6.88 g (0.0161 mol) of this brown oil was added 50 ml of tetrahydrofuran, and then 0.68 g of 60% sodium hydride.
(0.017 mol) was added. It was then heated in an oil bath heated to 75 ° C. for 13 hours.

After cooling, the solvent was distilled off under reduced pressure. 100 ml of water was added to the residue, and extracted with 200 ml of chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.68 g of pale yellow crystals. This was recrystallized from toluene-ethyl acetate to give 1-cyclopropyl-
1.84 g of ethyl 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-2-methylthio-4-oxoquinoline-3-carboxylate was obtained as colorless crystals.

MS spectrum (CI): m / e406 (M ⁺⁺ 1) 4.68 g (0.0115 mol) of 1- in 100 ml of methylene chloride.
2.74 g of 80% m-chloroperbenzoic acid in a solution of ethyl cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-2-methylthio-4-oxoquinoline-3-carboxylate (0.012 mol) was added in portions. The mixture was stirred at room temperature (24 ° C. for 2 hours and left overnight). This solution was washed with dilute sodium hydrogen carbonate solution, dried over magnesium powder, anhydrous magnesium sulfate, and concentrated under reduced pressure. ,
The crystals were collected to give 3.85 g of ethyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-2-methylsulfinyl-4-oxoquinoline-3-carboxylate as colorless crystals. Was.

MS spectrum (CI): m / e422 (M ⁺⁺ 1) 1.45 g (0.0034 mol) of 1 in 20 ml of tetrahydrofuran
-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-2-methylsulfinyl-
Ethyl 4-oxoquinoline-3-carboxylate and 3.5 ml of IN sodium hydrosulfide were added, and the mixture was stirred at room temperature for 2 hours and left for 3 days. 30 ml of water, 2.02 g (0.0240 mol) of sodium hydrogen carbonate and 0.97 g (0.0085 mol) of hydroxylamine-0-sulfonic acid were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted by adding 50 ml of water, extracted with ether (50 ml × 2), and the aqueous layer was acidified with dilute hydrochloric acid to obtain a precipitate. This was taken out and washed with ether, and 9-cyclopropyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo [5.4-b] quinoline-3,4-dione 0.51 g
(0.0014 mol) as a pale yellow powder.

Melting point: 215-221 ° C MS spectrum (CI): m / e361 (M ⁺⁺ 1) [Example 1] 6-Fluoro-8-difluoromethoxy-1- (4-fluorophenyl) -7- (1-piperazinyl) -1,4-
Dihydro-4-oxoquinoline carboxylic acid 6,7-difluoro-8-difluoromethoxy-1-
To 2.00 g (0.0052 mol) of (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 15 ml of pyridine and 1.30 g (0.0156 mol) of piperazine were added.
Stir at 05-110 ° C for 2 hours. After allowing to cool, the mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (solvent: chloroform-methanol 4: 1 mixture) to give 6-fluoro-
8-difluoromethoxy-1- (4-fluorophenyl) -7- (1-piperazinyl) -1,4-dihydro-4
-Oxoquinoline carboxylic acid 0.95 was obtained as a colorless powder.

Melting point: 247-249 ° C MS spectrum (CI): m / e452 (M ⁺ +1) Elemental analysis (%): C N N theoretical as C ₂₁ H ₁₇ F ₄ N ₃ O ₄ .H ₂ O 53.74 4.08 8.95 Analysis Value 53.48 4.17 8.69 The following compounds were synthesized as in Example 1.

Example 24 5-Amino-1-ethyl-6-fluoro-8-difluoromethoxy-7- (4-methyl-1-piperazinyl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid To 2.00 g (0.006 mol) of 5-amino-1-ethyl-6,7-difluoro-8-fluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added 20 ml of pyridine and 1.80 g of N-methylpiperazine. (0.018 mol)
Stirred at ~ 110 ° C for 2 hours. After cooling, the precipitated crystals were collected and subjected to silica gel column chromatography (solvent: chloroform-methanol 4: 1 mixture) to give 5-amino-1-ethyl-6-fluoro-8-difluoromethoxy-7. -(4-methyl-1-piperazinyl) -1,4-
1.95 g of dihydro-4-oxoquinoline-3-carboxylic acid
Was obtained as a yellow powder.

Melting point: 300 ° C. or higher MS spectrum (CI): m / e415 (M ⁺⁺ 1) The following compound was synthesized in the same manner as in Example 24.

Example 33 7-Fluoro-9-difluoromethoxy-8- (4-methyl-1-piperazinyl) -5-oxo-5H-thiazolo [3.2-a] quinoline-4-carboxylic acid To 0.90 g (0.0026 mol) of 7,8-difluoro-9-difluoromethoxy-5-oxo-5H-thiazolo [3.2-a] quinoline-4-carboxylic acid was added 10 ml of pyridine and 0.80 g (0.0078 mol) of N-methylpiperazine. In addition, the mixture was stirred at 105 to 110 ° C for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were collected and subjected to silica gel column chromatography (solvent: chloroform-methanol 7: 3 mixture) to give 7-fluoro-9-difluoromethoxy-8- (4-methyl-1-piperazinyl) -5.
0.26 g of -oxo-5H-thiazolo [3.2-a] quinoline-4-carboxylic acid was obtained as a slightly yellow powder.

Melting point: 261-264 ° C MS spectrum (CI): m / e428 (M ⁺ +1), 383 (M ⁺ -CO ₂ ) Elemental analysis value (%): C ₁₈ H ₁₆ F ₃ N ₃ O ₄ S · 1 / to synthesize a compound of the following in the same manner as C H N theoretical values 49.54 3.93 9.63 analytical values 49.68 3.75 9.52 example 33 as 2H _2.

[Example 37] 6-fluoro-8-difluoromethoxy-1-methylamino-7- (4-methyl-1-piperazinyl) -1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 6,7-difluoro-8-difluoromethoxy-1-methylamino-1,4 dihydro-4-oxoquinoline-3-
1.05 g (0.0032 mol) of carboxylic acid and 0.98 g (0.0098 mol) of N-methylpiperazine were added to 10 ml of pyridine,
Stirred at 110 ° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a residue. Silica gel column chromatography of the residue (solvent: 9: 1 mixture of chloroform-methanol)
6-fluoro-8-difluoromethoxy-1-
Methylamino-7- (4-methyl-1-piperazinyl)
0.41 g of -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as colorless crystals.

Melting point: 224-227 ° C. [Example 38] 9-cyclopropyl-6-fluoro-8-difluoromethoxy-7- (1-piperazinyl) -2,3,4,9-tetrahydroisothiazolo [5.4-b] quinoline Synthesis of −3,4-dione 0.40 g (0.0011 mol) of 9-cyclopropyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo [5.4-b] quinoline-3,4-dione and 0.47 g of piperazine ( 0.0054 mol) to pyridine 10m
The mixture was stirred at 105 to 110 ° C for 2 hours. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure, 30 ml of ethanol was added, and the mixture was refluxed under heating for 5 minutes and cooled. The precipitated crystals were washed with ethanol and water to give 9-cyclopropyl-6-fluoro-8-.
Difluoromethoxy-7- (1-piperazinyl) -2,3,
4,9-tetrahydroisothiazolo [5.4-b] quinoline-
0.09 g of 3,4-dione was obtained as a yellow powder.

Melting point: 258-262 ° C Elemental analysis value (%): C ₁₈ N ₁₇ F ₃ N ₄ O ₃ S · 1 / 2H ₂ CH N Theoretical value 49.65 4.02 12.86 Analytical value 49.56 4.15 12.53 In the same manner as in Example 38 The following compounds were synthesized.

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI A61K 31/54 603 A61K 31/54 603 C07D 498/04 C07D 513/04 343 513/04 343 345 345 498/04 112T (72) Inventor Yoshimi Fujiwara 5 Ube Kosan, Ube City, Ube City, Yamaguchi Prefecture 5 Ube Industries, Ltd.Ube Research Institute (72) Inventor Masayuki Iwata 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (58) Field surveyed (Int. Cl. ⁶ , DB name) CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) Expression And salts and esters thereof. In the formula, R ¹ is a lower alkyl group, a halogeno lower alkyl group,
A lower alkenyl group, a lower alkylamino group, or a phenyl group which may have at least one of a lower alkyl group, a hydroxyl group, a lower alkoxy group and a halogen atom as a substituent, and R ² represents a hydrogen atom or an amino group; R ³ represents a fluorine-substituted methoxy group, and R ⁴ has at least one of a lower alkyl group, a halogeno lower alkyl group, a cycloalkyl group, or a lower alkyl group, a hydroxyl group, a lower alkoxy group or a halogen atom as a substituent. X represents a phenyl group which may be (Wherein, R ⁵ is a hydrogen atom, a hydroxyl group, an amino group, an aralkyl group, a lower aliphatic acyl group or a hydroxyl group as a substituent, a lower alkoxy group, a lower aliphatic acyloxy group, a lower aliphatic acyl group, a carboxy group, a lower alkoxy group. carbonyl group, a sulfo group, an amino group, a lower aliphatic acylamino group, a mono-lower alkylamino group or di-lower alkylamino group substituted lower alkyl group optionally having, R ⁶
Represents a hydrogen atom or a hydroxyl group as a substituent, a lower alkoxy group or a lower alkyl group which may have a halogen atom, A is an ethylene group, a trimethylene group, or a group of the formula -COCH ₂ - represents a group, m is 1 or 2 Is shown. ), (Where W is (Wherein, R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group, and n ′ represents 0 or 1), a hydroxyl group or a lower alkoxy group, and R ⁷ represents a hydrogen atom , A hydroxyl group, a hydroxyl group as a substituent, a lower alkoxy group or a lower alkyl group which may have a halogen atom or a lower alkoxy group which may have a fluorine atom in an alkyl portion, B is a methylene group, an ethylene group , A trimethylene group or a tetramethylene group, and n represents 1 or 2. ), (In the formula, R ¹⁰ represents a hydrogen atom or a lower alkyl group.) (Wherein Q represents an oxygen atom or a sulfur atom), and Y represents an alkylene chain having 1 to 5 carbon atoms which may be substituted with a lower alkyl group or a halogen-substituted lower alkyl group. The chain may contain unsaturated bonds in the chain. Z represents an oxygen atom or a sulfur atom. 2. The equation (20 ') (Wherein, R ¹ and R ³ have the same meanings as described above;
^{2 'represents} a hydrogen atom, an amino group or a nitro group, R ¹³ represents a lower alkyl group. ), An intermediate (20 ′),
Its salt. 3. Equation (8) (Wherein, R ¹ , R ² , and R3 have the same meanings as described above)
Intermediate (8) represented by the formula: or a salt thereof.