JPH0899958A - Intermediate for producing 8-methoxyquinolonecarboxylic acid derivative - Google Patents

Abstract

(57) Abstract: A synthetic intermediate of a quinolonecarboxylic acid derivative useful as an antibacterial agent is provided. SOLUTION: The compound of formula (1) or (2)

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate for producing a 1-cyclopropyl-8-methoxyquinolonecarboxylic acid derivative having excellent antibacterial activity.

[0002]

2. Description of the Related Art Among so-called fluoroquinolonecarboxylic acids having a fluorine atom at the 6-position, a compound having a cyclopropyl group at the 1-position and a methoxy group at the 8-position has not been known.

[0003]

DISCLOSURE OF THE INVENTION In order to develop an excellent fluoroquinolonecarboxylic acid type antibacterial agent having a cyclopropyl group at the 1-position and a methoxy group at the 8-position, the inventors of the present invention have earnestly studied the production method thereof. The present invention has been completed by repeatedly discovering a series of novel compounds which are useful intermediates.

[0004]

[Means for Solving the Problems] The general formula (XXX
II) is

[0005]

[Chemical 3]

(Wherein Q represents an amino group, a cyano group, a carbamoyl group or a carboxy group, and Y ¹ and Y ² are the same or different and represent a halogen atom).

The first invention of the present application is represented by the general formula (XXXIII)

[0008]

[Chemical 4]

(In the formula, Y ² represents a halogen atom, and R ¹¹
Represents a hydrogen atom or a lower alkyl group), and the second invention of the present application is represented by the general formula
(XXXIV)

[0010]

[Chemical 5]

(Wherein Y ² has the same meaning as described above)
It relates to a compound represented by.

In the present invention, the compounds (XXXIII) and (X
Y ² in XXIV) is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.

In the compound (XXXII), Y ¹ and Y ² may be different.

Q in the compound (XXXII) represents an amino group, a cyano group, a carbamoyl group or a carboxy group.

R ¹¹ in the compound (XXXIII) represents a hydrogen atom or a C _1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl, particularly a hydrogen atom, A methyl group or an ethyl group is preferred.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Compounds (XXXII) and (XXXIII) can be obtained by the following reaction route [F ′],
V) can be produced by (B 'method). In addition,
Compound (XXXIIa) in which Q of compound (XXXII) is an amino group can also be produced by reaction pathway [G].

[0017]

[Chemical 6]

[0018]

[Chemical 7]

[0019]

[Chemical 8]

[0020]

[Chemical 9]

(In the above formula, Y ¹ , Y ² and R ¹¹ have the same meanings as described above, and R ¹² is methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
indicating a C _1-4 alkyl group such as t-butyl).

Each step (steps 1 to 19) of the reaction route [F '], the (B' method) and the reaction route [G] will be described in detail below.

The first to seventh steps of the reaction route [F '] include the compounds (XXXIIa), (XXXIIb), (XXXIIc) and (XXXII).
This is a process for obtaining d).

First step: This step is a step of obtaining a methoxy compound (XIX ') by reacting the compound (XVIII') with sodium methylate in a solvent.

Solvents used in this reaction include amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene. Examples thereof include aliphatic hydrocarbons such as hexane and heptane, and methanol (preferably methanol).

The amount of sodium methylate used is 0.5-1.
It is a 5-fold molar amount (preferably equimolar).

The reaction temperature is 0 to 100 ° C. (preferably 10)
The reaction time is 1 to 48 hours (preferably 5 to 24 hours).

Second step: This step is a step of reacting the compound (XIX ') with ammonia in the presence of a solvent or without a solvent to obtain an amino compound (XX').

The solvent used in this reaction is the above-mentioned first solvent.
Although the same solvent as that used in the step can be mentioned, this reaction is preferably carried out without a solvent.

The amount of ammonia used may be equimolar or more. In the case of using no solvent, a large excess of ammonia is used in the autoclave.

The reaction temperature is 0 to 100 ° C. (preferably 10)
The reaction time is 1 to 48 hours (preferably 5 to 24 hours).

Third step: Fourth step: This step is the compound (XX
The cyano group of ′) is partially hydrolyzed with 80% (V / V) sulfuric acid to give an amide compound (XXI ′) (third step), and the amide group is further treated with 50% (V / V) sulfuric acid This is a step (fourth step) of obtaining the compound (XXXIIa) by hydrolyzing the compound to form the carboxylic acid compound (XXII ′) and simultaneously performing the decarboxylation reaction of (XXII ′).

The series of reactions are carried out at 50 to 150 ° C. (preferably 80 to 120 ° C.), and the reaction time is 15 minutes to 4 hours (preferably 30 minutes to 2 hours) for the third step, and the fourth step.
30 minutes to 6 hours (preferably 1 to 3 hours)
Is.

Fifth step: In this step, the amino group of the compound (XXXIIa) is diazotized and then converted to a cyano group to give a compound (XXXIIa).
IIb) is a process to obtain the literature (H.Koopman, Recl.Trav.Ch
im.Pays-Bas, 80, 1075 (1961)).

Sixth step: This step is a step of partially hydrolyzing the cyano group of the compound (XXXIIb) to obtain an amide compound (XXXIIc), and is carried out in the same manner as the above third step.

Step 7: This step is a step of hydrolyzing the amide group of the compound (XXXIIc) to obtain the compound (XXXIId).
This hydrolysis reaction is performed according to a conventional method under acidic or alkaline conditions.

Steps 8 to 14 of the reaction route [F '] are steps for obtaining the compounds (XXXIIIa) and (XXXIIIb).

Eighth step: In this step, the compound (XXIId) is reacted with thionyl chloride in a solvent or without a solvent to obtain the compound (XXV
II ') is a process of obtaining.

Examples of the solvent used in this reaction include benzene, toluene, chloroform, dichloromethane or diethyl ether.

The amount of thionyl chloride used in this reaction is equimolar or more based on the compound (XXXIId).

A catalytic amount of pyridine or dimethylformamide may be used in this reaction.

The reaction temperature is freely selected from room temperature to the boiling temperature of the solvent used. The reaction is continued until the generation of hydrogen chloride gas stops, and after the reaction is completed, the solvent and excess thionyl chloride are distilled off, and the residue may be directly used in the next reaction. May be.

The ninth step: This step is a step of obtaining a compound (XXVII ') with malonic acid diester ^{_{(CH 2 (CO 2 R 12}} ) 2) reaction with a compound of (XXVIII').

First, malonic acid diester is reacted with magnesium ethoxide to give ethoxy magnesium malonic acid diester. This reaction is usually diethyl ether,
It is carried out by stirring equimolar amounts of malonic acid diester and magnesium ethoxide for 1 to 10 hours with heating under reflux using ethers such as tetrahydrofuran or dioxane as a solvent. After the reaction, the reaction mixture is a suspension of magnesium ethoxymalonic acid diester, and equimolar acid chloride (XXVII ') is added dropwise thereto under cooling or at room temperature and stirred to give compound (XXVIII'). The reaction is complete within 5 hours.

Step 10: In this step, the compound (XXVIII
′) Is hydrolyzed and decarboxylated to give compound (XXIX
′) Is obtained.

Compound (XXVIII ') is used in the presence of a catalytic amount or equimolar amount of p-toluenesulfonic acid monohydrate and tetrahydrofuran or dioxane as a solvent in an amount of 3 to 20.
It is obtained by heating under reflux for a period of time.

Eleventh step: This step is carried out by using the compound (XXIX ')
Is a step of obtaining the compound (XXX ′) by reacting with ethyl orthoformate.

The compound (XXIX ') can be obtained by heating under reflux without solvent with an excess amount of acetic anhydride and ethyl orthoformate. The reaction is completed in 1 to 5 hours. After the reaction, excess acetic anhydride and ethyl orthoformate may be distilled off under reduced pressure, and the resulting residue may be directly used in the next reaction or may be purified by silica gel column chromatography.

Step 12: This step is a step of obtaining the compound (XXXI ') by reacting the compound (XXX') with cyclopropylamine.

The compound (XXX ') is reacted with equimolar to 2-fold molar amount of cyclopropylamine in an inert solvent such as benzene, toluene, diethyl ether, tetrahydrofuran, chloroform, dichloromethane or carbon tetrachloride under cooling or at room temperature. As a result, the compound (XXXI ′) is obtained. This reaction is usually completed in 1 to 3 hours.

Step 13: This step is a step of subjecting compound (XXXI ') to a ring closure reaction in a solvent in the presence of a base to obtain compound (XXXIIIa).

As the solvent used in this reaction, amides such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and hexamethylphosphoric triamide;
Examples thereof include 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-t-butoxide.

The compound (XXXIIIa) is obtained by reacting in the presence of an equimolar to 2-fold molar amount of the base with respect to the compound (XXXI ') at room temperature to the boiling temperature of the solvent used. The reaction time is usually 1 to 10 hours.

Step 14: In this step, compound (XXXIIIa)
Is a step of obtaining the compound (XXXIIIb) by hydrolysis of the compound, and is carried out according to a conventional method under acidic or alkaline conditions.

The fifteenth step of (Method B ') is compound (XXXIII)
Is a step for obtaining a boron fluoride chelate compound (XXXIV) from the above, and can be carried out by reacting borofluoric acid or boron trifluoride according to the method described in JP-A-59-67290, for example.

From the 16th step to the 19th step of the reaction route [G], a compound (XXXII) in which Q of the compound (XXXII) is an amino group is used.
This is another way to get a).

Sixteenth Step: In this step, compound (XXXV) is reacted with potassium phthalimide in a solvent to give compound (XXXVI).
Is a step of obtaining.

Solvents used in this reaction include amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; ethers such as diethyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile. Examples; alcohols such as methanol, ethanol, propanol, and isopropanol (preferably the above amides and sulfoxides) can be mentioned.

The amount of potassium phthalimide used is equimolar to
The reaction temperature is 0 to 100 ° C. (preferably 20 to 50 ° C.), and the reaction time is 0.5 to 20 hours (preferably 1 to 8 hours).

Step 17: This step is a step of reducing the nitro group of the compound (XXXVI) to obtain an amino compound (XXXVII), and a usual nitro group reduction reaction is applied.

Step 18: This step is a step of diazotizing the amino group of the compound (XXXVII) with alkyl nitrite in a solvent to remove the amino group to obtain the compound (XXXVIII).

Examples of the solvent used in this reaction include amides such as dimethylformamide and dimethylacetamide (preferably dimethylformamide).

Examples of the alkyl nitrite include methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite and isoamyl nitrite.

The reaction temperature is 0 to 100 ° C (preferably 10 ° C).
The reaction time is 15 minutes to 10 hours (preferably 30 minutes to 5 hours).

Step 19: This step is a step of hydrolyzing the phthalimido group of the compound (XXXVIII) to obtain the amino compound (XXXIIa), which is carried out by a conventional method using hydrazine hydrate.

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

[0068]

The compound (XXXIIIb) obtained by the present invention
And (XXXIV) are shown below (method A ′) and (B ″
Method), a fluoroquinolonecarboxylic acid compound having a cyclopropyl group at the 1-position and a methoxy group at the 8-position (I
It is guided by a). This fluoroquinolonecarboxylic acid derivative (Ia) exhibits excellent antibacterial activity.

Therefore, the compounds (XXXIII) and (XXX
IV) is a synthetic intermediate of quinolonecarboxylic acid derivatives useful as antibacterial agents.

[0070]

[Chemical 10]

[0071]

[Chemical 11]

(YH in the above formula represents piperazine, aminopyrrolidine or aminopiperidine derivative) The method of obtaining the compound (Ia) by the (A 'method) or the (B "method) is described in JP-A-63-198664. It is described in detail.

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

Examples relating to the compound (XXXIII) of the present invention include Examples 5-7.

[0075]

【Example】

Example 1 3-Methoxy-2,4,5-trifluoroaniline (XXX
IIa; Y ¹ = Y ² = F)

[0076]

[Chemical 12]

Pentafluorobenzonitrile (XVIII ′;
Y ¹ = Y ² = F) 160.0 g (0.83 mol) is dissolved in 2.5 liters of methanol and sodium methoxide 44.8 g is stirred at room temperature.
1.6 liter of a methanol solution of (0.83 mol) was added dropwise. After completion of the dropping, the mixture was left overnight at room temperature, the solvent was distilled off under reduced pressure, the residue was shaken with toluene-water, the toluene layer was washed with water, dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the remaining solid matter was removed by n.
-Washed with hexane 4-methoxy-2,3,5,6-
Tetrafluorobenzonitrile 160.7 g (XIX ′; Y ¹ = Y ² =
F) was obtained as colorless needle crystals.

MS spectrum: m / e 205 (M ⁺ ), 190 (M ⁺ -CH ₃ ),
162 (M ⁺ -CH ₃ -CO) 150 ml of liquid ammonia and 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX '; Y ¹ = Y ² = F) 100.0 g (0.49
Mol) and left overnight at room temperature. After removing the ammonia, the remaining solid matter was washed with water, and 2-amino-4-methoxy-3,5,6-trifluorobenzonitrile (XX '; Y ¹
= Y ² = F) 84.4 g was obtained as a colorless powder.

MS spectrum: m / e 202 (M ⁺ ), 172 (M ⁺ -CH ₂ =
^{O), 159 (M + -CH} 3 -CO) then this 2-amino-4-methoxy-3,5,6-trifluoro-benzonitrile ^{(XX '; Y 1 = Y} 2 = F) 84.4 g
50 ml of water and 200 ml of concentrated sulfuric acid were added to (0.42 mol), 10
After stirring at 0 ° C for 1 hour, 150 ml of water was added, and further 1 hour for 2 hours.
Stir at 10-120 ° C. After allowing to cool to room temperature, ice water was added and neutralized with potassium carbonate. The precipitated crystals were extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 3-methoxy-2,4,5-trifluoroaniline (XXXIIa; Y ¹ = Y ² = F). 57.6 g was obtained as colorless needle crystals.

Melting point 45-47 ° C. MS spectrum: m / e 177 (M ⁺ ), 147 (M ⁺ -CH ₂ = O) NMR spectrum (CDCl ₃ , δ); 3.65 (2H, br, -NH ₂ ), 4.02 (3
_{H, s, -OCH 3),} 6.22-6.36 (1H, m, aromH) [ Example 2] 3-methoxy-2,4,5-fluorobenzoyl Nitrile
(XXXIIb; Y ¹ = Y ² = F)

[0081]

[Chemical 13]

3-Methoxy-2,4,5 obtained in Example 1
-Trifluoroaniline (XXXIIa; Y ¹ = Y ² = F) 1.01 g (0.00
56 mol of acetic acid 3 ml, water 25 ml, concentrated sulfuric acid 1.68 g (0.0168
Mol) and then cooled to 0 ° C., and stirred with 1 ml of an aqueous solution containing 0.46 g (0.0066 mol) of sodium nitrite under stirring.
It was added dropwise at -3 ° C. After the dropping was completed, the mixture was stirred at the same temperature for 30 minutes to obtain a diazonium salt solution.

On the other hand, 1.80 g (0.0072 mol) of copper sulfate pentahydrate was dissolved in 10 ml of water, and 1.95 g of potassium cyanide was added thereto.
5 ml of an aqueous solution containing g (0.03 mol) was added dropwise with stirring at 20 ° C. or lower, and 4.02 sodium bicarbonate was added to the obtained brown transparent solution.
After addition of g (0.048 mol), 30 ml of benzene was added.

The above diazonium salt solution was added dropwise to this two-layer solution at 30 to 45 ° C. with vigorous stirring.
After the dropping was completed, the reaction mixture was heated to 65 ° C. After cooling to room temperature, the benzene layer was separated, washed with water, dried and evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; toluene) and treated with 3-methoxy-2,4,5-trifluorobenzo. 0.77 g of nitrile (XXXIIb; Y ¹ = Y ² = F) was obtained as a red oil.

IR spectrum (film method, ν _max cm
^-1 ): 2250,1620,1500,1480,1120,1080 [Example 3] 3-methoxy-2,4,5-trifluorobenzamide
Synthesis of (XXXIIc; Y ¹ = Y ² = F)

[0086]

[Chemical 14]

3-methoxy-2,4,5 obtained in Example 2
-Trifluorobenzonitrile (XXXIIb; Y ¹ = Y ² = F) 1.24 g
To (0.007 mol), add 5 ml of concentrated sulfuric acid and 1.2 ml of water, and add 10
After heating at 0-140 ° C for 30 minutes, the mixture was poured into ice water and extracted with ethyl acetate. After ethyl acetate layer was washed with water dried, evaporated to dryness under reduced pressure, 3-methoxy-2,4,5-trifluoro benzamide; was obtained ^{(XXXIIc Y 1 = Y 2 =} F) 1.10g as a light brown powder.

Melting point 131-133 ° C. MS spectrum: m / e 205 (M ⁺ ), 189 (M ⁺ -NH ₂ ) [Example 4] 3-methoxy-2,4,5-trifluorobenzoic acid (XXX
IId; Y ¹ = Y ² = F)

[0089]

[Chemical 15]

3-Methoxy-2,4,5 obtained in Example 3
-Trifluorobenzamide (XXXIIc; Y ¹ = Y ² = F) 46.4 g
(0.226 mol) was suspended in 900 ml of water, 226 ml (0.226 mol) of 1N sodium hydroxide was added, and the mixture was heated under reflux for 2 hours with stirring. After allowing to cool to room temperature, the reaction mixture was extracted with ethyl acetate to remove unreacted substances, and the aqueous layer was acidified with hydrochloric acid. The precipitated crystals were extracted with ethyl acetate, the organic layer was washed with water, dried and evaporated under reduced pressure to give 37.1 g of 3-methoxy-2,4,5-trifluorobenzoic acid (XXXIId; Y ¹ = Y ² = F). Obtained as colorless needle crystals.

Melting point 115-117 ° C. MS spectrum: m / e 206 (M ⁺ ), 189 (M ⁺ -OH), 161 (M ⁺ -COOH) NMR spectrum (CDCl ₃ , δ); 4.09 (3H, s, OCH ₃ ), 7.50-7.6
2 (1H, m, aromH), 8.0-10.0 (1H, br, COOH) [Example 5] 1-Cyclopropyl-6,7-difluoro-8-methoxy
Ci-1,4-dihydro-4-oxoquinoline-3-cal
The combination of ethyl borate (XXXIIIa; Y ² = F, R ¹² = ethyl)
Success

[0092]

[Chemical 16]

3-Methoxy-2,4,5 obtained in Example 4
-Trifluorobenzoic acid (XXXIId; Y ¹ = Y ² = F) 1.14 g (0.00
55 mol) was dissolved in 10 ml of dry benzene, 5 ml of thionyl chloride was added, and the mixture was heated under reflux for 1 hour. After the reaction, benzene and excess thionyl chloride were completely distilled off, and 3-methoxy-2,4,5-trifluorobenzoic acid chloride (XXVI
I ′; Y ¹ = Y ² = F).

On the other hand, magnesium ethoxide 0.68 g (0.
006 mol) and malonic acid diethyl ester 0.96 g (0.006
(Mole) was heated under reflux in 15 ml of anhydrous diethyl ether for 1 hour to obtain a suspension of ethoxy magnesium malonic acid diethyl ester in diethyl ether. A solution of the above acid chloride dissolved in 10 ml of diethyl ether was added dropwise thereto with stirring at room temperature, and the mixture was further stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and dried under reduced pressure to give 3-methoxy-2,4,5-trifluorobenzoylmalonic acid diethyl ester ( XXVIII ′; Y ¹ = Y ² = F, R ¹² =
1.8 g of ethyl) was obtained as a brown oil.

This was dissolved in 30 ml of dioxane, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 20 hours,
The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. Wash the ethyl acetate layer with an aqueous solution of sodium hydrogen carbonate and then with water,
After drying, the mixture was dried under reduced pressure to give 3-methoxy-2,4,5-trifluorobenzoylacetic acid ethyl ester (XXIX ′; Y ¹ =
Y ² = F, R ¹² = ethyl) 1.45 g was obtained as a pale brown oil.

MS spectrum: m / e 276 (M ⁺ ), 189 (M ⁺ -CH ₂ CO
OC ₂ H ₅ ), 161 (M ⁺ -COCH ₂ COOC ₂ H ₅ ) 3-methoxy-2,4,5-trifluorobenzoyl acetic acid ethyl ester (XXIX ′; Y ¹
= Y ² = F, R ¹² = ethyl) 1.40 g (0.005 mol) in acetic anhydride 3.
5 ml and 1.1 ml of ethyl orthoformate were added, and the mixture was heated under reflux for 1 hour and concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane and, while cooling with ice, 0.38 g of cyclopropylamine (0.
(006 mol) was added dropwise, and the mixture was stirred for another 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; toluene-ethyl acetate 9: 1 mixed solution) to give 3-cyclopropylamino-2- (3-methoxy-).
1.23 g of 2,4,5-trifluorobenzoyl) acrylic acid ethyl ester (XXXI ′; Y ¹ = Y ² = F, R ¹² = ethyl) was obtained as a light brown oil.

MS spectrum: m / e 343 (M ⁺ ), 189 (M ⁺ -Pr ^c -N)
H-CH = C (CO ₂ Et)) (indicating Pr ^c : cyclopropyl) and then 3-cyclopropylamino-2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester ( XXXI ′; Y ¹ = Y ² = F, R ¹² = ethyl) 1.20
g (0.0035 mol) is dissolved in 30 ml of anhydrous tetrahydrofuran and 60% sodium hydride 150 mg (0.0035 mol)
Was added, and the mixture was stirred at room temperature for 30 minutes, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure to give 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (XXXIIIa; Y ² = F,
R ¹² = ethyl) 0.83 g was obtained as colorless needle crystals.

Melting point 180-182 ° C. MS spectrum: m / e 323 (M ⁺ ), 251 (M ⁺ -CO ₂ Et), 41 (C ₃ H ₅ ⁺ ) [Example 6] 1-cyclopropyl-6, 7-difluoro-8-methoki
Ci-1,4-dihydro-4-oxoquinoline-3-cal
Synthesis of boric acid (XXXIIIb; Y ² = F)

[0099]

[Chemical 17]

1-Cyclopropyl-obtained in Example 5
6,7-Difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester
(XXXIIIa; Y ² = F, R ¹² = ethyl) 0.48 g (0.0015 mol) was dissolved in 20 ml of methanol, 10 ml of 4% (W / V) sodium hydroxide aqueous solution was added, and the mixture was allowed to stand at room temperature for 5 hours. The crystals that were made acidic with concentrated hydrochloric acid were collected by filtration to give 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (XXXIII
b; Y ² = F) 0.34 g was obtained as colorless powdery crystals.

Melting point 184-185 ° C. MS spectrum: m / e 295 (M ⁺ ), 251 (M ⁺ -CO ₂ ) Elemental analysis value% (as C ₁₄ H ₁₁ F ₂ NO ₄ ) Theoretical value C, 56.95; H , 3.76; N, 4.75 Analytical value C, 56.90; H, 3.84; N, 4.56 [Example 7] 1-Cyclopropyl-6,7-difluoro-8-methoxy
Ci-1,4-dihydro-4-oxoquinoline-3-cal
Synthesis of boric acid / BF ₂ -chelate (XXXIV; Y ² = F)

[0102]

[Chemical 18]

1-Cyclopropyl-obtained in Example 5
Ethyl 6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XXXIII
a; Y ² = F, R ¹² = ethyl) 1.0 g (0.003 mol) was suspended in 20 ml of 42% borofluoric acid, stirred at 90-100 ° C. for 3 hours, and then poured into water to precipitate crystals. Collect by filtration to give 1-cyclopropyl-6,7-difluoro-8-methoxy-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid · BF ₂ - chelate; a ^{(XXXIV Y 2 = F) 1.1} g as a colorless powdery crystals.

Melting point 224-226 ° C. Elemental analysis value% (as C ₁₄ H ₁₀ BF ₄ NO ₄ ) Theoretical value C, 49.01; H, 2.94; N, 4.08 Analytical value C, 49.24; H, 3.01; N, 3.79 [ Example 8] 3-Methoxy-2,4,5-trifluoroaniline (XXX
IIa; Y ¹ = Y ² = F) (alternate method of Example 1)

[0105]

[Chemical 19]

(1) 4-methoxy-2,3,5,6-tetrafluoronitrobenzene (XXXV; Y ¹ = Y ² = F) 5.41 g (0.
024 mol) in 100 ml of dimethylformamide,
4.62 g (0.025 mol) of potassium phthalimide was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure,
The residue was dissolved in toluene, the toluene layer was washed with water, dried and concentrated under reduced pressure, and the obtained oil was subjected to silica gel column chromatography (solvent: toluene) to give 4-methoxy-
2-phthalimido-3,5,6-trifluoro-nitrobenzene; as a ^{(XXXVI Y 1 = Y 2 =} F) 5.07g of a pale yellow powdery crystals.

MS spectrum: m / e 352 (M ⁺ ), 306 (M ⁺ -N)
O ₂ ), 291 (M ⁺ —NO ₂ —CH ₃ ) (2) 4-methoxy-2-phthalimido-3,5,6-
Trifluoronitrobenzene (XXXVI; Y ¹ = Y ² = F) 4.2 g
(0.012 mol) was dissolved in 150 ml of acetic acid, 1.3 g of 5% palladium-carbon was added, and hydrogen gas was bubbled through for 1 hour at room temperature with vigorous stirring. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the precipitated crystals were washed with toluene, and 4-methoxy-2-phthalimido-3,5,6-trifluoroaniline (XXXVII; Y ¹ = Y ² = F ) 2.93 g was obtained as colorless sandy crystals.

MS spectrum: m / e 322 (M ⁺ ), 307 (M ⁺ -CH ₃ ) (3) 1.66 g (0.0144 mol) of isoamyl nitrite was dissolved in 9 ml of dimethylformamide, and 4-methoxy-2 was added thereto.
-Phthalimide-3,5,6-trifluoroaniline (X
XXVII; Y ¹ = Y ² = F) 2.90 g (0.009 mol) of a dimethylformamide solution (18 ml) was added dropwise at 60 to 65 ° C with stirring. After completion of dropping, the mixture was stirred at the same temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene) to give N- (3-methoxy-2,4,5-trifluorophenyl). Phthalimide (XXXVIII; Y ¹ = Y ² = F) 2.
18 g was obtained as colorless powdery crystals.

MS spectrum: m / e 307 (M ⁺ ), 276 (M ⁺ -OC
_{H 3) (4) N- (} 3- methoxy-2,4,5-trifluorophenyl) phthalimide ^{(XXXVIII; Y 1 = Y 2} = F) 2.15g (0.
(007 mol) was suspended in 30 ml of ethanol, 1.1 g (0.02 mol) of hydrazine hydrate was added, and the mixture was heated under reflux for 2 hours with stirring. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in toluene, the toluene layer was washed with water, dried and concentrated under reduced pressure to give 3-methoxy-2,4,5-trifluoroaniline ( XXXIIa; Y ¹ = Y ² = F)) 1.06 g was obtained as light brown needle crystals.

MS spectrum: m / e 177 (M ⁺ ), 147 (M ⁺ -CH ₂ =
O) [Reference Example 1] 1-Cyclopropyl-6-fluoro-8-methoxy-7
-(1-Piperazinyl) -1,4-dihydro-4-oxy
Synthesis of soquinoline-3-carboxylic acid hydrochloride

[0111]

Embedded image

The chelate compound (XXXI obtained in Example 7)
0.11 g of (V; Y ² = F) was dissolved in 0.5 ml of dimethyl sulfoxide, 0.11 g (0.0012 mol) of anhydrous piperazine was added, and the mixture was allowed to stand at room temperature overnight. The reaction mixture is diluted with diethyl ether 50
Then, the precipitated yellow crystals of the chelate compound (VI ') were collected by filtration, dissolved in a mixed solution of 80% ethanol (30 ml) and triethylamine (5 ml), and heated under reflux for 4 hours. The reaction solution was filtered while hot to remove insoluble matter, and the filtrate was concentrated under reduced pressure, and the obtained crystal was washed with ethanol to give 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-piperazinyl) -1. 0.07 g of 4,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as colorless powdery crystals.
(Melting point: 177-178 [deg.] C.) The crystals were suspended in 30 ml of ethanol, 1 ml of concentrated hydrochloric acid was added, the solvent was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.06 g of the hydrochloride of the target compound as a colorless powder.

Melting point 246-248 ° C. (decomposition) Elemental analysis value% (as C ₁₈ H ₂₀ FN ₃ O ₄ .HCl.1 / 2H ₂ O) Theoretical value C, 53.14; H, 5.45; N, 10.33 Analytical value C , 53.31; H, 5.47; N, 10.36 [Reference Example 2] 1-cyclopropyl-6-fluoro-8-methoxy-7
-(4-Methyl-1-piperazinyl) -1,4-dihydride
Combined with 4--4-oxoquinoline-3-carboxylic acid / hydrochloride
Success

[0114]

[Chemical 21]

1-Cyclopropyl-obtained in Example 6
6,7-Difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (XXXIIIb; Y ² = F)
0.09 g (0.0003 mol) was dissolved in 0.5 ml of dimethyl sulfoxide, 0.12 g (0.0012 mol) of N-methylpiperazine was added, and the mixture was stirred at 70 ° C. for 6 hours. After the reaction, the solvent and excess N-methylpiperazine were distilled off under reduced pressure at the same temperature, the residue was washed with ethyl acetate and then subjected to silica gel column chromatography (solvent: methanol), and 1-cyclopropyl-6-fluoro- 0.03 g of 8-methoxy-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as colorless powdery crystals. (Melting point: 211-214 ° C.) From this, a hydrochloric acid salt of 0.1.
02 g was obtained as a colorless powder.

Melting point 225-228 ° C. (decomposition) Elemental analysis value% (as C ₁₉ H ₂₂ FN ₃ O ₄ .HCl.H ₂ O) Theoretical value C, 53.08; H, 5.86; N, 9.78 Analytical value C, 53.12 ; H, 5.54; N, 9.68 [Reference Example 3] 1-cyclopropyl-6-fluoro-8-methoxy-7
-(3-Methyl-1-piperazinyl) -1,4-dihydride
Combined with 4--4-oxoquinoline-3-carboxylic acid / hydrochloride
Success

[0117]

[Chemical formula 22]

1-Cyclopropyl-obtained in Example 7
6,7-Difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.BF ₂ -chelate 5.8 g (0.017 mol) was dissolved in dimethyl sulfoxide 4 ml to give 2-methylpiperazine 6.8 g. (0.068 mol) was added and left at room temperature overnight. After the reaction, the solvent and excess 2-methylpiperazine were distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain a yellow crystal of the chelate compound (VI '). This was dissolved in a mixed solution of 200 ml of 80% ethanol and 30 ml of triethylamine and heated under reflux for 4 hours.

After cooling to room temperature, insoluble materials were filtered off, the filtrate was concentrated under reduced pressure, and the crystals obtained were washed with ethanol. The crystals obtained were then suspended in 100 ml of ethanol, and concentrated hydrochloric acid 3
After adding ml, the solvent was distilled off under reduced pressure and the residue was washed with ethanol to give 1-cyclopropyl-6-fluoro-8-methoxy-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4. 2.7 g of -oxoquinoline-3-carboxylic acid / hydrochloride was obtained as a colorless powder.

Melting point 262-264 ° C. (decomposition) Elemental analysis value% (as C ₁₉ H ₂₂ FN ₃ O ₄ .HCl) Theoretical value C, 55.40; H, 5.63; N, 10.20 Analytical value C, 55.14; H , 5.67; N, 10.1
8

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshimi Fujiwara 5 1978, Koujigushi, Ube City, Yamaguchi Prefecture 5 1978, Ube Institute of Industrial Research, Ltd. Ube Institute Co., Ltd.

Claims (4)

[Claims] 1. A compound represented by the general formula (XXXIII): (In the formula, Y ² represents a halogen atom, and R ¹¹ represents a hydrogen atom or a lower alkyl group). 2. Y ² is a fluorine atom, R ¹¹ is a hydrogen atom,
The compound according to claim 1, which is a methyl or ethyl group. 3. A compound represented by the general formula (XXXIV): (In the formula, Y ² represents a halogen atom). 4. The compound according to claim 3, wherein Y ² is a fluorine atom.