JP3474593B2 - Preparation of quinolone carboxylic acid derivatives - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an intermediate for producing an antibacterial compound.

[0002]

2. Description of the Related Art Conventionally, a compound of formula (I) represented by Chemical formula 3 (hereinafter referred to as compound (I))

[0003]

[Chemical 3] A compound of formula (II) represented by Chemical formula 4 (hereinafter referred to as compound (II))

[0004]

[Chemical 4] The reaction for obtaining was carried out by a solid-liquid reaction of heating in the presence of a base in a solvent.

[0005]

However, this reaction requires a relatively long time to complete the reaction, and since it is also a reaction under heating, the decomposition reaction easily occurs, and the yield and quality of the product are reduced. It could have decreased. Further, when sodium hydride was used as the base, there was a risk of ignition during the reaction. Furthermore, when the reaction solvent is recovered and reused, it is necessary to recover it anhydrously, and therefore, it has been desired to develop a simpler manufacturing method as an industrial manufacturing method.

[0006]

Means for Solving the Problems The present inventor has found that the compound (I)
It was found that when the ring-closing reaction from the compound to the compound (II) is carried out in the presence of a base and a phase transfer catalyst, the ring-closing reaction proceeds at a relatively low temperature in a short time, and this process can be carried out by a simpler operation. The present invention has been completed.

[0007]

The present invention is of the formula (I)

[0008]

[Chemical 5] (In the formula, X ¹ , X ² and X ³ each independently represent a hydrogen atom or a halogen atom, X ⁴ represents a halogen atom, R represents a lower alkyl group or a benzyl group, wherein benzyl is The group may be substituted with a lower alkyl group, a lower alkoxyl group or a halogen atom.) The compound represented by the formula (II) is characterized in that it is treated in the presence of a base and a phase transfer catalyst.

[0009]

[Chemical 6] (In the formula, X ¹ , X ² and X ³ each independently represent a hydrogen atom or a halogen atom, X ⁴ represents a halogen atom, R represents a lower alkyl group or a benzyl group, wherein benzyl is The group may be substituted with a lower alkyl group, a lower alkoxyl group or a halogen atom.).

The compound of formula (I) can be produced by a known method (see JP-A-2-231475).
Further, although stereoisomers exist in the compound of formula (I), any isomer can be used in the method of the present invention.

The ring closure reaction of the present invention will be described below.

Various phase transfer catalysts can be used in the present invention. For example, a quaternary ammonium salt type phase transfer catalyst such as tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogen sulfate, tri-n-octylmethylammonium chloride, benzyltriethylammonium chloride or bromide is preferable.
Other than this, a phosphonium salt type phase transfer catalyst such as tetraphenylphosphonium chloride or bromide, tetra-n-butylphosphonium chloride, triphenylmethylphosphonium bromide, tri-n-octylphosphonium bromide and the like may be used.

The amount of the phase transfer catalyst used may be in the range of 1% to 30% (weight ratio) with respect to the compound (I), but usually about 5% is used.

The base used in the method of the present invention is generally an aqueous solution of an inorganic base such as a hydroxide of an alkali metal atom. Specifically, an aqueous solution of potassium hydroxide or sodium hydroxide is used. use. The concentration of the aqueous base solution is usually about 3N.
The amount of the aqueous base solution to be used is usually compound (I),
The amount may be about 5 times (volume / weight ratio).

A reaction solvent which is immiscible with water and inert to the reaction may be used. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, lower aliphatic hydrocarbons such as pentane, hexane, heptane and cyclohexane, and halogenated hydrocarbons such as dichloromethane and dichloroethane. Among these, aromatic hydrocarbons and halogenated hydrocarbons are preferable, and toluene and dichloroethane are preferable.

The amount of the solvent used is usually 5 with respect to the compound (I).
A double amount (volume / weight ratio) may be used.

The reaction temperature may be about room temperature, for example, 10
The temperature may be in the range of 30 to 30 ° C, preferably 1
It is in the range of 5 ° C to 25 ° C.

The reaction time may be in the range of 1 hour to 24 hours, and is usually completed in 1 hour to 4 hours.

The actual operation of the reaction may be carried out according to the reaction of a commonly known phase transfer catalyst. That is,
The target compound (II) can be obtained by dissolving the compound (I) in a reaction solvent, adding an aqueous base solution and a phase transfer catalyst, and stirring the mixture at room temperature for sufficient reaction. In addition, you may heat as needed.

[0020]

The present invention will be described below with reference to examples, but the present invention is not limited thereto.

Example 1 1.5 g of 3- (cis-2-fluorocyclopropyl) amino-2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester was dissolved in 7.5 ml of toluene and 3N hydroxylated. Aqueous sodium solution 7.5
ml, tetra n-butyl ammonium bromide 75 mg
Was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, 7.5 ml of water was added, 2.0 ml of concentrated hydrochloric acid was added under ice cooling, and the precipitated crystals were collected by filtration and washed with 30 ml of water. The washed crystals are dissolved in 80 ml of chloroform and dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to give 1- (cis-2-fluorocyclopropyl) -6,7-difluoro-1,4-dihydro-4.
-Oxoquinoline-3-carboxylic acid ethyl ester 1.39
got g.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.40 (3 H, t, J = 7
Hz), 1.5-1.9 (2H, m), 3.2-3.7 (1H, m), 4.39 (2H, q,
J = 7 Hz), 5.14 (1H, dm, J = 61 Hz), 7.64 (1H, dd, J
= 11 Hz, 7 Hz), 8.24 (1H, dd, J = 11 Hz, 8.5 Hz), 8.6
0 (1H, s).

Example 2: 3- (cis-2-fluorocyclopropyl) amino-2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester (1.5 g) was dissolved in toluene (7.5 ml), and 3N hydroxylated. Aqueous sodium solution 7.5
ml and tetra-n-butylammonium hydrogensulfate 75 mg were added, and the mixture was stirred at room temperature for 4 hours. After the reaction, 7.5 ml of water was added, 2.0 ml of concentrated hydrochloric acid was added under ice cooling, and the precipitated crystals were collected by filtration and washed with 30 ml of water. The washed crystals were dissolved in 80 ml of chloroform and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 1- (cis-2-fluorocyclopropyl) -6,7-difluoro-1,4-dihydro- 4-
Oxoquinoline-3-carboxylic acid ethyl ester 1.38
got g. ^{The 1} H-NMR spectrum was the same as that of the compound obtained in Example 1.

Example 3: 3- (cis-2-fluorocyclopropyl) amino-2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester (1.5 g) was dissolved in dichloroethane (7.5 ml), and 3N hydroxylated. 7.5 ml sodium aqueous solution, tetra-n-butylammonium bromide
450 mg was added and stirred at room temperature for 1 hour. After the reaction, water
7.5 ml was added, 2.0 ml of concentrated hydrochloric acid was added under ice cooling, and the precipitated crystals were collected by filtration and washed with 30 ml of water. The washed crystals were dissolved in 80 ml of chloroform and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 1- (cis-2-fluorocyclopropyl) -6,7-difluoro-1,4-dihydro- 1.30 g of 4-oxoquinoline-3-carboxylic acid ethyl ester was obtained. ^{The 1} H-NMR spectrum was the same as that of the compound obtained in Example 1.

Example 4: 1.5 g of 3- (cis-2-fluorocyclopropyl) amino-2- (3-chloro-2,5-difluorobenzoyl) acrylic acid ethyl ester was dissolved in 7.5 ml of toluene and dissolved in 3N water. 7.5 ml of sodium oxide aqueous solution, tetra-n-butylammonium bromide
75 mg was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, water 7.5
After the addition of 2.0 ml of concentrated hydrochloric acid under ice cooling, the precipitated crystals were collected by filtration and washed with 30 ml of water. The washed crystals were dissolved in 80 ml of chloroform, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1- (cis-2-fluorocyclopropyl) -7-chloro-6-fluoro-1,4-.
1.33 g of dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester was obtained.

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

Continuation of front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 215/56 B01J 31/02 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. Formula (I): (In the formula, X ¹ , X ² and X ³ each independently represent a hydrogen atom or a halogen atom, X ⁴ represents a halogen atom, R represents a lower alkyl group or a benzyl group, wherein benzyl The group is optionally substituted with a lower alkyl group, a lower alkoxyl group or a halogen atom.) Is treated in the presence of a base and a phase transfer catalyst. 2] (In the formula, X ¹ , X ² and X ³ each independently represent a hydrogen atom or a halogen atom, X ⁴ represents a halogen atom, R represents a lower alkyl group or a benzyl group, wherein benzyl The group may be substituted with a lower alkyl group, a lower alkoxyl group or a halogen atom.). 2. The method according to claim 1, wherein X ⁴ is a fluorine atom. 3. The method according to claim 1, wherein X ¹ is a fluorine atom and X ³ is a hydrogen atom. 4. The method according to claim 1, wherein X ¹ is a fluorine atom and X ³ is a chlorine atom.