JPH0656736A - Bis@(3754/24)2-halogeno-4,5-difluoro)benzophenone and new production method of 2-halogeno-4,5-difluorobenzoic acid through the same compound - Google Patents

Abstract

PURPOSE:To produce the 2-halogeno-4,5-difluorobenzoic acid useful as an intermediate for production of a synthetic antimicrobial agent, etc., through a new intermediate with industrial advantage. CONSTITUTION:A bis(2-halogeno-4,5-difluoro)benzophenone of formula I (X is a halogen). This compound is obtained by hydrolyzing (at 90 to 150 deg.C for 2 to 8hr) a bis(2-halogeno-4,5-difluorophenyl)dichloromethane of formula II in sulfuric acid. From the compound of formula I, a 2-halogeno-4,5-difluorobenzoic acid of formula III can be induced by a reaction with a basic compound (e.g. an alkali metal alkoxide or hydroxide) at a temperature within a range of -20 to 50 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound bis (2-halogeno-4,5-difluoro) benzophenone, which has not been described in the literature, and is useful as an intermediate raw material for a synthetic antibacterial agent (described in US Pat. No. 4,571,396). The present invention relates to a novel method for producing 2-halogeno-4,5-difluorobenzoic acid.

[0002]

2. Description of the Related Art As a conventional method for producing 2-chloro-4,5-difluorobenzoic acid, a method in which 2-chloro-4,5-difluorobenzotrihalide is hydrolyzed (Japanese Patent Laid-Open No. 108839/1987). 3-161450) and 3,
A method is known in which 4-difluorochlorobenzene is acetylated or chloroacetylated and then subjected to a haloform reaction (Japanese Patent Laid-Open No. 64-45322).

Further, as a method for introducing a carbonyl group of an analog compound, nitrile hydrolysis, which is a chemically conventional method (JP-A-60-72885), and Grignard reaction using carbon dioxide (JP-A-58-150543) are known. JP-A-58-1
88839) and the like are known.

However, in all of these methods, the yield of the method itself is low, or the yield of the raw material trihalide is low.
There are problems such as having special regulatory conditions for implementation such as treatment of a cyanide compound in the synthesis of the raw material nitrile, requiring equipment support for stability in Grignard reaction, etc. It wasn't an advantage.

[0005]

Conventionally, in the production of agricultural drugs such as synthetic antibacterial agents (described in US Pat. No. 4,571,396), novel compounds useful as intermediates for production have been used,
The advent of the efficient industrial manufacturing method has been long awaited.

[0006]

Means for Solving the Problems The present inventor has conducted earnest research to solve the industrial problems as described above, and surprisingly obtained from bis (2-halogeno-4,5-difluorophenyl) dichloromethane. Bis (2-halogeno-4,5-difluoro) benzophenone, which is a novel compound not described in the literature, and industrial and efficient 2-halogeno-4,5-difluoro as shown in (Chemical Formula 4) using the same We have found a new production technology for benzoic acid and completed the present invention based on these findings.

[0007]

[Chemical 4] (In the formula, X represents a halogen atom.) That is, the present invention provides (1)

[0008]

[Chemical 5] (In the formula, X represents the same meaning as described above.) A bis (2-halogeno-4,5-difluoro) benzophenone. (2)

[0009]

[Chemical 6] (Wherein X represents the same meaning as described above), bis (2-halogeno-4,5-difluorophenyl) dichloromethane is hydrolyzed in sulfuric acid.
A method for producing bis (2-halogeno-4,5-difluoro) benzophenone represented by Chemical formula 5. (3) Bis (2-halogeno-4, represented by Chemical formula 5)
Characterized by reacting 5-difluoro) benzophenone with a basic compound

[0010]

[Chemical 7] (In the formula, X represents the same meaning as described above.) 2
Method for producing halogeno-4,5-difluorobenzoic acid. (4) Bis (2-halogeno-4, represented by Chemical formula 6)
5-difluorophenyl) dichloromethane is hydrolyzed in sulfuric acid to give bis (2-halogeno-
A method for producing 2-halogeno-4,5-difluorobenzoic acid represented by (Chemical Formula 7), characterized in that 4,5-difluoro) benzophenone is obtained and a basic compound is further reacted. Is provided.

The present invention will be described in detail below.

The compound of the present invention, bis (2-halogeno-
4,5-Difluoro) benzophenone is obtained by hydrolyzing bis (2-halogeno-4,5-difluorophenyl) dichloromethane.

The hydrolysis reaction in the production of the compound of the present invention is carried out in sulfuric acid and the method of dropping water or 70 to 95%
The method using sulfuric acid is preferred.

The amount used may be 1 to 5 times the weight of the raw material bis (2-halogeno-4,5-difluorophenyl) dichloromethane.

Further, the reaction temperature and the reaction time during the hydrolysis are usually 90 to 150 ° C. and the range is 2 to 8 hours, so that the purpose can be achieved.

The compound of the present invention, bis (2-halogeno-
In the production of 4,5-difluoro) benzophenone, after the hydrolysis reaction, after confirming the disappearance of the raw materials by gas chromatography, the reaction liquid is cooled, and then ice water and toluene are added thereto to add an organic substance to a toluene layer. The resulting toluene layer is washed with water and the extraction solvent toluene is concentrated to give bis (2) which is the compound of the present invention.
-Halogeno-4,5-difluoro) benzophenone is obtained.

The bis (2-halogeno-4,5-difluorophenyl) dichloromethane used as a starting material in the production of the compound of the present invention is a method in which 3,4-difluorohalogenobenzene is reacted with carbon tetrachloride in the presence of aluminum chloride. Alternatively, it can be easily obtained by a method described as a by-product according to the method described in JP-A-3-161450.

The compound of the present invention, bis (2-halogeno-4,5-difluoro) benzophenone, is a synthetic antibacterial agent by reacting with a basic compound (US Pat.
No. 71396), etc., and it can be derivatized to 2-halogeno-4,5-difluorobenzoic acid useful for the production of agricultural drugs.

As the basic compound used in the method of the present invention, an alkali metal alkoxide or hydroxide can be used. Specifically, tertiary butoxy = potassium (t-BuOK), tertiary butoxy = sodium (t-BuONa), potassium hydroxide (KOH) and the like can be exemplified.

The amount used may be 3 to 10 times the molar amount of bis (2-halogeno-4,5-difluoro) benzophenone which is the compound of the present invention as a raw material.

The solvent used in the method of the present invention may be any solvent inert to the reaction, such as ether solvents,
Alcohol solvents, aprotic polar solvents, aromatic hydrocarbon solvents and the like can be used. Specifically, ether solvents such as monoglyme, etc., alcohol solvents such as tert-butanol (t-BuOH), aprotic polar solvents such as dimethyl sulfoxide (DMSO), etc. Examples of hydrogen solvents include benzene and toluene. Also, a mixed solvent of these solvents can be used, and a solvent system of the reaction can be prepared by adding water to these solvents.

The reaction temperature selected in the method of the present invention is
It is in the range of -20 to 50 ° C, and the reaction time is usually in the range of several minutes to 10 hours.

Further, in the method of the present invention, the bis (2-halogeno-4,5-difluoro) benzophenone represented by the formula (5), which is the compound of the present invention obtained by the above hydrolysis reaction, is not isolated and purified. For example, 2-halogeno-4,5-difluorobenzoic acid can be produced by directly subjecting the extracted toluene layer in the above hydrolysis reaction to the basic treatment of the method of the present invention.

[0024]

INDUSTRIAL APPLICABILITY The present invention is a novel compound bis (2-halogeno-4,5-difluoro) benzophenone, which has not been described in the literature, and bis (2-halogeno-
Method for producing the compound by hydrolyzing 4,5-difluorophenyl) dichloromethane in sulfuric acid, and method for producing 2-halogeno-4,5-difluorobenzoic acid by reacting the compound with a basic compound. The present invention can be suitably applied as a method that is easy to carry out and has a high yield in the production of agricultural drugs and the like.

Further, the compound of the present invention is represented by (Chemical Formula 5), bis (2-halogeno-4,5-difluoro) benzophenone, and (Chemical Formula 7) which can be easily obtained from the compound. 2-halogeno-4,5-difluorobenzoic acid is particularly useful as an intermediate for the production of synthetic antibacterial agents (described in US Pat. No. 4,571,396).

[0026]

EXAMPLES The present invention will be described in detail below with reference to examples and examples. Reference Example 1 Synthesis of bis (2-chloro-4,5-difluorophenyl) dichloromethane 100 equipped with thermometer, condenser, stirrer and dropping funnel
In a ml reaction flask, 14.9 g (0.1 mol) of 3,4-difluorochlorobenzene and 2 parts of aluminum chloride were added.
0.0g (0.15 mol) was charged, and then 11.5 g (0.075 mol) of carbon tetrachloride was added dropwise. Then 4
The reaction was carried out at 0 ° C. After cooling, the reaction solution was poured into 200 ml of ice water, and the precipitated crystals were extracted with ethyl acetate, washed with water, and concentrated to obtain 18.1 g of crude crystals. This was washed with cold toluene and then dried to obtain 17.0 g of bis (2-chloro-4,5-difluorophenyl) dichloromethane (yield 90.
%).

Melting point: 146.8-148.6 ° C. (Example 1) Production of bis (2-chloro-4,5-difluoro) benzophenone In a 50 ml reaction flask equipped with a thermometer, a condenser and a stirrer, 11.3 g (0.03 mol) of bis (2-chloro-4,5-difluorophenyl) dichloromethane and 8
Charge 30.0 g of 0% sulfuric acid and stir 130-140.
The reaction was carried out at ℃ for 5 hours. After confirming the disappearance of the raw materials by gas chromatography, after cooling, add ice water and toluene,
Organic matter was extracted into the toluene layer. After washing the obtained toluene layer with water, the toluene was concentrated to give bis (2-chloro-4,5
10.1 g of -difluoro) benzophenone was obtained (yield 95%).

Melting point: 121 to 122.5 ° C. Confirmation data: ¹ H-NMR (TMS / CDCl ₃ ): δ (ppm):
7.29 (1H, dd, J = 9.52, 9.53H
z), 7.43 (1H, dd, J = 9.52, 9.89)
Hz) MS (m / z): 322 (M ⁺ ) IR (KBr): 3140, 3060, 1690, 16
00, 1500, 1400, 1390, 1310, 11
70 cm ^-1 (Example 2) Production of 2-chloro-4,5-difluorobenzoic acid In a 100 ml reaction flask equipped with a thermometer, a condenser and a stirrer, 28 ml of t-BuOH and 28 m of toluene.
1 and t-BuOK 11.2g were charged. 15 ~ 20 ℃
Then 3.2 g (10 mmol) of bis (2-chloro-4,5-difluoro) benzophenone was added in small portions. 1
After the lapse of time, the reaction solution was poured into ice water, acidified with hydrochloric acid, extracted with ethyl acetate and washed with water. Then, the carboxylic acid content was extracted with an aqueous sodium hydrogen carbonate solution, and the alkaline water tank was again subjected to hydrochloric acid precipitation, extraction with ethyl acetate, washing with water, and concentration to obtain 1.6 g of 2-chloro-4,5-difluorobenzoic acid. (Yield 83%). (Example 3) Production of 2-chloro-4,5-difluorobenzoic acid In a 200 ml reaction flask equipped with a thermometer, a condenser and a stirrer, 140 g of monoglyme and t-BuOK 1
1.2 g and 0.05 g of water were charged, and bis (2
-Chloro-4,5-difluoro) benzophenone 3.2
g (10 mmol) was added in small portions. After 30 minutes, the reaction solution was poured into ice water and post-treated in the same manner as in (Example 2).
1.7 g of -chloro-4,5-difluorobenzoic acid was obtained (yield 88%).

Also, 3,4-difluorochlorobenzene
Was obtained in a yield of 80%. Example 4 Preparation of bis (2,4,5-trifluoro) benzophenone
50 ml reaction flask equipped with thermometer, condenser and stirrer
To bis (2,4,5-trifluoro) dichlorometa
4.5 g (0.013 mol) and 20.0 g concentrated sulfuric acid
Charge, add 2.0 g of water dropwise at 90-100 ° C with stirring.
Then, the reaction was continued for 2 hours. Gas chromatograph of disappearance of raw materials
After confirming with a topography, cool with ice water and toluene.
In addition, extracted. After washing with water, concentrate the toluene
(2,4,5-Trifluorophenyl) benzophenone
3.7 g was obtained (yield 98%). Melting point: 73.0-75.2 ° C Confirmation data:¹ H -NMR (TMS / CDCl₃): Δ (ppm):
7.00 (2H, ddd, J = 9.7, 9.6, 6.3
Hz), 7.59 (2H, ddd, J = 9.8, 9.
0, 6.3 Hz) MS (m / z): 290 (M⁺) IR (KBr): 3060, 1660, 1630, 15
10,1440,1420,1335cm^-1 Example 5 Production of 2,4,5-trifluorobenzoic acid Bis (2-chloro-4,5-difluoro) benzopheno
Bis (2,4,5-trifluoro) benzo instead of amine
Except for using 2.9 g (10 mmol) of phenone,
The same procedure as in Example 3 was performed. As a result, 2,4,5-tri
1.4 g of fluorobenzoic acid was obtained (yield 80%).

Claims (4)

[Claims] Claims: (In the formula, X represents a halogen atom.) Bis (2-halogeno-4,5-difluoro) benzophenone. 2. [Chemical formula 2] (Wherein X represents the same meaning as described above), bis (2-halogeno-4,5-difluorophenyl) dichloromethane is hydrolyzed in sulfuric acid.
A method for producing bis (2-halogeno-4,5-difluoro) benzophenone represented by Chemical formula 1. 3. A bis (2-halogeno-4,5-difluoro) benzophenone represented by (Chemical formula 1) is reacted with a basic compound. (In the formula, X represents the same meaning as described above.) 2
Method for producing halogeno-4,5-difluorobenzoic acid. 4. Bis (2-halogeno-4,5-difluorophenyl) dichloromethane represented by the chemical formula 2 is hydrolyzed in sulfuric acid, and bis (2-halogeno-4 represented by the chemical formula 1). A method for producing 2-halogeno-4,5-difluorobenzoic acid represented by (Chemical Formula 3), which comprises reacting with a basic compound.