JP2733789B2 - New 3-substituted-4-fluorobenzoyl fluorides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial application field) The novel compound 3-substituted-4-fluorobenzoylfluoride obtained by the present invention is a herbicide for pesticides, an antibacterial agent as a medicine, an anticancer agent, a remedy for Parkinson's disease. Or as an important intermediate for synthesizing liquid crystal materials.

(Prior art) Agrochemicals, drugs, and liquid crystal materials synthesized from 3,4-difluorobenzene derivatives as raw materials exhibit excellent performance by introducing two fluorine atoms at the 3- and 4-positions of the benzene ring. It is known. For example, 3,4-difluorobenzonitrile is an important intermediate of herbicides described in JP-A-64-66156, and 3,4-difluorobenzoic acid is a carcinostatic (J. Med.Chem., 25) . , 84, (1982)] and antibiotics (JP-A-60-123487).
On the other hand, 3,4-difluoroaniline is known for various uses. For example, pyridone carboxylic acid antibacterial agents (Pharmaceutical Magazine , 106 , 802 (1986)), herbicides (Belgium Patent No. 858059), therapeutic drugs for Parkinson's disease (USP3944675),
It is used as an intermediate in the synthesis of liquid crystal substances (JP-A-59-222460).

Conventionally, the above 3,4-difluorobenzene derivative is 3,4
-Difluorobenzoyl chloride was synthesized using a common raw material. However, synthesizing 3,4-difluorobenzoyl chloride requires a multi-step synthesis using orthodifluorobenzene obtained by repeating twice the Seaman reaction using hydrofluoric anhydride that is dangerous to handle. there were. That is, ortho-difluorobenzene is converted to 3,4-difluoroacetophenone by a Friedel-Crafts reaction using acetyl chloride and an equivalent or more of aluminum chloride, and then oxidized by an iodoform reaction to obtain 3,4-difluorobenzoic acid, which is further converted to a chlorinating agent. reacted with, it is an 3,4-difluorobenzoyl chloride [J.Org.Chem., 17 .142
6 (1952); J. Med. Chem., 25 , 84 (1982), etc.].

(Problems to be Solved by the Invention) In order to obtain 3,4-difluorobenzoyl chloride, first, when introducing a fluorine atom into a benzene ring, dangerous hydrofluoric anhydride must be treated. Moreover, the fluorine atom introduction reaction of the ortho-diaminobenzene derivative with hydrofluoric acid usually has a very low yield (Synth.Commun.,
17 , 685 (1987)]. Therefore, it is necessary to repeat the same reaction twice. Second, the synthesis process involves multiple steps. Thirdly, 3,4-difluorobenzoyl chloride has been difficult to handle industrially because it shows a positive result in a mutagenicity test, so-called Ames test.

(Means for Solving the Problems) In view of the above situation, the present inventors have found that 3,4-difluorobenzoyl fluoride is a novel compound that solves all the problems described in the preceding section, and the present invention Was completed.
That is, in order to synthesize 3,4-difluorobenzoyl fluoride and its precursor, 3-fluorosulfonyl-4-fluorobenzoyl fluoride, potassium fluoride that can be easily handled can be used. -Chlorosulfonyl-4-chlorobenzoic acid (Japanese Patent Publication No. 40-18736) can be synthesized in a small number of steps. Moreover, 3,4
-Difluorobenzoyl fluoride is negative for the Ames test and is safe to handle. Further, 3,4-difluorobenzoyl fluoride is superior in reactivity to 3,4-difluorobenzoyl chloride, and a reaction product can be obtained with a higher yield under milder reaction conditions.

General formula of the present invention (Wherein, R represents F or SO ₂ F). The 3-substituted-4-fluorobenzoyl fluoride represented by the formula: is represented by the formula: 3-chlorosulfonyl-4-chloro-benzoic acid (I
It can be easily synthesized according to the following formula from I).

(First Step) This is a step of converting 3-chlorosulfonyl-4-chlorobenzoic acid (II) into an acid chloride using a chlorinating agent. The starting compound (II) can be synthesized in high yield by the method described in JP-B-40-18736. As the chlorinating agent, thionyl chloride, phosphorus trichloride, oxalyl chloride and the like are used.
The reaction proceeds with or without a solvent such as benzene, and the reaction temperature is preferably room temperature to 150 ° C. The product can be isolated in high yield by distillation.

(Second Step) The present step is a step for preparing the 3-chlorosulfonyl-
4-Fluorobenzoyl chloride is fluorinated with anhydrous potassium fluoride to give 3-fluorosulfonyl-4-fluorobenzoyl fluoride. As the potassium fluoride, 2 to 6 equivalents, preferably 3 to 4 equivalents, of industrial or spray-dried potassium fluoride relative to the substrate is used. The reaction proceeds without solvent or in a solvent. When a solvent is used, aprotic polar solvents such as acetonitrile, sulfolane, and dimethylimidazolidinone are preferred. In order to promote the reaction, a quaternary ammonium salt or a phosphonium salt may be used. Of these, use of tetraphenylphosphonium bromide is preferred. The reaction proceeds if the reaction temperature is equal to or higher than room temperature, but is preferably performed at a temperature equal to or higher than the boiling point of acetonitrile.

(Third step) In this step, 3-fluorosulfonyl-4-fluorobenzoyl fluoride obtained in the second step is replaced with a fluoro atom by a fluoro atom with anhydrous potassium fluoride,
3,4-difluorobenzoyl fluoride. It is preferable to use 1 to 3 equivalents of potassium fluoride for industrial use or spray-dried potassium fluoride with respect to the substrate. The reaction proceeds without solvent, but the use of a solvent is preferred. Examples of the solvent used include aprotic polar solvents such as sulfolane and dimethylimidazolidinone. For promoting the reaction, a quaternary ammonium salt or a phosphonium salt may be used. Of these, use of tetraphenylphosphonium bromide is preferred. Reaction temperature is 150 ° C
If it is above, it proceeds, but it is preferably carried out at 200 ° C. or higher.

Further, it is effective to distill the product out of the reaction system while performing the reactive distillation in order to improve the yield of the product.

(Effect of the Invention) The novel 3-substituted-4-fluorobenzoyl fluoride of the present invention can be used for various 3,4 substances which are safe to handle and industrially important.
-A useful intermediate that can be effectively converted to a difluorobenzene derivative.

(Examples) Hereinafter, the present invention will be specifically described with reference to examples.

Reference Example 1 In a four-necked flask equipped with a condenser, a mechanical stirrer, and a thermometer, 3-chlorosulfonyl-4- was added.
255 g (1 mol) of chlorobenzoic acid and 500 ml of benzene were heated and refluxed, and 357 g (3 mol) of thionyl chloride was added dropwise thereto, and the reflux was continued for 7 hours. After confirming the disappearance of the raw materials by gas chromatography, the reaction solution was distilled under reduced pressure to recover benzene and excess thionyl chloride.
257 g (94% yield) of chlorobenzoyl chloride was obtained.

Example 1 In a 200 ml four-necked flask equipped with a condenser, a mechanical stirrer, and a thermometer, 23.2 g (0.4 mol) of spray-dried potassium fluoride (manufactured by Riedel) and 4.2 g (0.01 mol) of tetraphenylphosphonium bromide (manufactured by Hokuko Chemical) Mol), 100 ml of anhydrous acetonitrile and 27.3 g (0.1 mol) of 3-chlorosulfonyl-4-chlorobenzoyl chloride were refluxed for 16 hours. After the reaction is completed, the solid is filtered off,
Vacuum distillation was performed. 85 ° C./1 mmHg fraction, 16 g of 3-fluorosulfonyl-4-fluorobenzoyl fluoride
(71% yield). High-MS: Calculated 223.9754; Analytical value 22
3.9739; IR (neat): 1830, 1220 cm ^-1 Example 2 In a 100 ml four-necked flask equipped with a condenser, a mechanical stirrer, and a thermometer, 6.5 g (0.11 mol) of spray-dried potassium fluoride (manufactured by Riedel), tetra Phenylphosphonium bromide (Hokuko Chemical Co., Ltd.) (2.1 g, 0.005 mol) and anhydrous sulfolane (8.5 ml) were added. After azeotropic dehydration with toluene, the condenser was replaced with a fractionation head.
3-Fluorosulfonyl-4-fluorobenzoylfluoride (11.2 g, 0.05 mol) was added, and the mixture was added under reduced pressure of 270 mmHg.
The mixture was stirred at 4 ° C. for 4 hours while performing reactive distillation. As a distillate, 3.21 g of 3,4-difluorobenzoyl fluoride having a boiling point of 140 ° C./270 mmHg was obtained. The conversion was 92% and the selectivity was 49%. High-MS: calc. 160.0136; analytic 160.0135; IR
(Neat): 1820 cm ^-1 This 3,4-difluorobenzoyl fluoride was hydrolyzed to 3,4-difluorobenzoic acid, and the compound was identified. Melting point was 120 ° C. (Literature: 119.2 to 120.1
C; J. Org. Chem., 17 , 29 (1952)].

Reference Example 2 9.8 g of 25% ammonia water and 5.6 g of water in a 25 ml eggplant-shaped flask
And stirrer, and stir well at room temperature for 3,4
4.5 g of difluorobenzoyl fluoride were added dropwise. After stirring for 2 hours, the mixture was filtered and dried to obtain 3.6 g of 3,4-difluorobenzamide. (Yield 82%) Melting point 129-130
° C; IR (KBr); 3380, 3180, 1660 cm ^-1 Reference Example 3 1.79 g of thionyl chloride and 5 g of chlorobenzene were placed in a 25 ml eggplant-shaped flask, and 1.57 g of 3,4-difluorobenzamide was quickly charged with stirring. Then, the mixture was refluxed for 6 hours while attaching a condenser and stirring well. After confirming the disappearance of the raw materials by gas chromatography, the reaction solution was directly distilled under reduced pressure to recover chlorobenzene and excess thionyl chloride, and then 0.8 g of 3,4-difluorobenzonitrile was obtained under reduced pressure of 100 mmHg. (Yield 58%) Melting point 51-52 ° C
(Boiling point 95 ° C./45 mmHg); IR (KBr): 2225 cm ⁻¹ Reference Example 4 16 ml of water and 2.8 g of potassium hydroxide in a 25 ml eggplant-shaped flask
After stirring and dissolving with stirring, the mixture was cooled to 0 ° C., and 1.6 g of bromine was added dropwise. Then, 1.57 g of 3,4-difluorobenzamide was quickly charged, and initially,
After stirring for an hour, the temperature was gradually increased, and the temperature was raised to 88 ° C. in one hour. After confirming the disappearance of the raw materials by gas chromatography, the reaction solution was extracted with ether and distilled under reduced pressure.
3,4-difluoroaniline having a boiling point of 111 ° C / 100 mmHg
0.6 g (yield 47%) was obtained. IR (neat); 3375, 3450 cm ^-1 Reference Example 5 In a 25 ml eggplant-shaped flask, 215 mg of sodium azide (3.3 mm
ol), 20 ml of toluene and a stirrer, and a Dean-Stark water separator was attached. The mixture was concentrated until the amount of toluene became 15 ml. Remove the Dean-Stark water separator and remove 480 mg (3 mmol) of 3,4-difluorobenzoyl fluoride or 3,4
-530 mg (3 mmol) of difluorobenzoyl chloride and 100 mg of an internal standard substance 1,2,3-trichlorobenzene were quickly added, and the mixture was heated and refluxed with a condenser attached with good stirring. It was quantified by gas chromatography at regular intervals. The results are shown in FIG. In addition, since the result is applied to the first-order reaction rate equation, the respective reaction rate constants were obtained as follows. 3,4-difluorobenzoyl fluoride 3.06 × 10 ⁻⁴ sec ⁻¹ and 3,4-difluorobenzoyl chloride 2.38 × 10 ⁻⁴ sec ⁻¹ , and the reaction rate of 3,4-difluorobenzoyl fluoride is about 30%. Is fast.

Reference Example 6 7.5 ml of acetone, 160 mg of 3,4-difluorobenzoyl chloride, 176.5 mg of 3,4-difluorobenzoyl chloride and 50 mg of 1,2,3-trichlorobenzene as an internal standard substance were added to a 15 ml eggplant flask, and then 2.5 ml of water. ml was added and stirred. Each compound was quantified by gas chromatography at regular intervals after the introduction, and the results are shown in FIG. In addition, since the results were applied to the first-order reaction rate equation, the respective hydrolysis rate constants were determined. The results are shown below. 3,4-difluorobenzoyl fluoride 1.35 × 10 ⁻⁴ sec ⁻¹ and 3,4-difluorobenzoyl chloride 3.22 × 10 ⁻⁴ sec ⁻¹ and 3,4-
Difluorobenzoyl fluoride is safer because it is less likely to be hydrolyzed.

Test Example A mutagenicity test of 3,4-difluorobenzoyl fluoride and 3,4-difluorobenzoyl chloride, a so-called Ames test (new guidebook for mutagenicity tests using microorganisms, pp. 53-76) [Central occupational accidents Prevention Association Edition (198
6)]. As a result, 3,4-difluorobenzoyl chloride was negative, but 3,4-difluorobenzoyl chloride was positive.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the residual ratio of 3,4-difluorobenzoyl fluoride and 3,4-difluorobenzoyl chloride and the reaction time in Reference Example 5, and FIG.
Is a graph showing the relationship between the residual time of 3,4-difluorobenzoyl fluoride and 3,4-difluorobenzoyl chloride in Reference Example 6 and the reaction time.

Claims (1)

(57) [Claims] (1) General formula (Wherein, R represents F or SO ₂ F.)
Substituted-4-fluorobenzoyl fluoride.