JPH10168051A - Production of 2,3-dihalogeno-6-trifluoromethylbenzonitrile - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing a 2,3-dihalogeno-6-trifluoromethylbenzonitrile useful as an intermediate for agricultural/horticultural germicides, e.g. 2,3-dichloro-6-trifluoromethylbenzonitrile and 2,3-difluoro-6-trifluoromethylbenzonitrile. SOLUTION: One of the subject compounds, 2,3-dichloro-6- trifluoromethylbenzonitrile, is produced by brominating 2-chloro-5- trifluoromethylaniline to make 2-bromo-6-chloro-3-trifluoromethylaniline, which is converted to the corresponding diazonium salts, which is then made into 2-bromo-3,4-dichlorobenzotrifluoride by the reaction of cuprous or cupric chloride, followed by reacting a cyanide with the above 2-bromo-3,4- dichlorobenzotrifluoride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2,3-dihalogeno-6-trifluoromethylbenzonitrile, which is useful as an intermediate for producing agricultural chemicals and pharmaceuticals.

[0002]

2. Description of the Related Art 2,3-Dihalogeno such as 2,3-dichloro-6-trifluoromethylbenzonitrile and 2,3-difluoro-6-trifluoromethylbenzonitrile.
6-trifluoromethylbenzonitrile is described in WO96 /
As described in No. 19442, it is an intermediate for producing a benzamidoxime-based fungicide for agricultural and horticultural use. This intermediate material, 2,3-dichloro-6-trifluoromethylbenzonitrile, has been conventionally produced as follows (PC
T / JP96 / 01688).

[0003]

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However, in this production method, organolithium must be used as a reactant. However, since organolithium is ignitable in the air, it is difficult to handle it on an industrial scale. Because of this, there was a problem in manufacturing. Therefore, 2,3-dichloro-6-
There has been a demand for a method for industrially advantageously producing trifluoromethylbenzonitrile and 2,3-difluoro-6-trifluoromethylbenzonitrile.

[0005]

An object of the present invention is to provide 2,3-dichloro-6- useful as a fungicide intermediate for agricultural and horticultural use.
An object of the present invention is to provide a method for industrially and advantageously producing 2,3-dihalogeno-6-trifluoromethylbenzonitrile such as trifluoromethylbenzonitrile and 2,3-difluoro-6-trifluoromethylbenzonitrile. .

[0006]

The present invention provides a method for preparing 2,3-method by any one of the following eight production methods A to H:
Dichloro-6-trifluoromethylbenzonitrile [I
V], 3-chloro-2-fluoro-6-trifluoromethylbenzonitrile [XIV] or 2,3-difluoro-6-trifluoromethylbenzonitrile [XII]. The outline of the production method of the present invention is shown below.

[0007]

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[0008]

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[0009]

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Production method A A method for producing 2,3-dichloro-6-trifluoromethylbenzonitrile, comprising the following steps (1), (2) and (3): (1) Step of brominating 2-chloro-5-trifluoromethylaniline [I] to give 2-bromo-6-chloro-3-trifluoromethylaniline [II] (2) Step of 2-bromo-6- Chloro-3-trifluoromethylaniline [II] is converted into a diazonium salt, which is then reacted with cuprous chloride or cupric chloride to give 2-bromo-trifluoromethylaniline [II].
Step of converting into 3,4-dichlorobenzotrifluoride [III] (3) By reacting 2-bromo-3,4-dichlorobenzotrifluoride [III] with cyanide, 2,3-dichloro-6-trifluoride is obtained. Step of making fluoromethylbenzonitrile [IV]

Production method B A method for producing 2,3-dichloro-6-trifluoromethylbenzonitrile, comprising the following steps (1), (2), (3) and (4): (1) Step of brominating 2-chloro-5-trifluoromethylaniline [I] to give 2-bromo-6-chloro-3-trifluoromethylaniline [II] (2) Step of 2-bromo-6- Step of oxidizing chloro-3-trifluoromethylaniline [II] to give 2-bromo-4-chloro-3-nitrobenzotrifluoride [V] (3) 2-bromo-4-chloro-3-nitro Step of reacting benzotrifluoride [V] with cyanide to give 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] (4) 3-chloro-2-nitro-6-trifluoro A chlorinating agent is allowed to act on methylbenzonitrile [VI],
Step of converting into 3-dichloro-6-trifluoromethylbenzonitrile [IV]

Production method C A method for producing 2,3-dichloro-6-trifluoromethylbenzonitrile, comprising the following steps (1), (2), (3) and (4): (1) Step of brominating 2-chloro-5-trifluoromethylaniline [I] to give 2-bromo-6-chloro-3-trifluoromethylaniline [II] (2) Step of 2-bromo-6- By reacting chloro-3-trifluoromethylaniline [II] with cyanide, 2-cyano-6-chloro-3-trifluoromethylaniline [VI
(3) Oxidizing 2-cyano-6-chloro-3-trifluoromethylaniline [VII] to give 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI]. Step (4) 3-Chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] is reacted with a chlorinating agent to give 2,3-dichloro-6-trifluoromethylbenzonitrile [IV]. Process

Production method D Production of 2,3-difluoro-6-trifluoromethylbenzonitrile [XII] characterized by comprising the following steps (1), (2), (3) and (4): Law. (1) Step of reacting 3-trifluoromethylaniline [VIII] with bromine to give 2,6-dibromo-3-trifluoromethylaniline [IX] (2) 2,6-dibromo-3-trifluoro Methylaniline [IX] was converted into a diazonium salt, and then reacted with cuprous chloride or cupric chloride to give 3-chloro-2,4-dichloromethane.
Step of converting into dibromobenzotrifluoride [X] (3) 3-bromo-2,4-dibromobenzotrifluoride [X] is reacted with cyanide to give 3-bromo-
Step of converting into 2-chloro-6-trifluoromethylbenzonitrile [XI] (4) A fluorinating agent is allowed to act on 3-bromo-2-chloro-6-trifluoromethylbenzonitrile [XI],
Step of converting into 2,3-difluoro-6-trifluoromethylbenzonitrile [XII]

Production method E 2,3,4-trichlorobenzotrifluoride [XII
I] with cyanide,
A method for producing 3-dichloro-6-trifluoromethylbenzonitrile [IV].

Production method F: 3-Chloro-2-fluoro-6-trifluoromethyl characterized by reacting 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] with a fluorinating agent. A method for producing benzonitrile [XIV].

Process G: A fluorinating agent is allowed to act on 3-chloro-2-fluoro-6-trifluoromethylbenzonitrile [XIV], characterized in that 2,3-difluoro-6-trifluoromethylbenzonitrile [XIV] is used. XII].

Production method H 2,3,4-trifluorobenzotrifluoride [X
V] with cyanide, 2,
A method for producing 3-difluoro-6-trifluoromethylbenzonitrile [XII].

The present invention also relates to a novel intermediate compound, 2-bromo-6-chloro-3-trifluoromethylaniline, which is used in the above process for producing 2,3-dihalogeno-6-trifluoromethylbenzonitrile. II], 2-bromo-3,4-dichlorobenzotrifluoride [II
I], 2-bromo-4-chloro-3-nitrobenzotrifluoride [V], 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI], 2-amino-
3-chloro-6-trifluoromethylbenzonitrile [VII], 2,6-dibromo-3-trifluoromethylaniline [IX], 3-chloro-2,4-dibromobenzotrifluorofluoride [X], 3-bromo -2-chloro-6
Trifluoromethylbenzonitrile [XI].

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. For the production method A, the step of converting the compound represented by the formula [I] to the formula [II]
In a halogenated hydrocarbon solvent such as chloroform and carbon tetrachloride, and an aromatic hydrocarbon solvent such as benzene, toluene, xylene and chlorobenzene, the reaction temperature is 50 to 150 ° C.
And 1.0 to 1.0 mol per 1 mol of the compound represented by the formula [I].
A 2.0-fold molar amount of bromine is allowed to act.

The following process for preparing a compound represented by the formulas [II] to [III] is known as a so-called Sandmeyer reaction. The reaction is carried out in an inert solvent such as acetonitrile, acetone or ethyl acetate at a reaction temperature of -1.
At 0 ° C. to room temperature, 1.0 to 2.0 moles of sodium nitrite are added to 1 mole of the compound represented by the formula II], and 0.1 to 2.0 moles.
This is to make 1.3 times cuprous chloride or cupric chloride act.

In the step of converting the compound represented by the formula [III] into the compound represented by the formula [IV], N, N-dimethylformamide (DM
F) Compound 1 represented by the formula [III] in an amide system such as N, N-dimethylacetamide (DMA) or N-methylpyrrolidone, or in an aprotic polar solvent such as dimethyl sulfoxide (DMSO) or sulfolane. 0.
One or two moles of cyanide such as cuprous cyanide, potassium cyanide, and sodium cyanide are allowed to act. The cyanide can be used alone or as a mixture. If desired, a catalyst such as 0.01 to 0.1 moles of copper carbonate, copper sulfate, cuprous iodide, potassium iodide, sodium iodide, or the like can be added to the reaction system. The reaction proceeds smoothly in the range of 0 ° C. to the boiling point of the solvent.

For the production method B, the step of converting the compound represented by the formula [II] to the formula [V] into
Water, an organic acid such as acetic acid, or a halogen-based solvent such as chloroform or carbon tetrachloride, in an amount of 1.0 to 10 moles of hydrogen peroxide with respect to 1 mole of the compound represented by the formula [II];
An oxidizing agent such as metachloroperbenzoic acid acts. If desired, an acid such as sulfuric acid can be added. The reaction proceeds smoothly in the range of 0 ° C. to the boiling point of the solvent.

The step of converting the compound represented by the formula [V] into the compound represented by the formula [VI] is performed in an amide-based solvent such as DMF, DMA, N-methylpyrrolidone, or an aprotic polar solvent such as DMSO or sulfolane. V] is reacted with a cyanide such as cuprous cyanide, potassium cyanide, and sodium cyanide in an amount of 0.1 to 2 moles per 1 mole of the compound represented by the formula: The cyanide can be used alone or as a mixture. Also, if desired, 0.01 to
A catalyst such as 0.1 times mole of copper carbonate, copper sulfate, cuprous iodide, potassium iodide, sodium iodide and the like can be added to the reaction system. The reaction proceeds smoothly in the temperature range from room temperature to the boiling point of the solvent used.

The step of converting the compound represented by the formula [VI] into the compound represented by the formula [IV] is carried out in an amide system such as DMF, DMA and N-methylpyrrolidone, and in an aprotic polar solvent such as DMSO and sulfolane from room temperature to a solvent. In the temperature range up to the boiling point of 1 to 10 moles per mole of the compound represented by the formula [VI], alkali metal chlorides such as calcium chloride, sodium chloride, potassium chloride and lithium chloride or alkaline earths. It acts on a metal chloride. The reaction proceeds smoothly in a temperature range from room temperature to the boiling point of the solvent used.

The process for preparing the compound represented by the formula [II] to the formula [VII] is carried out in an amide system such as DMF, DMA and N-methylpyrrolidone, or in an aprotic polar solvent such as DMSO and sulfolane. 0.1 to 1 mol of the compound represented by the formula [II]
The reaction is carried out by reacting a cyanide such as cupric cyanide, potassium cyanide, sodium cyanide, etc. twice in mole. The cyanide can be used alone or as a mixture. If desired, a catalyst such as 0.01 to 0.1 moles of copper carbonate, copper sulfate, cuprous iodide, potassium iodide, sodium iodide, or the like can be added to the reaction system. The reaction proceeds smoothly from room temperature to the boiling point of the solvent.

The step of converting the compound represented by the formula [VII] into the compound represented by the formula [VI] includes water, an organic acid such as acetic acid, chloroform,
In a halogenated hydrocarbon solvent such as dichloromethane, 1.0 to 10 per 1 mol of the compound represented by the formula [VII] is used.
An oxidizing agent such as twice molar aqueous hydrogen peroxide and metachloroperbenzoic acid is allowed to act. If desired, an acid such as sulfuric acid can be added. The reaction proceeds smoothly from room temperature to the boiling point of the solvent.

Production Process D The step of converting the compound represented by the formula [VIII] to the compound represented by the formula [IX] includes a halogenated hydrocarbon solvent such as chloroform and carbon tetrachloride, benzene, toluene, xylene, In an aromatic hydrocarbon solvent such as chlorobenzene, at a reaction temperature of 50 to 150 ° C, 2.0 to 3.0 times mol of bromine is allowed to act on 1 mol of the compound represented by the formula [VIII]. .

The step of converting the compound represented by the formula [IX] into the compound represented by the formula [X] is carried out in an inert solvent such as acetonitrile, acetone and ethyl acetate at a reaction temperature of -10 ° C to room temperature. And 1.0 to 2.0 moles of sodium nitrite relative to 1 mole of the compound represented by the formula [IX],
It reacts with 0.1 to 1.3 times mol of cuprous chloride or cupric chloride.

The step of converting the compound represented by the formula [X] to the compound represented by the formula [XI] includes amides such as DMF, DMA and N-methylpyrrolidone, and aprotic polar solvents such as DMSO and sulfolane. Wherein 0.1 to 2 moles of cuprous cyanide is added to 1 mole of the compound represented by the formula [X],
It acts on cyanide such as potassium cyanide and sodium cyanide. The cyanide can be used alone or as a mixture. If desired, a catalyst such as 0.01 to 0.1 times mol of copper carbonate, copper sulfate, cuprous iodide, potassium iodide, sodium iodide or the like can be added to the reaction system. The reaction proceeds smoothly from room temperature to the boiling point of the solvent.

The step of converting the compound represented by the formula [XI] into the compound represented by the formula [XII] in the final step is carried out in a solvent-free or suitable solvent at a ratio of 0.1 to 0.1 per halogen atom.
A fluorinating agent such as potassium fluoride, sodium fluoride, or cesium fluoride is used in an amount of 1 to 2.0 times the molar amount. Solvents that can be used for the reaction include DM
Aprotic polar solvents such as F, DMA, N-methylpyrrolidone, DMSO, and sulfolane can be exemplified. Also, if desired, Ph ₄ PBr, (n-Bu) ₄ P
Phosphonium salts such as Br, ammonium salts such as (CH ₃ ) ₄ NCl, and crown ethers such as 18-crown-6 can also be used as the catalyst. The amount of these catalysts added to the reaction system depends on the amount of the compound 1 represented by the formula [XI].
It is preferably from 0.5 to 10% by weight based on the mole. The reaction temperature is 100 to 250 ° C, preferably around 200 ° C.

Regarding Production Method E The compound represented by the formula [XIII] is a known compound. This is, for example, 2-chloro-5-type represented by the formula [I].
It can be obtained by converting 2,6-dichloro-3-trifluoromethylaniline represented by the formula [XVI] from trifluoromethylaniline and then substituting an amino group with a chlorine atom by a so-called Sandmeyer reaction.

[0032]

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The compound represented by the formula [XIII] thus obtained is added to the compound represented by the formula [XIII] in an aprotic polar solvent such as DMF, DMA, N-methylpyrrolidone or the like, or DMSO, sulfolane or the like. A compound represented by the formula [IV] is obtained by reacting 0.1 to 2 moles of a cyanide such as cuprous cyanide, potassium cyanide, and sodium cyanide with respect to 1 mol of the compound represented by the formula. is there. The cyanide can be used alone or as a mixture. If desired, a catalyst such as 0.01 to 0.1 moles of copper carbonate, copper sulfate, cuprous iodide, potassium iodide, sodium iodide, or the like can be added to the reaction system.
The reaction proceeds smoothly from room temperature to the boiling point of the solvent.

Regarding Production Methods F and G Further, the compound [VI] obtained by the above Production Method B is used as a starting material in a solvent-free or suitable solvent in an amount of 0.1 to 2.0 times per halogen atom. Obtaining a 3-chloro-2-fluoro-6-trifluoromethylbenzonitrile represented by the formula [XIV] by reacting a mole of a fluorinating agent such as potassium fluoride, sodium fluoride, cesium fluoride, etc. Can be. Further, if fluorination proceeds, 2,3-difluoro-6-trifluoromethylbenzonitrile represented by the formula [XII] can be obtained. Solvents that can be used for the reaction include DM
Aprotic polar solvents such as F, DMA, N-methylpyrrolidone, DMSO, and sulfolane can be exemplified. Also, if desired, Ph ₄ PBr, (n-Bu) ₄ P
Phosphonium salts such as Br, ammonium salts such as (CH ₃ ) ₄ NCl, and crown ethers such as 18-crown-6 can also be used as the catalyst. The amount of these catalysts added to the reaction system depends on the amount of the compound 1 represented by the formula [VI].
It is preferably from 0.5 to 10% by weight based on the mole. The reaction temperature is 100 to 250 ° C, preferably around 200 ° C.

Production Method H In the same manner as in Production Method D, 2,3,4-trifluorobenzotrifluoride [XV] is added to amides such as DMF, DMA and N-methylpyrrolidone, and aprotic compounds such as DMSO. By reacting cyanide such as cuprous cyanide, potassium cyanide and sodium cyanide in a polar solvent in an amount of 0.1 to 2.0 moles per mole of the compound represented by the formula [XV], 2 , 3-difluoro-6-trifluoromethylbenzonitrile [XII]. The cyanide can be used alone or as a mixture. If desired, a catalyst such as 0.01 to 0.1 times mol of copper carbonate, copper sulfate, cuprous iodide, potassium iodide, sodium iodide or the like can be added to the reaction system. The reaction proceeds smoothly from room temperature to the boiling point of the solvent.

In any case, after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment. Also,
In each step, the reaction of the next step can be performed without removing the product. The structure of the compound is IR, NMR
And so on.

[0037]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Synthesis of 2-bromo-6-chloro-3-trifluoromethylaniline [II]

[0039]

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30 g (0.153 mol) of 2-chloro-5-trifluoromethylaniline [I] was added to chloroform 3
And heated to 50 ° C. with stirring to obtain 29.5 ml of bromine.
g was added dropwise in 30 minutes. After stirring at 50 ° C for 2 hours,
Further, 7.4 g of bromine was added dropwise in 30 minutes. After dropping 5
After further stirring at 0 ° C. for 3 hours, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Water and chloroform were added to the obtained residue, and the mixture was neutralized with a 10% aqueous sodium hydroxide solution and separated. The organic layer was washed with water, an aqueous solution of sodium thiosulfate, and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane solvent) to obtain 21.9 g of the desired 2-bromo-6-chloro-3-trifluoromethylaniline [II] (yield: 52%). ¹ H-NMR (CDCl ₃ , δ ppm): 7.01
(1H, d), 7.31 (1H, d)

Example 2 Synthesis of 2-bromo-6-chloro-3-trifluoromethylaniline [II]

[0042]

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20 g (0.102 mol) of 2-chloro-5-trifluoromethylaniline [I] was added to 400 parts of benzene.
The solution was heated to 80 ° C. with stirring, and 19.2 g of bromine was added dropwise over 60 minutes. After stirring at 80 ° C. for 30 minutes, another 4.8 g of bromine was added dropwise over 30 minutes, and a further 1 hour at 80 ° C.
Stirred for hours. The reaction was cooled to room temperature, water was added and 1
The mixture was neutralized with a 0% aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and the mother liquor was concentrated under reduced pressure. Hexane was added to the residue, and insolubles were filtered. The mother liquor was concentrated under reduced pressure and then distilled (84 to 106 ° C (4 mmHg)) to obtain the desired 2-
18.44 g (yield: 64%) of bromo-6-chloro-3-trifluoromethylaniline [II] was obtained (GC analysis purity: 97%).

Example 3 Synthesis of 2-bromo-3,4-dichlorobenzotrifluoride [III]

[0045]

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10 g (0.036 mol) of 2-bromo-6-chloro-3-trifluoromethylaniline [II] was dissolved in 20 ml of acetonitrile, 20 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to 0 ° C., and a solution of 3 g of sodium nitrite dissolved in 10 ml of water was added dropwise at 0 ° C. The reaction solution obtained by stirring for 30 minutes as it is was mixed with 4.7 g of cuprous chloride, which was previously cooled to 0 ° C.
It was added dropwise to a solution of 0 ml and 25 ml of water at 0-5 ° C. with stirring. After completion of the dropwise addition, the mixture was further heated at this temperature for 30 minutes and at room temperature
After stirring for an hour, the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (hexane solvent).
9.5 g (yield: 89%) of the desired 2-bromo-3,4-dichlorobenzotrifluoride [III] was obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 7.56 (2
H, S)

Example 4 Synthesis of 2,3-dichloro-6-trifluoromethylbenzonitrile [IV]

[0048]

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In 40 ml of DMF, 2-bromo-3,4-
3.56 g of dichlorobenzotrifluoride [III]
(0.012 mol) and 1.4 g of cuprous cyanide were dissolved and heated under reflux for 7 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted twice with ethyl acetate. The organic layer was washed with water, diluted hydrochloric acid aqueous solution, water and saturated saline in this order, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography of the obtained residue (hexane solvent)
To obtain 1.9 g (yield: 65%) of 2,3-dichloro-6-trifluoromethylbenzonitrile [IV]. 53-54 ° C

Example 5 Synthesis of 2-bromo-4-chloro-3-nitrobenzotrifluoride [V]

[0051]

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13.7 g (0.05 mol) of 2-bromo-6-chloro-3-trifluoromethylaniline [II],
In a mixture of 6.4 g of concentrated sulfuric acid and 130 ml of acetic acid, 28.3 g of 30% hydrogen peroxide was added dropwise at 60 ° C. with stirring. After completion of the dropwise addition, the mixture was further stirred at 60 to 65 ° C for 12 hours. The reaction mixture was cooled, poured into water, and the precipitated crystals were collected by filtration. After washing the crystals with water, the crystals were dissolved in ethyl acetate, washed with a dilute aqueous sodium thiosulfate solution and then with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product is washed with hexane to give the desired 2-bromo-4-chloro-
9. Crystals of 3-nitrobenzotrifluoride [V]
2 g were obtained. Further, the mother liquor was concentrated under reduced pressure, separated and purified by silica gel chromatography (hexane solvent), and further, 1.2 g of 2-bromo-4-chloro-3-nitrobenzotrifluoride [V] crystal was obtained (total). Yield: 75%). ¹ H-NMR (CDCl ₃ , δ ppm): 7.64 (1
H, d), 7.78 (1H, d)

Example 6 Synthesis of 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI]

[0054]

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2.2 g of 2-bromo-4-chloro-3-nitrobenzotrifluoride [V] is added to 22 ml of DMF.
(0.0072 mol), and 0.78 cuprous cyanide
g was added and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution was poured into water, insoluble matter was removed by filtration through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (hexane solvent) to obtain 0.25 g of the desired 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] (yield:
14%). ¹ H-NMR (CDCl ₃ , δ ppm): 7.93 (1
H, d), 7.97 (1H, d)

Example 7 Synthesis of 2,3-dichloro-6-trifluoromethylbenzonitrile [IV]

[0057]

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3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] was added in 2 ml of DMSO.
2 g and 0.44 g of calcium chloride to add 110
The mixture was stirred with heating at 2 ° C. for 2 hours. After cooling, the reaction solution was separated and purified by silica gel chromatography (hexane solvent) to obtain 0.1 g of the desired crystal of 2,3-dichloro-6-trifluoromethylbenzonitrile [IV] (yield: 52).
%).

Example 8 Synthesis of 2-amino-3-chloro-6-trifluoromethylbenzonitrile [VII]

[0060]

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8.2 g of 2-bromo-6-chloro-3-trifluoromethylaniline [II], cuprous cyanide
94 g was dissolved in DMF (80 ml) and heated and stirred for 8 hours.
After cooling, the reaction solution was poured into water, insoluble matter was removed with Celite, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane solvent),
4.5 g of the desired 2-amino-3-chloro-6-trifluoromethylbenzonitrile [VII] (yield: 68
%). ¹ H-NMR (CDCl ₃ , δ ppm): 7.01 (2
H, d), 7.56 (2H, d)

Example 9 Synthesis of 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI]

[0063]

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4.0 g of 2-amino-3-chloro-6-trifluoromethylbenzonitrile [VII] was added to concentrated sulfuric acid.
2 g and 30 ml of acetic acid, and 4.5 g of 30% aqueous hydrogen peroxide were added dropwise at 60 to 70 ° C. After completion of the dropwise addition, the mixture was further stirred at 60 ° C. for 12 hours, and then further
3 g of aqueous hydrogen peroxide solution was added, and the mixture was stirred at 70 ° C. for 12 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a diluted aqueous solution of sodium thiosulfate and then with water, then dehydrated and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (hexane solvent) to obtain 0.4 g of the desired 3-chloro-2-nitro-6-trifluorobenzonitrile [VI] (yield: 9).
%).

Reference Example 1 Synthesis of 2,6-dichloro-3-trifluoromethylaniline [XVI]

[0066]

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1.96 g of 2-chloro-5-trifluoromethylaniline [I] was dissolved in 20 ml of chloroform.
Heat to 50 ° C under stirring, and add 5.05wt% of chlorine
21.0 g of a chloroform solution was added dropwise over 30 minutes.
After completion of the dropwise addition, the mixture was further stirred at the same temperature for 2 hours, allowed to cool to room temperature, and water and chloroform were added to the reaction solution, and 10%
After the whole was neutralized with an aqueous sodium hydroxide solution, the layers were separated. The organic layer was washed with water, an aqueous solution of sodium thiosulfate, and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2,6-dichloro-3.
1.8 g (yield: 78%) of trifluoromethylaniline [XVI] was obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 6.97 (2
H, d), 7.21 (2H, d)

Reference Example 2 2,3,4-Trichlorobenzotrifluoride [XII
Synthesis of I]

[0069]

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1.0 g of the 2,6-dichloro-3-trifluoromethylaniline [XVI] obtained above was dissolved in a mixture of 4 ml of acetonitrile and 4 ml of concentrated sulfuric acid, and the whole was dissolved in 0 ml.
Cooled to ° C. 0.36g of sodium nitrite
Was dissolved in 2 ml of water, and a solution prepared at 0 ° C. was added dropwise thereto. After completion of the addition, the mixture was further stirred at the same temperature for 30 minutes. This solution was previously mixed with 0.5 ml of cuprous chloride in 5 ml of concentrated hydrochloric acid and 5 ml of water.
6 g was added dropwise to the solution at 0 to 5 ° C. After stirring at the same temperature for 15 minutes and at room temperature for 1 hour, ethyl acetate was added to the reaction solution to carry out liquid separation. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 1.0 g of 2,3,4-trichlorobenzotrifluoride [XIII] (yield: 92%)
I got ¹ H-NMR (CDCl ₃ , δ ppm): 7.51 (2
H, d), 7.57 (2H, d)

Example 10 Synthesis of 2,3-dichloro-6-trifluoromethylbenzonitrile [IV]

[0072]

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1.0 g of 2,3,4-trichlorobenzotrifluoride [XIII] was dissolved in 10 ml of DMF, and 0.43 g of cuprous cyanide and 0.12 g of sodium iodide were added thereto. Heated to reflux. After completion of the reaction, the reaction solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane solvent).
0.15 g (yield: 16%) of 2,3-dichloro-6-trifluoromethylbenzonitrile [IV] was obtained.

Example 11 Synthesis of 2,3-difluoro-6-trifluoromethylbenzonitrile [XII]

[0075]

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The previously obtained 3-chloro-2-nitro-6
-Dissolve 0.3 g of trifluoromethylbenzonitrile [VI] in 30 ml of sulfolane and add potassium fluoride 0.28
g and 0.03 g of 18-crown-6,
The mixture was heated and stirred at 00 to 110 ° C for 4 hours. G of this reaction solution
According to C (gas chromatography) analysis, 3-chloro-2-fluoro-6-trifluoromethylbenzonitrile [XIV]
Was generated. This is further
After heating and stirring at 0 to 190 ° C for 4 hours, and after cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.05 g (yield: 20%) of 2,3-difluoro-6-trifluoromethylbenzonitrile [XII]. Boiling point: 98-100 ° C / 25mmHg

Reference Example 3 Synthesis of 2,6-dibromo-3-trifluoromethylaniline [IX]

[0078]

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3-trifluoromethylaniline [VIII]
8 g was dissolved in 100 ml of chloroform.
17.6 g of bromine was added dropwise at 50 ° C. while stirring. After completion of the dropwise addition, the mixture was further stirred at 50 ° C. for 2 hours. Water and chloroform were added to the reaction solution, the whole was neutralized with a 10% aqueous sodium hydroxide solution, and then separated. The organic layer was washed with water, an aqueous solution of sodium thiosulfate, and saturated saline in that order, and then dehydrated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 6.1 g of 2,6-dibromo-3-trifluoromethylaniline [IX].
(Yield: 58%) was obtained. ¹ H-NMR (CDCl ₃ , δ ppm): 6.88 (1
H, d), 7.39 (1H, d)

Reference Example 4 Synthesis of 3-chloro-2,4-dibromobenzotrifluoride [X]

[0081]

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2.0 g of 2,6-dibromo-3-trifluoromethylaniline [IX] obtained above was dissolved in 8 ml of acetonitrile, 8 ml of concentrated hydrochloric acid was added, and the mixture was cooled to 0 ° C. A solution of 0.72 g of sodium nitrite in 4 ml of water was added dropwise thereto, and after the completion of the addition, the mixture was further stirred at room temperature for 30 minutes.
The obtained reaction solution was prepared using cuprous chloride 1.
It was added dropwise to a solution of 12 g of concentrated hydrochloric acid 10 ml and water 10 ml.
After completion of the dropwise addition, the mixture was stirred at 0 ° C to 5 ° C for 15 minutes and further at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, dehydrated, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography to obtain 1.5 g of 3-chloro-2,4-dibromobenzotrifluoride [X] (yield: 71).
%). ¹ H-NMR (CDCl ₃ , δ ppm): 7.47
(1H, d), 7.73 (1H, d)

Example 12 Synthesis of 3-bromo-2-chloro-6-trifluoromethylbenzonitrile [XI]

[0084]

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1.5 g of 3-chloro-2,4-dibromobenzotrifluoride [X] and 0.1 g of cuprous cyanide.
42 g was added to 10 ml of DMF, and the mixture was heated under reflux for 6 hours. After the reaction solution was cooled, it was poured into water, filtered to remove insolubles by celite filtration, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 0.1 g of the desired 3-bromo-2-chloro-6-trifluoromethylbenzonitrile [XI]. ¹ H-NMR (CDCl ₃ , δ ppm): 7.57 (1
H, d), 8.01 (1H, d)

[0086]

As described above, the present invention provides an industrially advantageous method for producing eight routes of 2,3-dihalogeno-6-trifluoromethylbenzonitrile. This compound is useful as an intermediate for agricultural chemicals / medicines, particularly fungicides for agricultural and horticultural use.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 205/12 C07C 205/12 211/52 211/52 253/14 253/14 253/30 253/30 255/58 255/58 // C07B 61/00 300 C07B 61/00 300

Claims (16)

[Claims] 1. A method for producing 2,3-dichloro-6-trifluoromethylbenzonitrile [IV], comprising the following steps (1), (2) and (3). (1) Step of brominating 2-chloro-5-trifluoromethylaniline [I] to give 2-bromo-6-chloro-3-trifluoromethylaniline [II] (2) Step of 2-bromo-6- Chloro-3-trifluoromethylaniline [II] is converted into a diazonium salt, which is then reacted with cuprous chloride or cupric chloride to give 2-bromo-trifluoromethylaniline [II].
Step of converting into 3,4-dichlorobenzotrifluoride [III] (3) By reacting 2-bromo-3,4-dichlorobenzotrifluoride [III] with cyanide, 2,3-dichloro-6-trifluoride is obtained. Step of making fluoromethylbenzonitrile [IV] 2. The following (1), (2), (3) and (4)
2,3-dichloro-6-
A method for producing trifluoromethylbenzonitrile [IV]. (1) Step of brominating 2-chloro-5-trifluoromethylaniline [I] to give 2-bromo-6-chloro-3-trifluoromethylaniline [II] (2) Step of 2-bromo-6- Step of oxidizing chloro-3-trifluoromethylaniline [II] to give 2-bromo-4-chloro-3-nitrobenzotrifluoride [V] (3) 2-bromo-4-chloro-3-nitro Step of reacting benzotrifluoride [V] with cyanide to give 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] (4) 3-chloro-2-nitro-6-trifluoro A chlorinating agent is allowed to act on methylbenzonitrile [VI],
Step of converting into 3-dichloro-6-trifluoromethylbenzonitrile [IV] 3. The following (1), (2), (3) and (4)
2,3-dichloro-6-
A method for producing trifluoromethylbenzonitrile [IV]. (1) Step of brominating 2-chloro-5-trifluoromethylaniline [I] to give 2-bromo-6-chloro-3-trifluoromethylaniline [II] (2) Step of 2-bromo-6- Step of reacting chloro-3-trifluoromethylaniline [II] with cyanide to give 2-amino-3-chloro-6-trifluoromethylbenzonitrile [VII] (3) 2-amino-3-chloro -6-trifluoromethylbenzonitrile [VII] is oxidized to give 3-chloro-2
-Nitro-6-trifluoromethylbenzonitrile [V
(4) A chlorinating agent is allowed to act on 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] to give 2,3-dichloro-6-trifluoromethylbenzonitrile [VI]. IV] 4. The following (1), (2), (3) and (4)
2,3-difluoro-6, characterized by comprising the step of
-A method for producing trifluoromethylbenzonitrile [XII]. (1) Step of reacting 3-trifluoromethylaniline [VIII] with bromine to give 2,6-dibromo-3-trifluoromethylaniline [IX] (2) 2,6-dibromo-3-trifluoro Methylaniline [IX] was converted into a diazonium salt, and then reacted with cuprous chloride or cupric chloride to give 3-chloro-2,4-dichloromethane.
Step of converting into dibromobenzotrifluoride [X] (3) 3-bromo-2,4-dibromobenzotrifluoride [X] is reacted with cyanide to give 3-bromo-
Step of converting into 2-chloro-6-trifluoromethylbenzonitrile [XI] (4) A fluorinating agent is allowed to act on 3-bromo-2-chloro-6-trifluoromethylbenzonitrile [XVI],
Step of converting into 2,3-difluoro-6-trifluoromethylbenzonitrile [XII] 5. A process for producing 2,3-dichloro-6-trifluoromethylbenzonitrile [IV], comprising reacting 2,3,4-trichlorobenzotrifluoride [XIII] with cyanide. 6. A 3-chloro-2-fluoro-6 characterized by reacting 3-chloro-2-nitro-6-trifluoromethylbenzonitrile [VI] with a fluorinating agent.
-A process for producing trifluoromethylbenzonitrile [XIV]. 7. A method according to claim 1, wherein a fluorinating agent is allowed to act on 3-chloro-2-fluoro-6-trifluoromethylbenzonitrile [XIV]. ] The manufacturing method of. 8. A process for producing 2,3-difluoro-6-trifluoromethylbenzonitrile [XII], wherein cyanide is allowed to act on 2,3,4-trifluorobenzotrifluoride [XV]. . 9. A 2-bromo-6-chloro-3-trifluoromethylaniline 10. A 2-bromo-3,4-dichlorobenzotrifluoride 11. A 2-bromo-4-chloro-3-nitrobenzotrifluoride 12. 3-Chloro-2-nitro-6-trifluoromethylbenzonitrile 13. A 2-amino-3-chloro-6-trifluoromethylbenzonitrile 14. A 2,6-dibromo-3-trifluoromethylaniline 15. A 3-chloro-2,4-dibromobenzotrifluoride 16. Bromo-2-chloro-6-trifluoromethylbenzonitrile