JP2993877B2 - Method for producing halogen-containing aromatic nitrile compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the following general formula (II):

[0002]

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(Wherein X represents chlorine or bromine. Also, j, k, l, m and n are those wherein j and k are 0 to 3, l and n are 1 to 5 and m is 1 to 2 And l ≧ n, j + k + 1 +
It is an integer satisfying m = 6. However, at the same time, l = n,
k = 0. )) (Hereinafter also simply referred to as halogen-containing aromatic nitrile compound of the following general formula (II)) and the following general formula (III)

[0004]

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(Wherein, X represents chlorine or bromine; and j, k, l, m, n and s are those wherein j and k are 0 to 3,
l is 2 to 5, n and s are 1 to 4, m is 1 to 2, and 0 <
It is an integer that satisfies lns <3, j + k + 1 + m = 6. The present invention relates to a method for producing a halogen-containing aromatic nitrile compound represented by the following formula (hereinafter, also simply referred to as a halogen-containing aromatic nitrile compound of the following general formula (III)).

The above general formula (I) provided by the present invention
The halogen-containing aromatic nitrile compound (I) and the halogen-containing aromatic nitrile compound of the above general formula (III) are useful as starting materials for polymer materials, agricultural chemicals, pharmaceuticals, etc., and particularly useful as starting materials in pharmaceutical synthesis. is there.

[0007]

2. Description of the Related Art Among the halogen-containing aromatic nitrile compounds in the present invention, for example, a method for producing 3,5,6-trifluorophthalonitrile is disclosed in U.S. Pat.
No. 3,350. The method is 3,4
After dehalogenating 5,6-tetrachlorophthalonitrile at 60 ° C. for 5 minutes using zinc and sulfuric acid in a mixed solvent of tetrahydrofuran and water, 3,5,6-trichlorophthalonitrile is isolated. A halogen exchange reaction with potassium fluoride in tetramethylene sulfone at 185 ° C. for 6 hours to obtain 3,5,6-trifluorophthalonitrile. However, in the dehalogenation reaction of this method, the starting material 3,4,5,6-tetrachlorophthalonitrile is not dissolved in a solvent, and zinc is used in an excessive amount of three times the required amount. Therefore, there is a problem that the control of the reaction is very difficult. Also, as described in Reference Example 1 below, 3,6-dichlorophthalonitrile, in which the dehalogenation reaction has excessively proceeded, is produced in a considerably large amount, and the purity of the target product is reduced. Have. Furthermore, in order to carry out a halogen exchange reaction thereafter, it is necessary to once isolate 3,5,6-trichloronitrile and dissolve it again in a solvent,
There is also a problem that the manufacturing process becomes very complicated.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to solve the problems of the prior art such as difficulty in controlling the reaction, low purity, and complicated production steps. Which is industrially and simply represented by the above general formula (II)
And a method for producing the halogen-containing aromatic nitrile compound of the above general formula (III).

[0009]

The present invention can be achieved by the following dehalogenation reaction and halogen exchange reaction.

(1) Dehalogenation reaction That is, the object of the present invention is to provide the following general formula (I)

[0011]

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(Wherein X represents chlorine or bromine. Also, j, k, l and m are such that j and k are 0 to 3 and l is 1 to 3)
5, m is 1 or 2, and j + k + 1 + m = 6
Is an integer that satisfies (Hereinafter simply referred to as a compound of the general formula (I)) is reacted with a solid metal in a mixed solvent of water and a solvent which is in a two-phase state with water to react with a solid metal of the general formula (II). This is achieved by a method for producing a halogen-containing aromatic nitrile compound.

An object of the present invention is to provide a compound of the general formula (I)
X of the compound of the formula and the compound of the general formula (II) is chlorine,
This is achieved by a method for producing a halogen-containing aromatic nitrile compound of the general formula (II) wherein m is 2.

Further, an object of the present invention is that the compound of the general formula (I) is 3,4,5,6-tetrachlorophthalonitrile, and the halogen-containing aromatic nitrile compound of the general formula (II) is It is also achieved by a method for producing a halogen-containing aromatic nitrile compound of the general formula (II) which is 3,5,6-trichlorophthalonitrile.

Still another object of the present invention is to provide a compound represented by the general formula (I) wherein the solvent which is in a two-phase state with water is benzonitrile.
It is also achieved by the method for producing a halogen-containing aromatic nitrile compound of I).

(2) Halogen exchange reaction Another object of the present invention is to contain chlorine or bromine in the halogen-containing aromatic nitrile compound of the general formula (II) obtained by the dehalogenation reaction of the above (1). This is achieved by a method for producing a halogen-containing aromatic nitrile compound of the general formula (III) by heating the compound with a fluorinating agent in a solvent.

Further, an object of the present invention is to provide a compound represented by the above general formula (I)
The halogen-containing aromatic nitrile compound represented by the formula (I) and the solvent are obtained by separating water from the reaction mixture for producing the halogen-containing aromatic nitrile compound represented by the formula (II). Is also achieved by the method for producing a halogen-containing aromatic nitrile compound described above.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, an embodiment of the method for producing a halogen-containing aromatic nitrile compound according to the present invention will be described.
The embodiments will be described in detail separately for (1) a production method by a dehalogenation reaction and (2) a production method by a halogen exchange reaction.

(1) An embodiment in the case of a production method by a dehalogenation reaction will be described.

In the production method by the dehalogenation reaction, the compound of the general formula (I) is reacted with a solid metal in a mixed solvent of water and a solvent which is in a two-phase state with water, and contains the compound of the general formula (II). It is intended to obtain a halogen aromatic nitrile compound.

The compound of the general formula (I) used in the dehalogenation reaction of the above (1) includes, for example, 3,4,4
5,6-tetrachlorophthalonitrile, pentachlorobenzonitrile, 3,5-dichloro-2,4,6-trifluorobenzonitrile, 3,4,5,6-tetrabromophthalonitrile, pentabromobenzonitrile, and 3,5-dibromo-2,4,6-trifluorobenzonitrile and the like. Examples of the halogen-containing aromatic nitrile compound of the general formula (II) obtained by the dehalogenation reaction of the above (1) include, for example, 3,5,6-trichlorophthalonitrile, 2,3,5,6-tetra Examples include chlorobenzonitrile, 2,4,6-trifluorobenzonitrile, 3,5,6-tribromophthalonitrile, and 2,3,5,6-tetrabromobenzonitrile.

The solvent used in the dehalogenation reaction of the above (1) is a mixed solvent of water and a solvent which is in a two-phase state with water at room temperature or at the reaction temperature. By using a solvent which becomes a two-phase state with water as the solvent, the above-mentioned general formula (I)
Can be completely dissolved, the reaction can proceed uniformly, and the presence of an aqueous phase facilitates temperature control and control of the reaction. for that reason,
The reaction does not proceed excessively and the selectivity of the reaction is considerably improved.

The solvent capable of forming a two-phase state with water is one that can dissolve the compound of the above general formula (I) and the halogen-containing aromatic nitrile compound of the above general formula (II) which are the starting materials at room temperature or at the reaction temperature. If there is no problem, benzonitrile, toluene, xylene, methyl isobutyl ketone,
Diisopropyl ether, ethyl acetate and the like are preferred,
Particularly, benzonitrile is preferred. The amount of the solvent to be in a two-phase state with water is not particularly limited as long as it is an amount that dissolves the starting material, but usually 3 to 50 parts by weight based on 1 part by weight of the compound of the above general formula (I). And preferably 5 to 30 parts by weight. When the amount of the solvent used is small, the control of the reaction becomes difficult, and when the amount of the solvent used is large, the production efficiency decreases, which is not preferable. Although the amount of water used is not particularly limited, the compound 1 of the above general formula (I) is usually used.
It is preferable to use 1 to 50 parts by weight, preferably 5 to 30 parts by weight with respect to parts by weight. When the amount of water used is small, it is difficult to control the reaction, and when the amount of water used is large, the production efficiency decreases, which is not preferable. When used as the above-mentioned mixed solvent, as long as the respective components of the solvent and water which are in a two-phase state with water are appropriately blended within the above-described ranges,
The mixing ratio of both components is not particularly limited.

The solid metal used in the dehalogenation reaction of the above (1) may be a simple metal such as zinc, tin, iron, nickel and aluminum, and may be zinc amalgam,
Alloys such as tin amalgam, aluminum amalgam, and aluminum / nickel alloy may be used. Among these, it is preferable to use a simple metal, particularly zinc, from the viewpoint of availability and reactivity.

Since the amount of zinc used is theoretically one molecule of zinc required for dehalogenating one molecule of halogen, the halogen 1 in the compound of the above general formula (I) is used.
In order to dehalogenate a molecule, one molecule may be present, but usually 0.8 to 2.0 molecules, preferably 0.9 to 1.
It is preferable to have 5 molecules. In order to carry out a dehalogenation reaction of two molecules of halogen, twice the amount of zinc described above may be used. Note that, here, zinc, which is a preferred embodiment of the above solid metal, has been described.However, the same principle applies to other solid metals, and the amount of use suitable for each solid metal may be appropriately selected. good.

In the dehalogenation reaction (1), the reaction may be carried out by adding an inorganic acid, an organic acid, an inorganic salt, an organic salt or the like as a catalyst, although it is not particularly necessary to add it.
These may be used alone or as a mixture of two or more. By adding these, the reaction speed is increased and the reaction can be performed efficiently. As the catalyst to be added, examples of the inorganic acid include sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, and examples of the organic acid include:
Acetic acid, oxalic acid, benzoic acid, phthalic acid and the like,
Examples of the inorganic salt include ammonium sulfate, sodium sulfate, sodium hydrogen sulfate, potassium sulfate, potassium hydrogen sulfate, ammonium chloride, sodium chloride, potassium chloride, calcium chloride, barium chloride, ammonium nitrate, sodium nitrate, potassium nitrate, calcium nitrate, and barium nitrate. , Ammonium phosphate, ammonium monohydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, etc. Examples of the organic salt include, for example, ammonium acetate, sodium acetate, potassium acetate, ammonium citrate, ammonium hydrogen citrate, sodium citrate, sodium hydrogen citrate, potassium citrate, and citric acid. Potassium hydrogencarbonate, ammonium tartrate, ammonium hydrogen tartrate, sodium tartrate,
Sodium hydrogen tartrate, potassium tartrate, potassium bitartrate, ammonium phthalate, ammonium hydrogen phthalate, sodium phthalate, sodium hydrogen phthalate,
Potassium phthalate, potassium hydrogen phthalate and the like can be mentioned. Among these, it is preferable to use an inorganic acid, and it is particularly preferable to use sulfuric acid.

The catalyst is used in an amount of 0.01 to 10 mol, preferably 0.1 to 10 mol, per 1 mol of the compound of the formula (I), in the total amount of the inorganic acid, organic acid, inorganic salt and organic salt. ~ 5
It is preferable to use it in the molar range.

In the dehalogenation reaction (1), a phase transfer catalyst may be present in the reaction system. That is, the presence of the phase transfer catalyst has the advantage of increasing the reaction rate and shortening the reaction time.

As the phase transfer catalyst, for example, crown compounds such as dibenzo-18-crown-6-ether, quaternary ammonium salts such as tetrabutylammonium bromide, and phosphonium salts such as tetrabutylphosphonium bromide can be used.

The amount of the phase transfer catalyst to be added is suitably 0.01 to 0.25 mol per 1 mol of the compound of the formula (I).

The reaction temperature in the dehalogenation reaction of the above (1) can be usually carried out in the range of 40 to 180 ° C., preferably in the range of 60 to 160 ° C.
When the reaction temperature is high, problems such as difficulty in controlling the reaction and generation of by-products occur. If the reaction temperature is low, the reaction rate will decrease, and the productivity will deteriorate.

The reaction time in the dehalogenation reaction of the above (1) varies depending on the type and amount of the solid metal and catalyst used, the reaction temperature and the like, but can be usually from 0.25 to 12 hours.

After completion of the reaction, the reaction mixture is separated into two layers, an organic layer and an aqueous layer. When isolating the halogen-containing aromatic nitrile compound of the general formula (II), the aqueous layer can be removed and the organic layer can be evaporated to dryness.

(2) An embodiment in the case of a production method by a halogen exchange reaction will be described.

In the production method by the halogen exchange reaction, compounds containing chlorine and / or bromine among the halogen-containing aromatic nitrile compounds of the general formula (II) obtained by the production method by the dehalogenation reaction of the above (1) Is heated with a fluorinating agent in a solvent to obtain a halogen-containing aromatic nitrile compound of the general formula (III).

The halogen-containing aromatic nitrile compound of the general formula (II) used in the halogen exchange reaction of the above (2) is
Among the halogen-containing aromatic nitrile compounds of the general formula (II) obtained by the production method by the dehalogenation reaction of the above (1), any compounds containing chlorine or bromine may be used. Trichlorophthalonitrile, 2,3
5,6-tetrachlorobenzonitrile, 3,5,6-tribromophthalonitrile, and 2,3,5,6-tetrabromobenzonitrile and the like. And
General formula (III) obtained by halogen exchange reaction of (2)
Examples of the halogen-containing aromatic nitrile compound include, for example,
3,5,6-trifluorophthalonitrile, and 2,
3,5,6-tetrafluorobenzonitrile and the like.

The solvent used in the halogen exchange reaction of the above (2) is not particularly limited as long as the solvent can dissolve the halogen-containing aromatic nitrile compound of the general formula (II), but benzonitrile, sulfolane, Dimethylformamide, dimethylsulfoxide and the like are preferable. Among them, after the dehalogenation reaction of (1), a compound containing chlorine and / or bromine among the halogen-containing aromatic nitrile compounds of the general formula (II) is isolated from the reaction mixture. Instead, it is possible to use it for a halogen exchange reaction simply by performing a simple reaction operation such as separation of water, and the process is simplified. Therefore, among the halogen-containing aromatic nitrile compounds of the general formula (II), Water containing a compound containing chlorine and / or bromine and a two-phase mixture of water and water obtained by separating water from a mixed solvent of water and a solvent. The solvent to be state, specifically benzonitrile are especially preferred.

The amount of the solvent to be used is not particularly limited as long as it is at least as much as the starting material can be dissolved. However, it is usually 3 to 60 parts by weight based on 1 part by weight of the halogen-containing aromatic nitrile compound of the formula (II). It is good to use in the range of parts by weight, preferably in the range of 6 to 35 parts by weight. When the amount of the solvent used is small, it is difficult to control the reaction, and when the amount of the solvent used is large, the production efficiency decreases, which is not preferable.

The fluorinating agent used in the halogen exchange reaction of the above (2) is not particularly limited as long as it can perform a halogen exchange reaction. For example, fluorides of alkali metals such as sodium fluoride and potassium fluoride are used. Fluoride of alkaline earth metals such as calcium fluoride, barium fluoride and the like are used. Among these, it is preferable to use an alkali metal fluoride, and it is particularly preferable to use potassium fluoride. In the case of potassium fluoride, one molecule of potassium fluoride is required for one molecule of chlorine and / or bromine to be exchanged. It is preferably used in the range of 1 to 12 mol, and particularly preferably in the range of 1 to 8 mol, per 1 mol of the nitrile compound. Although potassium fluoride, which is a particularly preferred embodiment of the above fluorinating agent, has been described here, the same principle applies to other fluorinating agents. The amount may be appropriately selected.

The heating temperature at the time of the halogen exchange reaction (2) can be usually in the range of 120 to 400 ° C., preferably in the range of 150 to 300 ° C. If the heating temperature is high, carbides are generated and the yield is reduced. When the heating temperature is low, the reaction rate is reduced and productivity is deteriorated, and a compound in which chlorine and / or bromine to be exchanged are not completely substituted with fluorine tends to be produced, and the yield is reduced.

In the halogen exchange reaction (2), a phase transfer catalyst may be present in the reaction system. That is, the presence of the phase transfer catalyst has the advantage of increasing the reaction rate and shortening the reaction time. As the phase transfer catalyst,
For example, crown compounds such as dibenzo-18-crown-6-ether, polyethylene glycol having a molecular weight of 300 to 600, ammonium salts such as tetrabutylammonium bromide, and phosphonium salts such as tetrabutylphosphonium bromide can be used.

The amount of the phase transfer catalyst to be added is suitably from 0.01 to 0.25 mol per 1 mol of the halogen-containing aromatic nitrile compound of the general formula (II).

The reaction time of the halogen exchange reaction of the above (2) varies depending on the type and amount of the fluorinating agent, the heating temperature, the presence or absence of the phase transfer catalyst, and the like, but can usually be carried out for 2 to 48 hours.

After the completion of the halogen exchange reaction of the above (2), the inorganic salts of potassium chloride and sodium chloride by-produced in the reaction are separated by filtration, and then evaporated to dryness, distilled, and the like to obtain the compound of the above general formula (III). )) Can be obtained.

[0045]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1 10 g (37.6 mmol) of 3,4,5,6-tetrachlorophthalonitrile was added to benzonitrile 2 in a 500 ml three-necked flask equipped with a stirrer, a cooling reflux tube and a thermometer.
Dissolved in 00 ml. There, 3.18 g of zinc (48.
7 mmol), 50 ml of water and 3.84 g of concentrated sulfuric acid (3
(7.6 mmol) was added. Thereafter, the mixture was heated to 100 ° C. and reacted for 4 hours. After the completion of the reaction, the mixture was cooled, and the aqueous layer was separated by liquid separation. The obtained organic layer was evaporated to dryness to obtain 7.8 g of a product. Analysis by gas chromatography revealed that 3,4,5,6-tetrachlorophthalonitrile was 3.0%, 3,5,6-trichlorophthalonitrile was 79.1%, and 3,6-dichlorophthalonitrile. Was found to be 17.9%.

Example 2 10 g (37.6 mmol) of 3,4,5,6-tetrachlorophthalonitrile was added to benzonitrile 2 in a 500 ml three-necked flask equipped with a stirrer, a cooling reflux tube and a thermometer.
Dissolved in 00 ml. 2.7 g of zinc (41.3)
mmol), 50 ml of water and 7.68 g of concentrated sulfuric acid (7
5.2 mmol) was added. Thereafter, the mixture was heated to 100 ° C. and reacted for 4 hours. After the completion of the reaction, the mixture was cooled, and the aqueous layer was separated by liquid separation. The obtained organic layer was analyzed by gas chromatography to find that 3,4,5,6-tetrachlorophthalonitrile was 12.8%, 3,5,6-trichlorophthalonitrile was 79.4%, , 6-dichlorophthalonitrile was found to be 7.8%.

The obtained organic layer and 13 g of potassium fluoride (224 g) were placed in a 300 ml autoclave equipped with a stirrer.
mmol) and reacted at 250 ° C. for 10 hours.
After completion of the reaction, the solution was cooled, and the obtained solution was filtered and distilled to obtain 4.9 g of 3,5,6-trifluorophthalonitrile having a purity of 99.0%.

Example 3 10 g of pentachlorobenzonitrile (3 g) was placed in a 500 ml three-necked flask equipped with a stirrer, a cooling reflux tube and a thermometer.
6 mmol) were dissolved in 150 ml of benzonitrile.
There, 2.62 g (40 mmol) of zinc and 10 ml of water
And 3.53 g (36 mmol) of concentrated sulfuric acid were added. Thereafter, the mixture was heated to 80 ° C. and reacted for 6 hours. After the completion of the reaction, the mixture was cooled, and the aqueous layer was separated by liquid separation. When the obtained organic layer was analyzed by gas chromatography,
2,3,5,6-tetrachlorobenzonitrile is 83.
5% and 2,3,4,5-tetrachlorobenzonitrile were found to be 5.0%.

The obtained organic layer and 16.73 g of potassium fluoride were placed in a 300 ml autoclave equipped with a stirrer.
(288 mmol) and reacted at 200 ° C. for 8 hours. After completion of the reaction, the mixture was cooled, and the obtained solution was filtered and distilled to obtain 4.72 g of 2,3,5,6-tetrafluorobenzonitrile having a purity of 99.0%.

Example 4 10 g (44 mmol) of 3,5-dichloro-2,4,6-trifluorobenzonitrile was dissolved in 100 ml of benzonitrile in a 500 ml three-necked flask equipped with a stirrer, a cooling reflux tube and a thermometer. . There, 6.54 zinc
g (100 mmol), 20 ml of water and concentrated sulfuric acid.
77 g (120 mmol) were added. Then 130 ° C
And reacted for 3 hours. After the reaction, cool down
The aqueous layer was separated by liquid separation. When the obtained organic layer was analyzed by gas chromatography, it was found that 2,4,6-trifluorobenzonitrile was 95%.

Reference Example 1 In a 500 ml three-necked flask equipped with a stirrer, a cooling reflux tube, and a thermometer, 10 g (37.6 mmol) of 3,4,5,6-tetrachlorophthalonitrile, 250 ml of water, and 60 ml of tetrahydrofuran were added and mixed. did. There, 7.4 g (112.8 mmol) of zinc, 7.5 ml of concentrated sulfuric acid
Was added. Thereafter, the solution was stirred until the solution became homogeneous, and further reacted at 50 ° C. for 5 minutes. After completion of the reaction, the mixture is filtered,
Tetrahydrofuran was removed under reduced pressure. The resulting aqueous solution was extracted twice with 120 ml of dichloromethane. When the obtained organic layer was analyzed by gas chromatography, 3,4,5,6-tetrachlorophthalonitrile was 0% and 3,5,6-trichlorophthalonitrile was 6%.
0.3%, 3,5.6 dichlorophthalonitrile 35.6
%.

[0053]

According to the method for producing a halogen-containing aromatic nitrile compound of the present invention, there are problems that the prior art has, such as difficulty in controlling the reaction, low purity, and complicated production steps. This makes it possible to provide an industrial and simple method for producing a halogen-containing aromatic nitrile compound of the above general formula (II) and a halogen-containing aromatic nitrile compound of the above general formula (III). Things.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-61-22059 (JP, A) JP-A-64-71844 (JP, A) JP-A-2-154 (JP, A) JP-A-2- 115156 (JP, A) JP-A-2-117643 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 253/30 C07C 255/50-255/51

Claims (6)

(57) [Claims] 1. A compound represented by the following general formula (I) (Wherein, X represents chlorine or bromine; and j, k, l
And m are integers in which j and k are 0 to 3, l is 1 to 5, m is 1 or 2, and j + k + 1 + m = 6. ) Is reacted with a solid metal in a mixed solvent of water and a solvent that is in a two-phase state with water, characterized by the following general formula (II): (Wherein, X represents chlorine or bromine; and j, k,
l, m and n are such that j and k are from 0 to 3, l and n are from 1 to 5,
m is an integer satisfying 1 to 2 and satisfying l ≧ n and j + k + 1 + m = 6. However, it is not at the same time that l = n and k = 0. A method for producing a halogen-containing aromatic nitrile compound represented by the formula (1). 2. The compound of the general formula (I) and the compound of the general formula (II) wherein X is chlorine and m is 2.
The production method described in 1. 3. The compound of the general formula (I) is 3,4,4
3. The method according to claim 1, wherein the compound is 5,6-tetrachlorophthalonitrile, and the compound of the general formula (II) is 3,5,6-trichlorophthalonitrile. 4. The method according to claim 1, wherein the solvent which is in a two-phase state with water is benzonitrile. 5. A method for producing a compound containing chlorine and / or bromine among the halogen-containing aromatic nitrile compounds represented by the general formula (II) obtained in any one of claims 1 to 4, wherein the compound comprises fluorine in a solvent. The following general formula (III) characterized by heating with an agent: (Wherein, X represents chlorine or bromine; and j, k,
l, m, n and s are such that j and k are from 0 to 3, l is from 2 to 5,
n and s are 1-4, m is 1-2, and 0 <l-ns <
3, an integer satisfying j + k + 1 + m = 6. A method for producing a halogen-containing aromatic nitrile compound represented by the formula (1). 6. The method according to claim 1, wherein the halogen-containing aromatic nitrile compound represented by the general formula (II) and the solvent separate water from the reaction mixture for producing the halogen-containing aromatic nitrile compound represented by the general formula (II). The method according to claim 5, wherein