JPH08217740A - Production of fluoroaromatic amino compound - Google Patents

Abstract

PURPOSE: To easily, efficiently obtain, in high yield and purity with easy removal of byproduct NH4 F, the subject compound useful as a starting material for e.g. medicines/agrochemicals, by reaction between a specific fluoroaromatic nitrile compound and ammonia in a water-organic solvent two-phase state. CONSTITUTION: In a two-phase state using water and such an organic solvent as to form two-phase state with water (e.g. an aliphatic ester such as ethyl acetate, ketone such as methyl isobutyl ketone, benzonitrile), (A) a compound of formula I (n is 1 or 2) (e.g. pentafluorobenzonitrile) is reacted with (B) ammonia to obtain the objective compound of formula II (m is 1 or 2) (e.g. 4- amino-2,3,5,6-tetrafluorobenzonitrile). It is preferable that the reaction be conducted in the presence of a phase-transfer catalyst at <=70 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a fluorine-containing aromatic amino compound represented by the following general formula (II).

General formula (II):

[0003]

Embedded image

(Where n is 1 or 2 and m is 1 or 2
Is. The fluorine-containing aromatic amino compound provided by the present invention is useful as a starting material for polymer materials, agricultural chemicals, pharmaceuticals, and the like, and is particularly useful as a starting material in pharmaceutical synthesis.

[0005]

2. Description of the Related Art Among the fluorine-containing aromatic amino compounds in the present invention, for example, a method for producing 4-amino-2,3,5,6-tetrafluorobenzonitrile is described in J.
Chem. Soc. (C), p. 1345 (1971)
To J. M. Birchall et al. Describe a method in which pentafluorobenzonitrile and an aqueous ammonia solution are heated to 60 ° C. in a sealed tube to obtain 4-amino-2,3,5,6-tetrafluorobenzonitrile. However, this method has a low yield of 70% and is not sufficient for industrial use.

The method for producing 4-amino-3,5,6-trifluorophthalonitrile is described in Journal of Synthetic Organic Chemistry, Vol. 29, No. 8, p. 794 (1971).
Ishikawa et al. Reacted tetrafluorophthalonitrile at 0 ° C. in a mixed solvent of aqueous ammonia and acetonitrile,
A method for obtaining amino-3,5,6-trifluorophthalonitrile has been described and is also described in Journal of Chemical Society [J. Chem. Soc. (C)],
p. 456 (1970). M. Birchall et al. Describe a method in which tetrafluorophthalonitrile is reacted in a mixed solvent of aqueous ammonia and dioxane at a reflux temperature to obtain 4-amino-3,5,6-trifluorophthalonitrile. However, J. M. Birchall
These methods have a problem that the yield is low and it is difficult to adopt as a method for carrying out on an industrial scale.

Further, as a problem common to the above-mentioned methods, when it is attempted to remove the by-product ammonium fluoride, the product is once dissolved in a poorly water-soluble organic solvent and then washed with water. However, there is a problem that the purification method becomes very complicated.

[0008]

The object of the present invention is to solve the problems of the prior art, such as low yield and complicated purification method, and it is industrial and simple. The present invention provides a method for producing a fluorine-containing aromatic amino compound represented by the general formula (II).

Another object of the present invention is that when used in various applications while ammonium fluoride in the fluorine-containing aromatic amino compound remains above a certain level, depending on the purpose, hydrofluoric acid may be generated and cause corrosion. Since it is necessary to remove ammonium fluoride easily and easily, a method for removing the ammonium fluoride is provided.

[0010]

The present invention has the following general formula (I):

[0011]

[Chemical 4]

A fluorine-containing aromatic nitrile compound represented by the formula (wherein n is 1 or 2) is reacted with ammonia and the following general formula (II):

[0013]

Embedded image

(Where n is 1 or 2 and m is 1 or 2)
Is. ) In producing a fluorine-containing aromatic amino compound represented by the formula (1), a reaction is carried out in a two-phase state using water and an organic solvent which is in a two-phase state with water. The present invention relates to a manufacturing method.

That is, according to the method of the present invention, when a fluorine-containing aromatic nitrile compound is reacted with ammonia to produce a fluorine-containing aromatic amino compound, water and an organic solvent which is in a two-phase state with water are used. By carrying out the reaction in a phase state, after the reaction is completed, the organic solvent layer is separated from the aqueous layer,
A fluorinated aromatic amino compound can be easily obtained. Further, ammonium fluoride produced as a by-product can be easily removed by performing a series of separation operations in which water is newly added to the organic solvent layer separated from the aqueous layer and washing is performed.

In the method for producing a fluorine-containing aromatic amino compound by reacting a fluorine-containing aromatic nitrile compound with ammonia, for example, when the fluorine-containing aromatic nitrile compound is a liquid, when it is reacted with an aqueous ammonia solution, it is newly added with water. A biphasic reaction can be achieved without adding an organic solvent that produces a biphasic state. However, since the fluorine-containing aromatic amino compound obtained by the reaction of the liquid fluorine-containing aromatic nitrile compound and the aqueous ammonia solution is usually a solid at room temperature, after the reaction is completed, the by-product ammonium fluoride is removed by washing with water. In order to do so, it is necessary to use an organic solvent that can dissolve the resulting fluorine-containing aromatic amino compound. Although it is possible to use a fluorine-containing aromatic nitrile compound as an organic solvent that is in a two-phase state with water, from the viewpoint of dissolving the product, a large excess of raw materials with respect to ammonia is present in the reaction system. Therefore, there is a drawback that the selectivity of the reaction is lowered. Therefore, as in the method of the present invention, even when the fluorinated aromatic nitrile compound is a liquid, it is necessary to use an organic solvent that is inactive to ammonia and is in a two-phase state with water as a reaction solvent.

The fluorine-containing aromatic nitrile compound used in the present invention includes pentafluorobenzonitrile, 3,
4,5,6-tetrafluorophthalonitrile, 2,4
5,6-Tetrafluoroisophthalonitrile, etc., and 4-amino-2,3,5,6 represented by a fluorine-containing aromatic amino compound by reacting with ammonia.
-Tetrafluorobenzonitrile, 2-amino-3,
4,5,6-tetrafluorobenzonitrile, 4-amino-3,5,6-trifluorophthalonitrile, 4-amino-2,5,6-trifluoroisophthalonitrile,
2,4-diamino-3,5,6-trifluorobenzonitrile and the like can be obtained.

Examples of ammonia used in the present invention include aqueous ammonia and ammonia.

The water used in the present invention includes water and an aqueous ammonia solution.

The organic solvent used in the reaction of the present invention which is in a two-phase state with water is in a two-phase state with water when a fluorine-containing aromatic nitrile compound is reacted with ammonia to produce a fluorine-containing aromatic amino compound. It is a thing.

The organic solvent used in the reaction of the present invention which is in a two-phase state with water is an organic solvent which is inert to ammonia, a fluorine-containing aromatic nitrile compound and a fluorine-containing aromatic amino compound and is in a two-phase state with water. There is no particular limitation as long as it is an organic solvent having a solubility of 15% by weight or less of water at 20 ° C., and particularly preferably 20 ° C.
The water is an organic solvent having a solubility of 10% by weight or less.
It is preferable to use at least one selected from the group consisting of fatty acid esters, ketones and benzonitriles. As the fatty acid ester, for example, ethyl acetate or isopropyl acetate may be used. As the ketones, for example, methyl isopropyl ketone or methyl isobutyl ketone may be used. Benzonitrile is preferably used, for example, as benzonitrile. These may be used alone, or two or more kinds may be mixed and used.

In the present invention, the concentration of the fluorinated aromatic nitrile compound relative to the organic solvent that forms a two-phase state with water is
It depends on the organic solvent and type used, but usually 1 to
The reaction can be carried out at a concentration of 70% by weight, in particular 3-5
It is preferred to carry out the reaction at a concentration of 0% by weight. When the concentration is low, the productivity is lowered, and when the concentration is high, it becomes difficult to control the reaction.

In the present invention, the ratio of the fluorinated aromatic nitrile compound to ammonia is represented by the following general formula (II):

[0024]

[Chemical 6]

(Where n is 1 or 2 and m is 1 or 2)
Is. ) M of the fluorine-containing aromatic amino compound represented by
In order to obtain a monoamino compound in which 1 is 1, it is usually necessary to use at least 2 parts by mole of ammonia with respect to 1 part by mole of the fluorine-containing aromatic nitrile compound, and the diamino compound in which m of the fluorine-containing aromatic amino compound is 2. To obtain the above, it is usually necessary to use at least 4 parts by mole of ammonia per 1 part by mole of the fluorine-containing aromatic nitrile compound. The upper limit of the ratio of ammonia used is not particularly limited, but from the viewpoint of reaction selectivity, economic efficiency, etc.,
The ratio of the fluorinated aromatic nitrile compound and ammonia is
When obtaining the monoamino compound, it is preferable to use 2 to 20 parts by mole of ammonia per 1 part by mole of the fluorine-containing aromatic nitrile compound, and when obtaining the diamino compound, the fluorine-containing aromatic nitrile compound. It is preferable to use 4 to 40 parts by mole of ammonia with respect to 1 part by mole.

In the method for producing a fluorine-containing aromatic amino compound by reacting the fluorine-containing aromatic nitrile compound of the present invention with ammonia, a phase transfer catalyst can be used during the reaction. By using the phase transfer catalyst, the reaction rate can be increased and the target product can be efficiently produced. Phase transfer catalysts include, but are not limited to, quaternary ammonium salts, quaternary phosphonium salts and crown ethers. For example, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, triethylbenzyl chloride, dodecylpyridinium chloride, tetrabutylphosphonium chloride, tetra Butylphosphonium bromide, 12-crown-4, dibenzo-
18-crown-6, dicyclohexyl-18-crown-6 and the like can be mentioned. Preferably, tetraethylammonium bromide and tetrabutylammonium bromide are used.

The phase transfer catalyst used in the reaction in the present invention may be used alone or in combination of two or more. The amount of the phase transfer catalyst used in the reaction is not particularly limited, but 0.1 to 10 parts by weight of the phase transfer catalyst is preferably used with respect to 100 parts by weight of the fluorine-containing aromatic nitrile compound.

In the present invention, if the reaction temperature is such that the concentration of ammonia in the reaction solution is usually below the saturation concentration, the reaction can be carried out without problems, and the reaction temperature is below 70 ° C.
In particular, it can be performed in the range of 55 ° C or lower.

In the present invention, the reaction time depends on the type of the fluorine-containing aromatic nitrile compound used in the reaction, the type and amount of the organic solvent which forms a two-phase state with water, the presence or absence of a phase transfer catalyst, the reaction temperature, etc. Determined, but usually 1-24
It can be done in a range of times.

After completion of the reaction, the organic solvent layer of the reaction solution is separated, and then, as a washing step, water is added to the organic solvent layer and washed with
Ammonium fluoride can be easily removed by performing an operation such as liquid separation. The number of times of washing depends on the type and amount of the organic solvent used in the reaction, the amount of water to be washed, the amount of ammonium fluoride allowed in the fluorinated aromatic amino compound after evaporation to dryness, and the like. Normally, the ammonium fluoride remaining in the organic matter contained in the fluorine-containing aromatic amino compound is 100 ppm as the fluorine ion concentration.
Hereinafter, it is desirable to operate so that the concentration becomes 30 ppm or less. After completion of the washing step, the desired fluorine-containing aromatic amino compound represented by the general formula (II) can be obtained by evaporating the organic solvent layer to dryness.

[0031]

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

Example 1 10 g (0.052 mol) of pentafluorobenzonitrile, 0.1 g of tetraethylammonium bromide and 0.1 g of isopropyl acetate [water were placed in a 100 ml four-necked flask equipped with a stirrer, a cooling reflux tube, a thermometer and a dropping device. Solubility of 1.9% by weight (20 ° C.)]
The mixture was stirred at 25 ° C. and 8.5 g of 28% by weight aqueous ammonia (N
(H3 0.14 mol) was added from a dropping device to give 25
The reaction was carried out at 0 ° C for 4 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, water 20 is added to the organic layer.
g was added, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. It was confirmed that the concentration of fluorine ions contained in the organic layer was 30 ppm or less in terms of the measured value of fluorine ions contained in the final water washing liquid. The obtained organic layer was evaporated to dryness to obtain 9.5 g of 4-amino-2,3,5,6-tetrafluorobenzonitrile (yield 96.5 mol% based on pentafluorobenzonitrile, purity 97). .5
%).

Example 2 Using the same apparatus as in Example 1, 10 g (0.052 mol) of pentafluorobenzonitrile, 0.5 g of tetraethylammonium bromide and methyl isobutyl ketone [solubility of water 1.8 to 2.2% by weight]. (20 ° C)] 5
0 g was added, and the mixture was stirred at 5 ° C., 8.5 g of 28% by weight aqueous ammonia (0.14 mol as NH 3) was added from a dropping device, and the mixture was reacted at 5 ° C. for 6 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 15 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. The concentration of fluorine ions contained in the organic layer is 30 pp converted from the measured value of fluorine ions contained in the final water washing liquid.
It was confirmed that it was m or less. The obtained organic layer was evaporated to dryness to obtain 9.4 g of 4-amino-2,3,5,6-tetrafluorobenzonitrile (yield 95.5 mol% based on pentafluorobenzonitrile, purity 9).
7.3%).

Example 3 Using the same apparatus as in Example 1, 10 g (0.052 mol) of pentafluorobenzonitrile, 0.3 g of tetrabutylammonium bromide and 90 g of benzonitrile [solubility of water 1% by weight (20 ° C.)] Was added, and the mixture was stirred at 50 ° C., 8.5 g of 28% by weight aqueous ammonia (0.14 mol as NH 3) and 100 g of water were added from a dropping device, and the mixture was reacted at 50 ° C. for 2 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. The concentration of fluorine ions contained in the organic layer is 30 ppm calculated from the measured value of the fluorine ions contained in the final water washing liquid.
The following was confirmed. The obtained organic layer was evaporated to dryness to obtain 9.4 g of 4-amino-2,3,5,6-tetrafluorobenzonitrile (yield 95.5 mol% based on pentafluorobenzonitrile, purity 9).
7.4%).

Example 4 Using the same apparatus as in Example 1, 10 g (0.052 mol) of pentafluorobenzonitrile and 70 g of ethyl acetate [solubility of water 3.6% by weight (room temperature)] were added, and 2
The mixture was stirred at 5 ° C, and 8.5 g of 28 wt% ammonia water (NH
(0.14 mol as 3) and 10 g of water were added from a dropping device and reacted at 25 ° C. for 6 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. The concentration of fluorine ions contained in the organic layer is 30 p calculated from the measured value of the fluorine ions contained in the final water washing liquid.
It was confirmed to be pm or less. By evaporating the obtained organic layer to dryness, 4-amino-2,3,5,6-
9.2 g of tetrafluorobenzonitrile was obtained (yield of 93.4 mol% based on pentafluorobenzonitrile, purity 97.0%).

Example 5 Using the same apparatus as in Example 1, 10 g (0.050 mol) of 3,4,5,6-tetrafluorophthalonitrile,
Tetraethylammonium bromide (0.2 g) and isopropyl acetate (70 g) were added, and the mixture was stirred at 15 ° C., and 28% by weight aqueous ammonia (6.7 g, 0.13 mol as NH 3) was added.
1) was added from a dropping device and reacted at 15 ° C. for 4 hours.
After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. The fluorine ion concentration contained in the organic layer is
It was confirmed from the measured value of the fluorine ion contained in the final water washing liquid that it was 30 ppm or less. The resulting organic layer was evaporated to dryness to give 4-amino-
9.7 g of 3,5,6-trifluorophthalonitrile was obtained (yield to tetrafluorophthalonitrile: 98.5 mo)
1%, purity 97.4%).

Example 6 Using the same apparatus as in Example 1, 10 g (0.050 mol) of 3,4,5,6-tetrafluorophthalonitrile,
0.5 g of tetrabutylammonium bromide and 70 g of methyl isopropyl ketone were added and stirred at 50 ° C., 6.7 g of 28% by weight ammonia water (0.11 mol as NH3) and 50 g of water were added from a dropping device,
The reaction was carried out at 50 ° C for 3 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated.
Then, the washing step was performed twice more. It was confirmed that the concentration of fluorine ions contained in the organic layer was 30 ppm or less in terms of the measured value of fluorine ions contained in the final water washing liquid. The obtained organic layer was evaporated to dryness to obtain 9.6 g of 4-amino-3,5,6-trifluorophthalonitrile (yield 97.5 mol% based on tetrafluorophthalonitrile, purity 97.2). %).

Example 7 Using the same apparatus as in Example 1, 10 g (0.050 mol) of 3,4,5,6-tetrafluorophthalonitrile,
Tetraethylammonium bromide (0.1 g) and benzonitrile (90 g) were added, and the mixture was stirred at 25 ° C., and 6.7 g of 28% by weight ammonia water (0.13 mol as NH 3) was added.
1) was added from a dropping device, and the mixture was reacted at 25 ° C. for 4 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. It was confirmed that the concentration of fluorine ions contained in the organic layer was 30 ppm or less in terms of the measured value of fluorine ions contained in the final water washing liquid. The resulting organic layer was evaporated to dryness to give 4-amino-
9.5 g of 3,5,6-trifluorophthalonitrile was obtained (yield to tetrafluorophthalonitrile: 96.4 mo).
1%, purity 97.3%).

Example 8 Using the same apparatus as in Example 1, 10 g (0.050 mol) of 3,4,5,6-tetrafluorophthalonitrile and 90 g of isopropyl acetate were added and stirred at 25 ° C.
6.7 g of 28% by weight ammonia water (0.1% as NH3)
1 mol) was added from a dropping device and reacted at 25 ° C. for 4 hours. After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. It was confirmed that the concentration of fluorine ions contained in the organic layer was 30 ppm or less in terms of the measured value of fluorine ions contained in the final water washing liquid. The resulting organic layer was evaporated to dryness to give 4-amino-3,5,6-trifluorophthalonitrile 9.5.
g was obtained (yield to tetrafluorophthalonitrile: 96.
4 mol%, purity 97.2%).

Example 9 Using the same apparatus as in Example 1, 10 g (0.052 mol) of pentafluorobenzonitrile, 0.1 g of tetraethylammonium bromide and 7 of isopropyl acetate were used.
0 g was added and the mixture was stirred at 55 ° C., 17.0 g of 28% by weight aqueous ammonia (0.28 mol as NH 3) and water 2
0 g was added from a dropping device and reacted at 55 ° C. for 4 hours.
After completion of the reaction, the organic layer was separated by liquid separation. Then, as a washing step, 20 g of water was added to the organic layer, and the mixture was sufficiently stirred and allowed to stand, and then the organic layer was separated. Then, the washing step was performed twice more. The fluorine ion concentration contained in the organic layer is
It was confirmed from the measured value of the fluorine ion contained in the final water washing liquid that it was 30 ppm or less. The obtained organic layer was evaporated to dryness to obtain 9.3 g of a fluorine-containing aromatic amino compound. As a result of analysis by gas chromatography, 88% by weight of 4-amino-2,3,5,6-tetrafluorobenzonitrile and 1% of 2,4-diamino-3,5,6-trifluorobenzonitrile were obtained.
It produced 0% by weight.

[0041]

According to the method of the present invention, when a fluorine-containing aromatic nitrile compound is reacted with ammonia to produce a fluorine-containing aromatic amino compound, water and an organic solvent which is in a two-phase state with water are used. By carrying out the reaction in a two-phase state, after the reaction is completed, the organic solvent layer is separated from the aqueous layer, and a series of separation operations of newly adding water and washing with water is carried out to easily produce by-product ammonium fluoride. It can be removed, and the fluorine-containing aromatic amino compound can be easily obtained with high yield, high purity and efficiency.

Claims (7)

[Claims] 1. General formula (I): (In the formula, n is 1 or 2.) A fluorine-containing aromatic nitrile compound represented by the formula is reacted with ammonia to give a compound represented by the general formula (II): (In the formula, n is 1 or 2, and m is 1 or 2.) When the fluorine-containing aromatic amino compound represented by the formula (2) is produced, water and an organic solvent that is in a two-phase state with water A method for producing a fluorine-containing aromatic amino compound, which comprises reacting in a phase state. 2. The production of a fluorine-containing aromatic amino compound according to claim 1, wherein the organic solvent which is in a two-phase state with water is at least one selected from the group consisting of fatty acid esters, ketones and benzonitriles. Method. 3. The method for producing a fluorine-containing aromatic amino compound according to claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst. 4. The reaction temperature is 70 ° C. or lower.
5. The method for producing a fluorinated aromatic amino compound according to any one of 1. 5. The fluorine-containing aromatic nitrile compound is pentafluorobenzonitrile, and the fluorine-containing aromatic amino compound is 4-amino-2,3,5,6-tetrafluorobenzonitrile. The method for producing a fluorine-containing aromatic amino compound described in. 6. The fluorine-containing aromatic nitrile compound is 3,4.
The fluorine-containing aromatic amino compound according to any one of claims 1 to 4, wherein the 5,6-tetrafluorophthalonitrile and the fluorine-containing aromatic amino compound are 4-amino-3,5,6-trifluorophthalonitrile. Production method. 7. The method for producing a fluorine-containing aromatic amino compound according to claim 1, wherein after the reaction, the organic solvent layer is separated from the aqueous layer, and water is newly added to wash with water.