JP3234838B2 - Method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel process for producing 2,4,5-trifluoro-3-hydroxybenzoic acid. 2,4,5- provided by the present invention
Trifluoro-3-hydroxybenzoic acid is a polymer material,
It is useful as a raw material in agrochemicals, pharmaceuticals, especially quinolone carboxylic acid antibacterial agents.

[0002]

2. Description of the Related Art A method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid is disclosed in JP-A-63-2644.
0, JP-A-63-264439, JP-A-1-268
662 and JP-A-3-127755.

[0003] All of these hydroxylate 3,4,5,6-tetrafluorophthalic acid to give 3,5,6-
In this method, trifluoro-4-hydroxyphthalic acid is obtained and then decarboxylated to produce 2,4,5-trifluoro-3-hydroxybenzoic acid.

[0004]

In the above-mentioned synthesis route, 3,4,5,6-tetrafluorophthalic acid is used as a starting material. It is an object of the present invention to provide a novel method for easily and inexpensively producing 2,4,5-trifluoro-3-hydroxybenzoic acid using a 5,6-tetrafluorophthalonitrile derivative.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have prepared, as a raw material, 3,5,6-trifluoro-4-hydroxyphthalonitrile obtained by hydroxylating 3,4,5,6-tetrafluorophthalonitrile. As a result of examining a method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid by hydrolysis and decarboxylation of
When hydroxylating 5,6-tetrafluorophthalonitrile, many 3-hydroxy isomers are generated, and 3,5,6-trifluoro-4-hydroxyphthalonitrile as a raw material can be obtained with high purity. In the end, it was found that there was a problem that the target product 2,4,5-trifluoro-3-hydroxybenzoic acid could not be obtained with high purity in high yield.

As a result of further studies, the present inventors have found that when 3,4,5,6-tetrafluorophthalonitrile is alkoxylated, 3,5,6-trifluoro-4-alkoxyphthalonitrile is selectively produced. When this compound is used as a starting material, 2,4,5-trifluoromethane can be obtained in one step without isolating various intermediates in decarboxylation, dealkylation, and hydrolysis. It has been found that -3-hydroxybenzoic acid can be produced with high yield and high purity. The present invention has been completed based on such findings.

That is, the present invention is characterized in that 3,5,6-trifluoro-4-alkoxyphthalonitrile is heated in an aqueous sulfuric acid solution,
This is a method for producing 3-hydroxybenzoic acid.

[0008]

DETAILED DESCRIPTION OF THE INVENTION 3,5,6-Trifluoro-4-alkoxyphthalonitrile used as a raw material in the present invention can be synthesized from 3,4,5,6-tetrafluorophthalonitrile (Journal of the Society of Synthetic Organic Chemistry, Vol. 29, No. 8, May
(1971) pp. 792-795). For example, 3,5,6-trifluoro-4-methoxyphthalonitrile is prepared by dissolving potassium hydroxide in a methanol solution in which 3,4,5,6-tetrafluorophthalonitrile is dissolved at a low temperature. It can be synthesized by dropping. Further, it can also be synthesized by using a base such as triethylamine or potassium fluoride instead of potassium hydroxide. Alternatively, it can be synthesized by using, for example, acetonitrile, DMF, or nitromethane instead of methanol.

The starting materials of the present invention, 3,5,6-trifluoro-4-alkoxyphthalonitrile, include:
3,5,6-trifluoro-4-methoxyphthalonitrile, 3,5,6-trifluoro-4-ethoxyphthalonitrile, 3,5,6-trifluoro-4-propoxyphthalonitrile, 3,5,6 And phthalonitrile having a lower alkoxy group such as -trifluoro-4-butoxyphthalonitrile. From the viewpoint of the simplicity of the reaction and the yield of the target product, use of 3,5,6-trifluoro-4-methoxyphthalonitrile is preferred.

The present invention relates to the hydrolysis of 3,5,6-trifluoro-4-alkoxyphthalonitrile in an aqueous sulfuric acid solution,
This is a method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid by performing a decarboxylation and dealkylation reaction in one step in a so-called one pot. As a result, the production process can be simplified, and the production cost can be reduced.

In the present invention, heating is performed in an aqueous sulfuric acid solution.
The concentration of sulfuric acid at this time is in the range of 40 to 80% by weight, preferably in the range of 50 to 70% by weight. If the sulfuric acid concentration is too low, the reaction rate of the dealkylation reaction is particularly lowered, which is not preferable. If the sulfuric acid concentration is too high, high boiling compounds and the like are by-produced and 2,4,5-trifluoro-3-
It is not preferable because the purity of hydroxybenzoic acid is deteriorated.

In the present invention, the reaction temperature is from 120 to 17
It is preferably carried out in the range of 0 ° C., particularly preferably 130 ° C.
It is good to carry out in the range of -150 ° C. If the reaction temperature is too high, a high-boiling point compound or the like is produced as a by-product to lower the purity. In the present invention, the reaction time is desirably in the range of 5 to 40 hours. The concentration of 3,5,6-trifluoro-4-alkoxyphthalonitrile in the aqueous sulfuric acid solution is 10 to 5 from the viewpoint of productivity.
A range of 0% by weight is desirable.

In the present invention, the reaction can be carried out with higher yield by reacting while removing the alcohol produced during the reaction to the outside of the system. As for the method, it may be continuously extracted under normal pressure or reduced pressure, or may be discontinuously extracted.
In the case of continuous withdrawal, the amount of alcohol withdrawn by the end of the reaction is from 3,5,6-trifluoro-4-alkoxyfuronitrile to 2,4,5-trifluoro-3-
When the conversion to hydroxybenzoic acid is 100%, this is 30% or more of the theoretical amount of alcohol produced, and it is preferable to continuously distill the alcohol within 5 to 40 hours. At that time, normal water can also be distilled off together, and a considerable amount of the distilled water is preferably added to the reaction system as needed in order to maintain the sulfuric acid concentration. In addition, in the case of discontinuous extraction, 2,5,6-trifluoro-4-alkoxyphthalonitrile can be
30% of the theoretical amount of alcohol formed when the conversion to 4,5-trifluoro-3-hydroxybenzoic acid is 100%.
% Or more of the alcohol is distilled off in the middle of the reaction one to several times during 15 to 40 hours, and the reaction is preferably continued for 5 to 20 hours. At that time, water can also be distilled off when distilling off the alcohol in the same manner as in the continuous case, and a considerable amount of the water distilled off at this time is added to the reaction system as necessary to maintain the sulfuric acid concentration. It is preferable to add.

In the present invention, the reaction of dealkylation occurs simultaneously. In the present invention, a dealkylating agent which is usually used for promoting this reaction can be added. For example, Lewis acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoroacetic acid and the like can be mentioned. After cooling the reaction product thus obtained, the target product can be isolated by a method such as filtration, dilution if necessary, extraction, and evaporation to dryness.

Hereinafter, the production method of the present invention will be specifically described with reference to examples.

[0016]

EXAMPLE 1 A 100 ml four-necked flask was charged with 5 g (23.6 mmol) of 3,5,6-trifluoro-4-methoxyphthalonitrile and 25 g of a 70% by weight aqueous sulfuric acid solution, and stirred.
It was kept at 40 ° C. for 30 hours. After cooling, the mixture was poured into 50 g of water, extracted with ethyl acetate, washed with water, dried, evaporated to dryness, and 4.1 g of light brown 2,4,5-trifluoro-3-hydroxybenzoic acid (versus 3,5,5). 6-trifluoro-4-methoxyphthalonitrile yield 90%) was obtained (GC-MASS).
M / e 192 (M ⁺ ), purity 90%).

Example 2 5 g (23.6 mmol) of 3,5,6-trifluoro-4-methoxyphthalonitrile and 25 g of a 55% by weight sulfuric acid aqueous solution were charged into a 100 ml four-necked flask, and stirred under stirring.
It was kept at 30 ° C. for 40 hours. After cooling, the mixture was poured into 50 g of water, extracted with ethyl acetate, washed with water, dried, evaporated to dryness, and 4.1 g of light brown 2,4,5-trifluoro-3-hydroxybenzoic acid (vs. 3,5,5). A 90% yield of 6-trifluoro-4-methoxyphthalonitrile was obtained (m / e 192 (M ⁺ ) by GC-MASS, purity 89%).

Example 3 5 g (23.6 mmol) of 3,5,6-trifluoro-4-methoxyphthalonitrile and 25 g of a 60% by weight sulfuric acid aqueous solution were charged into a 100 ml four-necked flask, and stirred under stirring.
It was kept at 40 ° C. for 30 hours. After cooling, the mixture was poured into 50 g of water, extracted with ethyl acetate, washed with water, dried, evaporated to dryness, and 4.1 g of light brown 2,4,5-trifluoro-3-hydroxybenzoic acid (vs. 3,5,5). A 6-trifluoro-4-methoxyphthalonitrile yield of 91% was obtained (m / e 192 (M ⁺ ) by GC-MASS, purity 91%).

Example 4 5 g (23.6 mmol) of 3,5,6-trifluoro-4-methoxyphthalonitrile and 25 g of a 70% by weight aqueous sulfuric acid solution were charged into a 100 ml four-necked flask, and stirred under stirring.
It was kept at 40 ° C. for 15 hours. Further reduce the pressure of the reactor to 1
While maintaining the temperature at 40 ° C., about 3 ml of methanol and water were extracted. 0.6 ml of methanol in this was 60% of the theoretical amount.
%. Then, after adding 2.4 ml of water, 140
The reaction was performed at 15 ° C. for 15 hours. After cooling, the mixture was poured into 50 g of water, extracted with ethyl acetate, washed with water, dried, evaporated to dryness, and light brown 2,4,5-trifluoro-3-hydroxybenzoic acid.
5 g (based on 3,5,6-trifluoro-4-methoxyphthalonitrile, 97% yield) were obtained by GC-MASS.
m / e 192 (M ⁺ ), purity 98.5%).

Example 5 A 100 ml four-necked flask was charged with 5 g (23.6 mmol) of 3,5,6-trifluoro-4-methoxyphthalonitrile and 25 g of a 60% by weight aqueous sulfuric acid solution, and stirred.
Water was continuously extracted together with methanol at normal pressure while the reaction was maintained at 40 ° C., and then a total of 3 ml was extracted in 15 hours. The amount of methanol in the extracted methanol-water mixed solution was 0.7 ml. This corresponds to 78% of the theoretically produced methanol. 2.3 ml of water was added thereto, and the mixture was further cooled at 140 ° C. for 5 hours, filtered, and the crystals were poured into 10 g of water, extracted with ethyl acetate, washed with water, dried, evaporated to dryness, and dried to give a light brown 2,4. , 5-trifluoro-3
-Hydroxybenzoic acid (4.4 g, based on 3,5,6-trifluoro-4-methoxyphthalonitrile 96%) was obtained (m / e 192 (M ⁺ ) by GC-MASS, purity 98).
%).

[0021]

The 3,5,6-trifluoro-4 of the present invention
According to the method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid, wherein the alkoxyphthalonitrile is heated in an aqueous sulfuric acid solution, the 3,5,6-trifluoro-4-alkoxyphthaloyl Hydrolysis of nitriles,
Since the decarboxylation and dealkylation reactions can be performed in a single step, so-called one pot, the production process can be simplified and the production cost can be reduced. Further, according to the method of the present invention, 2,4,5-trifluoro-3-hydroxybenzoic acid can be produced with high purity and high yield.

Further, the reaction can be carried out with higher yield by removing the alcohol produced during the reaction to the outside of the system.

Continuation of the front page (56) References JP-A-64-6235 (JP, A) JP-A-63-264440 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 51 / 08 C07C 65/03

Claims (2)

(57) [Claims] 1. A method for producing 2,4,5-trifluoro-3-hydroxybenzoic acid, comprising heating 3,5,6-trifluoro-4-alkoxyphthalonitrile in an aqueous sulfuric acid solution. 2. The method according to claim 1, wherein the reaction is carried out while removing the produced alcohol to the outside of the reaction system.