JPH0662498B2 - Method for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention is 2,3,5,6-tetrafluoro-4-, a compound useful as a starting material for polymer materials, liquid crystal materials, pharmaceuticals and agricultural chemicals. TECHNICAL FIELD The present invention relates to an improved method for safely and industrially producing a highly pure product by using hydroxybenzoic acid and pentafluorobenzoic acid as a starting material.

<Prior Art> The present inventors have already disclosed in JP-A-60-204742 that pentafluorobenzoic acid is mixed with an alkaline substance in an aqueous solution in an amount of 70-1.
The reaction was carried out at 00 ° C. to form a salt of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, and then 2,3,5
Add 5,6-tetrafluoro-4-hydroxybenzoate to p
Provided is a method for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, which comprises contacting with an acidic aqueous solution in the range of H2 to H6.

<Problems to be Solved by the Invention> However, according to the subsequent studies, this method is not suitable for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid on an industrial large scale. It turned out that it has the following problems.

That is, it is difficult to control the reaction temperature because of the exothermic reaction, and the bumping phenomenon occurs.

During the reaction, it becomes a whipped cream-like slurry, and the reaction product overflows outside the container due to foaming.

Toxic hydrogen fluoride is generated in the acid treatment process performed after the reaction.

Is.

Therefore, the object of the present invention is improved to solve the above problems and produce 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid from pentafluorobenzoic acid with high purity in a safe and industrial manner. To provide a method.

<Means for Solving Problems> As a result of intensive studies to achieve the above object, the present inventors have found that pentafluorobenzoic acid is neutralized with a necessary amount of an alkali salt substance to form an alkali salt of pentafluorobenzoic acid. And a hydroxylation step are separated into two steps.

In the hydroxylation reaction, a method of gradually dropping an aqueous solution of an alkaline substance into an aqueous medium containing an alkali salt of pentafluorobenzoic acid is adopted. From these two points, it becomes possible to control the reaction temperature and the bubbling phenomenon.

Preference is given to using sodium hydroxide and / or sodium carbonate as alkaline substance. The reason is,
Most of the fluorides generated by using these are not dissolved in water, and thus the fluorides can be separated from the reaction solution in advance by an excessive method or the like. Therefore, generation of a large amount of hydrogen fluoride can be prevented in the acid treatment step performed after the reaction.

The present invention has been completed based on the above findings.

That is, the present invention is a method for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid using pentafluorobenzoic acid as a starting material, and includes the following steps (a) to (d): And a method for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid.

(A) Pentafluorobenzoic acid is reacted with pentafluorobenzoic acid in an aqueous medium at a temperature range of 5 to 40 ° C. to react 0.7 to 1.3 mol of an alkaline substance per 1 mol of the pentafluorobenzoic acid. Neutralization step to obtain an alkali salt.

(B) In an aqueous medium containing the alkali salt of pentafluorobenzoic acid obtained in the step (a), 1.7 to 2.5 mol of sodium hydroxide and 1 mol of the alkali salt of pentafluorobenzoic acid, and / Or an aqueous solution of sodium carbonate is added dropwise, and an alkali salt of pentafluorobenzoic acid is reacted with sodium hydroxide and / or sodium carbonate within a temperature range of 70 to 95 ° C to give 2,3,5,6-tetrafluoro- A hydroxylation reaction step to obtain a dialkali salt of 4-hydroxybenzoic acid.

(C) A step of separating and removing sodium fluoride produced as a by-product from the aqueous solution containing the dialkali salt of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid obtained in the step (b).

(D) The dialkali salt of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid obtained in step (c) is adjusted to pH.
2,3,5,6 by contacting with an acidic aqueous solution in the range of 2 to 6
An acid treatment step to obtain tetrafluoro-4-hydroxybenzoic acid.

Hereinafter, specific embodiments of the present invention will be described.

In the present invention, as the first step, a neutralization reaction step of forming an alkaline salt of pentafluorobenzoic acid from pentafluorobenzoic acid and an alkaline substance in an aqueous medium is performed. As the alkaline substance, one which shows alkalinity in an aqueous solution of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide, or an alkali metal carbonate such as sodium carbonate or potassium carbonate. If so, either can be used.

The amount of the alkaline substance used is 0.7 to 1.3 parts by mole with respect to 1 part by mole of pentafluorobenzoic acid, and particularly preferably 0.9 to 1.1 parts by mole. . When added in a large amount, the exothermic reaction becomes remarkable, and the bubbling phenomenon easily occurs. When the amount is small, the exothermic reaction becomes remarkable in the next step, and the bubbling phenomenon easily occurs.

The neutralization reaction is performed in the temperature range of 5 to 40 ° C. If the reaction temperature is too high, an alkaline salt of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid is likely to be formed, and a bubbling phenomenon is likely to occur in the next step. Therefore, it is desirable to carry out the reaction at the lowest possible temperature.

When carrying out the neutralization operation, it is preferable to gradually drop the aqueous solution of the alkaline substance into the aqueous medium containing pentafluorobenzoic acid. The dropping rate is in the range of 0.3 to 1.0 part by mole of the alkaline substance per unit time with respect to 1 part by mole of pentafluorobenzoic acid, preferably 0.4 to 0.
A range of 8 parts by mole is preferred.

Next, in the present invention, as the second step, the alkali salt of pentafluorobenzoic acid obtained in the first step is reacted with sodium hydroxide and / or sodium carbonate to give 2,3,5,
A hydroxylation reaction step is performed which produces a dialkali salt of 6-tetrafluoro-4-hydroxybenzoic acid. The amount of sodium hydroxide and / or sodium carbonate used is in the range of 1.7 to 2.5 mole times per mole of the alkali salt of pentafluorobenzoic acid according to the following reaction formula, and particularly 1.9 to 2. It is preferable to add it in the range of 3 mol times.

(However, Me represents an alkali metal, and Me ′ represents a sodium metal.) At that time, an aqueous solution of sodium hydroxide and / or sodium carbonate was gradually added dropwise to an aqueous medium of an alkali salt of pentafluorobenzoic acid. It is good to add to As the dropping rate, sodium hydroxide and / or sodium carbonate per unit time is in the range of 0.1 to 0.6 part by mole, particularly 0.2 to 0.4, relative to 1 part by mole of the alkali salt of pentafluorobenzoic acid. It is preferable to do it in the molar range. When the dropping rate is high, it becomes difficult to control the reaction temperature, and the bubbling phenomenon easily occurs. If the dropping speed is slow, the productivity is deteriorated, which is not preferable. The reaction temperature in the hydroxylation reaction step is in the range of 70 to 95 ° C, particularly 75 to 95 ° C.
The range of 90 ° C is preferred. If the reaction temperature is high, 2, 3, 5,
A dialkali salt of tetrafluoroorthooxybenzoic acid, which is an isomer of a dialkali salt of 6-tetrafluoro-4-hydroxybenzoic acid, and an alkali salt of tetrafluorophenol in a decarboxylated form are easily produced,
The yield of the dialkali salt of 3,5,6-tetrafluoro-4-hydroxybenzoic acid decreases. When the reaction temperature is low, unreacted sodium hydroxide and / or sodium carbonate accumulates because the hydroxylation reaction becomes significantly slower than the dropping rate, and the reaction rapidly occurs at some point, making it difficult to control the reaction. .

Further, since sodium fluoride produced as a by-product in the hydroxylation reaction step produces toxic hydrogen fluoride in the subsequent acid treatment step, it is preferable to remove it from the reaction solution as much as possible after the completion of the hydroxylation reaction step. As a result of various investigations by the present inventors, if a method is adopted in which sodium hydroxide and / or sodium carbonate is used to carry out the hydroxylation reaction to separate and remove the hardly soluble sodium fluoride in by-product water from the reaction solution. , 2,3,5,6-tetrafluoro-
It has been found to be most advantageous throughout the process in the preparation of 4-hydroxybenzoic acid. That is, potassium hydroxide gives the highest yield among the alkaline substances used in the hydroxylation reaction step, but potassium fluoride, which is a by-product, has high solubility in water, so potassium fluoride is removed. Therefore, there are many inconveniences such as the need to take measures against hydrogen fluoride generation in the acid treatment step. In contrast, sodium hydroxide and /
Alternatively, when sodium carbonate is used, the yield of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid is slightly sacrificed, but steps such as measures for virtually eliminating hydrogen fluoride generation are not necessary. And has operational advantages.

For the above reason, in the present invention, sodium fluoride produced as a by-product is separated and removed as the third step.

Next, in the present invention, as the fourth step, the generated 2,3,5,6-
An acidic aqueous solution was added to an aqueous solution containing a tetraalkali-4-hydroxybenzoic acid dialkali salt so as to have a pH of 2 to 6, and so-called acid precipitation was performed to obtain 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid. Generate (acid treatment step). As the acid for preparing the acidic aqueous solution used at this time, any acid can be used as long as it can neutralize the above alkali salt. Among them, sulfuric acid or acid salt generally used for acid precipitation is suitable.

Separation of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, which has been acidified, is carried out using an extraction solvent such as ether, methylene chloride, benzene, toluene, etc. 6
-Tetrafluoro-4-hydroxybenzoic acid is extracted into the organic layer and the liquid is evaporated to dryness. The thus obtained 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid is a white highly pure substance.

Therefore, 2,3,5,6-obtained by the method of the present invention
Although tetrafluoro-4-hydroxybenzoic acid can be used as a product as it is, it can be further purified by a method such as recrystallization to obtain a higher purity product.

<Examples> Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 5.0 kg of pentafluorobenzoic acid (23.
6 mol) and 5.0 kg of water were charged. 2.46 kg (sodium hydroxide conversion; 23.6 mol) of a sodium hydroxide aqueous solution having a concentration of 38.5% by weight was added dropwise thereto at a rate of 1.23 kg / hr while maintaining the temperature at room temperature with stirring. To give pentafluorobenzoic acid sodium salt. After that, the temperature was raised to 85 ° C, and while maintaining the same temperature, 3
5.65 kg of sodium hydroxide having a concentration of 8.5% by weight (calculated as sodium hydroxide; 54.2 mol) was added dropwise at a rate of 0.71 kg / hr using a metering pump.

Next, the white sodium fluoride (dry weight equivalent; 90.1 g) that had precipitated after cooling was separated, and then 6.26 kg of a 44% by weight aqueous sulfuric acid solution was added dropwise to the solution to prepare 2,3,
5,6-Tetrafluoro-4-hydroxybenzoic acid was obtained. Isopropyl ether 20 was added to the obtained aqueous solution containing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid.
Was added, and 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid was extracted into the organic layer. This extraction procedure was repeated twice, and the obtained ether layer was evaporated to dryness to give white 2,3,
5,6-Tetrafluoro-4-hydroxybenzoic acid monohydrate 5.27 kg (relative to pentafluorobenzoic acid yield 97.5)
Mol%, purity 99.3%).

Claims (1)

[Claims] 1. A method for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid using pentafluorobenzoic acid as a starting material, which comprises the following steps (a) to (d): A method for producing 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, which is characterized in that (A) An alkali of pentafluorobenzoic acid obtained by reacting pentafluorobenzoic acid with 0.7 to 1.3 mol of an alkaline substance per 1 mol of the pentafluorobenzoic acid in an aqueous medium in a temperature range of 5 to 40 ° C. Neutralization step to obtain salt. (B) In an aqueous medium containing the alkali salt of pentafluorobenzoic acid obtained in the step (a), 1.7 to 2.5 mol of sodium hydroxide and 1 mol of the alkali salt of pentafluorobenzoic acid, and / Or an aqueous solution of sodium carbonate is added dropwise, and an alkali salt of pentafluorobenzoic acid is reacted with sodium hydroxide and / or sodium carbonate within a temperature range of 70 to 95 ° C to give 2,3,5,6-tetrafluoro- A hydroxylation reaction step to obtain a dialkali salt of 4-hydroxybenzoic acid. (C) A step of separating and removing sodium fluoride produced as a by-product from the aqueous solution containing the dialkali salt of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid obtained in the step (b). (D) The dialkali salt of 2,3,5,6-tetrafluoro-4-hydroxybenzoic acid obtained in step (c) is adjusted to pH.
2,3,5,6 by contacting with an acidic aqueous solution in the range of 2 to 6
An acid treatment step to obtain tetrafluoro-4-hydroxybenzoic acid.