JP2000128827A - Production of hydroxybenzoic acid compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a hydroxybenzoic acid compound, capable of obtaining the hydroxybenzoic acid compound in a short time in a high yield and in simple operations. SOLUTION: This method for producing a hydroxybenzoic acid compound comprises subjecting an aminobenzoic acid compound as a raw material to a diazotization-hydrolysis reaction. Therein, an diazotizing agent is added to a mixture of the aminobenzoic acid compound, an acid and water in a range of 40 deg.C to the refluxing temperature of the reaction solution, thus obtaining the hydroxybenzoic acid compound in a short time and at a high yield.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for efficiently producing hydroxybenzoic acids which are useful as raw materials for producing pharmaceuticals, agricultural chemicals and the like by diazotization-hydrolysis of aminobenzoic acids in a short time.

[0002]

2. Description of the Related Art It is generally well known to use a diazotization-hydrolysis reaction as a method for producing phenols from an aromatic amine as a raw material. For example, from m-nitroaniline to m-nitrophenol (Org. Synth., 1, P40
4), 3-bromo-4-hydroxytoluene to 3-bromo-4-hydroxytoluene (Org.Synth., 3, P130), m-aminobenzaldehyde to m-hydroxybenzaldehyde (Org.
h., 3, P453).

[0003] In the above diazotization-hydrolysis reaction, a mixture of a raw material aromatic amine and an aqueous solution of sulfuric acid or hydrochloric acid is added with 5
After diazotization by adding an aqueous solution of sodium nitrite at a low temperature of not more than ° C, hydrolysis is performed by adding a diazotization reaction solution or a diazonium salt to an aqueous solution of sulfuric acid or water at a high temperature.

As an example of a diazotization-hydrolysis reaction using 3-amino-2-methylbenzoic acid, which is one of aminobenzoic acids, as a raw material, 3-amino-2-methylbenzoic acid and an aqueous sulfuric acid solution are used. To a mixture of the above and diazotization by adding an aqueous solution of sodium nitrite at a low temperature of 5 ° C or less, and then adding the diazotization reaction solution to a high-temperature aqueous solution of sulfuric acid to carry out hydrolysis (Org.Prep. Proced. Int., 11 (1), P27 (1979), JP-T-Hei 6-507153), a mixture of 3-amino-2-methylbenzoic acid and an aqueous solution of sulfuric acid, an aqueous solution of sodium nitrite at a low temperature of 5 ° C or less. Is added to diazotize and then diluted with an aqueous sulfuric acid solution, and the reaction solution is heated to 90 ° C. to carry out hydrolysis (US Pat. No. 5,527,829).

[0005]

The above Org. Prep. Proce
d. Int., 11 (1), P27 (1979), the method disclosed in JP-T-Hei 6-507153 discloses that the yield of hydroxybenzoic acid is 83
%, 97%. The method disclosed in U.S. Pat.No. 5,527,829 is compared with the method disclosed in Org.Prep.Proced.Int., 11 (1), P27 (1979) and JP-A-6-507153. The yield is as low as 69%.

However, in each of the above methods, the temperature of the diazotization reaction is as low as 5 ° C. or less. Therefore, in order to implement on an industrial scale, to control the heat generated by the diazotization reaction,
Not only is it necessary to have equipment that can cool to extremely low temperatures,
It takes a long time to drop the diazotizing agent. In addition, since each of the above-mentioned methods is usually carried out by separately performing a diazotization reaction and a hydrolysis reaction, not only the operation becomes complicated, but also it takes time and is disadvantageous in that it is not economical.

[0007] An object of the present invention is to solve the above-mentioned disadvantages of the prior art, to facilitate temperature control and operation, to greatly reduce the reaction time, and to obtain the desired hydroxybenzoic acid in high yield. It is an object of the present invention to provide a method for producing hydroxybenzoic acids.

[0008]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies to eliminate the above-mentioned drawbacks in the production of hydroxybenzoic acids. As a result, by using aminobenzoic acids in which the aromatic ring is inactivated by a carboxyl group as a raw material, and reacting the diazotizing agent in a temperature range from 40 ° C. to a reflux temperature, which is not conceivable in the past, a short time can be easily achieved. Further, the present inventors have found that the corresponding hydroxybenzoic acids can be obtained in a high yield in one step without separating the diazotization reaction and the hydrolysis reaction, and have reached the present invention.

[0009] The method for producing hydroxybenzoic acids of the present invention comprises:
A diazotizing agent is added to a mixture of aminobenzoic acids, acid and water at a temperature ranging from 40 ° C to the reflux temperature to form a diazotization step.
-It is characterized by performing a hydrolysis reaction. Thus, a mixture of aminobenzoic acids, an acid and water was added at 40 ° C.
By adding the diazotizing agent in the range of reflux temperature and performing the diazotization-hydrolysis reaction in one step, the corresponding hydroxybenzoic acids can be obtained in a short time, with a simple operation and in a high yield in a high yield. it can.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The aminobenzoic acids used as raw materials in the present invention include, for example, o-aminobenzoic acid, m-aminobenzoic acid, p-aminobenzoic acid, 2-amino-5
-Methylbenzoic acid, 2-amino-6-methylbenzoic acid, 3-amino-2-methylbenzoic acid, 3-amino-4-methylbenzoic acid, 5-
Amino-2-methylbenzoic acid and the like can be used.

The reason why the present invention can provide the corresponding hydroxybenzoic acids easily and in a short time with a simple operation in a high yield is not clear, but the aminobenzoic acids selected as the raw materials are converted into an electron-withdrawing carboxylic acid. It is considered that the presence of the group inactivates the aromatic ring, stabilizes the generated diazonium salt, and suppresses a side reaction. Aminobenzoic acids having a substituent at the p-position of the amino group are particularly desirable, and the reaction proceeds almost quantitatively.
This is probably because the generated hydroxybenzoic acid does not undergo a reaction such as nitrosation.

The acids used in the present invention include mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid, and lower aliphatic carboxylic acids such as acetic acid and formic acid. The amount of the acid to be used is 1 to 10 equivalents, preferably 1 to 8 equivalents, relative to the raw material aminobenzoic acid. If the amount of the acid used is less than 1 equivalent relative to aminobenzoic acid, it is not preferable because the by-products increase and the yield decreases, and there is no problem if it exceeds 10 equivalents,
Not only is the efficiency inferior, but also the amount of wastewater increases, which is not preferable.

[0013] In the conventional method in which the diazotization is carried out after the diazotization, when the diazotization reaction is carried out at a low temperature, an excess acid is required to stabilize the diazonium salt during the reaction, and the amount of the acid is at least aminobenzoic acid. 2.5 to 3 equivalents were used. However, in the case of the present invention, an acid for stabilizing the diazonium salt is unnecessary since the process proceeds to hydrolysis in one step. Therefore, in the present invention, the amount of acid can be reduced to 1 equivalent relative to aminobenzoic acid, which is advantageous from the viewpoint of wastewater treatment.

The water used in the present invention may be any of industrial water, ion-exchanged water, pure water, distilled water, etc., and is not particularly limited. The amount of water used is adjusted so that the acid concentration in the aqueous solution is 1 to 30%. If the acid concentration is high, the decomposition of the diazotizing agent increases, so that the amount of the diazotizing agent used increases. Conversely, if the acid concentration is low, the efficiency is deteriorated and it is not economical.

In the method of the present invention, a diazotization-hydrolysis reaction is carried out in one step by adding a diazotizing agent to a mixture of aminobenzoic acids, an acid and water. Examples of the diazotizing agent used for this purpose include sodium nitrite and nitrosylsulfuric acid. In the case of sodium nitrite, since it is a solid, it may be added as it is, but usually, it is dissolved in water and added. The method of adding the diazotizing agent is not particularly limited, and may be either dropwise addition to the reaction solution or addition.

The amount of the diazotizing agent used depends on the reaction temperature, the method of addition,
Since the stirring efficiency and the like are more variable, they cannot be unconditionally determined.
1.5 equivalents. If the amount of the diazotizing agent is less than 0.9 equivalent to the aminobenzoic acid, the conversion rate of the aminobenzoic acid as a raw material is undesirably low. Conversely, if the amount exceeds 1.5 equivalents, the generated hydroxybenzoic acids are further reacted, and the yield of hydroxybenzoic acids is undesirably reduced. In particular, those having no substituent at the p-position of the hydroxyl group are significantly affected.

The addition temperature and reaction temperature of the diazotizing agent are 40 ° C.
To the reflux temperature. If the temperature is lower than 40 ° C., the hydrolysis reaction hardly proceeds, and a large amount of by-products is formed, which is not preferable.
On the other hand, if the reflux temperature is exceeded, it is necessary to increase the pressure,
In addition, there is no significant difference in yield, which is not economical.

The time for adding the diazotizing agent is not particularly limited, and may be determined according to the state of foaming by the nitrogen gas generated by the reaction and the cooling capacity, and is usually about 0.1 to 24 hours. The reaction may be terminated immediately after the addition of the diazotizing agent, but stirring is continued for about 0.1 to 2 hours to complete the reaction.

After completion of the reaction, the reaction solution is cooled,
Since crystals of hydroxybenzoic acids are precipitated, the crystals are collected by a conventional method such as centrifugation, filtration in a vacuum oven, or the like. In addition, the reaction solution is ethyl acetate, methyl ethyl ketone,
It can also be recovered by extraction with a solvent such as ether or butanol. The collected hydroxybenzoic acids are purified, if necessary, by means of recrystallization or the like using an appropriate solvent.

[0020]

Hereinafter, the method of the present invention will be specifically described based on examples. In the examples,% for the concentration of hydroxybenzoic acids is% by weight, and% for the yield is mol%.

EXAMPLE 1 16.2 g of 3-amino-2-methylbenzoic acid was placed in a 200 ml glass flask equipped with a stirrer, thermometer and reflux condenser.
(Purity 93%, 0.10 mol), sulfuric acid 11.8 g (0.12 mol) and water 10
8 g was charged and heated to 80 ° C. with stirring. Next, 21.7 g (0.11 mol) of an aqueous solution of sodium nitrite adjusted to a concentration of 35% using a dropping funnel was added dropwise over 0.5 hours while maintaining the reaction temperature at 80 to 90 ° C, and further stirred at the same temperature for 1 hour. ,
A diazotization-hydrolysis reaction was performed. After the reaction is completed,
After cooling to 0 ° C., 3-hydroxy-2-methylbenzoic acid was extracted with ethyl acetate, and 141.2 g of an ethyl acetate layer was recovered. When 3-hydroxy-2-methylbenzoic acid in this ethyl acetate layer was quantified using high performance liquid gas chromatography, the concentration of 3-hydroxy-2-methylbenzoic acid was 9.31%, and the yield was 86.5%. Met. The results are shown in Table 1.

Examples 2 to 5 The amount of 3-amino-2-methylbenzoic acid shown in the reaction conditions column of Table 1,
The amount of sulfuric acid, the amount of water, the amount of aqueous sodium nitrite solution, the reaction temperature and the dropping time of the aqueous sodium nitrite solution were determined as in Example 1.
Diazotization-hydrolysis reaction to give 3-hydroxy-2-
Methylbenzoic acid was extracted with ethyl acetate, and 3-hydroxy-2-methylbenzoic acid in the ethyl acetate layer was quantified. The results are shown in Table 1.

[0023]

【table 1】

Examples 6 to 10 The amount of 3-amino-2-methylbenzoic acid shown in the reaction condition column of Table 2,
The amount of sulfuric acid, the amount of water, the amount of aqueous sodium nitrite solution, the reaction temperature and the dropping time of the aqueous sodium nitrite solution were determined as in Example 1.
Diazotization-hydrolysis reaction to give 3-hydroxy-2-
Methylbenzoic acid was extracted with ethyl acetate, and 3-hydroxy-2-methylbenzoic acid in the ethyl acetate layer was quantified. The results are shown in Table 2.

[0025]

[Table 2]

As shown in Tables 1 and 2, 3-hydroxy-2-methylbenzoic acid was obtained in a yield of 70.7 to 86.5% in a diazotization-hydrolysis reaction time of 1 to 3.5 hours.

Comparative Example 1 16.2 g of 3-amino-2-methylbenzoic acid was placed in a 200-ml glass flask equipped with a stirrer, a thermometer and a reflux condenser.
(Purity 93%, 0.10 mol), sulfuric acid 11.8 g (0.12 mol) and water 10
8 g was charged and heated to 28 ° C. with stirring. Next, 19.7 g (0.10 mol) of an aqueous solution of sodium nitrite adjusted to a concentration of 35% using a dropping funnel was added dropwise over 3 hours while maintaining the reaction temperature at 28 to 33 ° C, and further stirred at the same temperature for 2 hours. And a diazotization-hydrolysis reaction. After the completion of the reaction, 3-hydroxy-2-methylbenzoic acid was extracted using ethyl acetate, and 130.1 g of an ethyl acetate layer was recovered. 3- in this ethyl acetate layer
When hydroxy-2-methylbenzoic acid was quantified using high performance liquid gas chromatography, 3-hydroxy-2-
The methylbenzoic acid concentration was 6.38%, and the yield was 54.6%. The results are shown in Table 3.

Comparative Example 2 16.2 g of 3-amino-2-methylbenzoic acid was placed in a 200-ml glass flask equipped with a stirrer, a thermometer and a reflux condenser.
(Purity 93%, 0.10 mol), sulfuric acid 24.5 g (0.25 mol) and water 60
g was charged and cooled to 2 ° C. with stirring. Next, 19.7 g (0.10 mol) of an aqueous solution of sodium nitrite adjusted to a concentration of 35% using a dropping funnel, while maintaining the reaction temperature at 5 ° C or less.
After dropwise addition over 1 hour and stirring at the same temperature for another 2 hours, the reaction solution was heated to 80 ° C., stirred at 80 ° C. for 1 hour, and diazotized.
The hydrolysis reaction was performed. After completion of the reaction, 3-hydroxy-2-methylbenzoic acid was extracted using ethyl acetate, and 128.2 g of an ethyl acetate layer was recovered. When 3-hydroxy-2-methylbenzoic acid in this ethyl acetate layer was quantified by using high performance liquid gas chromatography, the concentration of 3-hydroxy-2-methylbenzoic acid was 7.03%, and the yield was 59.3%. there were. The results are shown in Table 3.

[0029]

[Table 3]

As shown in Table 3, the yields of 3-hydroxy-2-methylbenzoic acid in both Comparative Examples 1 and 2 were 60% or less.

EXAMPLE 11 16.2 g of 3-amino-2-methylbenzoic acid was placed in a 200 ml glass flask equipped with a stirrer, thermometer and reflux condenser.
(Purity 93%, 0.10 mol), 12.5 g (0.12 mol) of 35% hydrochloric acid and 100 g of water were charged, and heated to 80 ° C. with stirring.
Next, 21.7 g (0.11 mol) of an aqueous sodium nitrite solution adjusted to a concentration of 35% using a dropping funnel, the reaction temperature was 80 to 90 ° C.
The solution was added dropwise over 0.5 hour while maintaining the temperature, and further stirred at the same temperature for 1 hour to carry out a diazotization-hydrolysis reaction. After the reaction,
The reaction solution was cooled to 30 ° C., and 3-hydroxy-2-methylbenzoic acid was extracted using ethyl acetate, and 130.6 g of an ethyl acetate layer was extracted.
Was recovered. When 3-hydroxy-2-methylbenzoic acid in this ethyl acetate layer was quantified using high performance liquid gas chromatography, the concentration of 3-hydroxy-2-methylbenzoic acid was 9.15%, and the yield was 78.6%. there were. The result is displayed
See Figure 4.

Example 12 As shown in the reaction conditions column of Table 4, the diazotization-hydrolysis reaction was carried out under the same conditions as in Example 11 except that the concentration of hydrochloric acid at 35% and the amount of aqueous sodium nitrite solution were changed. -Hydroxy-2-methylbenzoic acid was extracted with ethyl acetate,
Hydroxy-2-methylbenzoic acid was quantified. The results are shown in Table 4.

[0033]

[Table 4]

As shown in Table 4, the diazotization-hydrolysis reaction time
1.5 hours, 3-hydroxy-2-methylbenzoic acid yield 77%
That's it.

Example 13 A glass flask equipped with a stirrer, a thermometer and a reflux condenser having a capacity of 200 ml was charged with 13.7 g (0.10 mol) of m-aminobenzoic acid, 24.5 g (0.25 mol) of sulfuric acid and 110 g of water. And heated to 80 ° C. with stirring. Next, 23.7 g (0.12 mol) of an aqueous sodium nitrite solution adjusted to a concentration of 35% using a dropping funnel was added dropwise over 0.5 hours while maintaining the reaction temperature at 80 to 90 ° C, and further stirred at the same temperature for 1 hour. , Diazotization-hydrolysis reaction. After completion of the reaction, the reaction solution was cooled to 30 ° C, and m-
Hydroxybenzoic acid was extracted using ethyl acetate, and 137.9 g of an ethyl acetate layer was recovered. When m-hydroxybenzoic acid in this ethyl acetate layer was quantified using high performance liquid gas chromatography, the m-hydroxybenzoic acid concentration was 8.
It was 32% and the yield was 83.1%. Table 5 shows the results.

Example 14 As shown in the reaction condition column of Table 5, the diazotization-hydrolysis reaction was carried out under the same conditions as in Example 13 except that the raw material m-aminobenzoic acid was changed to p-aminobenzoic acid. Then, p-hydroxybenzoic acid was extracted with ethyl acetate, and p-hydroxybenzoic acid in the ethyl acetate layer was quantified. Table 5 shows the results.

Comparative Examples 3 to 5 The diazotization-hydrolysis reaction was carried out under the same conditions as in Example 13 except that the raw material aminobenzoic acid was changed to the substances shown in Table 5. Then, similarly, the target substance in the reaction solution was extracted with ethyl acetate, and the target substance in the ethyl acetate layer was quantified. Table 5 shows the results.

[0038]

[Table 5]

As shown in Table 5, in Examples 13 and 14, m-hydroxybenzoic acid or p-hydroxybenzoic acid could be obtained in a yield of 83% or more in a diazotization-hydrolysis reaction time of 1.5 hours. Was. On the other hand, in Comparative Examples 3 to 5, a polymer was generated in the diazotization-hydrolysis reaction time of 1.5 hours, and the yield of the target phenol was as low as 46.8 to 65.3%.

[0040]

According to the process for producing hydroxybenzoic acids of the present invention, a mixture of aminobenzoic acids with an acid and water can be used.
By adding a diazotizing agent in the temperature range from ℃ to the reflux temperature and conducting the diazotization-hydrolysis reaction in one step, the corresponding hydroxybenzoic acids can be efficiently produced in a short time, with a simple operation and in a high yield. Obtainable.

Claims (1)

[Claims] Claims 1. A diazotization reaction using aminobenzoic acids as a raw material
In a method for producing hydroxybenzoic acids by hydrolysis, a diazotizing agent is added in a single step by adding a diazotizing agent to a mixture of aminobenzoic acids, an acid and water at a temperature ranging from 40 ° C. to a reflux temperature to carry out a diazotization-hydrolysis reaction. A process for producing hydroxybenzoic acids.