JP3076991B2 - Method for producing fluorophenols - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing fluorophenols, and more particularly, to a method for producing fluorophenols suitable for industrial-scale production. It is about.

(Prior art) Fluorophenols such as p-fluorophenol are known as important synthetic intermediates for fluorine-containing drugs and agricultural chemicals.

As a method for producing this fluorophenol, for example, Journal of Organic Chemistry, 26
Vol. 4641, (1961), a method of brominating fluorobenzene and reacting the obtained parafluorobromobenzene with a base such as potassium hydroxide to convert a bromine atom to a hydroxyl group. As disclosed in JP-A-62-29544 or JP-A-50-36431, a method of diazotizing fluoroanilines and further hydrolyzing to convert an amino group to a hydroxyl group has been conventionally used. The method disclosed in JP-A-62-29544 or JP-A-50-36431 is easier to obtain since the starting fluoroanilines are industrially produced. It is said that fluorophenols can be easily produced by diazotization and hydrolysis of fluoroanilines and that they are safe, and thus are preferred as industrial production methods.

(Problems to be solved by the invention) However, it has been pointed out that the above-mentioned conventional methods for producing fluorophenols have problems to be solved.

That is, in order to carry out the method described in the above-mentioned Journal of Organic Chemistry, a pressurized reactor is required, and there are many by-products. Since fluorobenzene used as a starting material is synthesized by a direct fluorination method using a fluorine gas or a fluorination by a Siman reaction of aniline, the direct fluorination method requires fluorine gas,
The Mann reaction has a problem that dangerous compounds such as anhydrous hydrofluoric acid must be used.

Further, in the method described in JP-A-62-29544, when hydrolyzing a diazotized product in an aqueous solution of copper sulfate at 60 to 160 ° C., copper sulfate must be used in an equimolar amount or more. Also, in the method described in JP-A-50-36431, when hydrolyzing a diazotized compound in an aqueous phosphoric acid solution at 100 to 160 ° C., the phosphoric acid aqueous solution must be used in an equimolar amount or more. As described above, since these methods use a large amount of a copper compound, phosphoric acid, or the like, they require treatment of wastewater or waste, and have the disadvantage of increasing the cost industrially.

On the other hand, besides the above prior art, for example, in Organic Synthesis Collective Volume 1,404 (1941), m-
A method for producing m-nitrophenol by diazotizing nitroaniline and hydrolyzing the resulting diazonium salt is described, but this method requires a large amount of diluting water for diazotization and requires operability. Not only is it inferior, but also the sulfuric acid concentration is reduced by a large amount of water, the tar temperature increases because the reaction temperature cannot be raised, the yield is not good, and when actually producing fluorophenols, It turns out that there is a disadvantage that the yield is not good.

An object of the present invention is to solve the conventional problems described above and to provide a method for producing fluorophenols which is safe and suitable for industrial production.

(Means for Solving the Problems) The configuration adopted by the present invention to achieve the above object is as follows.
General formula (1) (In the formula, R ₁ , R ₂ and R ₃ represent a hydrogen atom, a halogen atom or a haloalkyl group, provided that at least one of R ₁ , R ₂ and R ₃ represents a fluorine atom.) Anilines are diazotized in dilute sulfuric acid, and the obtained diazonium salt is hydrolyzed by dropping the resulting diazonium salt in a heated sulfuric acid solution while maintaining the concentration of the sulfuric acid in a concentration range in which the hydrolysis reaction sufficiently proceeds, Generated general formula (2) (Wherein R ₁ , R ₂ and R ₃ represent the same substituents as described above). The fluorophenols represented by the following formulae are separated from the reaction system by azeotropic distillation with water. .

That is, the inventors of the present invention have repeatedly studied industrial methods for producing fluorophenols, and found that in the method for producing fluorophenols from fluoroanilines, diazotization and subsequent hydrolysis were carried out. During the decomposition, the aqueous solution of the diazonium salt is hydrolyzed while being dropped into a heated sulfuric acid aqueous solution maintained at a concentration range in which the hydrolysis reaction sufficiently proceeds, whereby a fluorophenol is obtained with a high yield, and furthermore, the generated fluoro If phenols are distilled out of the reaction system by azeotropic distillation with water, polymerization of the obtained fluorophenol can be prevented, and sulfuric acid can exhibit excellent effects such as repeated use. The present invention has been completed.

 Hereinafter, the present invention will be described in detail.

In the present invention, general formula (1) used as a raw material
Are easily synthesized by reduction of fluoronitrobenzenes. Examples of the fluoroanilines include 4-fluoroaniline, 3-fluoroaniline, 3,4-difluoroaniline, and 3-fluoroaniline. -Chloro-4-fluoroaniline, 3-bromo-4-fluoroaniline, 3,4,5-trifluoroaniline, 3,5-dichloro-4-fluoroaniline, 4-fluoro-3-trifluoromethylaniline and the like Can be mentioned.

However, 2-fluoroanilines are not suitable as a raw material for use in the present invention because the generated diazonium salt tends to cause a side reaction due to a specific electron effect of an adjacent fluorine atom and has a low yield.

The fluoroanilines can be easily produced by reducing the corresponding fluoronitrobenzene.

Further, the diazotization reaction is carried out in dilute sulfuric acid.
Preferably, 1 to 1.2 equivalents are used.

Examples of the diazotizing agent include nitrosylsulfuric acid, alkyl nitrite, and nitrites such as sodium nitrite and potassium nitrite, and among them, sodium nitrite is preferable. The amount of the diazotizing agent to be used is about 1 to 2 equivalents, preferably 1 to 1.1 equivalents, based on the fluoroaniline.

The reaction temperature is in the range of -5 ° C to room temperature, especially 0 to 10 ° C.
It is preferable to carry out at. In addition, the reaction time is usually sufficient for 1 to 2 hours.

The diazonium salt thus prepared is easily hydrolyzed by dropping it into a pre-heated aqueous sulfuric acid solution to produce fluorophenols. The concentration of the aqueous sulfuric acid solution is 50 to 80% by weight, preferably 55 to 80% by weight.
70%.

When the concentration is 50% by weight or less, the reaction time is long and the yield is poor, and when the concentration is 80% by weight or more, sulfonated products and tar-like products are by-produced and the yield is poor. .

Thus, in the present invention, the concentration of sulfuric acid at the time of hydrolysis and, consequently, the reaction temperature greatly affect the reaction itself. In the present invention, the amount or rate of azeotropic distillation of fluorophenols and water is determined. By controlling or
Further, by controlling the amount or rate of dropping of the diazonium salt, the concentration of sulfuric acid is maintained in a concentration range in which the hydrolysis reaction sufficiently proceeds, that is, 50 to 80% by weight, preferably 55 to 70% by weight. The reaction temperature is maintained.

The amount of sulfuric acid used is, for example, in the range of 1.1 to 20 times mol, preferably 5.5 to 10 times mol, of the starting material fluoroaniline.

Furthermore, the resulting fluoropheno represented by the formula (2)
Under the reaction conditions of the present invention, benzene quickly azeotropes with water and distills out of the system, so that at the end of the reaction, little organic matter remains except for a small amount of decomposition products. Therefore, the sulfuric acid remaining in the kettle after the completion of the reaction can be recovered and further used to repeat the hydrolysis of a new diazonium salt. The sulfuric acid can be recovered and reused at least three to four times, and at this time, the yield of fluorophenol is almost constant.

In addition, decomposition of the diazonium salt involves sodium sulfate as a by-product, which crystallizes and precipitates from the recovered sulfuric acid and can be easily removed by excess. The reaction temperature is determined by the mixing ratio of water and sulfuric acid, and the dropping rate of the diazonium salt, etc., and is preferably from 100 to 170 ° C, preferably from 120 to 160 ° C.
And a reaction time of about 2 to 6 hours is sufficient.

The generated fluorophenols can be isolated from the azeotropic distillate by extraction with an appropriate organic solvent. At this time, if salting out with sodium chloride or the like, extraction loss can be prevented.

(Effect of the Invention) According to the present invention, easily available third, fourth or fifth position
Diazotization and hydrolysis are performed using an aniline derivative having at least one fluorinated position. This hydrolysis reaction is carried out by dropping an aqueous solution of a diazonium salt into a heated sulfuric acid aqueous solution. At this time, by maintaining the sulfuric acid concentration within the above-described range, the reaction can be carried out smoothly and at a high rate. Proceed to yield.

Further, since the generated fluorophenols are distilled out of the reaction system by azeotropic distillation with water, the polymerization reaction is suppressed and the yield is high.

Further, the present invention does not use copper sulfate or phosphoric acid, so that treatment of wastewater and waste is extremely easy, and the amount of diluting water used in the diazotization reaction can be reduced. No problems occur in the process, and the sulfuric acid used for the hydrolysis can be used repeatedly.
The present invention is a process for producing a highly useful fluorophenol.

(Examples) Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 (Production of p-fluorophenol) In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 100 ml of water and 11.7 g (0.11 mol) of 95% sulfuric acid were put, cooled on ice, and cooled to 0 to 5%. Stirred at ° C. When 11.1 g (0.1 mol) of p-fluoroaniline was further added dropwise at the same temperature, a white suspension was formed.

Next, 7.2 g (0.104 mol) of sodium nitrite was added to 50 ml of water.
And added at 6-9 ° C from a dropping funnel.
Stirring was continued at 5 ° C. for 1 hour.

Separately, prepare a 200 ml four-necked flask, attach a distillation apparatus such as a Liebig condenser, a thermometer, and a stirrer. Then, add 61.9 g (0.6 mol) of 95% sulfuric acid and 31 ml of water, and stir. The mixture was heated on an oil bath until the liquid temperature reached 150 ° C.

The aqueous solution of the above-mentioned p-fluorobenzenediazonium sulfate was added dropwise thereto over 2.5 hours while maintaining the temperature at 140 to 150 ° C.

The formed p-fluorophenol was eluted with water by azeotropic distillation. After the addition, the distillation was continued for another 30 minutes. After the distillate was extracted four times with 50 ml of dichloromethane, all the organic layers were mixed and analyzed by gas chromatography to find that the yield was 87.9%. (Dibenzyl was used as an internal standard substance.) Examples 2 to 4 When sulfuric acid remaining as a residue in Example 1 was cooled to room temperature, sodium sulfate crystals were precipitated. This is suctioned over glass fiber paper, and water 10
The reaction was carried out in the same manner as in Example 1 except that the recovered sulfuric acid was used.

In addition, by the same operation, sulfuric acid was recovered and the experiment was repeated. Table 1 shows the results.

Comparative Example To a sulfuric acid used for hydrolysis, 61.9 g of 95% sulfuric acid was added to 69 g of water, and a lower concentration than the sulfuric acid for hydrolysis in the above example was used. The reaction was carried out at 110 to 120 ° C. for 2 hours. The reaction was carried out in the same manner as in Example 1 except that the yield of p-fluorophenol was reduced to 70.1%.

Example 5 In a 300 ml four-necked flask equipped with a thermometer, a reflux condenser, and a stirrer, 28.0 (0.5 mol) of iron powder, 2.8 g (0.01 mol) of ferrous sulfate heptahydrate and 100 ml of water were placed. The temperature was raised to 95 ° C. on an oil bath with stirring. Further, at the same temperature, when 28.2 g (0.2 mol) of p-fluoronitrobenzene was gradually added dropwise, heat generation and reflux occurred, and the reaction temperature rose to 100 ° C. The dropwise addition was continued for another 30 minutes, and the mixture was stirred at the same temperature for 2.5 hours after the addition. Next, after attaching the distillation device, add water to the flask.
100 ml was added and the produced p-fluoroaniline was azeotropically distilled with water.

Next, 22.7 g (0.22 mol) of 95% sulfuric acid was used and diluted with 20 ml of water, while 14.4 g (0.21 mol) of sodium nitrite was used.
Example 1 except that (mol) was dissolved in 100 ml of water and used.
The reaction was carried out in the same manner as described above.

As a result, 19.5 g of p-fluorophenol having a boiling point of 74 to 77 ° C./11 mmHg was obtained. The yield was 86.9%.

Examples 6 to 8 The same reaction as in Example 1 was carried out except that p-fluoroaniline was changed to the following anilines. Table 2 shows the results.

Comparative Examples 2 and 3 The reaction was carried out in the same manner as in Example 1 except that p-fluoroaniline was changed to the following anilines. Table 3 shows the results. Comparative Example 4 Hydrolysis of a diazonium salt without azeotropic distillation reduced the yield to 66.9%.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-50-36431 (JP, A) JP-A-50-117732 (JP, A) JP-A-62-29544 (JP, A) JP-A-1- 268658 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 39/24-39/27 C07C 37/05 CA (STN)

Claims (6)

(57) [Claims] 1. The general formula (1) (In the formula, R ₁ , R ₂ and R ₃ represent a hydrogen atom, a halogen atom or a haloalkyl group, provided that at least one of R ₁ , R ₂ and R ₃ represents a fluorine atom.) Anilines are diazotized in dilute sulfuric acid, and the obtained diazonium salt is hydrolyzed by dropping the resulting diazonium salt in a heated sulfuric acid solution while maintaining the concentration of the sulfuric acid in a concentration range in which the hydrolysis reaction sufficiently proceeds, Generated general formula (2) (Wherein R ₁ , R ₂ and R ₃ represent the same substituents as described above), wherein the fluorophenols are separated from the reaction system by azeotropic distillation with water. Manufacturing methods. 2. The method according to claim 1, wherein the concentration or rate of azeotropic distillation of the fluorophenol and water is controlled to maintain the concentration of sulfuric acid during the hydrolysis in a concentration range in which the hydrolysis reaction proceeds sufficiently. Item 4. The method for producing a fluorophenol according to Item 1. 3. The concentration of sulfuric acid during hydrolysis is controlled to a concentration range in which the hydrolysis reaction proceeds sufficiently by controlling the amount or rate of dropping of the diazonium salt and the amount or rate of azeotropic distillation of fluorophenols and water. The method for producing fluorophenols according to claim 1, wherein the method is maintained. 4. The concentration range in which the hydrolysis reaction proceeds sufficiently,
The method for producing fluorophenols according to any one of claims 1 to 3, wherein the content is 50 to 80% by weight, preferably 55 to 70% by weight. 5. The fluoroaniline according to claim 1, wherein said fluoroaniline represented by the formula (1) is produced by reducing the corresponding fluoronitrobenzene. A method for producing phenols. 6. The process for producing fluorophenols according to claim 1, wherein the sulfuric acid used for the hydrolysis is repeatedly used for another hydrolysis.