JP2915465B2 - Process for producing 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid and 2,3,5,6-tetrafluorophenol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid, which is useful as an intermediate material for pharmaceuticals, agricultural chemicals and liquid crystal materials. The present invention relates to a method for producing 3,5,6-tetrafluorophenol.

[Prior Art] As a method for producing 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid, several methods have been conventionally known. For example, JP-A-60-204742 discloses the method. Stands for pentafluorobenzoic acid (hereinafter sometimes abbreviated as F ₅ BA)
Is reacted with an alkaline substance in an aqueous solution at 70 to 100 ° C., and 4
A salt of hydroxy-2,3,5,6-tetrafluorobenzoic acid (hereinafter sometimes abbreviated as F ₄ HBA), and then forming the F ₄ HBA salt in an acidic pH range of 2 to 6. A method for producing F ₄ HBA characterized by being brought into contact with an aqueous solution has been proposed. According to this proposal, for example, when potassium hydroxide is used as an alkaline substance, the reaction proceeds as in the following reaction formula.

However, in the above method, the solubility of an alkali metal fluoride such as potassium fluoride by-produced during the reaction in an aqueous solvent is relatively high. Contains a considerable amount of fluorine ions, and the resulting 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid (hereinafter referred to as F ₄ H
There is a problem that hydrofluoric acid is generated when F ₄ HBA is liberated by adding an acidic aqueous solution to the filtrate containing a salt of (BA). Therefore, when the above method is carried out industrially, it is difficult to use not only a stainless steel reactor but also a glass lining reactor due to problems such as corrosion, and it is extremely expensive.
There is a drawback in that the efficiency of heat removal is insufficient and a fluororesin lining reaction apparatus or the like whose size is naturally limited must be used. As a method for removing such fluoride ions, there is a method in which a solution of calcium ions such as calcium chloride is added to the reaction solution after the reaction to form a precipitate of insoluble calcium fluoride, which is filtered off. However, generally, calcium fluoride produced by such a method becomes a gel-like precipitate, so that filtration is difficult and it is difficult to carry out industrially.

On the other hand, 2,3,5,6-tetrafluorophenol (hereinafter referred to as F
₄ P) may be referred to, for example, in Comparative Example 1 of the above-mentioned JP-A-60-204742, from F ₅ BA to F ₄
It is described that HBA is produced as a by-product when synthesizing HBA. That is, it is described that a part of the generated F ₄ HBA is further decarboxylated to produce F ₄ P as a by-product. This reaction involves the F ₅ BA and the F
The reaction is carried out at 115 to 120 ° C. (under reflux) in an aqueous solution containing 3 mol of sodium hydroxide per 1 mol of ₅ BA, but the amount of by-product F ₄ P is extremely small.

In addition, a similar decarboxylation reaction is disclosed in
No. 4439 discloses a method for producing 2,3,6-trifluorophenol by decarboxylation of 3-hydroxy-2,4,5-trifluorobenzoic acid. Since the reaction is carried out under high temperature and pressure, an acid-resistant pressure-resistant reactor must be used for industrialization.

[Problems to be Solved by the Invention] The present inventors have found that when industrially producing F ₄ HBA and F ₄ P,
As a result of conducting research to solve the above-mentioned problems of the conventional reactor, particularly the reaction apparatus, (1) When F ₅ BA and an alkaline compound are subjected to a hydroxylation reaction by heating in an aqueous solvent, When an alkaline earth metal compound such as calcium hydroxide is used together with an alkali metal compound such as sodium hydroxide as an alkaline compound, an alkaline earth metal fluoride precipitate such as calcium fluoride having low solubility in an aqueous solvent is produced as a by-product. In addition, since the precipitate does not become a gel and has a shape that can be easily filtered, it is possible to obtain a filtrate having a very small concentration of dissolved fluorine ions only by filtering the precipitate, As a result, even if the filtrate is treated with an acidic aqueous solution, generation of hydrofluoric acid does not become a problem, and therefore, using an inexpensive reactor such as a stainless steel reactor. Even easy F ₃
It can be produced HPA, and (2) when the F ₄ HBA is heated decarboxylation in an aqueous solvent, at normal pressure with an alkaline substance 0.1-1 equivalents relative to the F ₄ HBA1 mol The reaction proceeds at an industrially sufficient reaction rate only by heating, and F ₄ P can be easily produced. Therefore, it is not necessary to use a pressure-resistant reactor, and the pH of the reaction system in this case is about 3 8 and that it is possible to use inexpensive reactors such as stainless steel reactor is close to neutral, and further also (3) above the F ₅ BA in the same manner as in (1) hydroxylated reaction, the resulting filtrate By adding an acid such as sulfuric acid to the mixture to partially neutralize it and subjecting it to a heat decarboxylation reaction under normal pressure, F ₄ P can be easily produced without isolating F ₄ HBA during the process. In this case, it is not necessary to use a pressure-resistant reactor, and in this case, Since pH of the reaction system be close to about 3-8 and neutral it can be used an inexpensive reactor such as stainless steel reactor, thereby completing the heading invention like.

That is, the present invention is to solve the problems the prior art as described above, which had point, such as the reaction can be conducted at normal pressure by using an inexpensive reactor such as stainless steel reactor, F ₄ HBA Another object of the present invention is to provide a novel production method which is extremely excellent as an industrial production method of F ₄ P.

[Means for Solving the Problem] The first invention in the present invention is to heat pentafluorobenzoic acid and an alkaline compound in an aqueous solvent to form 4-
A method for producing hydroxy-2,3,5,6-tetrafluorobenzoic acid, characterized in that the alkaline compound comprises an alkaline earth metal compound. The present invention relates to a method for producing 5,6-tetrafluorobenzoic acid.

The alkaline compound according to the first aspect of the present invention contains an alkaline earth metal compound, and may be substantially composed of only the alkaline earth metal compound. Therefore, it is preferable to use an alkali metal compound in combination.

Examples of the alkaline earth metal compound include alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, and barium hydroxide; and alkaline earth metal oxides such as magnesium oxide, calcium oxide, and barium oxide. Substances; for example, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate and barium carbonate; and alkaline earth metal hydrogen carbonates such as magnesium hydrogen carbonate, calcium hydrogen carbonate and barium hydrogen carbonate. it can. Of these, the starting material F ₅ BA
And a compound of magnesium or calcium which does not form a water-soluble salt with the product F ₄ HBA is preferred, and a compound of calcium which is easily available and forms a salt which is most insoluble with fluorine ions, for example, calcium hydroxide , Calcium oxide, calcium carbonate and the like are particularly preferred.

Examples of the alkali metal compound that can be used together with the above alkaline earth metal compound include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; for example, lithium carbonate, sodium carbonate, potassium carbonate, and the like. And alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate. Of these, sodium hydroxide is most preferably used from the viewpoints of easy availability, good reaction operability, good reactivity, and the like.

The first invention in the present invention is to carry out a hydroxylation reaction by heating F ₅ BA and an alkaline compound containing an alkaline earth metal compound as described above in an aqueous solvent,
After the precipitate in the reaction system mainly composed of by-product alkaline earth metal fluoride is filtered off, the obtained filtrate is treated with an acidic aqueous solution to cause corrosion of the reaction apparatus due to hydrofluoric acid generation. The present invention relates to a method for producing a novel F ₄ HBA which basically solves the above problem.

When calcium hydroxide is used as the alkaline earth metal compound and sodium hydroxide is used in combination with the alkali metal compound, the hydroxylation reaction is considered to proceed according to the following formula.

The amount of the alkaline compound used is theoretically the starting material
Is a 3 equivalents relative to F ₅ BA1 moles, generally 3 to 25 equivalents, preferably, 1 to 10 equivalents alkaline earth metal compound (more preferably 1-4 equivalents, particularly preferably 1 to 2
Equivalent) and 2 to 15 equivalents (more preferably 2 to 10 equivalents, particularly preferably 2 to 4 equivalents) of the alkali metal compound.

If the amount of the alkaline earth metal compound used is equal to or less than the above upper limit, the filterability may be reduced when the precipitates such as the alkaline earth metal fluoride and unreacted alkaline earth metal compound by-produced are separated by filtration. If the concentration is not less than the above lower limit, the concentration of dissolved fluoride ions in the filtrate obtained by the filtration can be suppressed to a very small amount. It is preferable to determine the value appropriately. Further, if the amount of the alkali metal compound is not more than the above upper limit, the amount of acid used in the step of isolating F ₄ HBA from the aqueous solution of F ₄ HBA salt described below, and the third of the present invention In the present invention, the amount of acid used in the partial neutralization step prior to the decarboxylation reaction following the hydroxylation reaction can be reduced, and the operability, yield and reaction rate in these steps are kept high. The hydroxylation reaction rate can be kept high as long as it is not less than the above lower limit, so that the amount of the alkali metal compound to be used is preferably appropriately determined within the above range.

The aqueous solvent used in the hydroxylation reaction refers to water or a mixed solvent of water and a water-soluble organic solvent. By using the water-soluble organic solvent, when the hydroxylation reaction is performed under reflux temperature conditions as described later, the reflux temperature can be adjusted.

Such a water-soluble organic solvent can be used without particular limitation as long as it dissolves in 50 parts by weight or more with respect to 100 parts by weight of water and does not cause a harmful side reaction in the hydroxylation reaction. For example, aliphatic monohydric alcohols having 1 to 3 carbon atoms such as methyl alcohol, ethyl alcohol, n- or i-propyl alcohol; other monohydric alcohols such as allyl alcohol and furfuryl alcohol; Aliphatic polyhydric alcohols having 2 to 3 carbon atoms such as glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerin, etc .; for example, polyethylene glycol liquid at room temperature; for example, ethylene glycol monomethyl ether, ethylene glycol mono Ethyl ether, ethylene glycol monobutyl ether , 1-4 ethylene glycol and carbon atoms such as ethylene glycol dimethyl ether
Mono- or dietherified products with aliphatic monohydric alcohols; for example, diethylene glycol such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether; and an aliphatic monohydric alcohol having 1 to 4 carbon atoms. A mono- or dietherified product of
For example, a monoetherified product of glycerin such as 1-glycerin monomethyl ether and an aliphatic monohydric alcohol having 1 to 3 carbon atoms; for example, cyclic ethers such as tetrahydrofuran, 1,3-dioxane, and 1,4-dioxane; Can be mentioned.

These organic solvents can be used alone or in combination of two or more. When these organic solvents are used, among these, aliphatic monohydric alcohols can be particularly preferably used from the viewpoint of availability and economics.

The hydroxylation reaction can be generally performed at a temperature of 50 ° C. or higher, and is preferably performed at 70 ° C. or higher from the viewpoint of a high reaction rate. This reaction can be carried out at a high temperature and a high pressure in a closed pressure-resistant reaction vessel. However, from the viewpoint of the cost of the reaction equipment, the reaction is preferably carried out at a normal pressure in a range from 70 ° C. to the reflux temperature of the aqueous solvent.

The reaction time is not particularly limited, but generally,
It is good to carry out for 15 minutes to 20 hours, preferably for about 30 minutes to 10 hours.

After the completion of the reaction, the reaction solution is cooled preferably to 0 to 40 ° C., and a precipitate mainly composed of by-product alkaline earth metal fluoride and unreacted alkaline earth metal compound is removed by filtration.

The filtrate thus obtained is an aqueous solution of an F ₄ HBA salt, and after adding an aqueous solution of an inorganic acid such as sulfuric acid or hydrochloric acid to adjust the pH to about 1 to 4, ether, i-propyl ether, ethyl acetate, etc. The desired F ₄ HBA can be isolated by extracting the resulting organic layer with a conventional method using the above organic solvent, separating, concentrating and drying the obtained organic layer.

A second invention of the present invention is to heat pentafluorobenzoic acid and an alkaline compound containing an alkaline earth metal compound in an aqueous solvent, filter off the generated water-insoluble components, and add an acid to the obtained filtrate. The present invention relates to a method for producing 2,3,5,6-tetrafluorophenol, which is characterized in that after addition and partial neutralization, heating and decarboxylation are performed under normal pressure.

In the second invention, first, similarly to the first invention,
An alkaline compound comprising F ₅ BA and an alkaline earth metal compound is heated in an aqueous solvent to hydroxylation reaction.

The “alkaline compound containing an alkaline earth metal compound” is preferably composed of an alkaline earth metal compound and an alkali metal compound, as in the first invention. Examples of the alkaline earth metal compound include hydroxides, oxides, carbonates, bicarbonates and the like of alkaline earth metals, and the use of magnesium or calcium compounds is preferred.In particular, calcium compounds, for example, The use of calcium hydroxide, calcium oxide, calcium carbonate and the like is preferred. Examples of the alkali metal compound include hydroxides, oxides, carbonates, and hydrogen carbonates of alkali metals, and the use of sodium hydroxide is most preferable.

The amount of the alkaline compound to be used is generally 3 to 3 with respect to 1 mol of F ₅ BA as the starting material in the second invention.
25 equivalents, preferably alkaline earth metal compound 1.
It is preferable to use 10 to 10 equivalents (more preferably 1 to 4 equivalents, particularly preferably 1 to 2 equivalents) and 2 to 15 equivalents (more preferably 2 to 10 equivalents, particularly preferably 2 to 4 equivalents) of the alkali metal compound.

As the aqueous solvent that can be used in the second invention, water or a mixed solvent of water and a water-soluble organic solvent can be used as in the first invention. Thus, when the hydroxylation reaction of the third invention is performed under reflux temperature conditions, the reflux temperature can be adjusted.

Examples of such a water-soluble organic solvent are the same as those exemplified in the first invention, that is, aliphatic monohydric alcohols having 1 to 3 carbon atoms, other monohydric alcohols,
Aliphatic polyhydric alcohols having 2 to 3 carbon atoms, polyethylene glycol liquid at room temperature, mono- or dietherified product of ethylene glycol and aliphatic monohydric alcohol having 1 to 4 carbon atoms, diethylene glycol and fat having 1 to 4 carbon atoms Mono- or di-etherified compounds with aliphatic monohydric alcohols, mono-etherified compounds of glycerin with aliphatic monohydric alcohols having 1 to 3 carbon atoms, cyclic ethers, etc., each of which can be used alone or in combination of two or more. Can be used. When these organic solvents are used, among these, aliphatic monohydric alcohols can be particularly preferably used from the viewpoint of availability and economics.

The reaction temperature of the hydroxylation reaction is generally 50 ° C. or higher, preferably 70 ° C. or higher, as in the case of the first invention. It is preferred that The reaction time is generally
It is good to carry out for 15 minutes to 20 hours, preferably for about 30 minutes to 10 hours.

After the completion of the reaction, the reaction solution is cooled preferably to 0 to 40 ° C., and a precipitate mainly composed of by-product alkaline earth metal fluoride and unreacted alkaline earth metal compound is removed by filtration.

The filtrate thus obtained is an aqueous solution of an F ₄ HBA salt, which is partially neutralized by adding an acid thereto, and subsequently heated under normal pressure to carry out a decarboxylation reaction, whereby the desired F ₄ P is obtained. Generate.

The acid is not particularly limited, and examples thereof include organic acids such as acetic acid, monochloroacetic acid, trifluoroacetic acid, propionic acid, malonic acid, succinic acid, and benzoic acid;
For example, any inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid and the like can be used as long as it can neutralize alkalinity. However, it is most preferable to use an inorganic acid such as sulfuric acid or hydrochloric acid from the viewpoint of easiness of the isolation operation of F ₄ P after completion of the reaction.

The amount of these acids used is such that the F ₄ HBA in the filtrate is in the form of a free acid as shown in the following formula, or in the form of a monohydrogen salt in which a carboxyl group is neutralized as shown in the following formula, or
It is added so that it is present in the form of a mixture of both.

(Where A represents Na, K, Li, 1 / 2Mg, 1 / 2Ca, 1 / 2Ba, etc.) Specifically, the amount of excess alkaline compound present in the filtrate is determined by titration (x Mol), and the amount of F ₃ HPA salt dissolved in the filtrate is measured by liquid chromatography (y mol), and the amount of acid used is calculated based on the following formula.

Amount of acid used = (x + ay equivalent) wherein a is preferably 1 to 1.9,
It is particularly preferred to be 1.05 to 1.5. When the value of a is equal to or greater than the lower limit, the yield of F ₄ P, which is the target product, can be increased, and preferably, when the value is equal to or less than the upper limit, the reaction rate can be kept high. It is preferable that the value of a be within the above range.

The decarboxylation reaction in the second invention can be generally performed at a temperature of 50 ° C. or higher, and from the viewpoint of the reaction rate,
The reaction is preferably performed at a temperature in the range of 70 ° C to the reflux temperature of the aqueous solvent.

The reaction time is not particularly limited, but generally,
It is good to carry out for 15 minutes to 20 hours, preferably for about 30 minutes to 10 hours.

The reaction solution thus obtained is an aqueous solution of an F ₄ P salt, and after adding an aqueous solution of an inorganic acid such as sulfuric acid or hydrochloric acid to adjust the pH to about 1 to 4, ether, i-propyl ether, ethyl acetate The desired 2,3,5,6-tetrafluorophenol can be isolated by extracting the resulting organic layer with a conventional method using an organic solvent such as those described above, and separating, concentrating and drying the resulting organic layer.

Examples Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Reference Examples.

Example 1 300 ml of 4 equipped with a stirrer, thermometer and reflux condenser
53.0 g of pentafluorobenzoic acid (F ₅ BA)
(Approximately 0.25 mol), 25 wt% sodium hydroxide aqueous solution 88.0
g (about 0.55 equivalent), distilled water 50g and calcium hydroxide 13.9
g (about 0.376 equivalents) was charged and subjected to a hydroxylation reaction under heating to reflux (about 104 ° C.) for 2 hours. The end point of the reaction is liquid chromatography (hereinafter sometimes abbreviated as LC)
Confirmed. After the completion of the reaction, the reaction solution was cooled to room temperature (20 ° C.), and the by-product precipitate was removed by suction filtration, and the desired product, 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid (F
171.3 g of a filtrate which was an aqueous solution of ₄ HBA) salt was obtained. This filtrate is
Analysis by LC confirmed an F ₄ HBA salt in a yield equivalent to 96.6%. Further, the concentration of fluorine ions in this filtrate was measured by an ion meter and found to be 134 ppm.

Next, sulfuric acid was added to the filtrate to adjust the pH to 1 to 2, followed by extraction with ether. The obtained ether layer was dried over anhydrous calcium chloride, and the solvent was distilled off under reduced pressure to obtain the target compound F ₄ 48.8 g (purity: 97.9% by weight, yield: 91.0%) of white crystals of HBA were obtained.

The physical properties of the obtained F ₄ HBA are as follows.

Mp: 146 to 148 ° C. Mass spectrum (EI): m / z = 210 (M +), 193,166, to 300ml eggplant type flask equipped with a Comparative Example 1 reflux condenser, F ₅ BA53.
0 g (about 0.25 mol) and 25 wt% sodium hydroxide aqueous solution
140 g (approximately 0.875 equivalents) were charged and subjected to a hydroxylation reaction for 4 hours while heating under reflux. After the reaction solution was cooled to room temperature (20 ° C.), the by-produced sodium fluoride crystals were separated by filtration to obtain 177 g of a filtrate which was an aqueous solution of the target F ₄ HBA salt. The concentration of fluorine ions in this filtrate was determined by an ion meter to be 4600 ppm.

Comparative Example 2 A hydroxylation reaction was carried out in the same manner as in Comparative Example 1 to obtain 177 g of a filtrate as an aqueous solution of F ₄ HBA salt containing 4600 ppm of fluorine ions. When 6.04 g (about 44.6 meq) of a 27.3% by weight aqueous solution of calcium chloride was added to the filtrate, a gel-like precipitate of calcium fluoride was formed, and suction filtration could not be performed.

Example 2 In a 20-liter stainless steel reaction vessel equipped with a stirrer, a thermometer, and a reflux condenser, 5.00 kg (about 23.6 mol) of F ₄ BA, 8.30 kg (about 51.9 equivalents) of a 25% by weight aqueous sodium hydroxide solution, 1.31 kg (about 35.4 equivalents) of calcium hydroxide and 6.00 kg of distilled water
And subjected to a hydroxylation reaction under heating and refluxing (about 104 ° C.) for 3 hours. After cooling the reaction solution to room temperature (about 20 ° C.), the by-product precipitate was filtered off with a Nutsche filter, and the filtrate was 18.5 kg.
I got When this filtrate was measured by LC, it was 25.9% by weight.
A salt of F ₄ HBA corresponding to the concentration of F ₄ HBA (yield 96.6%) was confirmed. The concentration of fluorine ions in the filtrate measured by an ion meter was 14 ppm. Further, the amount of excess alkali present in the filtrate was determined by titration,
It was 0.32 equivalents / l and the neutralization inflection point was pH 8.65.

Then, 1.00 kg of distilled water and 1.55 kg of concentrated sulfuric acid (about 98% by weight) (about 31.0 equivalents; about 5.9 equivalents of excess alkali in the filtrate) and 1.10 equivalents of the F ₄ HBA content, that is, about 25.1 equivalents, were added to the filtrate.
(Equivalent to the total of equivalents) was added thereto, and the aqueous solution was heated and stirred under reflux (about 104 ° C.) for 1 hour to carry out a decarboxylation reaction, thereby obtaining 19.8 kg of a reaction solution. When the obtained reaction solution was measured by LC, F ₄ P having a concentration of 18.9% by weight (yield to F ₅ BA
Corresponding F ₄ P salt was observed at%).

1.005 kg (about 20.1%) of concentrated sulfuric acid (about 98% by weight)
(Equivalent) and 800 g of toluene were separated to give 5.27 kg of a toluene layer. This toluene layer was transferred to a 5-liter eggplant-shaped flask equipped with a moisture metering tube and a reflux condenser, and subjected to azeotropic dehydration under heating and reflux to remove water in the toluene layer. By rectifying the remaining toluene layer, 2,3,
To obtain a 5,6-tetrafluorophenol (73.0% yield based on _{F 4 BA) (F 4 P} ) 2.92kg. The physical properties of the obtained F ₄ P were as follows.

Boiling point: 153.6-154.3 ° C

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-60-204742 (JP, A) JP-A-63-264439 (JP, A) JP-A-1-268662 (JP, A) Zh. Org. Khim. (1974), 10 (2), 340-350 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 65 / 03,51 / 367 C07C 39 / 26,37 / 50 CA (STN) REGISTRY ( STN)

Claims (3)

(57) [Claims] 1. A method for producing 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid by heating pentafluorobenzoic acid and sodium hydroxide comprising calcium hydroxide in an aqueous solvent. In 2 to 4 equivalents of sodium hydroxide and 1 to 1 mole of pentafluorobenzoic acid
A method for producing 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid, comprising using 2 equivalents of calcium hydroxide. 2. Heating pentafluorobenzoic acid and sodium hydroxide containing calcium hydroxide in an aqueous solvent, filtering off the water-insoluble matter generated, and adding an acid to the obtained filtrate, A method for producing 2,3,5,6-tetrafluorophenol, which comprises subjecting to neutralization and heating and decarboxylation under ordinary pressure at pH 3 to 8. 3. The use amount of an acid is x + ay equivalent (where x is an excess molar amount of an alkaline compound in a filtrate, y is a molar amount of 4-hydroxy-2,3,5,6-tetrafluorobenzoate, and a is 1 to
3. The method according to claim 2, wherein the integer is 1.9.