JPH07233117A - Production of halogenobenzoic acids - Google Patents

Abstract

PURPOSE:To safely produce halogenobenzoic acids in high yield without using hazardous reagents and operations by reacting an easily available halogenophthalic acid anhydride with a hydroxy compound and subjecting the reaction product to decarbonation and hydrolysis. CONSTITUTION:This process for the production of a halogenobenzoic acid of formula V comprises the reaction of a halogenophthalic acid anhydride of formula I (X<1> to X<4> each is a halogen or H and at least one of X<1> to X<4> is F) with a hydroxy compound to obtain a halogenophthalic acid monoester of formula II and formula III (R is a univalent group obtained by removing OH from the hydroxy compound), the decarbonation of the ester and the hydrolysis of the resultant halogenobenzoic acid ester of formula IV. The halogenophthalic acid monoester is preferably a halogenophthalic acid monoalkyl ester, a halogenophthalic acid monofluoroalkyl ester or a halogenophthalic acid monoaryl ester. The reaction is carried out preferably in the presence of a catalyst. The reaction proceeds under mild reaction condition and is advantageous for industrial use.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing halogenobenzoic acid and halogenobenzoic acid ester, which are useful as intermediates for medicines and agricultural chemicals and liquid crystals.

[0002]

2. Description of the Related Art Halogenobenzoic acids are important compounds as intermediates for medical and agricultural chemicals and liquid crystals. In particular, among halogenobenzoic acids, fluorinated benzoic acids are particularly important intermediates because various effects can be expected by introducing a fluorine atom into the structure of the compound.

The following methods have been proposed as methods for synthesizing fluorinated benzoic acids. (1) 3,
By heating 4,5,6-tetrafluorophthalic acid in the presence of a tertiary amine to decarboxylate it, 2,3,4,5
-Method for synthesizing tetrafluorobenzoic acid (JP-A-1-
13700). (2) A method for synthesizing 2,3,4,5-tetrafluorobenzoic acid by heating 3,4,5,6-tetrafluorophthalic acid in water in the presence of a metal oxide to decarboxylate (JP-A 61-85349).
(3) Use 4,5-difluorophthalic acid with N-methyl-2-
A method for synthesizing 3,4-difluorobenzoic acid by heating in pyrrolidone in the presence of copper oxide to decarboxylate (JP-A-3-161461).

(4) A method for synthesizing 2,4,5-trifluorobenzoic acid by heating 3,4,6-trifluorophthalic anhydride in dimethylacetamide in the presence of copper oxide to decarboxylate it. (JP-A-3-161462).

(5) 2,3,4,5-by fluorinating 2,3,4,5-tetrachlorobenzonitrile
Method using tetrafluorobenzoic acid (Japanese Patent Laid-Open No. 4-492)
63). (6) A method of fluorinating 3,4-difluorobenzochloride to synthesize 3,4-difluorobenzoic acid (JP-A-4-26651).

[0006]

The above-mentioned conventional methods have various problems. (1), (2), and (3)
In the method of using fluorinated phthalic acid as a starting material, it is difficult to synthesize the raw material, and it is necessary to use a large amount of polar solvent in the purification step after the synthesis. Moreover, the target substance must be obtained from the aqueous layer side. There is a problem that does not happen. The method (4) using fluorinated phthalic anhydride as a starting material has a low yield. Also,
Since highly toxic copper oxide is used, there is also a problem of waste liquid treatment, which is an industrially disadvantageous method. The methods (5) and (6) have problems such as low fluorination yield and tar formation of the solvent.

[0007]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art and provides an industrially advantageous halogenobenzoic acid ester and a method for producing halogenobenzoic acid.

That is, according to the present invention, the halogenophthalic anhydride represented by the general formula (1) is reacted with a hydroxy compound to give a halogenophthalic acid monoester, and the halogenophthalic acid monoester is decarboxylated to obtain a halogenobenzoic acid. Provided is a method for producing a halogenobenzoic acid, which is an ester and hydrolyzes the halogenobenzoic acid ester.

[0009]

[Chemical 3]

However, in the general formula (1), X ^{1 to} X
⁴ may be the same or different, respectively,
It represents a halogen atom or a hydrogen atom, and at least one is a fluorine atom.

In the following description, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, etc.
A fluorine atom is preferred. The “alkyl group” has a straight chain structure,
It may have either a branched structure or a part or all of a ring structure. The alkyl group has 1 to 1 carbon atoms
0 is preferable, and 1 to 6 is particularly preferable. Preferred specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group,
Examples thereof include an isopropyl group, an isobutyl group, a t-butyl group, a pentyl group and a hexyl group.

The "fluoroalkyl group" means a group having a structure in which some or all of the hydrogen atoms of the above "alkyl group" are substituted with fluorine atoms. The fluoroalkyl group is preferably a perfluoroalkyl group having a structure in which all the hydrogen atoms of the “alkyl group” are substituted with fluorine atoms, or a structure in which the perfluoroalkyl group exists at the terminal portion of the fluoroalkyl group. For example, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a heptafluoropropyl group and the like can be mentioned.

The "aryl group" means a monovalent aromatic hydrocarbon group, which may have a substituent (eg, lower alkyl group, halogen atom, lower alkoxyl group, lower alkylamino group, etc.). The aryl group is preferably a phenyl group or a derivative thereof, for example, a phenyl group,
Examples thereof include a tolyl group, a p-halophenyl group (eg, p-chlorophenyl group, p-bromophenyl group, etc.), an alkoxyphenyl group (eg, methoxyphenyl group, ethoxyphenyl group, etc.).

The starting material of the present invention is halogenophthalic anhydride represented by the general formula (1).

[0015]

[Chemical 4]

However, in the general formula (1), X ^{1 to} X
⁴ may be the same or different, respectively,
It represents a halogen atom or a hydrogen atom, and at least one is a fluorine atom.

In the general formula (1), X ^{1 to} X ⁴ may be the same or different and each represents a halogen atom or a hydrogen atom.
Fluorine atoms are preferred. X ^{1 to} X ⁴ in the general formula (1) are
If all are the same, or X ¹ and X ⁴ , X ² and X ³
Are preferably the same.

Specific examples of the halogenophthalic anhydride represented by the general formula (1) include 3,4,5,6-tetrafluorophthalic anhydride, 3,5,6-trifluorophthalic anhydride, and 3,5,6-trifluorophthalic anhydride. 4,5-Trifluorophthalic anhydride, 4,5-
Difluorophthalic anhydride, 3,4-difluorophthalic anhydride, 4,6-difluorophthalic anhydride, 3,6-difluorophthalic anhydride, 3,5,6-trifluoro-4-
Chlorophthalic anhydride, 3,4,5-trifluoro-6-
Chlorophthalic anhydride, 3,6-dichloro-4,5-difluorophthalic anhydride, 3,4-dichloro-5,6-difluorophthalic anhydride, 3,5-dichloro-4,6-difluorophthalic anhydride, 4,5-dichloro-3,6-difluorophthalic anhydride, 3-fluorophthalic anhydride, 4-
Examples thereof include fluorophthalic anhydride.

The compounds of the above general formula (1) are all compounds that are easily available or easily synthesized. For example, the corresponding fluorinated phthalic anhydride can be easily synthesized by reacting chlorinated phthalic anhydride with KF. In the case of 3,4,5,6-tetrafluorophthalic anhydride, chlorination of tetrachlorophthalic anhydride
3,3,4,5,6,7-hexachloro-1- [3H]
-Converted to isobenzofuranone and further reacted with KF to give tetrafluorophthaloyl fluoride and 3,3,4,
A preferred method is to convert it to a mixture of 5,6,7-hexafluoro-1- [3H] -isobenzofuranone and then react the mixture with sodium carbonate to synthesize it.

The halogenophthalic anhydride represented by the above general formula (1) is converted to a halogenophthalic acid monoester by reacting with a hydroxy compound.

The hydroxy compound is not particularly limited, but alcohols and hydroxyaryl compounds are preferable. As the alcohol, an alcohol having one hydroxyl group is preferable. As the alcohol having one hydroxyl group, alkyl alcohol and fluoroalkyl alcohol are preferable. The hydroxyaryl compound is preferably a compound in which one aryl group and one hydroxyl group are bonded.

Alkyl alcohol has a carbon number of 1
Alcohol having 10 to 10, preferably 1 to 6 alkyl groups is preferable, and any of primary alcohol, secondary alcohol, and tertiary alcohol may be used. The primary alcohol is preferably methanol, ethanol or the like, the secondary hydroxy compound is preferably isopropanol, 2-butanol or the like, and the tertiary hydroxy compound is preferably t-butanol or 2-methyl-2-butanol.

As the fluoroalkyl alcohol, trifluoroethanol, heptafluoropropanol and the like are preferable from the viewpoint of easy availability.

As the hydroxyaryl compound, phenol or alkoxyphenol is preferable, and phenol, p-methoxyphenol, p-ethoxyphenol and the like are preferable.

The reaction of the compound of the general formula (1) with the hydroxy compound is preferably carried out in the presence of an acid catalyst or a base catalyst.

As the acid catalyst, inorganic acids such as hydrochloric acid, phosphoric acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid, acetic acid and trifluoroacetic acid are preferable. Examples of the base catalyst include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, and organic bases such as triethylamine, tri-n-butylamine, and tri-n-octylamine. Classes are preferred. The amount of the acid catalyst and the base catalyst is about 0.001 to 100 mol, preferably 0.01 to 2 mol, based on 1 mol of the compound of the general formula (1).

The reaction temperature between the compound of the general formula (1) and the hydroxy compound is 0 ° C to 220 ° C, which can be changed depending on the type and concentration of the acid and alkali used.

The halogenophthalic acid monoester formed by the reaction of the compound of the general formula (1) and the hydroxy compound is a compound of the general formula (2) and the general formula (5).

[0029]

[Chemical 5]

[0030]

[Chemical 6]

However, the general formula (2) and the general formula (5)
In, X ^{1 to} X ⁴ are the same as the corresponding general formula (1). R is 1 excluding the hydroxyl group from the hydroxy compound
It is a valence group.

When all of X ^{1 to} X ⁴ are the same, or when X ¹ and X ⁴ are the same and X ² and X ³ are the same, the formula (2) The compound and the compound of the general formula (5) are the same compound. In other cases, the compound of general formula (2) and the compound of general formula (5) are different compounds. In the present invention, the halogenophthalic acid monoester includes both the compound of the general formula (2) and the compound of the general formula (5).

In the following reaction, the compound of the general formula (2) will be described as a representative example even when the compound of the general formula (2) is different from the compound of the general formula (5). In the case of the compound of 5), the same reaction proceeds. In addition, the following reactions in the general formula (5) are also included in the present invention.

When the compound of the general formula (2) and the compound of the general formula (5) are different, both compounds can be separated by an operation such as distillation or chromatography, if necessary. It is also possible to react both compounds as a mixture and separate them at a required stage.

The halogenophthalic acid monoester obtained by the above method is converted to the halogenobenzoic acid ester of the general formula (3) by decarboxylation. The halogenobenzoic acid ester obtained by decarboxylating the halogenophthalic acid monoester of the general formula (2) can be represented by the general formula (3).

[0036]

[Chemical 7]

However, in the general formula (3), X ^{1 to} X
⁴ and R are the same as above.

The decarboxylation reaction can be carried out by heating without solvent or in the presence of a solvent, preferably in the presence of a solvent. Examples of the solvent include water, a protic organic solvent (eg, glycols such as ethylene glycol), an aprotic polar organic solvent (eg, dimethylacetamide, sulfolane, etc.), or an aprotic apolar organic solvent (eg, toluene, Xylene, etc.) is preferred.

Further, a catalyst may be present in the decarboxylation reaction. As the catalyst, 3 such as triethylamine, tri-n-butylamine, tri-n-octylamine and the like are used.
Hydroxides, fluorides, carbonates, bicarbonates of primary amines, ammonia, alkali metals or alkaline earth metals,
Sulfates, organic acid salts and the like can be used. Further, it may be an acid catalyst such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid. The amount of the catalyst is 0.01 to 10 mol, preferably 0.1 to 5 mol, based on 1 mol of the compound represented by the general formula (2).

The reaction temperature for the decarboxylation reaction is 100 to 200 ° C.
The degree is preferable, and it can be changed depending on the types and concentrations of the acid and alkali used.

The halogenobenzoic acid ester produced by the above reaction is converted into halogenobenzoic acid by a hydrolysis reaction. The halogenobenzoic acid obtained by subjecting the halogenobenzoic acid ester of the general formula (3) to a hydrolysis reaction can be represented by the general formula (4).

[0042]

[Chemical 8]

However, in the general formula (4), X ^{1 to} X
⁴ is the same as above.

The hydrolysis reaction can be carried out according to a known or known method. Usually, it is preferable to react under acidic or basic conditions in the presence of water. The amount of water is not particularly limited, but in the normal case, it can be represented by the general formula (3)
About 1 to 10 parts by weight is preferable with respect to 1 part by weight of the compound represented by. As the acid, hydrochloric acid, phosphoric acid, sulfuric acid and the like are preferable. As the base, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like are preferable. The amount of the acid or base is 0.01 to 10 mol, preferably 0. 1 mol, relative to 1 mol of the halogenobenzoate represented by the general formula (3).
1-5 mol is preferred.

The reaction temperature of the hydrolysis reaction is 30 to 220 ° C.
The degree is preferable, but it can be changed depending on the types and concentrations of the acid and alkali. The above monoesterification, decarboxylation and hydrolysis reactions may be carried out in one step.

Specific examples of the halogenobenzoic acid obtained by the present invention include 2,3,4,5-tetrafluorobenzoic acid, 2,4,5-trifluorobenzoic acid, 2,3,3.
4-trifluorobenzoic acid, 3,4-difluorobenzoic acid, 3,5-difluorobenzoic acid, 2,4-difluorobenzoic acid, 2,4,5-trifluoro-3-chlorobenzoic acid, 2,3,3 4-trifluoro-5-chlorobenzoic acid, 2,5-dichloro-3,4-difluorobenzoic acid,
2,3-dichloro-4,5-difluorobenzoic acid, 2,
4-dichloro-3,5-difluorobenzoic acid, 3,4-
Examples thereof include, but are not limited to, dichloro-2,5-difluorobenzoic acid, 2-fluorobenzoic acid and 3-fluorobenzoic acid.

[0047]

EXAMPLES Examples of the present invention will be described more specifically below.

[Reference Example 1] In a 2 liter glass reactor equipped with a reflux condenser and a stirrer, 500 g (1.748 mol) of tetrachlorophthalic anhydride and 441 g (2.1 g of phosphorus pentachloride) were added.
0 mol) and 100 g of phosphorus oxychloride were charged, and the mixture was heated to 135 ° C. without stirring. Then 134-145
The mixture was stirred for 18 hours while maintaining the temperature at ℃. Then the phosphorus oxychloride was removed by distillation. Then, phosphorus oxychloride and phosphorus pentachloride were distilled off under reduced pressure. Lower the kettle temperature to 120 ° C,
200 g of toluene and 2 liters of hexane were gradually added, and the mixture was left standing overnight. When the crystalline substance is filtered and dried under reduced pressure 3, 3, 4,
430.0 g of 5,6,7-hexachloro-1- [3H] -isobenzofuranone was obtained. The yield was 72.1%.

[Reference Example 2] 3,3,4,5,6,7-hexachloro-1- [3H] synthesized in Reference Example 1 in a 100 ml glass reactor equipped with a reflux condenser and a stirrer.
-Isobenzofuranone 80 g (0.235 mol), spray-dried potassium fluoride 109.0 g (1.88 mol) and sulfolane 320 g were charged and reacted at 130 ° C for 5 hours while vigorously stirring.
Then, the reaction solution was separated by distillation, and a mixture of tetrafluorophthaloyl fluoride and 3,3,4,5,6,7-hexafluoro-1- [3H] -isobenzofuranone (1: 1) 42.8 g Got The yield was 75.2%.

Reference Example 3 In a 500 ml glass reactor equipped with a reflux condenser and a stirrer, the tetrafluorophthaloyl fluoride synthesized in Reference Example 2 and 3, 3, 4,
A mixture of 5,6,7-hexafluoro-1- [3H] -isobenzofuranone (1: 1) 100 g (0.413 mol), sodium carbonate 43.8 g (0.413 mol) and xylene 200 g were charged and stirred vigorously. The reaction was carried out at ℃ for 3 hours. After that, the inorganic substances are removed by filtration, and distillation separation is performed.
83.1 g of 4,5,6-tetrafluorophthalic anhydride was obtained. The yield was 91.5%.

Example 1 In a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 3,4,5,6-tetrafluorophthalic anhydride 20 g (0.
(091 mol) and 40 ml of methanol were charged, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the methanol was distilled off to give 3, 4,
5,6-Tetrafluorophthalic acid monomethyl ester 2
Obtained 2.5 g. The yield was 98.0%.

[Example 2] 3,4,5,6-tetrafluorophthalic acid monomethyl ester synthesized in Example 1 in a 100 ml three-necked flask 20 g (0.079 mol) tri-n-octylamine 27.9 g ( (0.079 mol), and at 140 ℃ 4
The mixture was heated and stirred for an hour. After completion of the reaction, distillation separation is performed,
3,4,5-Tetrafluorobenzoic acid methyl ester 1
5.5g was obtained. The yield was 94.2%.

Example 3 20 g (0.079 mol) tri-n-octylamine 2.8 g (0.079 mol) of 3,4,5,6-tetrafluorophthalic acid monomethyl ester synthesized in Example 2 was placed in a 100 ml three-necked flask. (0.0079 mol) at 140 ° C for 2
The mixture was heated and stirred for 4 hours. After completion of the reaction, distillation separation is performed,
3,4,5-Tetrafluorobenzoic acid methyl ester 1
Obtained 4.2 g. The yield was 86.3%.

Example 4 A 100 ml three-necked flask was charged with 20 g (0.096 mol) of 2,3,4,5-tetrafluorobenzoic acid methyl ester synthesized in Example 2 and 40 g of 70% by weight sulfuric acid. The mixture was reacted at 140 ° C for 10 hours with stirring.
Next, 100 ml of water was added to these reaction solutions, allowed to cool, and then extracted with hot toluene. Then, the solvent was distilled off to obtain 17.1 g of 2,3,4,5-tetrafluorobenzoic acid. The yield was 92%.

Example 5 20 g (0.09) of 3,4,5,6-tetrafluorophthalic anhydride synthesized in Reference Example 3 was placed in a 100 ml glass reactor equipped with a reflux condenser and a stirrer.
1 mol) and 32.2 g (0.091 mol) of tri-n-octylamine were charged, and 3.5 g (0.109 mol) of methanol was added dropwise.
Then, the mixture was reacted at 140 ° C for 4 hours. After completion of the reaction, distillation separation was carried out to obtain 17.5 g of 3,4,5,6-tetrafluorobenzoic acid methyl ester. The yield was 92.3%.

Example 6 A 100 ml glass reactor equipped with a reflux condenser and a stirrer was charged with 20 g (0.109 mol) of 4,5-difluorophthalic anhydride and 38.6 g (0.109 mol) of tri-n-octylamine. Charged, and 5.2 g of methanol
(0.164 mol) was added dropwise. Then, the mixture was reacted at 140 ° C for 8 hours. After completion of the reaction, distillation separation was carried out to obtain 17.3 g of 3,4-difluorobenzoic acid methyl ester. The yield was 92.2%.

Example 7 A 100 ml three-necked flask was charged with 20 g (0.116 mol) of 3,4-difluorobenzoic acid methyl ester synthesized in Example 6 and 40 g of 70% by weight sulfuric acid at 140 ° C. with stirring. Reacted for hours. Next, 100 ml of water was added to these reaction solutions, allowed to cool, and then extracted with hot toluene. Then, the solvent was distilled off to obtain 17.2 g of 3,4-difluorobenzoic acid. The yield was 94.0%.

Example 8 In a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 20 g (0.099 mol) of 3,4,6-trifluorophthalic anhydride and 35.0 g (0.099 mol) of tri-n-octylamine were added. ) And methanol
4.8 g (0.149 mol) was added dropwise. Then, the mixture was reacted at 140 ° C for 8 hours. After completion of the reaction, analysis by gas chromatography revealed that 87% of 2,4,5-trifluorobenzoic acid methyl ester had been formed.

Example 9 A 100 ml three-necked flask was charged with 20 g (0.105 mol) of 2,4,5-tetrafluorobenzoic acid methyl ester synthesized in Example 8 and 40 g of 70% by weight sulfuric acid at 140 ° C. The mixture was reacted for 8 hours with stirring. Next, 100 ml of water was added to these reaction solutions, allowed to cool, and then extracted with hot toluene. Then, the solvent is distilled off,
15.8 g of 2,4,5-difluorobenzoic acid was obtained. The yield is
It was 85.2%.

[0060]

EFFECTS OF THE INVENTION According to the method of the present invention, a target compound can be safely obtained by using easily available raw materials without using dangerous reagents or operations. Further, the present method is a very advantageous method even when it is carried out industrially, since the yield is good and the reaction conditions are mild.

Claims (5)

[Claims] 1. A halogenophthalic anhydride represented by the general formula (1) is reacted with a hydroxy compound to give a halogenophthalic acid monoester, and the halogenophthalic acid monoester is decarboxylated to give a halogenobenzoic acid ester. A method for producing halogenobenzoic acid by hydrolyzing a halogenobenzoic acid ester. [Chemical 1] (However, in the general formula (1), X ^{1 to} X ⁴ may be the same or different and each represents a halogen atom or a hydrogen atom, and at least one is a fluorine atom.) 2. A production of a halogenobenzoic acid ester by reacting a halogenophthalic anhydride represented by the general formula (1) with a hydroxy compound to give a halogenophthalic acid monoester, and decarboxylating the halogenophthalic acid monoester. Method. [Chemical 2] (However, in the general formula (1), X ^{1 to} X ⁴ may be the same or different and each represents a halogen atom or a hydrogen atom, and at least one is a fluorine atom.) 3. The method according to claim 1, wherein the general formulas X ^{1 to} X ⁴ represent a fluorine atom or a hydrogen atom, and at least one is a fluorine atom. 4. The method according to claim 1, wherein the halogenophthalic acid monoester is a halogenophthalic acid monoalkyl ester, a halogenophthalic acid monofluoroalkyl ester, or a halogenophthalic acid monoaryl ester. 5. The method according to claim 1, wherein a catalyst is present together with the hydroxy compound.