JPH0717904A - Method for producing 2,3,4,5-tetrafluorobenzoic acid - Google Patents

Abstract

PURPOSE:To produce 2,3,4,5-tetrafluorobenzoic acid according to an industrialy advantageous and safe method. CONSTITUTION:A 3,4,5,6-tetrafluorophthalic acid diester is hydrolyzed to provide 3,4,5,6-tetrafluorophthalic acid, which is then subjected to the decarboxylating reaction to afford 2,3,4,5-tetrafluorobenzoic acid. The 3,4,5,6-tetrafluorophthalic acid diester is obtained by fluorinating 3,4,5,6-tetrachlorophthalic acid diester.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing 2,3,4,5-tetrafluorobenzoic acid, which is useful as an intermediate for pharmaceuticals, particularly synthetic antibacterial agents.

[0002]

2. Description of the Related Art Conventionally, the following methods have been known as methods for obtaining 2,3,4,5-tetrafluorobenzoic acid. (1) A method in which phthalonitrile is chlorinated to be converted into 3,4,5,6-tetrachlorophthalonitrile, and then fluorinated, hydrolyzed and decarboxylated (JP-A-61-85349).

(2) 3,4,5,6-tetrachlorophthalic anhydride is reacted with phosphorus pentachloride to give 3,3,4,5,
6,7-Hexachloro-1- [3H] -isobenzofuranone, which was then fluorinated to give 3,3,4,5,6,7
-Hexafluoro-1- [3H] -isobenzofuranone, further hydrolyzed to 3,4,5,6-tetrafluorophthalic acid, and then decarboxylation (JP-A-62-62)
-61948).

(3) 3,4,5,6-tetrachlorophthalic anhydride is reacted with amines to give 3,4,5,6-tetrachlorophthalimides, and then fluorination, hydrolysis and decarboxylation. Method (JP-A-63-58442, U
SP5047553 etc.).

[0005]

However, the conventional method has the following problems. In the method (1), since the chlorination reaction is carried out in the gas phase, it is necessary to vaporize phthalonitrile having a high melting point, and there are problems such as deactivation of the chlorination catalyst, which makes industrial implementation difficult. . Further, 3,4,5,6-tetrachlorophthalonitrile is highly toxic and has a problem in handling.

The method (2) is not economical because the yield of fluorination is low and the required amount of the fluorinating reagent is large, and hydrofluoric acid is generated during hydrolysis.
There are problems such as corrosion of the reactor.

In the method (3), since the fluorination reaction is carried out at a high temperature, the stability of the imide compound is lowered and the yield is lowered.

[0008]

The present invention solves the above-mentioned drawbacks of the prior art and is industrially advantageous.
The present invention provides a method for producing 4,5-tetrafluorobenzoic acid. The present invention also provides intermediates 3, 4, 5, 6-
The present invention provides a method for producing tetrafluorophthalic acid diester, and a specific intermediate compound in these production methods.

That is, the manufacturing method of the present invention is 3, 4, 5,
By hydrolyzing 6-tetrafluorophthalic acid diester to give 3,4,5,6-tetrafluorophthalic acid, and then by decarboxylating 3,4,5,6-tetrafluorophthalic acid 2, Method for producing 3,4,5-tetrafluorobenzoic acid, and 3,4,5,6
-A method for producing 3,4,5,6-tetrafluorophthalic acid diester, which comprises reacting tetrachlorophthalic acid diester with fluorine.

The 3,4,5,6-tetrafluorophthalic acid diester in the present invention has the following general formula (1)
Compounds represented by are preferred.

[0011]

[Chemical 1]

In the general formula (1), R ¹ and R ²
May be the same or different and each represents an alkyl group, a fluoroalkyl group or an aryl group.

The alkyl group preferably has 1 to 20 carbon atoms, and particularly preferably has 6 or less carbon atoms. The structure of the alkyl group may be a linear, branched or cyclic structure, and the cyclic structure may be a part of the alkyl group.

Examples of the alkyl group are listed below, but are not limited thereto. Methyl group, ethyl group, n-propyl group, isopropyl group, isobutyl group, t-butyl group, n
-Butyl group, pentyl group, hexyl group, cyclohexyl group, heptyl group, n-octyl group and the like.

The fluoroalkyl group is the above-mentioned alkyl group in which some or all of the hydrogen atoms are replaced with fluorine atoms, and some of the fluorine atoms may be replaced with chlorine or bromine atoms. It is preferred that some of the hydrogens on the radical are replaced by fluorine atoms. Especially - (CH _{2) k}
A fluoroalkyl group represented by Rf (where Rf is a perfluoroalkyl group having 1 to 8 carbon atoms, and k is 1 or 2) is preferable.

Examples of fluoroalkyl groups are given below.
However, it is not limited to these. -CH₂ CF₃ , -CH₂ 
CH₂ CF₃ , -CH (CF₃ )₂ , -CH₂ CH₂ C
F₂ CF₃ , -CH₂ CH₂ CF₂ CF₂ CF₃ , -C
H₂ CH (CF₃ ) ₂ , -CH₂ CH₂ CF₂ Cl,-
CH₂ CH₂ CF₂ Br.

The aryl group is a monovalent aromatic hydrocarbon group, and may have a halogen atom, an alkyl group or the like bonded to the phenyl group or the aromatic ring of the phenyl group. Examples of aryl groups include, but are not limited to: Examples thereof include a phenyl group, a tolyl group, a xylyl group, a 4-chlorophenyl group, a 4-fluorophenyl group, a perfluorophenyl group and a 4-methylphenyl group.

3, 4, 5, 6-represented by the general formula (1)
Non-limiting examples of tetrafluorophthalic acid diesters are given below. 3,4,5,6-tetrafluorophthalic acid bis (2,2,2-trifluoroethyl) ester, 3,4,5,6-tetrafluorophthalic acid dimethyl ester, 3,4,5,6-tetra Fluorophthalic acid diethyl ester, 3,4,5,6-tetrafluorophthalic acid diisopropyl ester, 3,4,5,5
6-tetrafluorophthalic acid di (n-propyl) ester, 3,4,5,6-tetrafluorophthalic acid dibutyl ester, 3,4,5,6-tetrafluoroacid diphenyl ester, 3,4,5,6 -Tetrafluorotalic acid propyl methyl ester.

The 3,4,5,6-tetrafluorophthalic acid diester is converted into 3,4,5,6-tetrafluorophthalic acid by a hydrolysis reaction.

The hydrolysis reaction can be carried out according to the usual hydrolysis reaction method and conditions. For example, it can be hydrolyzed by reacting in water or an organic solvent under acidic or alkaline conditions.

The acid when carried out under acidic conditions includes
Hydrochloric acid, phosphoric acid, sulfuric acid and the like are suitable. The amount of acid is usually about 0.5 to 48 equivalents, preferably about 1 to 20 equivalents, relative to 1 equivalent of 3,4,5,6-tetrafluorophthalic acid diester.

When carried out under alkaline conditions, the alkali includes sodium hydrogen carbonate, potassium hydrogen carbonate,
Sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like are suitable. The amount of alkali is usually about 0.01 to 20 equivalents, preferably about 0.01 to 2 equivalents, relative to 1 equivalent of 3,4,5,6-tetrafluorophthalic acid diester.

The reaction temperature of the hydrolysis reaction is usually 3
0 ~ 220 ℃, reaction time 0.5 ~ 36 hours,
The reaction pressure may be normal pressure, increased pressure, or reduced pressure,
The conditions can be appropriately changed depending on the type of 3,4,5,6-tetrafluorophthalic acid diester, the type of acid or alkali, and the concentration.

In the present invention, 2,3,4,5-tetrafluorobenzoic acid is obtained by decarboxylating 3,4,5,6-tetrafluorophthalic acid.

The decarboxylation reaction is carried out by the usual decarboxylation method,
And according to the conditions. For example, it can be carried out by heating without a solvent or in a solvent.

When it is carried out in a solvent, a water solvent, a protic solvent such as ethylene glycol or propylene glycol, an aprotic polar solvent such as dimethylacetamide or sulfolane, or an aprotic nonpolar solvent such as toluene or xylene. Etc. can be used. The amount of solvent is 3, 4,
About 3 parts by weight or less is preferable for 1 part by weight of 5,6-tetrafluorophthalic acid.

The decarboxylation reaction may be carried out in the presence of a catalyst. As the catalyst in this case, tertiary amines such as triethylamine and tributylamine, ammonia, hydroxides and fluorides of alkali metals or alkaline earth metals,
Carbonates, bicarbonates, sulfates, organic acid salts and the like can be used. Further, an acid catalyst such as sulfuric acid, hydrochloric acid or paratoluenesulfonic acid may be used. The amount of the catalyst depends on the type of the catalyst and the basic strength of the catalyst, but in the usual case, it is 3, 4,
It is preferably about 0.1 to 6 parts by weight per 1 part by weight of 5,6-tetrafluorophthalic acid.

The reaction temperature of the decarboxylation reaction is 100 to 220 ° C.
The reaction time is usually 0.5 to 24 hours, preferably about 1 to 3 hours, and the reaction pressure is usually atmospheric pressure, but may be reduced pressure or increased pressure.

The 3,4,5,6-tetrafluorophthalic acid diester can be synthesized by fluorinating 3,4,5,6-tetrachlorophthalic acid diester.

As the 3,4,5,6-tetrachlorophthalic acid diester, a compound represented by the following general formula (2) is preferable.

[0031]

[Chemical 2]

In the general formula (2), R ¹ and R ²
Are the same as the corresponding R ¹ and R ² of the general formula (1), and R ¹ and R ² may be the same or different, and each is an alkyl group, a fluoroalkyl group, or an aryl group. Represents

3,4,5,6-represented by the general formula (2)
Specific examples of the tetrachlorophthalic acid diester are shown below, but the invention is not limited thereto. 3,4,5,6-Tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester, 3,4,5,6-tetrachlorophthalic acid dimethyl ester, 3,4,5,6-tetra Chlorophthalic acid diethyl ester, 3,4,5,6-tetrachlorophthalic acid diisopropyl ester, 3,4,5,6-tetrachlorophthalic acid di-n-propyl ester, 3,
4,5,6-tetrachlorophthalic acid dibutyl ester,
3,4,5,6-tetrachlorophthalic acid diphenyl ester, 3,4,5,6-tetrachlorophthalic acid propyl methyl ester and the like.

The fluorination reaction is usually carried out using a fluorinating agent. As the fluorinating agent, NaF,
Alkali metal fluorides such as KF, RbF and CsF are preferable, and spray-dried potassium fluoride is particularly preferable. The amount of the fluorinating agent used is 1 to 15 mol, preferably 2 to 8 mol, based on 1 mol of 3,4,5,6-tetrachlorophthalic acid diester.

During the fluorination, it is preferable to add a phase transfer catalyst as a reaction accelerator. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetramethylammonium chloride and tetrabutylammonium bromide, N-neopentyl-4- (N, N-dimethylamino) pyridinium chloride, N- (2-ethylhexyl) -4-.
A pyridinium salt such as (N, N-dimethylamino) pyridinium chloride, tetrabutylphosphonium bromide,
Examples thereof include quaternary phosphonium salts such as tetraphenylphosphonium bromide, and the phase transfer catalyst of the present invention is preferably a quaternary phosphonium salt, particularly tetrabutylphosphonium bromide or tetraphenylphosphonium bromide.

The amount of the phase transfer catalyst added is 3,
100 of 4,5,6-tetrachlorophthalic acid diester
Usually, it is about 0.01 to 100 parts by weight, preferably about 0.05 to 20 parts by weight with respect to parts by weight.

The fluorination reaction can be carried out without solvent or in a solvent, but is preferably carried out in a solvent.

When it is carried out in a solvent, it is preferably carried out in an aprotic solvent. As the aprotic solvent, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphoryltriamide,
N-methyl-2-pyrrolidone, 1,3-dimethylimidazolidinone, acetonitrile, benzonitrile, dioxane, diglyme, tetraglyme and the like can be used, but sulfolane or N, N-dimethylformamide is preferable.

The amount of aprotic solvent used is 3, 4,
The amount is about 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight, based on 1 part by weight of 5,6-tetrachlorophthalic acid diester.

The reaction temperature for the fluorination reaction is 50 ° C. to 250 ° C.
The temperature is about 0 ° C, preferably 100 ° C to 230 ° C.

The 3,4,5,6-tetrachlorophthalic acid diester can be easily synthesized from readily available tetrachlorophthalic anhydride. For example, tetrachlorophthalic anhydride is chlorinated with a chlorinating agent such as phosphorus pentachloride or phosphorus oxychloride to give perchlorophthalide (JP-A-62-6194).
No. 8), and can be further synthesized by reacting with alcohol (Liebigs, Ann. Chem., 238, 327 (1887)).

[0042]

EXAMPLES Examples of the present invention will be described below in more detail, but the invention is not limited thereto.

Reference Example 1 Synthesis of 3,3,4,5,6,7-hexachloro-1- [3H] -isobenzofuranone A 2 liter glass reactor equipped with a reflux condenser and a stirrer. , 3,4,5,6-tetrachlorophthalic anhydride 500 g (1.8 mol), phosphorus pentachloride 441
g (2.1 mol) and 100 g of phosphorus oxychloride were charged. The mixture was heated to 135 ° C without stirring. afterwards,
It stirred for 12 hours, keeping at 134-145 degreeC. Further, 40 g of phosphorus pentachloride was added and stirred for 3 hours. Next,
Phosphorus oxychloride was removed by distillation. Furthermore, after refluxing was continued for 12 hours, the remaining phosphorus oxychloride and phosphorus pentachloride were distilled off under reduced pressure. Next, the temperature was lowered to 120 ° C., 200 g of toluene and 2 liters of hexane were gradually added and left overnight. When the crystals are filtered and then dried under reduced pressure, 3, 3, 4, 5, 6, 7-hexachloro-1- [3H]
430.0 g of isobenzofuranone were obtained. Yield 7
It was 2.1%.

Reference Example 2 Synthesis of 3,4,5,6-tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester 2 liter glass reaction equipped with reflux condenser and stirrer 300 g of 3,3,4,5,6,7-hexachloro-1- [3H] -isobenzofuranone
(0.9 mol) and 600 g of toluene were charged, and with vigorous stirring, 195.5 g (1.94 g) of triethylamine was added.
Mol) was slowly added dropwise over 30 minutes. Next,
21,2,2-trifluoroethanol 211.3g
(2.1 mol) was added dropwise over 1 hour, and the mixture was further stirred for 12 hours. Next, 500 g of toluene and 1 liter of water were added, and the extracted toluene phase was concentrated to give 3, 4, 5, 6-
379.7 g of tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester was obtained. Yield 92.2
%Met. The physical property values of 3,4,5,6-tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester were as follows. Melting point (° C): 75.1 to 75.4 ¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ) δ (ppm): -73.1 (t, J = 8.64 H
z) ¹ H-NMRR (CDCl ₃ , TMS) δ (ppm): 4.97 (q, J = 8.64 Hz)

[Example 1] Bis (2,2,2-trifluoroethyl) 3,4,5,6-tetrafluorophthalate
Synthesis of ester In a 100 ml glass reactor equipped with a reflux condenser and stirrer, 20 g of tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester was added.
(0.043 mol), 14.9 g (0.26 mol) of spray-dried potassium fluoride and 60 g of sulfolane were charged and reacted at 190 ° C. for 20 hours with vigorous stirring. After that, filtration and distillation separation are performed, and 3, 4, 5, 6-
11.2 g (0.028 mol) of tetrafluorophthalic acid bis (2,2,2-trifluoroethyl) ester was obtained. The yield was 65.0%.

[Example 2] Bis (2,2,2-trifluoroethyl) 3,4,5,6-tetrafluorophthalate
Synthesis of ester In a 100 ml glass reactor equipped with a reflux condenser and stirrer, 20 g of tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester was added.
(0.042 g mol), 14.9 g (0.26 mol) of spray-dried potassium fluoride, 2 g of tetrabutylphosphonium bromide and 60 g of sulfolane were charged and reacted at 140 ° C. for 6 hours with vigorous stirring. Then, filtration and distillation separation were performed to obtain 14.6 g (0.364 mol) of 3,4,5,6-tetrafluorophthalic acid bis (2,2,2-trifluoroethyl) ester. Yield 8
It was 5.2%.

[Example 3] Bis (2,2,2-trifluoroethyl) 3,4,5,6-tetrafluorophthalate
Synthesis of ester In a 100 ml glass reactor equipped with a reflux condenser and stirrer, 20 g of tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester was added.
(0.043 mol), 14.9 g (0.26 mol) of spray-dried potassium fluoride, 2 g of tetraphenylphosphonium bromide and 60 g of sulfolane were charged and reacted at 140 ° C. for 6 hours while vigorously stirring. afterwards,
Filtration and distillation separation were carried out to obtain 13.4 g (0.033 mol) of 3,4,5,6-tetrafluorophthalic acid bis (2,2,2-trifluoroethyl) ester. Yield 7
It was 8.2%.

Example 4 Synthesis of 3,4,5,6-tetrafluorophthalic acid bisisopropyl ester In a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 40 g of tetrachlorophthalic acid bisisopropyl ester was added. (0.12 mol), 42.3 g (0.732 mol) of potassium fluoride dried by spraying, 4 g of tetrabutylphosphonium bromide and 120 g of sulfolane were charged and reacted at 150 ° C. for 8 hours with vigorous stirring. After that, filtration and distillation separation are performed,
21.5 g (0.082 mol) of 3,4,5,6-tetrafluorophthalic acid bisisopropyl ester was obtained. The yield was 67.2%.

Example 5 Synthesis of 3,4,5,6-tetrafluorophthalic acid bismethyl ester In a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 3,4,5,6- 40 g (0.12 mol) of tetrachlorophthalic acid bisdimethyl ester, 41.8 g of spray-dried potassium fluoride
(0.73 mol), 4 g of tetrabutylphosphonium bromide and 120 g of sulfolane were charged and reacted at 150 ° C. for 8 hours with vigorous stirring. Then, filtration and distillation separation were carried out to obtain 20.1 g (0.076 mol) of 3,4,5,6-tetrafluorophthalic acid bismethyl ester. The yield was 63.0%.

[Example 6] Synthesis of 3,4,5,6-tetrafluorophthalic acid 3,4,5,6-tetrafluorophthalic acid bis synthesized in Example 5 was placed in a one-liter three-necked flask. (2,
2,2-trifluoroethyl) ester 30 g (0.0
75 mol) and 100 g of sulfuric acid diluted to 70% by weight were charged and reacted at 140 ° C. for 14 hours while stirring. Next, 200 ml of water was added, the mixture was allowed to cool, the white precipitate was filtered and dried to obtain 16.4 g of 3,4,5,6-tetrafluorophthalic acid. The yield was 92.3%.

[Example 7] Synthesis of 2,3,4,5-tetrafluorobenzoic acid 20 g of 3,4,5,6-tetrafluorophthalic acid synthesized in Example 6 (0.
(084 mol) and 60 g of water were charged, and the mixture was heated and stirred at 190 ° C. for 5 hours to cause a reaction. The suspension after completion of the reaction was cooled to room temperature, filtered, washed and dried to obtain 13.5 g of 2,3,4,5-tetrafluorobenzoic acid. The yield was 83.0%.

Example 8 Synthesis of 2,3,4,5-tetrafluorobenzoic acid 50 g of 3,4,5,6-tetrafluorophthalic acid synthesized in Example 6 was placed in a 500 ml three-necked flask.
(0.21 mol), tri (n-butyl) amine 190 g
(1.03 mol) was charged and stirred at 130 ° C. for 2 hours. 800 g of concentrated hydrochloric acid diluted to 20% by weight in this solution,
After adding 500 ml of ether and extracting with ether, an ether phase and an aqueous phase were separated. By adding 1 N KOH to the aqueous phase to make it alkaline (pH = 13), the tri (n
-Butyl) amine was recovered. After combining the aqueous phase and the ether phase, the aqueous phase was acidified (pH = 3) with 1N HCl and extracted with ether again. When the ether is distilled off,
White solid of 3,4,5-tetrafluorobenzoic acid 36.
3 g was obtained. The yield was 89.0%.

[0053]

According to the production method of the present invention, 2,3,4,5-tetrafluorobenzoic acid can be obtained by a safe method using easily available raw materials. In addition, this method
High yields of 2,3,4 without handling unstable compounds
Since it is a production method for obtaining 5-tetrafluorobenzoic acid, it is an industrially very advantageous method.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kiyosaku Kumai 1150, Hazawa-machi, Kanagawa-ku, Yokohama, Kanagawa Prefecture Asahi Glass Co., Ltd. Central Research Laboratory

Claims (9)

[Claims] 1. A method of hydrolyzing 3,4,5,6-tetrafluorophthalic acid diester to give 3,4,5,6-tetrafluorophthalic acid, and then decarboxylating tetrafluorophthalic acid. 2, 3,
Method for producing 4,5-tetrafluorobenzoic acid. 2. A fluorination reaction of 3,4,5,6-tetrachlorophthalic acid diester.
Process for producing 4,5,6-tetrafluorophthalic acid diester. 3. 3,4,5,6-Tetrachlorophthalic acid diester is subjected to a fluorine reaction to give 3,4,5,6-tetrafluorophthalic acid diester, and then 3,4,4.
Characterized by hydrolyzing 5,6-tetrafluorophthalic acid diester to give 3,4,5,6-tetrafluorophthalic acid, and further decarboxylating 3,4,5,6-tetrafluorophthalic acid Shall be 2, 3, 4, 5
-Method for producing tetrafluorobenzoic acid. 4. The method according to claim 2, wherein an alkali metal fluoride is used in the fluorination reaction. 5. The production method according to claim 2, wherein the fluorination reaction is carried out in the presence of a phase transfer catalyst. 6. The method according to claim 5, wherein the phase transfer catalyst is a quaternary phosphonium salt. 7. A bis (2,2,2-trifluoroethyl) ester of 3,4,5,6-tetrachlorophthalic acid. 8. A bisisopropyl ester of 3,4,5,6-tetrachlorophthalic acid. 9. A bisisopropyl ester of 3,4,5,6-tetrafluorophthalic acid.