JPH04321644A - Production of 2,4,5-trifluorobenzoic acid - Google Patents

Abstract

PURPOSE:To produce 2,4,5-trifluorobenzoic acid useful for an intermediate for drugs and agricultural chemicals and the intermediate thereof industrially, safely and simply from 2,4,5-trichlorobenzonitrile. CONSTITUTION:2,4 5-Trichlorobenzonitrile is fluorinated with a fluorinating agent such as KF to produce 5-chloro-2,4-difluorobenzonitrile or 2,4,5- trifluorobenzonitrile. 5-Chloro-2,4-difluorobenzonitrile is fluorinated in the presence of a phase transfer catalyst to produce 2,4,5-trifluorobenzonitrile. 2,4,5- Trifluorobenzonitrile is hydrolyzed to produce 2,4,5-trifluorobenzoic acid.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 2,4,5-trifluorobenzoic acid and its intermediates, which are useful as intermediates for medicines and agrochemicals.

0002

BACKGROUND OF THE INVENTION Conventionally, the following method has been known as a method for producing 2,4,5-trifluorobenzoic acid. 1) A method in which 2-amino-4,5-difluorobenzoic acid esters are diazofluorinated and then hydrolyzed (J.C.
hem. Eng. Data, 13 (4), 587
, 1968). 2) Method for obtaining phthalonitriles by chlorination, fluorination, defluorination, hydrolysis, and decarboxylation (EP-30789
7, JP-A-1-52737, etc.). 3) A method for hydrolyzing 2,4,5-trifluorobenzotrifluoride (Japanese Unexamined Patent Publication No. 108839/1983).

0003

[Problem to be solved by the invention] 1) 2-amino-4
, 5-difluorobenzoic acid esters as starting materials have production problems such as low yields and the use of fluoroboric acid, which is harmful to the human body. The method 2) using phthalonitriles as a starting material involves a multi-stage reaction and has many problems such as the toxicity of intermediate products. The method of hydrolyzing 2,4,5-trifluorobenzotrifluoride (3) uses concentrated sulfuric acid at a temperature of 140 DEG C., and has many problems, such as the formation of a hydrofluoric acid-sulfuric acid mixture as waste liquid.

0004

[Means for Solving the Problems] The present invention has been made to solve the problems of the prior art, such as low yield, toxicity of intermediate products, and multi-stage reactions, and is industrially safe. The present invention provides a simple method for producing 2,4,5-trifluorobenzoic acid and its intermediates.

[0005] The method for producing 2,4,5-trifluorobenzoic acid in the present invention involves fluorinating 2,4,5-trichlorobenzonitrile to produce 2,4,5-trifluorobenzonitrile. Hydrolyze 2,4,
This is a method to obtain 5-trifluorobenzoic acid.

[0006] Furthermore, a method for producing an intermediate of 2,4,5-trifluorobenzoic acid involves fluorinating 2,4,5-trichlorobenzonitrile to produce 5-chloro-2,4-difluorobenzonitrile or 2,4-trifluorobenzonitrile. , 5-trifluorobenzonitrile, and fluorination of 2,4,5-trichlorobenzonitrile to produce 5-chloro-2,4-difluorobenzonitrile, which is then fluorinated in the presence of a phase transfer catalyst. This is a method of fluorination to produce 2,4,5-trifluorobenzonitrile.

The starting material 2,4,5-trichlorobenzonitrile is a compound that is easily available industrially.
By fluorinating this, 5-chloro-2,4-difluorobenzonitrile or 2,4,5-trifluorobenzonitrile can be produced.

In the fluorination of 2,4,5-trichlorobenzonitrile, chlorine atoms at the meta position are less likely to be fluorinated than chlorine atoms at the ortho and para positions. Therefore, first, 2,4,5-trichlorobenzonitrile is fluorinated to produce 5-chloro-2,4-difluorobenzonitrile.
A method of producing 2,4,5-trifluorobenzonitrile by fluorinating -difluorobenzonitrile in the presence of a phase transfer catalyst is preferred in terms of reaction yield.

Fluorination of 5-chloro-2,4-difluorobenzonitrile is a method for fluorination of 5-chloro-2,4-difluorobenzonitrile in the reaction product produced by fluorination of 2,4,5-trichlorobenzonitrile.
Isolated chloro-2,4-difluorobenzonitrile may be used;
-chloro-2,4-difluorobenzonitrile and 2,4
, 5-trifluorobenzonitrile may be isolated or may be subjected to fluorination without isolation.

[0010] When fluorinating 2,4,5-trichlorobenzonitrile, a method in which a phase transfer catalyst is present from the beginning is also preferred. This method uses 5-chloro-2,4-
Difluorobenzonitrile can be isolated or 5-chloro-
This is because there is no need to isolate a mixture of 2,4-difluorobenzonitrile and 2,4,5-trifluorobenzonitrile, and there is no need to add a phase transfer catalyst during the fluorination reaction.

[0011] In the fluorination, it is preferable to react with a fluorinating agent without a solvent or in an aprotic solvent. As the fluorinating agent, alkali metal fluorides such as NaF, KF, RbF, and CsF are preferred, and spray-dried potassium fluoride is particularly preferred. The amount of the fluorinating agent to be used is 3 to 10 times the mole, preferably 3.3 to 5 times the mole of the chlorine atoms to be substituted with fluorine in the raw material. The reaction temperature for fluorination is 120-300°C, preferably 180-250°C.
It is. Fluorination can be accelerated by the presence of a phase transfer catalyst.

Such phase transfer catalysts include quaternary ammonium salts such as tetramethylammonium chloride and tetrabutylammonium bromide, N-neopentyl-4-(N',N'-dimethylamino)-pyridinium chloride, N- (2-ethyl-hexyl)-4-(N'
, N'-dimethylamino)-pyridinium chloride, and quaternary phosphonium salts such as tetrabutylphosphonium bromide and tetraphenylphosphonium bromide.

Examples of aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphorotriamide, N-methyl-2-
Pyrrolidone, acetonitrile, benzonitrile, dioxane, diglyme, tetraglyme, etc. can be used, but sulfolane and N,N-dimethylformamide are preferable. The amount used is equal to the weight of the raw material to 1
0 times the weight, preferably 1.0 times to 5 times the weight.

[0014] The hydrolysis of 2,4,5-trifluorobenzonitrile is preferably carried out under acidic conditions, and particularly preferred is a method in which 2,4,5-trifluorobenzonitrile is heated under reflux in an aqueous sulfuric acid solution. Sulfuric acid concentration is 5
0 to 70%, the amount used is preferably 2 to 10 times the weight of the raw material, and the hydrolysis temperature is preferably 100 to 160°C. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples.

[0015]

【Example】

Example 1 A 200 ml autoclave was charged with 30 g (0.145 mol) of 2,4,5-trichlorobenzonitrile, 33.7 g (0.581 mol) of spray-dried potassium fluoride, 3.0 g of tetraphenylphosphonium bromide, and 90 g of sulfolane. , with vigorous stirring, at 200 °C for 20
Allowed time to react. Gas chromatography analysis of the product revealed that 2
,4,5-trifluorobenzonitrile and 5-chloro-
A mixture with a ratio of 2,4-difluorobenzonitrile of 63:37 was obtained. After filtering the inorganic substances, distillation separation is performed using a distillation column with a reflux device, and the temperature is 94-95℃/50mm.
9.73 g of 2,4,5-trifluorobenzonitrile having a boiling point of Hg was obtained. The yield was 42.7%.

Example 2 In a 500 ml autoclave, 50 g (0.242 mol) of 2,4,5-trichlorobenzonitrile, 126 g (2.17 mol) of spray-dried potassium fluoride, 5.0 g of tetraphenylphosphonium bromide, 25 g of sulfolane
0 g was charged and reacted at 220° C. for 25 hours with vigorous stirring. Gas chromatography analysis of the product revealed that 2.
Yield of 4,5-trifluorobenzonitrile 76.2%
, the yield of 5-chloro-2,4-difluorobenzonitrile was 7.3%.

Example 3 In a glass reactor equipped with a reflux condenser and a stirrer,
150 g of 2,4,5-trichlorobenzonitrile (0.
73 mol), spray-dried potassium fluoride 126.39
(2.18 mol) and 500 g of sulfolane were charged, and the mixture was reacted at 200° C. for 13 hours with vigorous stirring. Gas chromatography analysis of the product revealed that the reaction rate of the raw materials was 99.6.
%, the yield of 5-chloro-2,4-difluorobenzonitrile was 91.8%.

40 g (0.23 mol) of the obtained 5-chloro-2,4-difluorobenzonitrile, 26.74 g (0.46 mol) of spray-dried potassium fluoride, 4 g of tetraphenylphosnium bromide, and 100 g of sulfolane.
was charged into a 200 ml autoclave, and reacted at 220° C. for 16 hours with vigorous stirring. Gas chromatography analysis of the product revealed that the reaction rate of the raw materials was 82.2%, 2,4,
The yield of 5-trifluorobenzonitrile was 96.7%.

Example 4 Using a 200 ml glass reactor equipped with a reflux condenser, 10 g of 2,4,5-trifluorobenzonitrile obtained in Example 1 and 100 ml of 60% sulfuric acid were refluxed for 12 hours. After cooling, the reaction solution was gradually poured into ice water, extracted with chloroform, and the extract was washed with water and dried. The solvent was distilled off and 2,4,5-trifluorobenzoic acid 10
．． 20g was obtained. Yield 91%. Melting point 93-95°C.

[0020]

Effects of the Invention According to the present invention, 2,4,5-trichlorobenzonitrile can be obtained from 2,4,5-trichlorobenzonitrile, which is useful as a pharmaceutical and agricultural intermediate.
, 5-trifluorobenzoic acid and its intermediates can be obtained industrially safely and easily.

Claims (5)

[Claims] 1. A 2,4,5-trichlorobenzonitrile, which is characterized in that 2,4,5-trifluorobenzonitrile is produced by fluorinating 2,4,5-trichlorobenzonitrile, and then this is hydrolyzed. Method for producing fluorobenzoic acid. 2. The method of claim 1, wherein the fluorination is carried out in the presence of a phase transfer catalyst. 3. A method for producing 5-chloro-2,4-difluorobenzonitrile or 2,4,5-trifluorobenzonitrile, which comprises fluorinating 2,4,5-trichlorobenzonitrile. 4. The method of claim 3, wherein the fluorination is carried out in the presence of a phase transfer catalyst. 5. A process characterized in that 2,4,5-trichlorobenzonitrile is fluorinated to produce 5-chloro-2,4-difluorobenzonitrile, which is then fluorinated in the presence of a phase transfer catalyst. A method for producing 2,4,5-trifluorobenzonitrile.