JPH03275647A - Production of fluorobenzene acids - Google Patents

Abstract

PURPOSE:To obtain the title compound in high yield without any problems in the aspects of working environment by Friedel Crafts acylation, haloformylation, nitration and denitrochlorination successively in this order of a fluorobenzene as starting material. CONSTITUTION:A fluorobenzene of formula I (X is F or Cl) is put to Friedel Crafts acylation into a 5-fluoroacetophenone of formula II, which is then put to haloformylation into a compound of formula III. This compound is then nitrated by a nitrating agent into a compound of formula IV, which is then finally reacted with a chlorinating agent to effect denitrochlorination into a compound of formula V. A compound of formula VI where X is Cl in the formula V is converted to an acyl chloride of formula VII, which is then fluorinated into a compound of formula VIII. This compound is then hydrolyzed to obtain the objective fluorobenzoic acid of formula IX. The present method is industrially advantageous, and the present compound is useful as e.g. an intermediate for antifungal agents.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides 2,3-dichloro-4,5-difluorobenzoic acid and 3-chloro- The present invention relates to a method for producing 2°4.5-)-lifluorobenzoic acid.

[Prior Art] The following methods are known for producing 3-chloro-2,4,5-trifluorobenzoic acid, and another method is 2,4,5-trifluorobenzoic acid.
．． This is a method of chlorinating 5-trifluorobenzoic acid.

(JP-A No. 62-145088, etc.) Furthermore, a method for producing 2,3 dichloro-4,5-difluorobenzoic acid using 3,4-dichlorobenzotrifluoride as a starting material is known. (Unexamined Japanese Patent Publication No. 62-1
08839, etc.) [Problems to be Solved by the Invention] In the method shown in JP-A-63-88157, Sandmeyer reaction is used as the chlorine introduction reaction. In this method, the diazonium salt as an intermediate product is extremely toxic, and there is a problem of burn injury to workers who handle it. Furthermore, this diazonium salt is unstable and easily decomposed, making it impossible to obtain the target compound in high yield. Furthermore, there are several drawbacks, such as low volumetric efficiency of the reaction and generation of a large amount of acidic waste liquid. Furthermore, in the method shown in JP-A-62-145088, perchlorinated products (3,6-dichloro-
Since 2,,4°5-trifluorobenzoic acid) is produced, it is necessary to stop the chlorination at a low reaction rate and recycle the raw material. Furthermore, in the method using 3,4-dichlorobenzotrifluoride as a starting material, the yield of 3,4-difluorobenzotrifluoride is low. Furthermore, in the hydrolysis process, HF-concentrated sulfuric acid waste liquid is produced, and its handling is difficult.

[Means for Solving the Problems] The present inventors have conducted repeated studies to find a method for obtaining fluorobenzoic acids that is industrially advantageous, and have found that there is no problem in the working environment and that the yield is low. We have completed and proposed a highly superior method. That is, the present invention is represented by the following reaction formula.

(I) (n) (III) (TV) (V) (VI) (VII) (■) (■) (In the formula, X and Y represent fluorine or chlorine.) (I) may be reacted with acetyl chloride and aluminum chloride.

The amount of acetyl chloride used is 1 to 3 times the mole of the raw material,
Preferably, 1 to 1.5 times the mole amount is used. The amount of aluminum chloride used is 1 to 4 times the mole of the raw material, preferably 2 times
~3 times the molar amount is used. The reaction temperature is 50°C to 200°C, preferably 100°C to 150°C.

The haloform reaction of compound (n) can be carried out by reaction with an aqueous sodium hypochlorite solution. The reaction temperature is 4
The temperature is 0°C to 100°C, preferably 70°C to 100°C, and the reaction time is 1 to 10 hours. The amount of sodium hypochlorite used is 3 to 20 times the molar amount, preferably 4 to 6 times the molar amount. After the reaction, compound (III) is obtained by acidifying with hydrochloric acid.

The nitration reaction of compound (III) can be carried out by dropping a mixed acid in a sulfuric acid solvent at a reaction temperature of from room temperature to 150°C. The amount of sulfuric acid used is 0 for compound (m)
．． 1 to 20 times equivalent, nitric acid used as mixed acid 1 to 1
O times the amount, especially 1.5 to 2.0 times the equivalent amount is preferred.

The denitrochlorination reaction of compound (IV) is carried out in a liquid phase or gas phase flow system. In a liquid phase system, it may be in the presence of a solvent or without a solvent. When a solvent is used, chlorinated paraffin, chlorotrifluoroethylene, etc. Preferred are low polymers and halogenated solvents such as tetrabromoethane. The amount of chlorinating agent such as chlorine gas used is 0.2 to 10 times the theoretical reaction amount, preferably 1
．． 0 to 5 times is appropriate. Reaction temperature is 150-350℃
, reaction pressure is normal pressure ~ 100 kg/cm'', reaction time is 2
~30 hours is appropriate.

When X represents chlorine, these carboxylic acids are then optionally reacted with thionyl chloride to form acid chloride (■).
The desired benzoic acid (IX) can be obtained via the acid fluoride (■) by converting the benzoic acid into fluoride and performing a fluorination reaction.

The fluorination reaction is carried out without solvent or in an aprotic solvent.
What is necessary is to react with a fluorinating agent. As a fluorinating agent,
NaF, KF, RbF.

Alkali metal fluorides such as CsF are preferred, particularly spray-dried potassium fluoride. The amount of the fluorinating agent to be used is 1 to 5 times the mole, preferably 1 to 2 times the mole relative to the halogen atom to be replaced. During fluorination, a phase transfer catalyst may be added as a reaction promoter. 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
Examples include pyridinium salts such as -ethyl-hexyl)-4-(N', N'-dimethylamino)-pyridinium chloride, and quaternary phosphonium salts such as tetrabutylphosphonium bromide and tetraphenylphosphonium bromide.

Aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphorotriamide, N-methyl-2-pyrrolidone, acetonitrile, benzonitrile, dioxane, and diglyme. , tetraglyme, etc. can be used, but sulfolane and N,N-dimethylformamide are preferable.

The amount used is from the same weight to 10 times the weight of the raw material, preferably from 2 times to 5 times the weight.

The reaction temperature is 50°C to 250°C, preferably 100°C to
Perform at 230°C.

The hydrolysis reaction of acid fluoride is carried out in an aqueous medium from room temperature to 1
This can be carried out by reacting at a reaction temperature of 00°C for 3 to 200 hours. In this case, an inert organic solvent may be added to promote the reaction.

Examples of the present invention will be described in more detail below.

Example 1 50 g of 3,4-difluorochlorobenzene, 39.2 g of acetyl chloride, and 88.8 g of aluminum chloride were charged into a 200 mJ2 glass reactor equipped with a reflux condenser, and the temperature was gradually raised to 140'C with vigorous stirring. . After continuing the reaction at 140° C. for an additional 4 hours, gas chromatography analysis revealed that the starting material had disappeared. After cooling, the reactant was poured into ice water, and the organic layer was extracted with 200 g of methylene chloride. The extract was distilled to a boiling point of 60°C and 75 m
47.25 g of 2-chloro-4,5-difluoroacetophenone of mHg was obtained. Purity 99.4%, yield 74%
Met.

Example 2 A reaction was carried out under the same conditions as in Example 1 except that the starting material was changed to 1,3-dichloro-4-fluorobenzene, and 2,4-dichloro-5-fluoroacetophenone with a boiling point of 94°C/5 mmHg was used. I got it.

The purity was 93% and the yield was 76%.

Example 3 A 2000 mj2 glass reactor equipped with a reflux condenser was charged with 100 g of 2-chloro-4,5-difluoroacetophenone and 1500 g of a 12% aqueous hypochlorous acid solution, and reacted at 100° C. for 4 hours with vigorous stirring. Analysis of the reaction solution revealed that the raw materials had disappeared. 2-chloro-4,5 by separating the aqueous layer and acidifying with hydrochloric acid.
-Difluorobenzoic acid was precipitated. Filter and dry 86
．． 2 g of 2-chloro-4,5-difluorobenzoic acid was obtained. The yield was 85.3%.

Example 4 A reaction was carried out under the same conditions as in Example 3 except that the starting material was changed to 2,4-dichloro-5-fluoroacetophenone to obtain 2,4-dichloro-5-fluorobenzoic acid. The yield was 83.5%.

Example 5 500ml with reflux condenser and dropping funnel
2 Into a glass reactor, 100 g of 2-chloro-4,5-difluorobenzoic M and 200 g of 100% sulfuric acid were charged.
Mixed acid 1 containing 65.4 g of nitric acid with vigorous stirring at room temperature.
63.5 g was added dropwise over 2 hours, and the reaction was continued for an additional 5 hours. Thereafter, methylene chloride was added to extract organic substances from the sulfuric acid layer. Two layers were separated, and the methylene chloride layer was washed with water and recrystallized to obtain 66.6 g of 2-chloro-4,5-difluoro-3-nitrobenzoic acid. The yield was 54%.

Example 6 A nitration reaction was carried out under the same conditions as in Example 5 except that the starting material was changed to 2,4-dichloro-5-fluorobenzoic acid, and 2,4-dichloro-5-fluoro-3-nitro Benzoic acid was obtained. The yield was 89%.

Example 7 50 g of 2-chloro-4,5-difluoro-3-nitrobenzoic acid was charged into a 100 mβ glass reactor equipped with a reflux condenser and a chlorine introduction tube, and chlorine was added at 180"C for 20 hours with vigorous stirring. Gas was introduced.After the reaction, the product was analyzed and the reaction rate of the raw material was 8.
The selectivity to 4%, 2,3-dichloro-4,5-difluorobenzoic acid was 80%.

Example 8 Using the same reaction apparatus as in Example 7, 2,4-dichloro-
Prepare 100g of 5-fluoro-3-nitowbenzoic acid,
Chlorine gas was introduced for 17 hours while stirring vigorously at 180"C. After the reaction, the product was analyzed and found that the reaction rate of the raw material was 95% and the selectivity to 2,3°4-trichloro-5-fluorobenzoic acid. was 88%.

Example 9 2.3.4-Trichloro-5-fluorobenzoic acid 10 was added to a 200 mj glass reactor equipped with a reflux condenser.
0g of thionyl chloride, 97.8g of thionyl chloride, and several drops of dimethylformamide were charged, and the mixture was reacted at a reflux temperature of 60°C to 80°C for 4 hours. The product was then simply distilled to yield 98.9 g.
2.3.4-trichloro-5-fluorobenzoic acid chloride was obtained. The yield was 92%.

Example 10 100 g of 2.3.4-trichloro-5-fluorobenzoic acid chloride, 100 g of spray-dried potassium fluoride in a 500 mf2 glass reactor equipped with a reflux condenser.
, add 250g of sulfolane and stir vigorously.
The reaction was carried out at 170°C for 15 hours. After the reaction, the product was distilled off under reduced pressure and then purified by distillation to obtain 70.2 g of 3-chloro-2,4,5-trifluorobenzoic acid fluoride. The yield was 86%. Example 11 3-chloro-2 was placed in a 1000mj2 polyethylene reactor.
, 50 g of 4,5-trifluorobenzoic acid fluoride and 100 g of ethyl acetate were added, and while stirring vigorously, 50 g of water was added.
g was added dropwise to perform hydrolysis.

The reaction was continued until the raw material in the organic layer disappeared by gas chromatography. After the reaction, the ethyl acetate layer was separated and washed with water. Thereafter, ethyl acetate was distilled off under reduced pressure, and 3-chloro-2,4,5-
)-Lifluorobenzoic acid 47. lg was obtained. Yield 9
It was 5%.

[Effects of the Invention] Compared to conventional methods, the method of the present invention is an excellent method that causes no problems in terms of working environment, has high reaction volume efficiency, and has a high yield.

Claims (1)

[Claims] 1. 5-fluoroacetophenone of formula (II) is produced by Friedel-Crafts acylation reaction of the fluorobenzenes represented by the following formula (I) ▼There are mathematical formulas, chemical formulas, tables, etc.▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) This is converted into formula (III) by haloform reaction. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) Next, this is converted into nitrated formula (IV) by reaction with a nitrating agent. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) A new method for producing fluorobenzoic acids, which is characterized by denitrochlorination to obtain formula (V) by reaction with a chlorinating agent. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (X in the above formula I-V represents fluorine or chlorine.) 2. Convert the following formula (VI) to acyl chloride (VII), ▲Mathematical formula, There are chemical formulas, tables, etc. ▼ (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) After converting to formula (VIII) by fluorination reaction, ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ (VIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IX) (In the formula, Y represents fluorine or chlorine.) A hydrolysis reaction is performed to produce fluorobenzoic acids of formula (IX). A method for producing fluorobenzoic acids, the method comprising: obtaining fluorobenzoic acids;