Method for synthesizing 2-chloro-4-fluorobenzoic acid through Meerwein arylation reaction

Abstract

The invention relates to the field of organic synthesis, in particular to a method for synthesizing 2-chloro-4-fluorobenzoic acid through Meerwein arylation reaction, which comprises the following steps: carrying out Meerwein arylation reaction on 2-chloro-4-fluoroaniline, tert-butyl nitrite and 1, 1-dichloroethylene under the catalysis of anhydrous copper chloride to generate 2-chloro-4-fluorotrichlorotoluene; and hydrolyzing the 2-chloro-4-fluorobenzotrichloride under an acidic condition to generate the 2-chloro-4-fluorobenzoic acid. The method for synthesizing 2-chloro-4-fluorobenzoic acid through Meerwein arylation reaction provided by the invention has the advantages that the use of an expensive noble metal catalyst and a highly toxic reagent is avoided, the used reagent is environment-friendly, the cost is reduced, the process is simplified, the yield is higher, the defects in the prior art are overcome, and the method is suitable for large-scale industrial production.

Description

technical field

[0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing 2-chloro-4-fluorobenzoic acid through Meerwein arylation reaction. Background technique

[0002] 2-Chloro-4-fluorobenzoic acid is an important fine chemical intermediate, which is widely used in the fields of medicine and pesticides, especially, it is the key intermediate of the herbicide saflufenacil, which has huge market potential.

[0003] About the synthesis technology of 2-chloro-4-fluorobenzoic acid, with reference to domestic and foreign literature, there are mainly the following methods:

[0004] 1. The current domestic traditional synthesis process usually uses dichromate as an oxidant to oxidize 2-chloro-4-fluorotoluene to 2-chloro-4-fluorobenzoic acid, but dichromate is highly toxic and pollutes the environment. Serious, and the product yield is low.

[0005]

[0006] 2. Chinese patent CN105732357A uses m-chloroaniline as raw material, ...

Examples

Embodiment 1

[0033]

[0034] In a 2000mL four-neck flask, add 100g acetonitrile, 43.23g anhydrous copper chloride (molecular weight 134.45, 321.52mmol, 1.3eq), 359.63g 1,1-dichloroethylene (molecular weight 96.94, 3709.81mmol, 15eq) and 38.26g in turn g tert-butyl nitrite (molecular weight 103.12, 370.98mmol, 1.5eq), the reaction system was cooled to 5°C, 108g acetonitrile solution of 2-chloro-4-fluoroaniline (molecular weight 145.56, 247.32mmol, 1eq, 36g 2-chloroaniline) was slowly added dropwise -4-Fluoroaniline was dissolved in 72 g of acetonitrile), and the addition was completed in about 1 h. After the addition, the reaction solution was moved to room temperature and stirred for 16 h; the reaction solution was suction filtered to remove the copper salt. The filtrate was subjected to negative pressure to remove acetonitrile and 1,1-dichloroethylene, then 100 g of ethyl acetate was added to dilute, and the ethyl acetate phase was washed with 80 g of 10% hydrochloric acid and 60 g of ...

Embodiment 2

[0036] In a 2000mL four-neck flask, add 100g acetonitrile, 36.58g anhydrous copper chloride (molecular weight 134.45, 272.05mmol, 1.1eq), 239.75g 1,1-dichloroethylene (molecular weight 96.94, 2473.2mmol, 10eq) and 30.60g g tert-butyl nitrite (molecular weight 103.12, 296.78mmol, 1.2eq), the reaction system was cooled to 0°C, and 108g of 2-chloro-4-fluoroaniline in acetonitrile solution (molecular weight 145.56, 247.32mmol, 1eq, 36g 2- Chloro-4-fluoroaniline was dissolved in 72 g of acetonitrile), and the addition was completed in about 1 h. After the addition, the reaction solution was moved to room temperature and stirred for 12 h; the reaction solution was suction filtered to remove the copper salt. The filtrate was subjected to negative pressure to remove acetonitrile and 1,1-dichloroethylene, then 100 g of ethyl acetate was added to dilute, and the ethyl acetate phase was washed with 80 g of 10% hydrochloric acid and 60 g of water successively. The organic phase was evapo...

Embodiment 3

[0038]

[0039] 96.81g of 98% concentrated sulfuric acid (molecular weight: 98, 968.13mmol, 5eq) and 48g of 2-chloro-4-fluorotrichlorotoluene (molecular weight: 247.90, 193.63mmol, 1.0eq) were successively added to a 500mL four-necked flask, and the reaction mixture was heated up. Stir to 80°C for 7h. The reaction solution was cooled to room temperature, and then slowly poured into 300 g of ice water. After pouring, a large amount of solid was precipitated and stirred for 0.5 h, filtered, and the filter cake was rinsed with 100 g of water. The filter cake was dug out and dried in an oven at 70 °C. , weighed to obtain 30.47g of white solid, the purity of liquid chromatography was 94.15%, that is, 2-chloro-4-fluorobenzoic acid (molecular weight 174.56, theoretically obtained 33.80g), and the mass yield was 90.15%.

technical field

[0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing 2-chloro-4-fluorobenzoic acid through Meerwein arylation reaction. Background technique

[0002] 2-Chloro-4-fluorobenzoic acid is an important fine chemical intermediate, which is widely used in the fields of medicine and pesticides, especially, it is the key intermediate of the herbicide saflufenacil, which has huge market potential.

[0003] About the synthesis technology of 2-chloro-4-fluorobenzoic acid, with reference to domestic and foreign literature, there are mainly the following methods:

[0004] 1. The current domestic traditional synthesis process usually uses dichromate as an oxidant to oxidize 2-chloro-4-fluorotoluene to 2-chloro-4-fluorobenzoic acid, but dichromate is highly toxic and pollutes the environment. Serious, and the product yield is low.

[0005]

[0006] 2. Chinese patent CN105732357A uses m-chloroaniline as raw material, ...

Examples

Embodiment 1

[0033]

[0034] In a 2000mL four-neck flask, add 100g acetonitrile, 43.23g anhydrous copper chloride (molecular weight 134.45, 321.52mmol, 1.3eq), 359.63g 1,1-dichloroethylene (molecular weight 96.94, 3709.81mmol, 15eq) and 38.26g in turn g tert-butyl nitrite (molecular weight 103.12, 370.98mmol, 1.5eq), the reaction system was cooled to 5°C, 108g acetonitrile solution of 2-chloro-4-fluoroaniline (molecular weight 145.56, 247.32mmol, 1eq, 36g 2-chloroaniline) was slowly added dropwise -4-Fluoroaniline was dissolved in 72 g of acetonitrile), and the addition was completed in about 1 h. After the addition, the reaction solution was moved to room temperature and stirred for 16 h; the reaction solution was suction filtered to remove the copper salt. The filtrate was subjected to negative pressure to remove acetonitrile and 1,1-dichloroethylene, then 100 g of ethyl acetate was added to dilute, and the ethyl acetate phase was washed with 80 g of 10% hydrochloric acid and 60 g of ...

Embodiment 2

[0036] In a 2000mL four-neck flask, add 100g acetonitrile, 36.58g anhydrous copper chloride (molecular weight 134.45, 272.05mmol, 1.1eq), 239.75g 1,1-dichloroethylene (molecular weight 96.94, 2473.2mmol, 10eq) and 30.60g g tert-butyl nitrite (molecular weight 103.12, 296.78mmol, 1.2eq), the reaction system was cooled to 0°C, and 108g of 2-chloro-4-fluoroaniline in acetonitrile solution (molecular weight 145.56, 247.32mmol, 1eq, 36g 2- Chloro-4-fluoroaniline was dissolved in 72 g of acetonitrile), and the addition was completed in about 1 h. After the addition, the reaction solution was moved to room temperature and stirred for 12 h; the reaction solution was suction filtered to remove the copper salt. The filtrate was subjected to negative pressure to remove acetonitrile and 1,1-dichloroethylene, then 100 g of ethyl acetate was added to dilute, and the ethyl acetate phase was washed with 80 g of 10% hydrochloric acid and 60 g of water successively. The organic phase was evapo...

Embodiment 3

[0038]

[0039] 96.81g of 98% concentrated sulfuric acid (molecular weight: 98, 968.13mmol, 5eq) and 48g of 2-chloro-4-fluorotrichlorotoluene (molecular weight: 247.90, 193.63mmol, 1.0eq) were successively added to a 500mL four-necked flask, and the reaction mixture was heated up. Stir to 80°C for 7h. The reaction solution was cooled to room temperature, and then slowly poured into 300 g of ice water. After pouring, a large amount of solid was precipitated and stirred for 0.5 h, filtered, and the filter cake was rinsed with 100 g of water. The filter cake was dug out and dried in an oven at 70 °C. , weighed to obtain 30.47g of white solid, the purity of liquid chromatography was 94.15%, that is, 2-chloro-4-fluorobenzoic acid (molecular weight 174.56, theoretically obtained 33.80g), and the mass yield was 90.15%.

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