A method for synthesizing a benzosulfuron intermediate, 2-chloro-4-fluorobenzoic acid

Abstract

The application discloses a synthesis method of a benzene pyrimidyl sulfonamide intermediate 2-chloro-4-fluorobenzoic acid, and specifically comprises the following steps: 1) taking 2-chloro-4-fluoroaniline as raw material, performing a diazotization reaction in the presence of sulfuric acid and sodium nitrite to generate aniline diazonium salt; 2) the diazonium salt reacts with acetaldoxime in the presence of a composite catalyst under a weak acid environment to generate 2-chloro-4-fluoroacetophenone oxime; 3) 2-chloro-4-fluoroacetophenone oxime is hydrolyzed by refluxing in a hydrochloric acid solution to generate 2-chloro-4-fluoroacetophenone; 4) 2-chloro-4-fluoroacetophenone is subjected to an oxidation reaction with sodium hypochlorite under alkaline conditions, and then is hydrolyzed in concentrated hydrochloric acid to generate 2-chloro-4-fluorobenzoic acid. The application selects 2-chloro-4-fluoroaniline as raw material, which is cheap and easy to obtain, so that the cost is reduced, and the reaction is performed by using a limited composite catalyst, so that the catalytic rate is fast, the reaction time is short, and the selectivity is high.

Description

Technical Field

[0001] This invention relates to the field of pesticide intermediate synthesis technology, specifically to a method for synthesizing 2-chloro-4-fluorobenzoic acid, an intermediate of pyrimisulfuron. Background Technology

[0002] Bensulfuron-methyl belongs to the pyrimidine class and is a protoporphyrinogen oxidase (PPO) inhibitor. It can be used as a non-selective herbicide and is also effective in controlling a variety of broadleaf weeds, including weeds resistant to glufosinate, ALS, and triazine. It has a rapid non-selective effect and its soil residues degrade quickly. Moreover, it can be mixed with grass herbicides such as glyphosate for better results. It can be applied in various crop fields and non-cultivated lands with few restrictions on crop rotation.

[0003] 2-Chloro-4-fluorobenzoic acid is an important intermediate in the synthesis of pyrimisulfuron. It is obtained through nitration, acylation, and reductive condensation. Currently, the main industrial routes for 2-chloro-4-fluorobenzoic acid are as follows: 1) Patent CN105732357A discloses a method using m-chloroaniline as a raw material, sequentially achieving amino protection via 2-(trimethylsilyl)ethoxymethyl chloride, formylation via the Vilsmeier-Haack reaction, followed by oxidation to a carboxylic acid, then hydrogenation to reduce the nitro group, and finally fluorination to prepare 2-chloro-4-fluorobenzoic acid. Although this method uses inexpensive and readily available raw materials, it involves many steps, and 2-(trimethylsilyl)ethoxymethyl chloride is expensive. Fluorination generates a large amount of wastewater and waste residue, and requires... High temperature and high pressure result in long reaction time and low overall yield, thus greatly limiting industrialization; 2) Patent CN113402378B discloses the preparation of 2-chloro-4-fluorobenzoic acid by oxidizing 2-chloro-4-fluorotoluene with nitric acid solution and oxygen. The raw materials used in this method are expensive, which is not conducive to reducing production costs. In addition, it is necessary to stack catalytic packing in a high-pressure reactor. The preparation conditions of the packing are complicated, which increases the difficulty of operation. The drying time is long, requiring 10 to 20 hours. The catalytic reaction time is 13 to 15 hours, and the yield is low, which is not conducive to large-scale production.

[0004] Therefore, the synthesis of 2-chloro-4-fluorobenzoic acid, a key intermediate of pyrimisulfuron, still faces problems such as high production costs and the generation of large amounts of wastewater and waste residue. There is an urgent need to develop a low-cost synthesis route with less waste and a high yield. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, the present invention aims to provide a method for synthesizing 2-chloro-4-fluorobenzoic acid, a key intermediate of pyrimisulfuron, which has low raw material price and easy availability, high yield, low waste, and is suitable for industrial production.

[0006] To achieve the objectives of the invention described above, the following technical solution is adopted:

[0007] The present invention discloses a method for synthesizing 2-chloro-4-fluorobenzoic acid, an intermediate of pyrimisulfuron-methyl, which specifically includes the following steps:

[0008] 1) Using 2-chloro-4-fluoroaniline as a raw material, a diazotization reaction is carried out in the presence of sulfuric acid and sodium nitrite to generate aniline diazonium salt. The reaction process is shown in formula (1):

[0009]

[0010] 2) The diazonium salt obtained in step 1) reacts with acetaldehyde oxime in a weakly acidic environment in the presence of a composite catalyst to generate 2-chloro-4-fluoroacetophenone oxime, and the reaction process is shown in formula (2):

[0011]

[0012] 3) The 2-chloro-4-fluoroacetophenone oxime obtained in step 2) is hydrolyzed under reflux in hydrochloric acid solution to generate 2-chloro-4-fluoroacetophenone, and the reaction process is shown in formula (3):

[0013]

[0014] 4) The 2-chloro-4-fluoroacetophenone obtained in step 3) first undergoes an oxidation reaction with sodium hypochlorite under alkaline conditions to generate sodium 2-chloro-4-fluorobenzoate, and then undergoes an oxidation reaction with concentrated hydrochloric acid to generate 2-chloro-4-fluorobenzoic acid. The reaction process is shown in formula (4):

[0015]

[0016] Furthermore, the present invention also specifies that the mass concentration of sulfuric acid in step 1) is 45% to 70%, preferably 55%.

[0017] Furthermore, the present invention also specifies that the molar ratio of 2-chloro-4-fluoroaniline to sulfuric acid in step 1) is 1:4 to 1:10, preferably 1:8.

[0018] Furthermore, the present invention also specifies that the reaction temperature in step 1) is 0 to 15°C, preferably 0 to 5°C.

[0019] Furthermore, the present invention also specifies that the mass concentration of acetaldehyde oxime in step 2) is 50%; the molar ratio of 2-chloro-4-fluoroaniline to acetaldehyde oxime is 1:1.5 to 2.0, preferably 1:1.8.

[0020] Furthermore, the present invention further specifies that the composite catalyst in step 2) is a mixture of disodium ethylenediaminetetraacetate and copper sulfate complex aqueous solution. Copper sulfate is first added to water and completely dissolved under stirring, and then disodium ethylenediaminetetraacetate is added and stirred until clear. The molar ratio of disodium ethylenediaminetetraacetate to copper sulfate is 1:2 to 3, preferably 1:2.5.

[0021] Furthermore, the present invention also specifies that the molar ratio of copper sulfate to 2-chloro-4-fluoroaniline in the composite catalyst in step 2) is 1:8 to 12, preferably 1:10.

[0022] Furthermore, the present invention also specifies that the weak acid environment in step 2) is pH 2 to 4.5, preferably 2.5 to 3.0.

[0023] Furthermore, the present invention also limits the reaction time in step 3) to 2 to 4 hours, preferably 3 hours.

[0024] Furthermore, the present invention also limits the reaction time of step 4) to 5 to 10 hours, preferably 8.5 hours.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention selects 2-chloro-4-fluoroaniline as raw material, which is inexpensive and readily available, thus reducing costs. At the same time, it uses a limited composite catalyst for the reaction, which has a fast catalytic rate, short reaction time and high selectivity. Detailed Implementation

[0026] The patent will be further described below with reference to specific embodiments. The embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, but are not intended to limit the content of the patent.

[0027] Example 1

[0028] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0029] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 34.15 g (0.16 mol, 45% mass concentration, the same below) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, and then the heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 95.2%.

[0030] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0031] 3.54 g (30 mmol, 50%) of acetaldehyde oxime aqueous solution was added to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer and thermometer. 35.90 g (20 mmol) of the diazonium salt solution from step 1) was added dropwise at a constant flow rate using a constant flow pump, while 30% sodium hydroxide solution was added dropwise. During the reaction, copper sulfate complex solution (0.32 g (2 mmol) of copper sulfate, 0.27 g (0.8 mmol) of disodium ethylenediaminetetraacetate and 0.36 g (20 mmol) of water) was slowly added, maintaining the flow rate of diazonium salt at 0.6 g / min, sodium hydroxide solution at 1.1 g / min, and copper sulfate complex solution at 0.02 g / min. The reaction temperature was 20–25 °C, and the pH was controlled at 2.5–3.0. After the addition was complete, the reaction was continued for 2.5 h. After the reaction was completed, the solution was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.42 g of brown solid with a purity of 98.8% and a yield of 92.6%.

[0032] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0033] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of concentrated hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 2 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.35 g of a pale yellow transparent liquid with a purity of 98.8% and a yield of 96.1%.

[0034] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0035] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 5.0 h, adjust the pH of the system to 3-4 with hydrochloric acid. A white solid precipitates out. After filtration, 3.18 g of white solid is obtained with a purity of 97.8% and a yield of 89.4%.

[0036] Example 2

[0037] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0038] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 27.94 g (0.16 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 98.2%.

[0039] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0040] 4.25 g (36 mmol, 50%) of acetaldehyde oxime was added to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. 35.90 g (20 mmol) of the diazonium salt solution from step 1) was added dropwise at a constant flow rate using a constant flow pump, while 30% sodium hydroxide solution was added dropwise. During the reaction, a copper sulfate complex solution (0.32 g (2 mmol) of copper sulfate, 0.27 g (0.8 mmol) of disodium ethylenediaminetetraacetate, and 0.36 g (20 mmol) of water) was slowly added. The flow rate of the diazonium salt solution was maintained at 0.6 g / min, the sodium hydroxide solution at 1.1 g / min, and the copper sulfate complex solution at 0.02 g / min. The reaction temperature was 20–25 °C, and the pH was controlled at 2.5–3.0. After the addition was complete, the reaction was continued for 2.5 h. After the reaction was completed, the solution was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.58 g of brown solid with a purity of 99.2% and a yield of 94.9%.

[0041] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0042] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of concentrated hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 2.2 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.38 g of a pale yellow transparent liquid with a purity of 98.6% and a yield of 96.9%.

[0043] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0044] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 6.0 h, adjust the pH of the system to 3-4 with hydrochloric acid, and a white solid precipitates. After filtration, 3.21 g of white solid is obtained with a purity of 97.9% and a yield of 90.3%.

[0045] Example 3

[0046] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0047] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 21.95 g (0.16 mol (70%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 97.6%.

[0048] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0049] 4.72 g (40 mmol, 50%) of acetaldehyde oxime was added to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. 35.90 g (20 mmol) of the diazonium salt solution from step 1) was added dropwise at a constant flow rate using a constant flow pump, while 30% sodium hydroxide solution was added dropwise. During the reaction, a copper sulfate complex solution (0.32 g (2 mmol) of copper sulfate, 0.27 g (0.8 mmol) of disodium ethylenediaminetetraacetate, and 0.36 g (20 mmol) of water) was slowly added. The flow rate of the diazonium salt solution was maintained at 0.6 g / min, the sodium hydroxide solution at 1.1 g / min, and the copper sulfate complex solution at 0.02 g / min. The reaction temperature was 20–25 °C, and the pH was controlled at 2.5–3.0. After the addition was complete, the reaction was continued for 2.5 h. After the reaction was completed, the solution was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.54 g of brown solid with a purity of 99.0% and a yield of 93.8%.

[0050] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0051] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 2.5 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.41 g of a pale yellow transparent liquid with a purity of 99.0% and a yield of 98.0%.

[0052] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0053] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 6.5 h, adjust the pH of the system to 3-4 with hydrochloric acid, and a white solid precipitates. After filtration, 3.24 g of white solid is obtained with a purity of 98.3% and a yield of 91.4%.

[0054] Example 4

[0055] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0056] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 13.97 g (0.08 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 95.8%.

[0057] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0058] 4.25 g (36 mmol, 50%) of acetaldehyde oxime was added to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. 35.90 g (20 mmol) of the diazonium salt solution from step 1) was added dropwise at a constant flow rate using a constant flow pump, while 30% sodium hydroxide solution was added dropwise. During the reaction, a copper sulfate complex solution (0.32 g (2 mmol) of copper sulfate, 0.34 g (1 mmol) of disodium ethylenediaminetetraacetate, and 0.36 g (20 mmol) of water) was slowly added. The flow rate of the diazonium salt was maintained at 0.6 g / min, the sodium hydroxide solution at 1.1 g / min, and the copper sulfate complex solution at 0.02 g / min. The reaction temperature was 20–25 °C, and the pH was controlled at 2.5–3.0. After the addition was complete, the reaction was continued for 2.5 h. After the reaction was completed, the product was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.57 g of brown solid with a purity of 98.7% and a yield of 94.2%.

[0059] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0060] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 2.8 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.37 g of a pale yellow transparent liquid with a purity of 99.0% and a yield of 97.0%.

[0061] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0062] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 7.0 h, adjust the pH of the system to 3-4 with hydrochloric acid. A white solid precipitates out. After filtration, 3.26 g of white solid is obtained with a purity of 98.5% and a yield of 92.3%.

[0063] Example 5

[0064] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0065] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 34.92 g (0.2 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 98.0%.

[0066] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0067] 4.25 g (36 mmol, 50%) of acetaldehyde oxime was added to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. 35.90 g (20 mmol) of the diazonium salt solution from step 1) was added dropwise at a constant flow rate using a constant flow pump, while simultaneously adding 30% sodium hydroxide solution. During the reaction, a copper sulfate complex solution (0.32 g (2 mmol) of copper sulfate, 0.23 g (0.67 mmol) of disodium ethylenediaminetetraacetate, and 0.36 g (20 mmol) of water) was slowly added, maintaining the diazonium salt flow rate at 0.6 g / min, the sodium hydroxide solution at 1.1 g / min, and the copper sulfate complex solution at 0.02 g / min. The reaction temperature was 20–25 °C, and the pH was controlled at 2.5–3.0. After the addition was complete, the reaction was continued for 2.5 h. After the reaction was complete, the solution was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.57 g of brown solid with a purity of 98.7% and a yield of 94.2%.

[0068] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0069] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 3 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The mixture was then distilled under reduced pressure to obtain 3.36 g of a pale yellow transparent liquid with a purity of 98.6% and a yield of 96.3%.

[0070] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0071] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 7.5 h, adjust the pH of the system to 3-4 with hydrochloric acid. A white solid precipitates out. After filtration, 3.30 g of white solid is obtained with a purity of 98.6% and a yield of 93.5%.

[0072] Example 6

[0073] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0074] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 27.94 g (0.16 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The temperature was raised to 5–10 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 97.1%.

[0075] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0076] 4.25 g (36 mmol, 50%) of acetaldehyde oxime was added to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. 35.90 g (20 mmol) of the diazonium salt solution from step 1) was added dropwise at a constant flow rate using a constant flow pump, while simultaneously adding 30% sodium hydroxide solution. During the reaction, a copper sulfate complex solution (0.40 g (2.5 mmol) of copper sulfate, 0.34 g (1 mmol) of disodium ethylenediaminetetraacetate, and 0.45 g (25 mmol) of water) was slowly added, maintaining the diazonium salt flow rate at 0.6 g / min, the sodium hydroxide solution at 1.1 g / min, and the copper sulfate complex solution at 0.02 g / min. The reaction temperature was 20–25 °C, and the pH was controlled at 2.0–2.5. After the addition was complete, the reaction was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.55 g of brown solid 2-chloro-4-fluoroacetophenone oxime with a purity of 98.8% and a yield of 93.9%.

[0077] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0078] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of concentrated hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 3.3 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The mixture was then distilled under reduced pressure to obtain 3.37 g of a pale yellow transparent liquid with a purity of 98.7% and a yield of 96.7%.

[0079] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0080] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 8.0 h, adjust the pH of the system to 3-4 with hydrochloric acid. A white solid precipitates out. After filtration, 3.34 g of white solid is obtained with a purity of 98.4% and a yield of 94.4%.

[0081] Example 7

[0082] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0083] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 27.94 g (0.16 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then the heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The temperature was raised to 10–15 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 96.5%.

[0084] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0085] Add 4.25 g (36 mmol, 50%) of acetaldehyde oxime to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. Simultaneously add 35.90 g (20 mmol) of the diazonium salt solution from step 1) dropwise using a constant flow pump at a constant rate, along with a 30% sodium hydroxide solution. During the reaction, slowly add a copper sulfate complex solution (0.27 g (1.67 mmol) of copper sulfate and 0.23 g (0.67 mmol) of disodium ethylenediaminetetraacetate). 1) Water 0.30 g (16.7 mmol), maintaining a diazonium salt flow rate of 0.6 g / min, sodium hydroxide solution 1.1 g / min, copper sulfate complex solution 0.02 g / min, reaction temperature 20–25 °C, pH controlled at 2.0–2.5. After the reaction was complete, the mixture was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to obtain 3.53 g of brown solid 2-chloro-4-fluoroacetophenone oxime, purity 98.6%, yield 93.1%.

[0086] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0087] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of concentrated hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 3.5 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.36 g of a pale yellow transparent liquid with a purity of 98.2% and a yield of 95.9%.

[0088] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0089] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 8.5 h, adjust the pH of the system to 3-4 with hydrochloric acid. A white solid precipitates out. After filtration, 3.37 g of white solid is obtained with a purity of 98.9% and a yield of 95.7%.

[0090] Example 8

[0091] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0092] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 26.19 g (0.15 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 97.9%.

[0093] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0094] Add 4.25 g (36 mmol, 50%) of acetaldehyde oxime to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. Using three constant flow pumps (one for adding diazonium salt, one for sodium hydroxide solution (to adjust pH), and one for adding a copper sulfate complex solution), add 35.90 g (20 mmol) of the diazonium salt solution from step 1), 30% sodium hydroxide solution, 0.32 g (2 mmol) of copper sulfate, and 0.27 g (1 mmol) of disodium ethylenediaminetetraacetate (EDTA-2). g (0.8 mmol), maintaining a diazonium salt flow rate of 0.6 g / min, sodium hydroxide solution of 1.1 g / min, and copper sulfate complex solution of 0.02 g / min, at a reaction temperature of 20–25 °C, and controlling the pH at 2.0–2.5, continued the reaction for 2.5 h after the addition was complete. After the reaction was complete, the product was extracted with toluene, dissolved by rotary evaporation, and recrystallized from petroleum ether to give 3.48 g of brown solid 2-chloro-4-fluoroacetophenone oxime, with a purity of 99.2% and a yield of 92.2%.

[0095] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0096] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of concentrated hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 3.7 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.35 g of a pale yellow transparent liquid with a purity of 98.8% and a yield of 96.1%.

[0097] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0098] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After refluxing for 9.0 h, adjust the pH of the system to 3-4 with hydrochloric acid, and a white solid precipitates. After filtration, 3.34 g of white solid is obtained with a purity of 98.3% and a yield of 94.3%.

[0099] Example 9

[0100] 1) Preparation of 2-chloro-4-fluoroaniline diazonium salt

[0101] 2.90 g (0.02 mol) of 2-chloro-4-fluoroaniline and 29.69 g (0.17 mol (55%)) of concentrated sulfuric acid were added to a 100 ml three-necked flask equipped with a thermometer. The mixture was heated and stirred until completely dissolved, then heating was stopped. After stirring and cooling, pink crystals gradually precipitated out. The mixture was transferred to an ice-water bath and cooled to 0 °C. Then, 5.06 g (0.022 mol, 30%) of sodium nitrite solution was slowly added dropwise at a rate of 0.16 g / min under controlled temperature of 0–5 °C. After the addition was complete, a pale yellow clear solution was obtained. The reaction was kept at 0–5 °C and stirred for 1 h to prepare a diazonium salt solution for later use. The yield was 97.8%.

[0102] 2) Preparation of 2-chloro-4-fluoroacetophenone oxime

[0103] Add 4.25 g (36 mmol, 50%) of acetaldehyde oxime to a 150 ml four-necked flask equipped with a pH meter, mechanical stirrer, and thermometer. Simultaneously add 35.90 g (20 mmol) of the diazonium salt solution from step 1) dropwise using a constant flow pump at a constant rate, while adding 30% sodium hydroxide solution dropwise. During the reaction, slowly add a copper sulfate complex solution (0.32 g (2 mmol) of copper sulfate, 0.27 g (0.8 mmol) of disodium ethylenediaminetetraacetate, and 0.3 g of water). 6 g (20 mmol) was added, and the flow rate of the diazonium salt was maintained at 0.6 g / min, the flow rate of the sodium hydroxide solution was 1.1 g / min, and the flow rate of the copper sulfate complex solution was 0.02 g / min. The reaction temperature was 20-25 °C, and the pH was controlled at 4.0-4.5. After the addition was complete, the reaction continued for 2.5 h. After the reaction was completed, the product was extracted with toluene, the solvent was removed by rotary evaporation, and the product was recrystallized from petroleum ether to give 3.52 g of brown solid 2-chloro-4-fluoroacetophenone oxime with a purity of 98.6% and a yield of 92.8%.

[0104] 3) Preparation of 2-chloro-4-fluoroacetophenone

[0105] 3.74 g (20 mmol) of 2-chloro-4-fluoroacetophenone oxime (from step 2) and 7.9 g (80 mmol, 36%) of concentrated hydrochloric acid were added to a three-necked flask equipped with a thermometer. The mixture was refluxed in an oil bath at 90 °C for 4.0 h until the reaction was complete. After cooling to room temperature, the mixture was extracted with toluene to separate the organic phase. The organic phase was washed with 5% sodium bicarbonate aqueous solution until neutral. Toluene was recovered by distillation. The product was then distilled under reduced pressure to obtain 3.25 g of a pale yellow transparent liquid with a purity of 98.1% and a yield of 92.7%.

[0106] 4) Preparation of 2-chloro-4-fluorobenzoic acid

[0107] Add 3.44 g (20 mmol) of 2-chloro-4-fluoroacetophenone (from step 3), 10 ml of sodium hypochlorite (13-16% available chlorine), 1 g of phase transfer catalyst PEG, and 1.6 g (40 mmol) of sodium hydroxide to a three-necked flask equipped with a thermometer. After stirring to dissolve, heat to 50 °C and react until the system turns brown. Gradually increase the temperature to reflux at a rate of 2 °C / min. After reflux for 10 h, adjust the pH of the system to 3-4 with hydrochloric acid, and a white precipitate will precipitate. After filtration, 3.33 g of white solid with a purity of 98.2% and a yield of 94.0% is obtained.

Claims

1. A method for synthesizing 2-chloro-4-fluorobenzoic acid, an intermediate of pyrimisulfuron-methyl, characterized in that... Includes the following steps: 1) Using 2-chloro-4-fluoroaniline as a raw material, a diazotization reaction is carried out in the presence of sulfuric acid and sodium nitrite to generate aniline diazonium salt. The reaction process is shown in formula (1): ； The diazonium salt obtained in step 1) reacts with acetaldehyde oxime in a weakly acidic environment in the presence of a composite catalyst to generate 2-chloro-4-fluoroacetophenone oxime. The composite catalyst is a mixture of sodium ethylenediaminetetraacetate and copper sulfate complex aqueous solution. Copper sulfate is first dissolved completely in water with stirring, and then sodium ethylenediaminetetraacetate is added and stirred until clear. The molar ratio of sodium ethylenediaminetetraacetate to copper sulfate is 1:2-3, and the molar ratio of copper sulfate to 2-chloro-4-fluoroaniline in the composite catalyst is 1:8-12. The reaction process is shown in formula (2): ； The 2-chloro-4-fluoroacetophenone oxime obtained in step 2) is hydrolyzed under reflux in hydrochloric acid solution to produce 2-chloro-4-fluoroacetophenone, and the reaction process is shown in formula (3): ； The 2-chloro-4-fluoroacetophenone obtained in step 3) first undergoes an oxidation reaction with sodium hypochlorite under alkaline conditions to produce sodium 2-chloro-4-fluorobenzoate, which is then hydrolyzed with concentrated hydrochloric acid to produce 2-chloro-4-fluorobenzoic acid. The reaction process is shown in formula (4): 。 2. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1, is characterized in that... The sulfuric acid concentration in step 1) is 45% to 70%.

3. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1 or 2, is characterized in that... In step 1), the molar ratio of 2-chloro-4-fluoroaniline to sulfuric acid is 1:4 to 1:

10.

4. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1, is characterized in that... The reaction temperature for step 1) is 0–15°C.

5. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1, is characterized in that... In step 2), the mass concentration of acetaldehyde oxime is 50%; the molar ratio of 2-chloro-4-fluoroaniline to acetaldehyde oxime is 1:1.5 to 2.

0.

6. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1, is characterized in that... In step 2), the molar ratio of disodium ethylenediaminetetraacetate and copper sulfate in the composite catalyst is 1:2.

5.

7. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 6, is characterized in that... In step 2), the molar ratio of copper sulfate to 2-chloro-4-fluoroaniline in the composite catalyst is 1:

10.

8. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to any one of claims 1 or 5-7, characterized in that... The weakly acidic environment in step 2) is a pH of 2 to 4.

5.

9. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1, is characterized in that... The reaction time in step 3) is 2 to 4 hours.

10. The method for synthesizing 2-chloro-4-fluorobenzoic acid, the intermediate of pyrimisulfuron-methyl, according to claim 1, is characterized in that... The reaction time for step 4) is 5 to 10 hours.

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