Method for preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid from 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor

Abstract

This invention discloses a method for preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid using 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor as raw material: the 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor is subjected to an oxidation reaction with sodium hypochlorite, and then acid is added to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid; the mixture is subjected to an esterification reaction with methanol to obtain a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid; the mixture is then subjected to vacuum distillation to remove methyl 2,4-dichloro-5-fluorobenzoate, leaving 2,6-dichloro-3-fluorobenzoic acid as the residue; the methyl 2,4-dichloro-5-fluorobenzoate is hydrolyzed and then converted with acid to obtain 2,4-dichloro-5-fluorobenzoic acid. The method of this invention has mild reaction conditions, uses inexpensive reagents, has a high comprehensive utilization rate of the crystallization mother liquor, low production costs, and high economic value of the obtained product, thus having great industrial prospects.

Description

(I) Technical Field

[0001] This invention relates to a method for preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid from 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor, belonging to the field of pharmaceutical and pesticide intermediate preparation. (II) Background Technology

[0002] Quinolones are synthetic antibacterial drugs with favorable pharmacokinetic properties. They offer advantages such as high bioavailability after oral administration, long half-life, high blood concentrations, and wide tissue distribution, making them suitable for a wide range of clinical applications. Quinolones are classified into four generations, with the third and fourth generations being the most commonly used in clinical practice. Commonly used quinolones include norfloxacin, ofloxacin, ciprofloxacin, fleroxacin, moxifloxacin, tofloxacin, sparfloxacin, and gatifloxacin.

[0003] 2,4-Dichloro-5-fluoroacetophenone is a major raw material for the preparation of fluoroquinolone drugs such as ciprofloxacin and difluorofloxacin. Oxidation of 2,4-dichloro-5-fluoroacetophenone yields 2,4-dichloro-5-fluorobenzoic acid, which is a basic intermediate in the preparation of fluoroquinolone drugs such as gatifloxacin, ofloxacin, levofloxacin, norfloxacin, barofloxacin, levofloxacin, and prifloxacin.

[0004] Currently, industrially, 2,4-dichloro-5-fluoroacetophenone is generally obtained via Friedel-Crafts acylation reaction using 2,4-dichlorofluorobenzene as a raw material, AlCl3 as a catalyst, and acetyl chloride as an acylating agent. This reaction produces the isomer byproduct 2,6-dichloro-3-fluoroacetophenone along with 2,4-dichloro-5-fluoroacetophenone. Manufacturers typically purify 2,4-dichloro-5-fluoroacetophenone using freeze-crystallization, repeatedly crystallizing at low temperatures, with 2,4-dichloro-5-fluoroacetophenone preferentially crystallizing out. However, as 2,4-dichloro-5-fluoroacetophenone precipitates, the content of 2,6-dichloro-3-fluoroacetophenone in the crystallization mother liquor gradually increases. When the content of 2,6-dichloro-3-fluoroacetophenone in the crystallization mother liquor reaches about 45%, further crystallization and purification become difficult, and 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone cannot be further separated. Each ton of 4-dichloro-5-fluoroacetophenone produced generates approximately 0.4 tons of crystallization mother liquor. This mother liquor contains no solvent and its main components are 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone.

[0005] Patent CN101747167 discloses a method for recovering 2,4-dichloro-5-fluoroacetophenone from crystallization mother liquor. Under the action of an acidic catalyst, 2,4-dichloro-5-fluoroacetophenone reacts with neopentyl glycol to form a ketal. After separating the ketal, it is hydrolyzed under the action of other acidic catalysts, and post-processing yields 2,4-dichloro-5-fluoroacetophenone. However, the ketal has a high boiling point, requiring distillation separation at high vacuum and temperature. Secondly, the neopentyl glycol used in the reaction has good water solubility, with a recovery rate of only about 80%, and a significant amount of the auxiliary reagent neopentyl glycol is lost during the separation process.

[0006] Patent CN104496772 reports another method for recovering 2,4-dichloro-5-fluoroacetophenone from crystallization mother liquor. In this method, 2,4-dichloro-5-fluoroacetophenone is heated and condensed with hydrazine hydrate, followed by vacuum distillation to remove 2,6-dichloro-3-fluoroacetophenone. Sulfuric acid and an acidolysis catalyst are added to the residue for acidolysis, and the mixture is then post-treated to obtain 2,4-dichloro-5-fluoroacetophenone. The auxiliary separation reagent hydrazine hydrate used in this process is difficult to recover and reuse. Although it can be converted into hydrazine sulfate as a byproduct, the hydrazine sulfate obtained from the aqueous phase contains the acidolysis catalyst, which affects its purity.

[0007] 2,6-Dichloro-3-fluoroacetophenone can be oxidized to prepare 2,6-dichloro-3-fluorobenzoic acid, which can be used to prepare the important pharmaceutical and pesticide intermediate 2,6-dichloro-3-fluorobenzonitrile (CN110372538), and can also be used to prepare other biologically active compounds. (III) Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid using 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor as raw material. This method has the advantages of not using expensive auxiliary reagents, high comprehensive utilization rate of crystallization mother liquor, and low production cost.

[0009] The objective of this invention can be achieved through the following technical solutions:

[0010] A method for preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid from 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor, the method comprising the following steps:

[0011] (a) Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, sodium hypochlorite was reacted with sodium hypochlorite to prepare aqueous solutions of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate.

[0012] The oxidation reaction is generally carried out with the addition of solvent A, which is tetrahydrofuran, dioxane, or water, preferably tetrahydrofuran; the mass of solvent A is preferably 2 to 6 times the mass of the 2,4-dichloro-5-fluoroacetophenone mother liquor.

[0013] In step (a), the ratio of the amount of sodium hypochlorite to the total amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone contained in the 2,4-dichloro-5-fluoroacetophenone mother liquor is 2 to 8:1, preferably 4 to 6:1.

[0014] In step (a), the reaction temperature of the oxidation reaction is 20–70°C, preferably 35–50°C.

[0015] In step (a), the oxidation reaction takes 4 to 8 hours.

[0016] In step (a), after the oxidation reaction is completed, an aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate is obtained through post-treatment. The post-treatment method is generally as follows: after the reaction is completed, the solvent in the obtained reaction solution A is removed by vacuum distillation, and the resulting aqueous phase is washed with organic solvent B to remove organic impurities, thereby obtaining an aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate.

[0017] The organic solvent B is dichloromethane, dichloroethane, ethyl acetate, or toluene.

[0018] (b) The aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate was adjusted to pH 1-2 with acid to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid; the mixture was subjected to esterification with methanol to obtain a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid; the mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid was subjected to vacuum distillation to obtain methyl 2,4-dichloro-5-fluorobenzoate as the distillate fraction, and the distillation residue was 2,6-dichloro-3-fluorobenzoic acid;

[0019] In step (b), the acid is hydrochloric acid or sulfuric acid.

[0020] In step (b), after adjusting the pH to 1-2 with acid, organic solvent C is generally added for extraction. The organic phase is then concentrated to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid.

[0021] The organic solvent C is dichloromethane, dichloroethane, ethyl acetate, or toluene.

[0022] In step (b), the esterification reaction is carried out using concentrated sulfuric acid as a catalyst, and the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to concentrated sulfuric acid is 1:0.05 to 0.3, preferably 1:0.1 to 0.2.

[0023] In step (b), the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to methanol is 1:4 to 40, preferably 1:8 to 20.

[0024] In step (b), the esterification reaction is generally carried out by heating to reflux.

[0025] In step (b), the reaction time for the esterification reaction is 2 to 8 hours, more preferably 3 to 6 hours.

[0026] In step (b), after the esterification reaction is completed, the resulting reaction solution B is post-treated to obtain a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. The post-treatment method is generally as follows: methanol is evaporated from reaction solution B, water and organic solvent D are added for extraction, the organic phase is taken and the solvent is evaporated to obtain a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid.

[0027] The organic solvent D is dichloromethane, dichloroethane, ethyl acetate, or toluene.

[0028] The vacuum distillation was performed at a pressure of 2 mmHg, and the fraction collected at 80–90 °C yielded methyl 2,4-dichloro-5-fluorobenzoate; the distillation residue was 2,6-dichloro-3-fluorobenzoic acid.

[0029] (c) 2,4-Dichloro-5-fluorobenzoate methyl ester was hydrolyzed under alkaline conditions, and then acid was added to adjust the pH to 1-2 to obtain 2,4-dichloro-5-fluorobenzoic acid.

[0030] The alkaline condition mentioned in step (c) is the addition of an alkaline solution, wherein the alkaline solution is a potassium hydroxide solution or a sodium hydroxide solution, preferably a sodium hydroxide solution;

[0031] The concentration of the alkaline solution is 1 mol / L to 5 mol / L;

[0032] The molar ratio of methyl 2,4-dichloro-5-fluorobenzoate to the base is 1:1 to 2.

[0033] The hydrolysis reaction described in step (c) is preferably carried out at reflux temperature, and the reaction time is 1 to 2 hours.

[0034] The acid mentioned in step (c) is hydrochloric acid or sulfuric acid.

[0035] In step (c), after adjusting the pH to 1-2 with acid, organic solvent E is generally added for extraction. The organic phase is then concentrated to obtain 2,4-dichloro-5-fluorobenzoic acid.

[0036] The organic solvent E is one or more of dichloromethane, dichloroethane, ethyl acetate, and toluene.

[0037] The reaction formula of the method of the present invention is as follows:

[0038]

[0039] Specifically, the method of preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid using 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor as raw material is recommended to be carried out according to the following steps:

[0040] Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, an aqueous solution of sodium hypochlorite was added to tetrahydrofuran and the oxidation reaction was carried out at 35-50°C for 4-8 hours. After the reaction, the tetrahydrofuran was removed by vacuum distillation. The resulting aqueous phase was washed with organic solvent B to remove organic impurities, yielding an aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate. The mass of the tetrahydrofuran used was 2-6 times the mass of the 2,4-dichloro-5-fluoroacetophenone mother liquor. The molar amount of sodium hypochlorite and the amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone contained in the 2,4-dichloro-5-fluoroacetophenone mother liquor were also considered. The total molar ratio of ketones is 4–6:1. The organic solvent B used for extraction is dichloromethane, dichloroethane, ethyl acetate, or toluene. The aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate is adjusted to pH 1–2 with acid, which is hydrochloric acid or sulfuric acid. Organic solvent C, which is dichloromethane, dichloroethane, ethyl acetate, or toluene, is added to the acidified aqueous phase for extraction. The organic solvent C is concentrated to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. Methanol and concentrated sulfuric acid are added to this mixture, and the mixture is heated under reflux for esterification for 3–6 hours. The mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to concentrated sulfuric acid is 1:0.1-0.2, and the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to methanol is 1:8-20. After the esterification reaction is completed, methanol is removed by rotary evaporation, and water and organic solvent D are added for extraction and separation. The organic solvent D is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase is taken and the organic solvent is removed by rotary evaporation. The remaining mixture is methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. The mixture is then distilled under reduced pressure to remove 2,4-dichloro-5-fluorobenzoic acid. 2,4-Dichloro-5-fluorobenzoate methyl ester, the residue being 2,6-dichloro-3-fluorobenzoic acid; the distilled 2,4-dichloro-5-fluorobenzoate methyl ester was mixed with a 1 mol / L to 5 mol / L sodium hydroxide aqueous solution and hydrolyzed under reflux for 1 to 2 hours, the molar ratio of 2,4-dichloro-5-fluorobenzoate methyl ester to sodium hydroxide being 1:1 to 2; after cooling, the pH was adjusted to 1 to 2 by adding acid, the acid being hydrochloric acid or sulfuric acid; organic solvent E was added to the acidified aqueous phase for extraction, the organic solvent E being dichloromethane, dichloroethane, ethyl acetate or toluene; the organic phase was concentrated to obtain 2,4-dichloro-5-fluorobenzoic acid.

[0041] The method of this invention uses the mother liquor from the crystallization of 2,4-dichloro-5-fluoroacetophenone as raw material to prepare 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. First, 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone are oxidized with sodium hypochlorite to obtain sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate. Then, acidification is performed to obtain 2,4-dichloro-5-fluoroacetophenone. 2,4-Dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid are further utilized to convert 2,4-dichloro-5-fluorobenzoic acid into methyl 2,4-dichloro-5-fluorobenzoate by taking advantage of the different activities of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid in the esterification reaction. The separated methyl 2,4-dichloro-5-fluorobenzoate is then subjected to alkaline hydrolysis and acidification to obtain 2,4-dichloro-5-fluorobenzoic acid.

[0042] This invention converts and separates 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone, which are difficult to separate from the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization, to obtain 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. 2,4-dichloro-5-fluorobenzoic acid is a basic intermediate for the preparation of fluoroquinolone drugs such as gatifloxacin, ofloxacin, levofloxacin, norfloxacin, barofloxacin, levofloxacin, and prifloxacin. 2,6-dichloro-3-fluorobenzoic acid can be used to prepare the pesticide intermediate 2,6-dichloro-3-fluorobenzonitrile and other bioactive compounds. Therefore, all products of this invention can be used independently in subsequent industrial production, improving economic efficiency.

[0043] The integrated processing technology of this invention features mild reaction conditions, avoiding harsh conditions such as high temperature and high pressure; the added reagents are all commonly used industrial acids and bases, which are inexpensive and do not require expensive auxiliary reagents; both the reaction solvent and the extraction solvent can be recycled, further reducing processing costs. This invention exhibits a high comprehensive utilization rate of the crystallization mother liquor, with a comprehensive utilization rate of over 90% for 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone. It boasts low production costs, a low safety risk factor, and high economic value of the obtained products, making it suitable for industrial-scale production and possessing significant industrial prospects. (IV) Detailed Implementation

[0044] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the present invention is not limited to these embodiments.

[0045] The raw material 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor in this invention is a byproduct of the production of 2,4-dichloro-5-fluoroacetophenone by Zhejiang Jitai New Material Co., Ltd.

[0046] Example 1:

[0047] In a flask equipped with a mechanical stirrer and a reflux condenser, add 100g of 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor (quantitative analysis by gas chromatography internal standard method showed that the content of 2,4-dichloro-5-fluoroacetophenone was 54%, the content of the isomer 2,6-dichloro-3-fluoroacetophenone was 45%, containing 54g of 2,4-dichloro-5-fluoroacetophenone and 45g of 2,6-dichloro-3-fluoroacetophenone) and 400mL of tetrahydrofuran. Add 1270g of 14% sodium hypochlorite solution dropwise at 40℃. After the addition is completed, keep the reaction at this temperature for 6h. Cool the reaction solution and extract and wash with ethyl acetate (300mL*2).

[0048] The aqueous solutions of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate were acidified with hydrochloric acid to a pH of 1-2. The aqueous phase was extracted with dichloromethane (300 mL x 3), the organic phases were combined, and the dichloromethane was recovered by distillation to obtain 97 g of a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. The resulting acid mixture was mixed with 1000 g of methanol and 15 g of concentrated sulfuric acid and heated under reflux for 4 h. After removing methanol by rotary evaporation, 150 mL of water was added, and the mixture was extracted with ethyl acetate (300 mL * 3). The organic phase was then removed by rotary evaporation to remove the solvent. The remaining mixture consisted of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. The mixture was then distilled under reduced pressure at a vacuum of 2 mmHg. 56 g of the fraction collected at 80–90 °C was identified as methyl 2,4-dichloro-5-fluorobenzoate. The remaining 43 g of the distillation residue was identified as 2,6-dichloro-3-fluorobenzoic acid.

[0049] 56 g of distilled methyl 2,4-dichloro-5-fluorobenzoate was mixed with 175 mL of 2 mol / L sodium hydroxide aqueous solution and hydrolyzed under reflux for 2 h. After cooling, the reaction solution was acidified with hydrochloric acid to make the pH 1-2. Ethyl acetate was added to the acidified aqueous phase for extraction (300 mL * 3). The organic phase was rotary evaporated to remove the solvent, yielding 49 g of 2,4-dichloro-5-fluorobenzoic acid.

[0050] Example 2:

[0051] In a flask equipped with a mechanical stirrer and a reflux condenser, add 100g of 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor (quantitative analysis by gas chromatography internal standard method showed that the content of 2,4-dichloro-5-fluoroacetophenone was 51%, the content of the isomer 2,6-dichloro-3-fluoroacetophenone was 44%, containing 51g of 2,4-dichloro-5-fluoroacetophenone and 44g of 2,6-dichloro-3-fluoroacetophenone) and 500mL of tetrahydrofuran. Add 1220g of 14% sodium hypochlorite solution dropwise at 45℃. After the addition is completed, maintain the reaction temperature for 5h. Cool the reaction solution and extract and wash with ethyl acetate (300mL*2).

[0052] The aqueous solutions of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate were acidified with hydrochloric acid to a pH of 1-2. The aqueous phase was extracted with dichloromethane (300 mL x 3), the organic phases were combined, and the dichloromethane was recovered by distillation to obtain 94 g of a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. The resulting acid mixture was mixed with 800 g of methanol and 13 g of concentrated sulfuric acid and heated under reflux for 4 h. After removing methanol by rotary evaporation, 150 mL of water was added, and the mixture was extracted with ethyl acetate (300 mL * 3). The organic phase was then removed by rotary evaporation to remove the solvent. The remaining mixture consisted of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. The mixture was then distilled under reduced pressure at a vacuum of 2 mmHg. 53 g of the fraction collected at 80–90 °C was identified as methyl 2,4-dichloro-5-fluorobenzoate. The remaining 41 g of the distillation residue was identified as 2,6-dichloro-3-fluorobenzoic acid.

[0053] 53g of distilled methyl 2,4-dichloro-5-fluorobenzoate was mixed with 175mL of 2mol / L sodium hydroxide aqueous solution and hydrolyzed under reflux for 2h. After cooling, the reaction solution was acidified with hydrochloric acid to make the pH 1-2. Ethyl acetate was added to the acidified aqueous phase for extraction (300mL*3). The organic phase was rotary evaporated to remove the solvent, yielding 47g of 2,4-dichloro-5-fluorobenzoic acid.

[0054] Example 3:

[0055] In a flask equipped with a mechanical stirrer and a reflux condenser, add 100g of 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor (quantitative analysis by gas chromatography internal standard method showed that the content of 2,4-dichloro-5-fluoroacetophenone was 47%, the content of the isomer 2,6-dichloro-3-fluoroacetophenone was 43%, containing 47g of 2,4-dichloro-5-fluoroacetophenone and 43g of 2,6-dichloro-3-fluoroacetophenone) and 600mL of tetrahydrofuran. Add 1200g of 14% sodium hypochlorite solution dropwise at 45℃. After the addition is completed, maintain the reaction temperature for 6h. Cool the reaction solution and extract and wash with ethyl acetate (300mL*2).

[0056] The aqueous solutions of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate were acidified with sulfuric acid to a pH of 1-2. The aqueous phase was extracted with dichloromethane (300 mL x 3), the organic phases were combined, and the dichloromethane was recovered to obtain 86 g of a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. The resulting acid mixture was mixed with 800 g of methanol and 13 g of concentrated sulfuric acid and heated under reflux for 4 h. After removing methanol by rotary evaporation, 150 mL of water was added, and the mixture was extracted with dichloromethane (300 mL * 3). The organic phase was then removed by rotary evaporation to remove the solvent. The remaining mixture consisted of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. The mixture was then distilled under reduced pressure at a vacuum of 2 mmHg. 47 g of the fraction collected at 80–90 °C was identified as methyl 2,4-dichloro-5-fluorobenzoate. The remaining 40 g of the distillation residue was identified as 2,6-dichloro-3-fluorobenzoic acid.

[0057] 47g of distilled methyl 2,4-dichloro-5-fluorobenzoate was mixed with 175mL of 2mol / L sodium hydroxide aqueous solution and hydrolyzed under reflux for 2h. After cooling, the reaction solution was acidified with sulfuric acid to make the pH 1-2. Dichloromethane was added to the acidified aqueous phase for extraction (300mL*3). The organic phase was rotary evaporated to remove the solvent, yielding 42g of 2,4-dichloro-5-fluorobenzoic acid.

Claims

1. A method for preparing 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid from the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization, characterized in that... The method includes the following steps: (a) Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, sodium hypochlorite is reacted with sodium hypochlorite to obtain an aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate; the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization contains 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone; the oxidation reaction is carried out with solvent A, which is tetrahydrofuran, dioxane, or water; the molar ratio of sodium hypochlorite to the total molar ratio of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone contained in the mother liquor of 2,4-dichloro-5-fluoroacetophenone is 2~8:1; the reaction temperature of the oxidation reaction is 20~70℃, and the reaction time is 4~8 h; (b) The aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate was adjusted to pH 1-2 with acid to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid; the mixture was subjected to esterification with methanol to obtain a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid; the mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid was subjected to vacuum distillation to obtain methyl 2,4-dichloro-5-fluorobenzoate as the distillate fraction, and 2,6-dichloro-3-fluorobenzoic acid as the distillation residue; the vacuum degree of the vacuum distillation was 2 mmHg, and 80-90 ml of the distillate was collected. The fraction was distilled at ℃ to give methyl 2,4-dichloro-5-fluorobenzoate; the distillation residue was 2,6-dichloro-3-fluorobenzoic acid. (c) 2,4-Dichloro-5-fluorobenzoate methyl ester was hydrolyzed under alkaline conditions, and then acid was added to adjust the pH to 1-2 to obtain 2,4-dichloro-5-fluorobenzoic acid.

2. The method as described in claim 1, characterized in that... In step (b), after adjusting the pH value to 1-2 with acid, organic solvent C is added for extraction. The organic phase is then concentrated to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. The organic solvent C is dichloromethane, dichloroethane, ethyl acetate, or toluene.

3. The method as described in claim 1, characterized in that... In step (b), the esterification reaction is carried out using concentrated sulfuric acid as a catalyst, and the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to concentrated sulfuric acid is 1:0.05 to 0.

3. In step (b), the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to methanol is 1:4 to 40. In step (b), the mixture is heated to reflux for esterification; the reaction time for esterification is 2–8 h.

4. The method as described in claim 1, characterized in that... In step (b), the esterification reaction is carried out using concentrated sulfuric acid as a catalyst, and the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to concentrated sulfuric acid is 1:0.05 to 0.

3. In step (b), the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to methanol is 1:4 to 40. In step (b), the mixture is heated to reflux for esterification; the reaction time for esterification is 2–8 h.

5. The method as described in claim 1, characterized in that... In step (c), the alkaline condition is the addition of an alkaline solution, which is a potassium hydroxide solution or a sodium hydroxide solution; the molar ratio of methyl 2,4-dichloro-5-fluorobenzoate to the alkali is 1:1 to 2.

6. The method as described in claim 1, characterized in that... In step (c), the hydrolysis reaction is carried out at reflux temperature for a reaction time of 1 to 2 hours.

7. The method as described in claim 1, characterized in that... The method is performed according to the following steps: Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, an aqueous solution of sodium hypochlorite was added to tetrahydrofuran and the oxidation reaction was carried out at 35-50°C for 4-8 h. After the reaction, the tetrahydrofuran was removed by vacuum distillation. The resulting aqueous phase was washed with organic solvent B to remove organic impurities, yielding an aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate. The mass of the tetrahydrofuran used was 2-6 times the mass of the 2,4-dichloro-5-fluoroacetophenone mother liquor, and the amount of sodium hypochlorite used was equal to the amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone contained in the 2,4-dichloro-5-fluoroacetophenone mother liquor. The total molar ratio of acetophenone is 4-6:

1. Organic solvent B is dichloromethane, dichloroethane, ethyl acetate, or toluene. The aqueous solution of sodium 2,4-dichloro-5-fluorobenzoate and sodium 2,6-dichloro-3-fluorobenzoate is adjusted to pH 1-2 with acid, which is hydrochloric acid or sulfuric acid. Organic solvent C, which is dichloromethane, dichloroethane, ethyl acetate, or toluene, is added to the acidified aqueous phase for extraction. The organic solvent C is then concentrated to obtain 2,4-dichloro-5-fluorobenzoate. A mixture of benzoic acid and 2,6-dichloro-3-fluorobenzoic acid; methanol and concentrated sulfuric acid are added to the mixture, and the mixture is heated under reflux for esterification for 3-6 hours. The mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to concentrated sulfuric acid is 1:0.1-0.2, and the mass ratio of the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid to methanol is 1:8-20. After the esterification reaction is completed, the methanol is removed by rotary evaporation. The alcohol was extracted and separated by adding water and organic solvent D, wherein organic solvent D is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase was then removed by rotary evaporation to remove the organic solvent, leaving a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. This mixture was then distilled under reduced pressure to distill off methyl 2,4-dichloro-5-fluorobenzoate, leaving 2,6-dichloro-3-fluorobenzoic acid as the residue. The distilled methyl 2,4-dichloro-5-fluorobenzoate was then reacted with 1 mol / L ~ 5 A mol / L sodium hydroxide aqueous solution is mixed and hydrolyzed under reflux for 1–2 h. The molar ratio of methyl 2,4-dichloro-5-fluorobenzoate to sodium hydroxide is 1:1–2. After cooling, the pH is adjusted to 1–2 by adding acid, which is hydrochloric acid or sulfuric acid. Organic solvent E is added to the acidified aqueous phase for extraction. Organic solvent E is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase is concentrated to obtain 2,4-dichloro-5-fluorobenzoic acid.

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