A comprehensive utilization method for the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization

Abstract

This invention discloses a comprehensive utilization method for the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization: The mother liquor is subjected to a pyrolysis reaction with alkali, followed by extraction and separation to obtain an organic phase (2,4-dichlorofluorobenzene) and an aqueous phase. The aqueous phase is then converted with acid to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. This mixture is then subjected to an esterification reaction with methanol. After removing the methanol by distillation, the mixture is extracted, and the organic phase is subjected to vacuum distillation after solvent removal. The distillate fraction is methyl 2,4-dichloro-5-fluorobenzoate, and the distillation residue is 2,6-dichloro-3-fluorobenzoic acid. The methyl 2,4-dichloro-5-fluorobenzoate is hydrolyzed and converted with acid to obtain 2,4-dichloro-5-fluorobenzoic acid. This method utilizes mild reaction conditions, inexpensive reagents, achieves high comprehensive utilization of the mother liquor, has low production costs, and yields products with high economic value, demonstrating significant industrial potential.

Description

(I) Technical Field

[0001] This invention relates to a method for the comprehensive utilization of 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. 2,4-Dichloro-5-fluorobenzoic acid can be prepared from 2,4-dichloro-5-fluoroacetophenone via oxidation with hypochlorous acid. 2,4-Dichloro-5-fluorobenzoic acid 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 comprehensive utilization method for the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization. This method can fully utilize 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone in the mother liquor of crystallization, converting them into 2,4-dichlorofluorobenzene, 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. This method has the advantages of not using expensive auxiliary reagents, high comprehensive utilization rate of the mother liquor of crystallization, and low production cost.

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

[0010] A method for the comprehensive utilization of the mother liquor from the crystallization of 2,4-dichloro-5-fluoroacetophenone, the method comprising the following steps:

[0011] (a) Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, a pyrolysis reaction was carried out under the action of alkali. The resulting reaction solution A was quenched with water, allowed to stand and separate into layers, and the organic phase was distilled to obtain 2,4-dichlorofluorobenzene; the aqueous phase was a mixed aqueous solution of 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoate.

[0012] The alkali is potassium hydroxide or sodium hydroxide, preferably potassium hydroxide.

[0013] The mother liquor for crystallizing 2,4-dichloro-5-fluoroacetophenone contains 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone, wherein the total amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone to the amount of alkali is recommended to be 1:1.5 to 6, preferably 1:2 to 3.

[0014] The pyrolysis reaction is generally carried out in an inert organic solvent A, which is one or more of toluene, xylene, and chlorobenzene, preferably toluene.

[0015] The preferred amount of the inert organic solvent A is 2 to 10 times the mass of the mother liquor from the crystallization of 2,4-dichloro-5-fluoroacetophenone.

[0016] The reaction temperature of step (a) is 85–145°C, preferably the reflux temperature of the inert organic solvent A.

[0017] The reaction time for step (a) is 2 to 8 hours, more preferably 3 to 5 hours.

[0018] The reaction is quenched by adding water to reaction solution A, usually until all the solids in the reaction system are dissolved.

[0019] (b) The resulting aqueous solution of 2,4-dichloro-5-fluorobenzoate and 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 obtained 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;

[0020] The acid mentioned in step (b) is hydrochloric acid or sulfuric acid.

[0021] In step (b), after adjusting the pH to 1-2 with acid, organic solvent B 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.

[0022] The organic solvent B is one or more of dichloromethane, dichloroethane, ethyl acetate, and toluene.

[0023] 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.

[0024] 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.

[0025] In step (b), the esterification reaction is generally carried out by heating to reflux. The esterification reaction time 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 C 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] In step (b), the organic solvent C is one or more of dichloromethane, dichloroethane, ethyl acetate, and 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 D is generally added for extraction. The organic phase is then concentrated to obtain 2,4-dichloro-5-fluorobenzoic acid.

[0036] The organic solvent D 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 recommended method for the comprehensive utilization of the 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor described in this invention is carried out according to the following steps:

[0040] Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, potassium hydroxide and toluene are added. The molar ratio of the total amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone contained in the mother liquor to the amount of potassium hydroxide is 1:2-3. The preferred amount of toluene is 2-10 times the mass of the mother liquor. The reaction is carried out at the reflux temperature of toluene for 3-5 hours. The reaction solution A is cooled, and water is added until all the solids in the reaction system are dissolved. After stirring, the mixture is allowed to stand and separate into layers. The upper organic phase is taken and distilled to obtain 2,4-dichlorofluoroacetophenone. Benzene, with an aqueous phase being a mixed aqueous solution of potassium 2,4-dichloro-5-fluorobenzoate and potassium 2,6-dichloro-3-fluorobenzoate; the aqueous phase is acidified to a pH of 1-2, wherein the acid is hydrochloric acid or sulfuric acid; organic solvent B is added to the acidified aqueous phase for extraction, wherein organic solvent B is dichloromethane, dichloroethane, ethyl acetate or toluene; the organic phase 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 refluxed for 3-6 hours, wherein the mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid... The mass ratio of the compound 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. The resulting reaction solution B is rotary evaporated to remove methanol, and water and organic solvent C are added for extraction and separation. Organic solvent C is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase is then rotary evaporated to remove the organic solvent, leaving a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. This mixture is then distilled under reduced pressure to remove methyl 2,4-dichloro-5-fluorobenzoate, leaving a residue of 2... 6-Dichloro-3-fluorobenzoic acid; methyl 2,4-dichloro-5-fluorobenzoate, after distillation, is mixed with a 1 mol / L to 5 mol / L aqueous solution of sodium hydroxide and subjected to hydrolysis under reflux for 1 to 2 hours. The molar ratio of methyl 2,4-dichloro-5-fluorobenzoate to sodium hydroxide is 1:1 to 2. After the hydrolysis reaction is completed, acid is added to adjust the pH to 1 to 2. The acid is hydrochloric acid or sulfuric acid. Organic solvent D is added to the acidified aqueous phase for extraction. The organic solvent D is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase is then 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. It utilizes the property that acetophenone compounds undergo a cracking reaction under strongly alkaline conditions to convert 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone into 2,4-dichloro-5-fluorobenzene, 2,4-dichloro-5-fluorobenzoate, and 2,6-dichloro-3-fluorobenzoate. Then, the 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzene... Formate is converted into 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid. Further utilizing the different activities of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid in the esterification reaction, 2,4-dichloro-5-fluorobenzoic acid is converted into methyl 2,4-dichloro-5-fluorobenzoate. 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-dichlorofluorobenzene, 2,4-dichloro-5-fluorobenzoic acid, and 2,6-dichloro-3-fluorobenzoic acid. The 2,4-dichlorofluorobenzene can be reused to further prepare 2,4-dichloro-5-fluoroacetophenone. 2,4-dichloro-5-fluorobenzoic acid is a basic intermediate in 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] Furthermore, the comprehensive processing technology of this invention operates under mild reaction conditions, without involving 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 technical solution of the present invention will be further described below through specific embodiments, but the scope of protection of 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, 500 g of 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor (quantitatively analyzed by gas chromatography with internal standard method showed a 2,4-dichloro-5-fluoroacetophenone content of 53% and an isomer of 2,6-dichloro-3-fluoroacetophenone of 45%, containing 265 g of 2,4-dichloro-5-fluoroacetophenone and 225 g of 2,6-dichloro-3-fluoroacetophenone), 280 g of potassium hydroxide, and 2000 mL of toluene were added. The mixture was heated under reflux and stirred for 3 h. The reaction solution was cooled, and water was added until all the solids in the reaction system were dissolved. After stirring, the mixture was allowed to stand and separate into layers. The upper organic phase was separated, and after recovering the toluene from the organic layer, 245 g of 2,4-dichlorofluorobenzene was obtained by vacuum distillation.

[0048] The aqueous phase obtained above was adjusted to pH 1-2 with concentrated hydrochloric acid, and extracted with dichloromethane (800 mL * 3). The organic phases were combined, and after recovering the dichloromethane, 178 g of a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid was obtained. The resulting acid mixture was mixed with 2600 g of methanol and 25 g of concentrated sulfuric acid and heated under reflux for 4 h. After removing the methanol by rotary evaporation, 200 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, and the remaining mixture consisted of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. This mixture was then distilled under reduced pressure at a vacuum of 2 mmHg, and 77 g of the fraction collected at 80-90 °C was collected. This fraction was methyl 2,4-dichloro-5-fluorobenzoate. The remaining 75 g of the distillation residue was 2,6-dichloro-3-fluorobenzoic acid.

[0049] 77 g of distilled methyl 2,4-dichloro-5-fluorobenzoate was mixed with 250 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 a pH of 1–2. Ethyl acetate was added to the acidified aqueous phase for extraction (300 mL * 3). The organic phase was then removed by rotary evaporation to obtain 69 g of 2,4-dichloro-5-fluorobenzoic acid. The combined utilization rate of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone was 92%.

[0050] Example 2:

[0051] In a flask equipped with a mechanical stirrer and a reflux condenser, 500 g of 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor (quantitatively analyzed by gas chromatography with internal standard method showed a 2,4-dichloro-5-fluoroacetophenone content of 50% and an isomer of 2,6-dichloro-3-fluoroacetophenone of 43%, containing 250 g of 2,4-dichloro-5-fluoroacetophenone and 215 g of 2,6-dichloro-3-fluoroacetophenone), 252 g of potassium hydroxide, and 2500 mL of toluene were added. The mixture was heated under reflux and stirred for 4 h. The reaction solution was cooled, and water was added until all the solids in the reaction system were dissolved. After stirring, the mixture was allowed to stand and separate into layers. The upper organic phase was separated, and after recovering the toluene from the organic layer, 230 g of 2,4-dichlorofluorobenzene was obtained by vacuum distillation.

[0052] The aqueous phase obtained above was adjusted to pH 1-2 with concentrated hydrochloric acid, and extracted with dichloromethane (800 mL * 3). The organic phases were combined, and after recovering the dichloromethane, 180 g of a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid was obtained. The resulting acid mixture was mixed with 2000 g of methanol and 30 g of concentrated sulfuric acid and heated under reflux for 5 h. After removing the methanol by rotary evaporation, 200 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, and the remaining mixture consisted of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. This mixture was then distilled under reduced pressure at a vacuum of 2 mmHg, and 72 g of the fraction collected at 80-90 °C was collected. This fraction was methyl 2,4-dichloro-5-fluorobenzoate. The remaining 70 g of the distillation residue was 2,6-dichloro-3-fluorobenzoic acid.

[0053] 72 g of distilled methyl 2,4-dichloro-5-fluorobenzoate was mixed with 150 mL of 4 mol / L sodium hydroxide aqueous solution and hydrolyzed under reflux for 2 h. After cooling, the reaction solution was acidified with sulfuric acid to a pH of 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 65 g of 2,4-dichloro-5-fluorobenzoic acid. The combined utilization rate of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone was 91%.

[0054] Example 3:

[0055] In a flask equipped with a mechanical stirrer and a reflux condenser, 500 g of 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor (quantitative analysis by gas chromatography internal standard method showed a 2,4-dichloro-5-fluoroacetophenone content of 48%, an isomer of 2,6-dichloro-3-fluoroacetophenone content of 43%, containing 240 g of 2,4-dichloro-5-fluoroacetophenone and 215 g of 2,6-dichloro-3-fluoroacetophenone), 250 g of potassium hydroxide, and 2500 mL of toluene were added. The mixture was heated under reflux and stirred for 4 h. The reaction solution was cooled, and water was added until all the solids in the reaction system were dissolved. After stirring, the mixture was allowed to stand and separate into layers. The upper organic phase was separated, and after recovering the toluene from the organic layer, 226 g of 2,4-dichlorofluorobenzene was obtained by vacuum distillation.

[0056] The aqueous phase obtained above was adjusted to pH 1-2 with concentrated hydrochloric acid, and extracted with dichloromethane (800 mL * 3). The organic phases were combined, and after recovering the dichloromethane, 172 g of a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid was obtained. The resulting acid mixture was mixed with 2600 g of methanol and 20 g of concentrated sulfuric acid and heated under reflux for 5 h. After removing the methanol by rotary evaporation, 200 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, and the remaining mixture consisted of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. This mixture was then distilled under reduced pressure at a vacuum of 2 mmHg, and 67 g of the fraction collected at 80-90 °C was collected. This fraction was methyl 2,4-dichloro-5-fluorobenzoate. The remaining 74 g of the distillation residue was 2,6-dichloro-3-fluorobenzoic acid.

[0057] 67 g of distilled methyl 2,4-dichloro-5-fluorobenzoate was mixed with 200 mL of 3 mol / L sodium hydroxide aqueous solution and hydrolyzed under reflux for 2 h. After cooling, the reaction solution was acidified with sulfuric acid to a pH of 1–2. Ethyl acetate was added to the acidified aqueous phase for extraction (300 mL * 3). The organic phase was then removed by rotary evaporation to obtain 61 g of 2,4-dichloro-5-fluorobenzoic acid. The combined utilization rate of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone was 92%.

Claims

1. A method for the comprehensive utilization of the mother liquor from the crystallization of 2,4-dichloro-5-fluoroacetophenone, characterized in that... The method includes the following steps: (a) Using the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization as raw material, a pyrolysis reaction was carried out under the action of alkali. The resulting reaction solution A was quenched with water, allowed to stand and separate into layers, and the organic phase was distilled to obtain 2,4-dichlorofluorobenzene; the aqueous phase was a mixed aqueous solution of 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoate; the 2,4-dichloro-5-fluoroacetophenone mother liquor contained 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone; The alkali is potassium hydroxide or sodium hydroxide; the total amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone contained in the mother liquor of 2,4-dichloro-5-fluoroacetophenone crystallization is in the molar ratio of alkali to 1:1.5-6; the pyrolysis reaction is carried out in an inert organic solvent A, which is one or more of toluene, xylene, and chlorobenzene; the reaction temperature of step (a) is 85-145℃, and the reaction time is 2-8 h; (b) The resulting aqueous solution of 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoate was adjusted to pH 1-2 with acid to prepare a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid; the resulting mixture was then subjected to esterification with methanol to prepare a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. A mixture of methyl chloro-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 distillation was performed under a vacuum of 2 mmHg, and the fraction collected at 80–90 °C was used to obtain 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 B 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 B is one or more of dichloromethane, dichloroethane, ethyl acetate, and 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. 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), 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 as follows: methanol is evaporated from the reaction solution B, water and organic solvent C 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. The organic solvent C is one or more of dichloromethane, dichloroethane, ethyl acetate, and toluene.

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 2,4-dichloro-5-fluoroacetophenone crystallization mother liquor as raw material, potassium hydroxide and toluene are added. The molar ratio of the total amount of 2,4-dichloro-5-fluoroacetophenone and 2,6-dichloro-3-fluoroacetophenone in the 2,4-dichloro-5-fluoroacetophenone mother liquor to the amount of potassium hydroxide is 1:2-3. The mass of toluene used is 2-10 times the mass of the 2,4-dichloro-5-fluoroacetophenone mother liquor. The reaction is carried out at the toluene reflux temperature for 3-5 days. h; Cool reaction solution A, add water until all solids in the reaction system are dissolved, stir and allow to stand for separation, take the upper organic phase for distillation to obtain 2,4-dichlorofluorobenzene, the aqueous phase is a mixed aqueous solution of potassium 2,4-dichloro-5-fluorobenzoate and potassium 2,6-dichloro-3-fluorobenzoate; add acid to the aqueous phase to a pH of 1-2, the acid being hydrochloric acid or sulfuric acid, add organic solvent B to the acidified aqueous phase for extraction, the organic solvent B being dichloromethane, dichloroethane, ethyl acetate or toluene, take the organic phase for concentration to obtain a mixture of 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid; add methanol and concentrated sulfuric acid to the mixture, reflux for 3-6 h, the 2,4-dichloro-5-fluorobenzoic acid and 2,6-dichloro-3-fluorobenzoic acid are then separated. The mass ratio of the benzoic acid mixture 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. The resulting reaction solution B is rotary evaporated to remove methanol, and water and organic solvent C are added for extraction and separation. Organic solvent C is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase is then rotary evaporated to remove the organic solvent, leaving a mixture of methyl 2,4-dichloro-5-fluorobenzoate and 2,6-dichloro-3-fluorobenzoic acid. This mixture is 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 is then reacted with 1 mol / L... 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 the hydrolysis reaction is completed, acid is added to adjust the pH to 1–2. The acid is hydrochloric acid or sulfuric acid. Organic solvent D is added to the acidified aqueous phase for extraction. The organic solvent D is dichloromethane, dichloroethane, ethyl acetate, or toluene. The organic phase is concentrated to obtain 2,4-dichloro-5-fluorobenzoic acid.

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