A process for the preparation of 2,4-difluorophenol by diazotization and hydrolysis

Abstract

The application relates to the field of organic matter synthesis, and particularly discloses a method for preparing 2,4-difluorophenol through diazotization and hydrolysis, which comprises the following steps: 2,4-difluorodiazonium salt / sulfuric acid aqueous solution is hydrolyzed under acidic conditions through a catalyst copper sulfate to obtain 2,4-difluorophenol; in the reaction, copper sulfate is used as the catalyst to catalyze the hydrolysis of diazonium salt to obtain the finished product; after the reaction is completed, the catalyst copper sulfate is recovered and applied to the next batch; the process operation is simple and easy to implement, the yield is high, the product quality is high, no waste is generated after the catalyst copper sulfate is applied, and the method is suitable for industrial production.

Description

Technical Field

[0001] This application relates to the field of organic synthesis, specifically a method for preparing 2,4-difluorophenol by diazotization hydrolysis. Background Technology

[0002] 2,4-Difluorophenol is an organic compound, CAS No.: 367-27-1, with the molecular formula C6H4F2O. It exists as a powder to a block to a transparent liquid, with a melting point of 22.4℃, a boiling point of 52-53℃ (19 mm Hg), and a density of 1.362 g / mL (25℃). In the market, it is an important pharmaceutical and pesticide intermediate, mainly used in the synthesis of herbicides, plant growth regulators, and liquid crystals. It can also be used in the synthesis of dyes, plastics, and rubber additives. In recent years, its fluorine-containing structure has shown broad application prospects in the synthesis of new antibiotics, such as antibiotic PC190723, the anti-inflammatory drug FK3311, and a new generation of DβH inhibitors (Etamicastat, also known as BIA 5-453) for the treatment of hypertension, coronary heart disease, and heart failure. As the core fragment of its structure, it holds great promise.

[0003] Its chemical structural formula is as shown in compound I: Currently, the main routes for synthesizing 2,4-difluorophenol include the trichlorobenzene method, the m-dichlorobenzene method, the phenol method, and the 3-aminoaniline method. However, the existing synthesis processes for 2,4-difluorophenol have various problems. How to ensure high process yields and simple and easy-to-operate process conditions to achieve good industrialization prospects is a problem worth solving. Summary of the Invention

[0004] The purpose of this application is to provide a method for preparing 2,4-difluorophenol by diazotization hydrolysis, so as to solve the problem of a large amount of copper sulfate waste generated during the preparation process, reduce the cost of production materials, and reduce the amount of waste generated.

[0005] This invention uses 2,4-difluorodiazonium salt as a raw material, and obtains the target product 2,4-difluorophenol through copper salt catalytic hydrolysis. The materials used in the reaction have low safety risks, do not use expensive metal catalysts, the process is simple and easy to operate, has high yield, and produces high-quality products, making it suitable for industrial production.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing 2,4-difluorophenol by diazotization hydrolysis includes the following steps: Step (1) Mix copper sulfate, the first organic solvent and water in a mass ratio of 3.7~5.7:9~11:4.8~5.2 to obtain a mixture; Step (2) The prepared 2,4-difluorodiazo salt / sulfuric acid aqueous solution is added dropwise to the mixture in step (1) for hydrolysis, separation, and temporary storage of copper sulfate aqueous solution; Step (3) Step (2) After separation, add alkaline solution to the organic layer, adjust pH to 8-10, separate the layers, adjust pH of the aqueous layer to 1-2 with acid, add a second organic solvent for extraction, concentrate the organic layer to dryness, and distill to obtain 2,4-difluorophenol. After the reaction in step (4) is completed, the copper sulfate aqueous solution separated in step (2) is extracted with a second organic solvent, and after reducing the pressure to concentrate some water, a concentrated copper sulfate aqueous solution is obtained for the next batch of reaction.

[0007] In this invention, copper sulfate aqueous solution and a first organic solvent are heated to 60-80 degrees Celsius, and a prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution is slowly added dropwise. After the reaction is qualified, the mixture is allowed to stand and separate into layers. The aqueous phase of copper sulfate is collected and temporarily stored. An alkaline aqueous solution is slowly added to the organic phase to adjust the pH to alkaline. The mixture is allowed to stand and separate into layers. An acidic aqueous solution is added to the aqueous layer to adjust the pH. A second organic phase is added for extraction. The organic phases are combined and concentrated under reduced pressure to obtain a crude product. 2,4-difluorophenol is obtained by distillation.

[0008] The obtained aqueous copper sulfate phase was added with a second organic phase to extract organic impurities once. The extracted aqueous copper sulfate phase was then concentrated under reduced pressure to its original volume to obtain a concentrated aqueous copper sulfate solution, which was to be used in the next batch of reaction.

[0009] The raw materials used in the preparation method are simple and readily available, with ample market supply, and the process cost is low. It does not involve easily explosive hazardous materials or expensive metal catalysts.

[0010] The copper sulfate catalyst used in this invention can be recycled and reused in the next batch of reaction, avoiding the generation of metal waste and having industrialization advantages.

[0011] The method of this invention has a simple synthetic route, high reaction conversion rate, and an overall yield exceeding 80%, reaching a maximum of 86%. The purity of the prepared product is high, reaching over 99.7%, with a maximum of 99.78%. The vacuum concentration and distillation involved in the embodiments of this invention are carried out using conventional methods.

[0012] As a preferred option, in step (1), the first organic solvent is an aromatic solvent, including toluene, chlorobenzene, dichlorobenzene or bromobenzene.

[0013] As a preferred embodiment, in step (2), the temperature of the droplet is 60-80 degrees Celsius, and the droplet time is 3-6 hours. As a preferred embodiment, in step (2), the amount of 2,4-difluorodiazonium salt / sulfuric acid aqueous solution added is 2.5-2.8 times the weight of copper sulfate.

[0014] As a preferred option, in step (3), the second organic solvent is a solvent with high solubility for organic substances, including dichloromethane or chloroform, and the amount of the second organic solvent added is 0.5 to 0.6 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

[0015] As a preferred option, in step (3), the acid used for acid adjustment includes: 10~37% hydrochloric acid, 40~98% sulfuric acid or 40~80% phosphoric acid.

[0016] As a preferred embodiment, in step (3), the alkaline solution includes a 10%~40% sodium hydroxide aqueous solution or a 10%~40% potassium hydroxide aqueous solution.

[0017] As a preferred option, in step (4), "for the next batch of reaction" specifically means: the first organic solvent is added directly to the concentrated copper sulfate aqueous solution to obtain a mixture, and the amount of the first organic solvent added is 8 to 9 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

[0018] As a preferred option, in step (4), the amount of the second organic solvent is 0.5 to 0.6 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

[0019] As a preferred option, in step (4), the copper sulfate aqueous solution is extracted with a second organic solvent and then concentrated to its original volume. Attached Figure Description

[0020] Figure 1 The gas phase detection spectrum of 2,4-difluorophenol shown in Formula I in Example 1 of this invention; Figure 2 The gas phase detection spectrum of 2,4-difluorophenol shown in Formula I in Example 2 of this invention; Figure 3 The gas phase detection spectrum of 2,4-difluorophenol shown in Formula I in Example 3 of this invention is shown. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased.

[0022] Unless otherwise stated, all percentages in this invention represent mass fractions. Ratios are mass percentages, and concentrations are mass concentrations.

[0023] The detailed route for synthesizing 2,4-difluorophenol is as follows: (1) Route 1: Trichlorobenzene process This route uses 1,2,4-trichlorobenzene as the starting material and produces 2,4-difluorophenol through five steps: nitration, fluorination, hydrogenation, diazotization, and hydrolysis. The specific reaction equations are as follows: This route has mature technology and certain market value, but the reaction conditions for hydrogenation dechlorination are quite harsh. The process parameters for this step involve high pressure, large amount of catalyst, and high cost.

[0024] (2) Route 2: m-dichlorobenzene process 2,4-Difluorophenol was prepared from m-dichlorobenzene via a five-step reaction involving nitration, fluorination, hydrogenation, diazotization, and hydrolysis. The specific reaction equations are as follows: This route offers higher atom utilization and milder nitro reduction reaction conditions, allowing for the selection of various catalysts. It is suitable for implementation using a fixed-bed hydrogenation method, where nitration, hydrogenation, and diazotization can be carried out in a continuous flow to ensure inherent safety and avoid high risks. Compared to the 1,2,4-trichlorobenzene method, it offers lower reaction conditions and costs, better economic efficiency, and significant industrialization advantages. However, the final step of diazotization hydrolysis requires a copper salt catalyst, and the recovery of the copper salt catalyst is crucial to ensuring continuous production.

[0025] (3) Route 3: 3-Aminoaniline method 2,4-Difluorophenol was synthesized from 3-aminoaniline via a six-step reaction involving diazotization, fluorination, nitration, hydrogenation, diazotization, and hydrolysis. The specific synthetic route is as follows: This route involves a relatively long process, and the diazonium salt fluorination substitution reaction is more difficult than the chlorobenzene fluorination reaction. The reaction has high impurities, resulting in lower process conversion and product yield. The purification process is also more difficult. In addition, the market price of 3-aminoaniline is higher than that of m-dichlorobenzene. The entire process route is longer and the cost of raw materials and auxiliary materials is higher, which are obvious disadvantages of this process.

[0026] (4) Route 4: Phenol method 2,4-Difluorophenol was prepared from phenol via a one-step method. The synthetic route is shown below: This process uses photocatalysis to prepare 2,4-difluorophenol. Phenol undergoes a direct gas-liquid reaction with fluorine / nitrogen to obtain a mixture of fluorinated phenols, including 2-fluorophenol, 4-fluorophenol, 2,4-difluorophenol, and 2,6-difluorophenol. The phenols are then separated by distillation based on their different physical properties to obtain pure products. This process requires harsh reaction conditions and sophisticated equipment. The resulting product is a multi-component mixture that necessitates multiple distillations for separation, making post-processing challenging.

[0027] To address the above problems, this invention provides a method for preparing 2,4-difluorophenol via diazotization hydrolysis, comprising the following steps: Step (1) Mix copper sulfate, the first organic solvent and water in a mass ratio of 3.7~5.7:9~11:4.8~5.2 to obtain a mixture; Step (2) The prepared 2,4-difluorodiazo salt / sulfuric acid aqueous solution is added dropwise to the mixture in step (1) for hydrolysis, separation, and temporary storage of copper sulfate aqueous solution; Step (3) Step (2) After separation, add alkaline solution to the organic layer, adjust pH to 8-10, separate the layers, adjust pH of the aqueous layer to 1-2 with acid, add a second organic solvent for extraction, concentrate the organic layer to dryness, and distill to obtain 2,4-difluorophenol. After the reaction in step (4) is completed, the copper sulfate aqueous solution separated in step (2) is extracted with a second organic solvent, and after reducing the pressure to concentrate some water, a concentrated copper sulfate aqueous solution is obtained for the next batch of reaction.

[0028] During the development of this invention, we found that diazo salt aqueous solution could not be hydrolyzed into products at high temperature without copper sulfate catalyst. Through experimentation, we added copper sulfate catalyst to solve this problem.

[0029] In this invention, copper sulfate aqueous solution and a first organic solvent are heated to 60-80 degrees Celsius, and a prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution is slowly added dropwise. After the reaction is qualified, the mixture is allowed to stand and separate into layers. The aqueous phase of copper sulfate is collected and temporarily stored. An alkaline aqueous solution is slowly added to the organic phase to adjust the pH value to alkaline. The mixture is allowed to stand and separate into layers. An acidic aqueous solution is added to the aqueous layer to adjust the pH. A second organic phase is added for extraction. The organic phases are combined and concentrated under reduced pressure to obtain a crude product. 2,4-Difluorophenol is obtained by distillation.

[0030] The obtained aqueous copper sulfate phase was added with a second organic phase to extract organic impurities once. The extracted aqueous copper sulfate phase was then concentrated under reduced pressure to its original volume to obtain a concentrated aqueous copper sulfate solution, which was to be used in the next batch of reaction.

[0031] The raw materials used in the preparation method are simple and readily available, with ample market supply, and the process cost is low. It does not involve easily explosive hazardous materials or expensive metal catalysts.

[0032] The copper sulfate catalyst used in this invention can be recycled and reused in the next batch of reaction, avoiding the generation of metal waste and having industrialization advantages.

[0033] The method of this invention has a simple synthetic route, high reaction conversion rate, and an overall yield exceeding 80%, reaching a maximum of 86%. The purity of the prepared product is high, reaching over 99.7%, with a maximum of 99.78%. The vacuum concentration and distillation involved in the embodiments of this invention are carried out using conventional methods.

[0034] In one embodiment, in step (1), the first organic solvent is an aromatic solvent, including toluene, chlorobenzene, dichlorobenzene or bromobenzene.

[0035] Diazo salts produce a large number of polymerization impurities during high-temperature hydrolysis. Therefore, we add a first organic solvent to dissolve the generated product, thereby reducing the probability of the product polymerizing with the diazonium salt and reducing the generation of byproducts.

[0036] In one implementation method, in step (2), the temperature of the drop is 60-80 degrees Celsius, and the drop time is 3-6 hours. Limiting the temperature and time can improve the formation of the product and prevent the generation of by-products.

[0037] In one embodiment, in step (2), the amount of 2,4-difluorodiazo salt / sulfuric acid aqueous solution added is 2.5 to 2.8 times the weight of copper sulfate. Limiting the amount added can increase the ratio of raw materials to copper sulfate and maximize the yield.

[0038] In one embodiment, in step (3), the second organic solvent is a solvent with high solubility for organic substances, including dichloromethane or chloroform, and the amount of the second organic solvent added is 0.5 to 0.6 times the mass of the 2,4-difluorodiazonium salt / sulfuric acid aqueous solution. The product is extracted from the aqueous solution by adding the second organic solvent.

[0039] In one embodiment, in step (3), the acid used for acid adjustment includes 10-37% hydrochloric acid, 40-98% sulfuric acid, or 40-80% phosphoric acid. Adjusting the pH will turn the generated product into a salt, which will then dissolve in water.

[0040] In one embodiment, in step (3), the alkaline solution includes a 10%~40% sodium hydroxide aqueous solution or a 10%~40% potassium hydroxide aqueous solution. Adjusting the alkali can release the product salt dissolved in the water, and then extract it with a second organic solvent.

[0041] In one embodiment, step (4) specifically refers to adding a first organic solvent directly to the concentrated copper sulfate aqueous solution to obtain a mixture, wherein the amount of the first organic solvent added is 8 to 9 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

[0042] This allows the recovered copper sulfate solution to be used as a raw material for the next reaction.

[0043] In one embodiment, in step (4), the amount of the second organic solvent is 0.5 to 0.6 times the mass of the 2,4-difluorodiazonium salt / sulfuric acid aqueous solution, and the product is extracted.

[0044] In one embodiment, in step (4), the copper sulfate aqueous solution is extracted with a second organic solvent and then concentrated to its original volume. After removing organic impurities from the copper sulfate aqueous solution with an organic solvent, it participates in the reaction again, thus avoiding the generation of metal waste.

[0045] To further illustrate the present invention, the following describes in detail a method for preparing 2,4-difluorophenol by diazotization hydrolysis provided by the present invention, in conjunction with embodiments.

[0046] The preparation method of 2,4-difluorodiazonium salt / sulfuric acid aqueous solution in the example is as follows: Prepare two clean reaction flasks, add 12V of water to one of them and stir, slowly add 7eq of concentrated sulfuric acid, after the addition is complete, control the temperature at 0~5℃ and add 1.0eq of 2,4-difluoroaniline raw material, add 1.1eq of sodium nitrite / 1.8V aqueous solution at 0~5℃, after the addition is complete, add 0.1eq of urea to quench the reaction, and store at 0~5℃ for later use.

[0047] The examples used an Agilent gas chromatograph equipped with a flame ionization detector (FID), a split device, a temperature programmed device, and a chromatography workstation. The chromatographic conditions were as follows: Instrument: Agilent 8890 gas chromatograph Column: Agilent 19091j-413 (HP-530m×320μm×0.25μm) Detector: FID detector 300℃ Carrier gas: Nitrogen Carrier gas flow rate: 20 ml / min Diluent: Methanol Inlet temperature: 250℃ Injection volume: 1.0 μl Temperature program: Initial temperature 80℃, hold for 1 minute, increase to 150℃ at a rate of 15℃ per minute, hold for 0 minutes, increase to 250℃ at a rate of 30℃ per minute, hold for 5 minutes. (Total 14 min) Example 1 The method for preparing 2,4-difluorophenol by diazotization hydrolysis in this embodiment follows the following reaction route: The specific synthesis method is as follows: Add 250g water, 433g toluene, and 235g copper sulfate to a 1000ml three-necked flask. Start stirring and heat to 70 degrees Celsius. Slowly add 600g of the prepared 2,4-difluorodiazo salt / sulfuric acid aqueous solution (compound II, 0.387 mol) over 4 hours. After the addition is complete, stir for 10 minutes, cool to 30 degrees Celsius, allow to stand and separate into layers, and collect the aqueous phase of copper sulfate for temporary storage.

[0048] Slowly add 30% sodium hydroxide aqueous solution to the toluene organic phase to adjust the pH to 10, let stand and separate the layers, add 50% sulfuric acid aqueous solution to the aqueous layer to adjust the pH to 2, add 300g dichloromethane to extract twice, combine the dichloromethane phases, concentrate the dichloromethane under reduced pressure, and distill the crude product to obtain 41g 2,4-difluorophenol (compound I) with a purity of 99.77%.

[0049] Add 300g of dichloromethane to the obtained aqueous copper sulfate phase to extract organic impurities once. Concentrate the extracted aqueous copper sulfate phase under reduced pressure and distill off 450g of water to obtain a concentrated aqueous copper sulfate solution for the next batch of reaction.

[0050] Example 2 The method for preparing 2,4-difluorophenol by diazotization hydrolysis in this embodiment is as follows: Add 5000g xylene to the copper sulfate aqueous solution recovered in Example 1, start stirring, heat to 72 degrees Celsius, and slowly add 606g of the prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution (0.391mol) dropwise over 3 hours. After the addition is complete, stir for 10 minutes, cool to 25 degrees Celsius, and allow to stand for separation. Collect the aqueous phase of copper sulfate for temporary storage. Slowly add 30% sodium hydroxide aqueous solution to the toluene organic phase to adjust the pH to 9.5. Allow to stand and separate the layers. Add 50% sulfuric acid aqueous solution to the aqueous layer to adjust the pH to 2. Add 305g dichloromethane for extraction twice. Combine the dichloromethane phases and concentrate under reduced pressure to obtain dichloromethane. Distill the crude product to obtain 43g of 2,4-difluorophenol with a purity of 99.78%.

[0051] Add 310g of dichloromethane to the obtained aqueous copper sulfate phase to extract organic impurities once. Concentrate the extracted aqueous copper sulfate phase under reduced pressure and distill off 550g of water to obtain a concentrated aqueous copper sulfate solution for the next batch of reaction.

[0052] Example 3 The method for preparing 2,4-difluorophenol by diazotization hydrolysis in this embodiment is as follows: Add 5000g of chlorobenzene to the copper sulfate aqueous solution recovered in Example 2, start stirring, heat to 80 degrees Celsius, and slowly add 600g of the prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution (0.387mol) dropwise over 5 hours. After the addition is complete, stir for 10 minutes, cool to 25 degrees Celsius, and allow to stand for separation. Collect the aqueous phase of copper sulfate and store it temporarily. Slowly add 30% sodium hydroxide aqueous solution to the toluene organic phase to adjust the pH to 10, allow to stand and separate the layers. Add 50% sulfuric acid aqueous solution to the aqueous layer to adjust the pH to 2, and add 350g of dichloromethane for extraction twice. Combine the dichloromethane phases, concentrate the dichloromethane under reduced pressure, and distill the crude product to obtain 40.5g of 2,4-difluorophenol with a purity of 99.78%.

[0053] Add 300g of dichloromethane to the obtained aqueous phase of copper sulfate to extract organic impurities once. Concentrate the extracted aqueous phase of copper sulfate under reduced pressure and distill off 500g of water to obtain a concentrated aqueous solution of copper sulfate, which will be used in the next batch of reaction.

[0054] Comparative Example 1 Unlike Example 1, no first organic solvent was added.

[0055] Add 250 ml of water and 235 g of copper sulfate to a 1000 ml three-necked flask, start stirring, heat to 70 degrees Celsius, and slowly add 600 g of the prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution (compound II, 0.387 mol) dropwise over 4 hours. After the addition is complete, stir for 10 minutes, cool to 30 degrees Celsius, and slowly add 30% sodium hydroxide aqueous solution to the reaction system to adjust the pH to 10. Allow to stand and separate the layers. Add 50% sulfuric acid aqueous solution to the aqueous layer to adjust the pH to 2, and add 300 g of dichloromethane for extraction twice. Combine the dichloromethane phases, concentrate under reduced pressure to obtain dichloromethane, and distill the crude product to obtain 23 g of 2,4-difluorophenol (compound I) with a purity of 93.23%.

[0056] Comparative Example 2 Unlike Example 1, no copper sulfate catalyst was added.

[0057] Add 250 ml of water and 500 ml of toluene to a 1000 ml three-necked flask, start stirring, heat to 70 degrees Celsius, and slowly add 600 g of the prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution (compound II, 0.387 mol) dropwise over 4 hours. After the addition is complete, stir for 10 minutes, cool to 30 degrees Celsius, and slowly add 30% sodium hydroxide aqueous solution to the reaction system to adjust the pH to 10. Allow to stand and separate the layers. Add 50% sulfuric acid aqueous solution to the aqueous layer to adjust the pH to 2, and add 300 g of dichloromethane for extraction twice. Combine the dichloromethane phases and concentrate under reduced pressure to remove dichloromethane. If distillation is not possible, obtain the product 2,4-difluorophenol (compound I).

[0058] Comparative Example 3 Unlike Example 1, the first organic solvent and the second organic solvent are interchanged.

[0059] Add 250 ml of water, 235 g of copper sulfate, and 500 ml of dichloromethane to a 1000 ml three-necked flask. Start stirring and heat to 70°C. Slowly add 600 g of the prepared 2,4-difluorodiazonium salt / sulfuric acid aqueous solution (compound II, 0.387 mol) over 4 hours. After the addition is complete, stir for 10 minutes and cool to 30°C. Slowly add 30% sodium hydroxide aqueous solution to the reaction system to adjust the pH to 10. Allow to stand and separate the layers. Add 50% sulfuric acid aqueous solution to the aqueous layer to adjust the pH to 2. Add 300 g of toluene and extract twice. Combine the toluene phases and concentrate under reduced pressure to remove toluene. Distill the crude product to obtain 18.3 g of 2,4-difluorophenol (compound I) with a purity of 94.39%.

[0060] Detection: Samples of 2,4-difluorophenol prepared in the examples and comparative examples were taken. The gas chromatogram of 2,4-difluorophenol prepared in Example 1 is shown below. Figure 1 As shown. Figure 1 It can be seen that the purity of product 2,4-difluorophenol is 99.77%.

[0061] The gas chromatogram of 2,4-difluorophenol prepared in Example 2 is shown below. Figure 2 As shown. Figure 2 It can be seen that the purity of the product 2,4-difluorophenol is 99.78%.

[0062] The gas chromatogram of 2,4-difluorophenol prepared in Example 3 is shown below. Figure 3 As shown, the purity of the product 2,4-difluorophenol is 99.78%. Other specific results are shown in Table 1. Table 1 Comparison of the yield and purity of 2,4-difluorophenol in the examples and comparative examples. As can be seen from Comparative Example 1, since a large number of polymerization impurities are generated during the high-temperature hydrolysis of diazonium salts, the selection and addition of the first organic solvent is crucial to dissolve the generated products, prevent the products from polymerizing with diazonium salts, and reduce by-products. Otherwise, the yield and purity will be affected.

[0063] As can be seen from Comparative Example 2, diazo salt aqueous solution cannot be hydrolyzed into the product at high temperature without copper sulfate catalyst.

[0064] As can be seen from Comparative Example 3, the choice of the first and second organic solvents also affects the yield and purity of the final product, especially the yield.

[0065] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 2,4-difluorophenol by diazotization hydrolysis, characterized in that: Includes the following steps: Step (1) Mix copper sulfate, the first organic solvent and water in a mass ratio of 3.7~5.7 : 9~11 : 4.8~5.2 to obtain a mixture; Step (2) The prepared 2,4-difluorodiazo salt / sulfuric acid aqueous solution is added dropwise to the mixture in step (1) for hydrolysis, separation, and temporary storage of copper sulfate aqueous solution; Step (3) Step (2) After separation, add alkaline solution to the organic layer, adjust pH to 8-10, separate the layers, adjust pH of the aqueous layer to 1-2 with acid, add a second organic solvent for extraction, concentrate the organic layer to dryness, and distill to obtain 2,4-difluorophenol. After the reaction in step (4) is completed, the copper sulfate aqueous solution separated in step (2) is extracted with a second organic solvent, and after reducing the pressure to concentrate some water, a concentrated copper sulfate aqueous solution is obtained for the next batch of reaction.

2. The method according to claim 1, characterized in that: In step (1), the first organic solvent is an aromatic solvent, including toluene, chlorobenzene, dichlorobenzene or bromobenzene.

3. The method according to claim 1, characterized in that: In step (2), the temperature of the drop is 60-80 degrees Celsius and the drop time is 3-6 hours.

4. The method according to claim 1, characterized in that: In step (2), the amount of 2,4-difluorodiazo salt / sulfuric acid aqueous solution added is 2.5 to 2.8 times the weight of copper sulfate.

5. The method according to claim 1, characterized in that: In step (3), the second organic solvent is a solvent with high solubility for organic substances, including dichloromethane or chloroform, and the amount of the second organic solvent added is 0.5 to 0.6 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

6. The method according to claim 1, characterized in that: In step (3), the acid used for acid adjustment includes: 10-37% hydrochloric acid, 40-98% sulfuric acid or 40-80% phosphoric acid.

7. The method according to claim 1, characterized in that: In step (3), the alkaline solution includes a 10%~40% sodium hydroxide aqueous solution or a 10%~40% potassium hydroxide aqueous solution.

8. The method according to claim 1, characterized in that, In step (4), "for the next batch of reaction" specifically means: the first organic solvent is added directly to the concentrated copper sulfate aqueous solution to obtain a mixture, and the amount of the first organic solvent added is 8 to 9 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

9. The method according to claim 1, characterized in that, In step (4), the amount of the second organic solvent added is 0.5 to 0.6 times the mass of the 2,4-difluorodiazo salt / sulfuric acid aqueous solution.

10. The method according to claim 1, characterized in that: In step (4), the copper sulfate aqueous solution is extracted with a second organic solvent and then concentrated to its original volume.

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