Continuous preparation method of fluorophenol
By carrying out the diazotization and hydrolysis reaction of fluoroaniline with nitrite in a continuous reactor, combined with continuous extraction and multi-stage distillation purification processes, the safety hazards and environmental pollution problems of the batch reaction process of fluorophenol have been solved, and efficient and safe production of fluorophenol has been achieved.
Patent Information
- Application Number
- CN202511266162.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-05
- Publication Date
- 2026-01-13
AI Technical Summary
The existing batch reaction process for fluorophenols has problems such as safety hazards, environmental pollution and low production efficiency, making it difficult to achieve large-scale industrial production.
A continuous reactor is used to carry out the diazotization and hydrolysis reaction of fluoroaniline and nitrite, combined with continuous extraction and multi-stage distillation purification processes to achieve the continuous production of fluorophenol throughout the entire process.
It improved production safety and efficiency, reduced organic wastewater discharge, lowered environmental impact and treatment costs, and increased production capacity.
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Figure CN121318673A_ABST
Abstract
Description
Technical Field
[0001] This application relates to a continuous preparation method of fluorophenols, belonging to the field of compound preparation technology. Background Technology
[0002] Fluorophenols are key intermediates in the synthesis of pharmaceuticals and pesticides, and are widely used in these processes. The industrial production of fluorophenols mainly employs a batch reaction process, in which the diazotization reaction is carried out in batches within a reactor. Due to uneven mixing and low heat transfer efficiency, the concentration of highly reactive aryl diazonium salts can easily become excessively high in certain areas, leading to violent exothermic reactions or even decomposition accidents, posing significant safety hazards.
[0003] Furthermore, the post-reaction processing requires multiple extractions and separations using organic solvents, generating large amounts of phenol-containing organic wastewater and highly toxic wastewater, resulting in high environmental remediation costs. At the same time, phenolic substances are prone to volatilization and diffusion during intermittent open-boiler operation, causing pollution to the work environment.
[0004] Furthermore, each production unit relies on manual batch feeding, transfer, and separation, resulting in long equipment downtime and limited capacity expansion due to operational efficiency. These safety hazards, environmental pressures, and production efficiency constraints hinder large-scale industrial production. Summary of the Invention
[0005] The purpose of this application is to overcome the shortcomings of the existing background technology and provide a continuous preparation method for fluorophenols, thereby improving the safety of industrial production of fluorophenols.
[0006] To achieve the above objectives, the technical solution adopted in this application is as follows:
[0007] This application provides a continuous preparation method for fluorophenols, comprising:
[0008] Fluoroaniline was dissolved in an acid solution and then pumped separately into a continuous reactor along with an aqueous nitrite solution to carry out a diazotization reaction.
[0009] The mixture after diazotization was subjected to hydrolysis to obtain the hydrolysate.
[0010] The hydrolysate was separated into organic phases by extraction and separation.
[0011] The organic phase was purified by distillation to obtain fluorophenol.
[0012] Furthermore, the acid solution is a hydrochloric acid solution or a sulfuric acid solution, and the mass ratio of the fluoroaniline to the acid solution is 1:2 to 1:10.
[0013] Furthermore, the concentration of the nitrite aqueous solution is 5% to 35%, wherein the molar ratio of nitrite to fluoroaniline is 1:1 to 3:1.
[0014] Furthermore, the diazotization reaction is carried out at a temperature of 0 to 60°C and for a reaction time of 10 seconds to 5 minutes.
[0015] Furthermore, the hydrolysis reaction includes directly hydrolyzing the mixture after the diazotization reaction, or adding water not exceeding 50 times the mass of fluoroaniline to carry out the hydrolysis reaction.
[0016] Furthermore, the reaction temperature in the hydrolysis reaction is 80℃~120℃, and the reaction time is 1~40 minutes.
[0017] Furthermore, the diazotization reaction and / or hydrolysis reaction are carried out in a tubular reactor, a microchannel reactor, or a continuous stirred tank.
[0018] Furthermore, the extraction is carried out in a continuous extraction manner, and the solvent used is any one or more of toluene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, dichloromethane or isopropyl ether. The continuous extraction is carried out in a tubular reactor or a microchannel reactor.
[0019] Furthermore, the distillation adopts a multi-stage distillation method, first concentrating and recovering the solvent and reusing it in the extraction process, and then heating and distilling to remove impurities to obtain fluorophenol.
[0020] The fluorophenol prepared according to any of the methods described above has the following general structural formula:
[0021] ,
[0022] In the formula, R is methyl, and the fluorophenols include: 4-fluoro-2-methylphenol, 4-fluoro-3-methylphenol, 5-fluoro-2-methylphenol, 2-fluoro-5-methylphenol, 3-fluoro-4-methylphenol, 2-fluoro-4-methylphenol and 3-fluoro-2-methylphenol.
[0023] Compared with the prior art, the beneficial effects achieved by this application are as follows:
[0024] This application provides a continuous preparation method for fluorophenols, which realizes the continuous production of fluorophenols throughout the entire process through integrated continuous operation, avoiding manual intervention, material transfer and equipment idleness in intermittent operation, and improving production capacity and operational safety.
[0025] By using continuous extraction and separation and multi-stage continuous distillation purification processes, the solvent can be efficiently recovered and recycled, reducing the discharge of organic waste liquid and lowering environmental impact and treatment costs.
[0026] By controlling the mass ratio of fluoroaniline to acid solution to 1:2 to 1:10, the molar ratio of nitrite to fluoroaniline to 1:1 to 3:1, and the diazotization reaction conditions, local overheating and side reactions can be avoided, thereby improving the stability of the reaction process.
[0027] By using a continuous reactor for diazotization and hydrolysis, the reaction time can be reduced from several hours to less than 6 minutes, significantly improving production efficiency, reducing the risk of intermediate heavy nitrogen salt decomposition, and enhancing process safety. Attached Figure Description
[0028] Figure 1 These are schematic diagrams of a continuous preparation method of fluorophenol provided in Examples 1 to 13;
[0029] Figure 2 This is a schematic diagram of a continuous preparation method of fluorophenol provided in Examples 14 to 19;
[0030] Figure 3 These are schematic diagrams of a continuous preparation method of fluorophenol provided in Examples 20 to 27;
[0031] Figure 4 This is a schematic diagram of a continuous preparation method of fluorophenol provided in Example 28. Detailed Implementation
[0032] The present application will be further described below with reference to the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solutions of the present application and should not be used to limit the scope of protection of the present application. Unless otherwise specified, the concentrations in the specific embodiments are all mass concentrations, and the purity of the products is obtained by high performance liquid chromatography.
[0033] This application provides a continuous preparation method for fluorophenols, which specifically includes the following steps:
[0034] The feeding and mixing of raw materials fluoroaniline, acid and nitrite aqueous solution result in a diazotization reaction;
[0035] The mixture after diazotization is then subjected to a hydrolysis reaction.
[0036] The mixture after the hydrolysis reaction was extracted and separated to obtain an extract solution containing phenol;
[0037] The extract containing phenol was purified by continuous distillation to obtain fluorophenol. The general formula of the obtained fluorophenol is as follows:
[0038]
[0039] In the formula, R is methyl, and the fluorophenols include 4-fluoro-2-methylphenol, 4-fluoro-3-methylphenol, 5-fluoro-2-methylphenol, 2-fluoro-5-methylphenol, 3-fluoro-4-methylphenol, 2-fluoro-4-methylphenol, and 3-fluoro-2-methylphenol.
[0040] In the process of feeding and mixing the raw material fluoroaniline, acid and nitrite aqueous solution, and in the continuous diazotization reaction, the raw material fluoroaniline can be dissolved in acid for feeding. The acid can be hydrochloric acid or sulfuric acid, and the mass ratio is 1:2 to 1:10, preferably 1:3 to 1:4.
[0041] The acid can be diluted with water, and the mass ratio of water to the raw material fluoroaniline is (0-50):1, preferably (5-15):1.
[0042] The nitrite is dissolved in water and fed into the feed, with a concentration between 5% and 35%, preferably 20% to 30%.
[0043] The molar ratio of nitrite to raw material fluoroaniline is 1.0~3.0, preferably 1.05~1.1, and sodium nitrite is preferred in this application.
[0044] The reaction temperature for the continuous diazotization reaction is 0~60℃, preferably 30℃~40℃. The reaction time is 10 seconds to 5 minutes, preferably 20~40 seconds.
[0045] The continuous diazotization reaction can be carried out in a tubular reactor, a microchannel reactor, a continuously stirred reactor, or a combination of different reactors.
[0046] In the process of hydrolyzing the above-mentioned diazotization mixture to generate fluorophenol, the ratio of water added to the raw material fluoroaniline in the hydrolysis reaction is 0 to 50 times, preferably 10 to 20 times. The hydrolysis reaction temperature is 80℃ to 120℃, preferably 100℃ to 110℃. The reaction time is 1 to 40 minutes, preferably 5 to 10 minutes.
[0047] Hydrolysis can be carried out in a tubular reactor, a microchannel reactor, a continuously stirred reactor, or a combination of different reactors.
[0048] In the continuous post-processing extraction and separation process, extraction can be performed using either batch extraction or continuous multiple extraction and separation methods. Continuous extraction and separation is preferred, and more preferably, the product and aqueous phases are separated first, followed by solvent extraction of the aqueous phase once or twice. The solvent used for extraction is any one or more of toluene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, dichloromethane, and isopropyl ether, with dichloromethane and methyl tert-butyl ether being preferred.
[0049] Continuous extraction can be carried out in a tubular reactor, a microchannel reactor, or a continuously stirred reactor, with a tubular reactor being preferred. The continuous separation can be achieved through gravity settling, membrane separation, or centrifugal separation, with gravity separation being the preferred method.
[0050] The continuous distillation purification process can be carried out in an intermittent manner or in a continuous concentration distillation manner. The continuous concentration distillation method is preferred, and the multi-stage distillation method is even more preferred. First, the solvent obtained by concentration and condensation is recycled for the extraction process, and then the temperature is raised to concentrate and distill to remove impurities to obtain high-purity fluorophenol.
[0051] Comparative Example 1:
[0052] Existing technologies use a batch process to synthesize the product 2-methyl-5-fluorophenol, including the following steps:
[0053] Add 5 g of 4-fluoro-2-methylaniline, 21 g of water, and 14 g of concentrated sulfuric acid to a reaction flask. Cool to 0°C and add an aqueous solution of sodium nitrite dropwise (sodium nitrite, 3.4 g, 48 mmol, 1.2 eq.; water 10 g). After the addition is complete, stir the reaction mixture at 0°C for 1 hour. Add a solution of 20 g water and 0.3 g urea to the reaction mixture and stir for 30 min. Then add this solution dropwise to a mixed solution of 10 g water, 15 g sodium sulfate, and 15 g sulfuric acid at 130°C. Stir the reaction mixture for 10 min. Cool to room temperature and extract three times with 100 mL of dichloromethane. Wash the combined dichloromethane solution twice with 50 mL of water and extract the product to the aqueous phase with 50 mL of 10% sodium hydroxide solution. Adjust the aqueous phase with hydrochloric acid and then extract three times with 100 mL of dichloromethane. Combine the dichloromethane extracts, wash twice with 50 mL of brine, dry with sodium sulfate, and filter. The filtrate was concentrated, and the residue was subjected to column chromatography with dichloromethane and n-heptane as elution to obtain 4.3 g of a brownish-red liquid, which was 2-methyl-5-fluorophenol with a purity of 98% and a yield of 85%.
[0054] like Figure 1 The diagram shown is a schematic diagram of a continuous preparation method of fluorophenol provided in Examples 1 to 13 of this application. Examples 1 to 7 involve a continuous diazotization reaction, including the following steps:
[0055] 4-Fluoro-2-methyl-aniline was dissolved in 6 times its mass ratio of water and 4 times its mass ratio of concentrated hydrochloric acid to obtain an aqueous solution of aniline hydrochloric acid;
[0056] Sodium nitrite was prepared into a 30% aqueous solution;
[0057] Aniline hydrochloric acid aqueous solution and sodium nitrite solution are pumped separately into tubular reactors for precooling or preheating, and then mixed through a three-way valve for diazotization reaction;
[0058] After the diazotization reaction, the outflowing reaction solution is dripped into hot water at 100°C for hydrolysis reaction for 30 minutes, and samples are taken for control.
[0059] Table 1 shows the results of the intermediate control for different raw material ratios and reaction conditions in Examples 1 to 7.
[0060] Table 1:
[0061]
[0062] Specifically, taking Example 2 as an example: After the diazotization reaction, the reaction solution after 20 minutes of hydrolysis was collected, and then the reaction was stirred for 30 minutes. The reaction solution was cooled to room temperature and extracted three times with 100 mL of dichloromethane. The extracted dichloromethane solutions were combined and washed twice with 50 mL of water and once with 50 mL of brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was subjected to column chromatography, eluted with a mixed solvent of dichloromethane and n-heptane, to obtain 4.9 g of a pale yellow liquid, which was 4-fluoro-2-methylphenol, with a purity of 99% and a yield of 81%.
[0063] Examples 8 to 13 involved a continuous diazotization reaction, comprising the following steps:
[0064] 4-Fluoro-2-methylaniline is dissolved in diluted hydrochloric acid or sulfuric acid to obtain an aqueous solution of aniline hydrochloric acid;
[0065] Sodium nitrite was prepared into a 30% aqueous solution;
[0066] A aniline hydrochloric acid or sulfuric acid solution and sodium nitrite solution are pumped into pipelines at a molar ratio of 1.2:1 and preheated to 30℃~40℃. Then, they are mixed and subjected to a diazotization reaction at 40℃ for 60 seconds. After the system stabilizes, the outflowing reaction solution is dripped into hot water at 100℃ for a hydrolysis reaction for 30 minutes, and samples are taken for control.
[0067] Table 2 shows the results of the central control for different ratios and reaction conditions in Examples 8 to 13.
[0068] Table 2:
[0069]
[0070] Specifically, taking Example 11 as an example: The aniline hydrochloric acid aqueous solution was pumped in at 5.0 g / min. After the system stabilized, the reaction solution was collected for 20 min. The reaction solution was cooled to room temperature and extracted three times with 100 mL of dichloromethane. The combined dichloromethane solution was washed twice with 50 mL of water and once with 50 mL of brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was subjected to column chromatography, eluting with a mixed solvent of dichloromethane and n-heptane to obtain 3.2 g of a pale yellow liquid product, 4-fluoro-2-methylphenol, with a purity of 99% and a yield of 80%.
[0071] like Figure 2 The diagram shown is a schematic diagram of a continuous preparation method of fluorophenol provided in Examples 14 to 19, which involves continuous diazotization and continuous hydrolysis reactions, including the following steps:
[0072] 4-Fluoro-2-methylaniline was dissolved in 5 times the mass ratio of hydrochloric acid and 10 times the mass ratio of water to obtain an aqueous solution of aniline hydrochloric acid;
[0073] Sodium nitrite was prepared into a 20% aqueous solution;
[0074] Aniline hydrochloric acid aqueous solution and sodium nitrite solution were pumped separately into pipelines at a molar ratio of 1.05:1 and mixed for a diazotization reaction at 40°C for 30 seconds. The outflowing reaction solution was then heated in the pipeline for hydrolysis, with a back pressure of 5 bar. After cooling and gas-liquid separation, the outflowing reaction solution was sampled and controlled.
[0075] Table 3 shows the control results for different hydrolysis temperatures and hydrolysis times in Examples 14 to 19.
[0076] Table 3:
[0077]
[0078] Specifically, taking Example 18 as an example: Aniline hydrochloric acid aqueous solution was pumped in at 5.0 g / min for the reaction. After the system stabilized, the reaction solution was collected after 20 min. The collected reaction solution was extracted twice with 100 mL of dichloromethane. The combined dichloromethane solution was washed twice with 50 mL of water and once with 50 mL of brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was subjected to column chromatography, eluting with a mixed solvent of dichloromethane and n-heptane to obtain 4.9 g of a pale yellow liquid, 4-fluoro-2-methylphenol, with a purity of 99% and a yield of 77%.
[0079] like Figure 3 The diagram shown illustrates a continuous preparation method of fluorophenol provided in Examples 20 to 27; wherein Examples 20 to 22 involve continuous diazotization and continuous hydrolysis reactions, including the following steps:
[0080] 4-Fluoro-2-methylaniline was dissolved in 4 times its mass of hydrochloric acid and 6 times its mass of water, with sodium nitrite prepared as a 20% aqueous solution. The aniline hydrochloric acid solution and the sodium nitrite solution (molar ratio 1.05) were separately pumped into pipelines, mixed, and subjected to a diazotization reaction at 40°C for 20 seconds. The outflowing reaction solution was mixed with hot water and subjected to a hydrolysis reaction at 100°C to 110°C in a series of two-stage continuously stirred reactors for a total residence time of 5 minutes. The outflowing reaction solution was then cooled to room temperature.
[0081] In Example 21, an aqueous solution of aniline hydrochloric acid was pumped in at a flow rate of 5.0 g / min. After the system stabilized, the reaction solution was collected for 20 min. The solution was extracted twice with 100 mL of dichloromethane. The combined dichloromethane solution was washed twice with 50 mL of water and once with 50 mL of brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to recover the solvent. The residue was further distilled under reduced pressure to remove low-boiling impurities, yielding 7.2 g of a yellow liquid product, 4-fluoro-2-methylphenol, with a purity of 97% and a yield of 79%.
[0082] Table 4 shows the intermediate control results for different water mass ratios used in hydrolysis in Examples 20 to 22.
[0083] Table 4:
[0084]
[0085] Examples 23-27: Continuous diazotization reaction, continuous hydrolysis reaction
[0086] Aniline was dissolved in 4 times its mass of hydrochloric acid and 6 times its mass of water, and sodium nitrite was prepared into a 20% aqueous solution. The aniline hydrochloric acid aqueous solution and the sodium nitrite solution were pumped separately into pipelines at a flow rate of 5.0 g / min and 1.25 g / min (molar ratio 1.05), respectively. After preheating to 30-40°C, the mixture was subjected to a diazotization reaction at 40°C for 20 seconds. The outflowing reaction solution was mixed with hot water pumped in at 10.0 g / min and subjected to a hydrolysis reaction in a series of three-stage continuously stirred reactors at 100-110°C for a total residence time of 5 minutes. The outflowing reaction solution was cooled to room temperature. After the system stabilized, the 20-minute reaction solution was collected. The reaction solution was extracted twice with 100 mL of dichloromethane. The combined dichloromethane solutions were washed twice with 50 mL of water and once with 50 mL of brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to recover the solvent, and the residual liquid is further distilled under reduced pressure to remove low-boiling-point impurities, thus obtaining the product.
[0087] Table 5 shows the products obtained from different raw materials in Examples 23 to 27.
[0088] Table 5:
[0089]
[0090] like Figure 4 The diagram shown is a schematic of a continuous preparation method for fluorophenol provided in Example 28, which involves continuous diazotization reaction, continuous hydrolysis reaction, continuous extraction and distillation, specifically including the following steps:
[0091] 5-Fluoro-2-methylaniline was dissolved in 3 times its mass ratio of hydrochloric acid and 7 times its mass ratio of water, and sodium nitrite was prepared into a 10% aqueous solution. The aniline hydrochloric acid aqueous solution and the sodium nitrite solution were pumped into pipelines at a flow rate of 50 g / min and 12.5 g / min respectively (molar ratio 1.05). After preheating to 30°C to 40°C, the mixture was subjected to a diazotization reaction at 40°C for 20 seconds. The outflowing reaction solution was mixed with hot water pumped in at 100 g / min and subjected to a hydrolysis reaction in a series of three-stage continuously stirred reactors at 100°C to 110°C for a total residence time of 5 minutes.
[0092] The outflowing reaction solution is cooled to room temperature via a heat exchanger and then enters separator 1 for phase separation. The lower oil phase is the product, while the upper aqueous phase is pumped into a pipeline to be mixed and extracted with methyl tert-butyl ether (MTBE) pumped in at a rate of 25 g / min for 1 minute. The outflowing mixture enters separator 2 for further phase separation. The upper MTBE extract is mixed with the product separated in separator 1 and then concentrated in a rotary evaporator. The condensed and recovered MTBE is reused in the extraction process.
[0093] After the system stabilized, the product was collected after 30 minutes. The concentrated residue was then further distilled under reduced pressure to remove low-boiling-point impurities, yielding 104.1g of a yellow oily product, which was 5-fluoro-2-methyl-phenol, with a purity of 98% and a yield of 76%.
[0094] Compared with Comparative Example 1, the continuous preparation method of fluorophenol disclosed in this application achieves continuous synthesis and separation of fluorophenol. The process involves continuous addition of raw materials and uninterrupted synthesis and separation of products, greatly improving process efficiency, with the total reaction time controlled within 6 minutes.
[0095] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of this application, and these improvements and modifications should also be considered within the scope of protection of this application.
Claims
1. A process for the continuous production of a fluorophenol, characterized in that, The application relates to a method for preparing fluorophenol. The fluorophenylamine is dissolved in an acid solution, and a nitrite aqueous solution is pumped into a continuous reactor to perform a diazotization reaction; A hydrolysis reaction is performed on the mixed solution after the diazotization reaction to obtain a hydrolyzed solution; The hydrolyzed solution is separated into an organic phase through extraction and separation; The organic phase is purified through distillation to obtain fluorophenol.
2. The method of claim 1, wherein, The acid solution is a hydrochloric acid solution or a sulfuric acid solution, and the mass ratio of the fluorophenylamine to the acid solution is 1:2 to 1:
10.
3. The method of claim 1, wherein, The concentration of the nitrite aqueous solution is 5% to 35%, and the molar ratio of the nitrite to the fluorophenylamine is 1:1 to 3:
1.
4. The method of claim 1, wherein, The reaction temperature of the diazotization reaction is 0 to 60 DEG C, and the reaction time is 10 seconds to 5 minutes.
5. The method of claim 1, wherein, The hydrolysis reaction includes directly performing a hydrolysis reaction on the mixed solution after the diazotization reaction, or adding water not more than 50 times the mass of the fluorophenylamine to perform the hydrolysis reaction.
6. The method of claim 1, wherein, The reaction temperature of the hydrolysis reaction is 80 DEG C to 120 DEG C, and the reaction time is 1 to 40 minutes.
7. The method of claim 1 wherein, The diazotization reaction and / or the hydrolysis reaction are performed in a tubular reactor, a microchannel reactor or a continuous stirred tank.
8. The method of claim 1, wherein, The extraction is performed in a continuous extraction mode, and any one or more of toluene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, dichloromethane or isopropyl ether is used as a solvent, and the continuous extraction is performed in a tubular reactor or a microchannel reactor.
9. The method of claim 1 wherein, The distillation is performed in a multistage distillation mode, solvent is recovered and reused in the extraction process through concentration, and fluorophenol is obtained through impurity removal through temperature rising distillation.
10. The fluorophenol produced according to the process of any one of claims 1 to 9, characterized in that, The structural general formula of the fluorophenol is shown in the following formula: ， In the formula, R is a methyl group, and the fluorophenol includes 4-fluoro-2-methylphenol, 4-fluoro-3-methylphenol, 5-fluoro-2-methylphenol, 2-fluoro-5-methylphenol, 3-fluoro-4-methylphenol, 2-fluoro-4-methylphenol and 3-fluoro-2-methylphenol.