A method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology
By employing continuous flow technology and modified Sn-Beta molecular sieve catalysts, the safety and environmental issues of batch-type BV oxidation process have been resolved, enabling efficient and green synthesis of 4-phenoxyphenol and improving product quality and production safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGXI DEJING MATERIAL TECH CO LTD
- Filing Date
- 2026-04-01
- Publication Date
- 2026-06-26
AI Technical Summary
The existing batch-type BV oxidation process has problems such as poor safety, environmental unfriendliness and unstable product quality. In particular, it poses a risk of explosion and significant environmental pollution in large-scale production, and the reaction selectivity is limited.
By employing continuous flow technology and modified Sn-Beta molecular sieve as a solid catalyst, oxidation and hydrolysis reactions are carried out through a micro-mixer and tubular reactor, combined with temperature-programmed crystallization technology, to replace traditional peroxyacid and concentrated sulfuric acid, achieving a green and efficient synthesis of 4-phenoxyphenol.
The synthesis of 4-phenoxyphenol, which is safe and environmentally friendly, has been achieved with few byproducts, high yield and purity, and is suitable for industrial production.
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Figure CN122277376A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology. Background Technology
[0002] 4-Phenoxyphenol is a key intermediate in the synthesis of insect growth regulators such as fenvalerate and other fine chemicals. In the existing "diphenyl ether method" synthetic route, the Baeyer-Villiger (BV) oxidation step is the core transformation step, which involves oxidizing and rearranging 4-phenoxybenzophenone into the corresponding ester (4-phenoxybenzoate), and then hydrolyzing it to obtain the target product.
[0003] Traditional batch-type BV oxidation processes typically use m-chloroperoxybenzoic acid (m-CPBA) and sulfuric acid as oxidants. This process has significant drawbacks: 1. Poor safety: Peroxy acids are unstable and easily decompose and release heat; concentrated sulfuric acid is highly corrosive and oxidizing, posing an explosion risk in large-scale production; the reaction itself is highly exothermic, easily leading to localized overheating in the batch reactor, causing side reactions or safety accidents; 2. Environmentally unfriendly: The reaction generates stoichiometric amounts of m-chlorobenzoic acid and other organic waste acids, which are difficult to treat and cause significant environmental pollution; 3. Product quality and efficiency issues: Reaction selectivity is limited by mixing and heat transfer efficiency, easily producing byproducts such as over-oxidation, resulting in unstable yields and purity, and large batch-to-batch variations.
[0004] In view of this, developing a BV oxidation synthesis process that combines a green oxidation system and continuous flow technology is of great significance for the safe, efficient and clean production of 4-phenoxyphenol. Summary of the Invention
[0005] In view of the above-mentioned content, the purpose of this invention is to provide a method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology, aiming to overcome the shortcomings of the prior art and provide a safe, efficient and green continuous flow synthesis process.
[0006] To achieve the above objectives, the present invention specifically adopts the following technical solution: This invention provides a method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology, comprising the following steps: S1. Take hydrogen peroxide aqueous solution and 4-phenoxybenzophenone solution respectively and place them in the first and second feed units; S2. Hydrogen peroxide aqueous solution and 4-phenoxybenzophenone solution are pumped into a micro mixer by an injection pump and thoroughly mixed. Then, the mixture is passed into a tubular reactor filled with solid catalyst and kept in a constant temperature oil bath. S3. Place the sodium hydroxide aqueous solution in the third feed unit, pump the reaction product of S2 into the sodium hydroxide solution and mix thoroughly, then pass it into the hydrolysis tubular reactor and keep it in a constant temperature water bath. S4. The reaction product of S3 is continuously separated and purified, and the organic phase is separated, the solvent is evaporated, and the product is crystallized by temperature program to obtain 4-phenoxyphenol needle crystals.
[0007] In a preferred embodiment, the concentration of the hydrogen peroxide aqueous solution in S1 is 15 wt.%-30 wt.%; the concentration of the 4-phenoxybenzophenone solution is 0.05-0.2 mol / L, and the solvent used is hexafluoroisopropanol or acetonitrile.
[0008] In a preferred embodiment, the volume ratio of hydrogen peroxide aqueous solution to 4-phenoxybenzophenone solution in S2 is (1.02-1.05):1.
[0009] In a preferred embodiment, the solid catalyst in S2 is a modified Sn-Beta molecular sieve with SiO2 / SnO2=100. The modification method is as follows: the Sn-Beta molecular sieve is first immersed in ammonium nitrate solution for activation, centrifuged, washed and dried, then immersed in sodium carbonate solution for ultrasonic treatment, centrifuged, washed and dried again to obtain the modified Sn-Beta molecular sieve.
[0010] This invention preferably uses Sn-Beta molecular sieves for further activation and modification: ammonium ions exchange residual impurity cations in the molecular sieve framework or pores, subsequently decomposing into hydrogen ions that combine with framework oxygen to form acid sites, which helps purify the pores and allows for more complete exposure of the acid sites on the Sn-Beta molecular sieve. After ion exchange activation, a weakly alkaline environment is introduced to moderately neutralize some of the strong acid sites. Carbonate and bicarbonate ions can interact with the silanol or tinol groups on the molecular sieve surface, forming weakly alkaline sites that constitute acid-base pairs, effectively reducing side reactions initiated in the target reaction. The Sn-Beta molecular sieve modified by this invention can precisely catalyze the target pathway, enhance intrinsic catalytic activity, significantly reduce side reactions, and improve the cycle stability of the reaction.
[0011] In a preferred embodiment, the temperature of the constant temperature oil bath in S2 is 38-42℃, and the time is 4-6 h.
[0012] In a preferred embodiment, the concentration of the sodium hydroxide aqueous solution in S3 is 1-2 mol / L.
[0013] As a preferred embodiment, the temperature of the constant temperature water bath in S3 is 75-85℃, and the time is 10-20 min.
[0014] As a preferred embodiment, the specific operation of continuous separation and purification in S4 is as follows: first, the organic phase is separated by a continuous separatory membrane, then the organic phase is passed into an evaporator to evaporate the solvent, and the residue is introduced into a continuous crystallizer. The solid is precipitated by programmed cooling, thus obtaining 4-phenoxyphenol crystals.
[0015] As a preferred embodiment, the parameters for the programmed cooling in S4 are as follows: cooling to 70°C at a rate of 15-20°C / h, holding at that temperature for 1-1.5 h, then cooling to 40°C at a rate of 3-8°C / h, holding at that temperature for 0.5-1 h, and finally cooling to room temperature at a rate of 10-12°C, stabilizing for 0.5-1 h.
[0016] Compared with the prior art, the beneficial effects of the present invention are: This invention overcomes the shortcomings of existing processes by replacing liquid acids such as peroxyacid or concentrated sulfuric acid with a precisely designed and easily separated and recovered solid catalyst, ensuring good safety and environmental friendliness. The process constructs a green reaction system, utilizing the high mass and heat transfer efficiency of microreactors to transform a strongly exothermic reaction into a safe, controllable, and precise continuous process, thus solving the scale-up effect. The overall process has low by-products, high yield, conforms to green chemistry principles, and is suitable for industrial production. Attached Figure Description
[0017] Figure 1 This is a process flow diagram of the present invention. Detailed Implementation
[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with embodiments. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.
[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.
[0020] Example 1 A method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology includes the following steps: 1. Dissolve 2.5 mmol of 4-phenoxybenzophenone in an appropriate amount of hexafluoroisopropanol (HFIP) to prepare a 0.1 mol / L solution, and place it in the first feed unit. Place a 24 wt.% H2O2 aqueous solution in the second feed unit. Place a 1.5 mol / L NaOH aqueous solution in the third feed unit.
[0021] 2. Take Sn-Beta molecular sieve (SiO2 / SnO2=100), immerse it in 0.5 mol / L ammonium nitrate solution at a solid-liquid ratio of 1:10, let it stand at 50℃ for 2 h, then centrifuge, wash and dry; immerse the activated molecular sieve in 0.2 mol / L sodium carbonate solution at a solid-liquid ratio of 1:5, sonicate at 30℃ for 10 min, centrifuge, wash and dry to obtain modified Sn-Beta molecular sieve.
[0022] 3. Using two precision syringe pumps, the 4-phenoxybenzophenone solution and the H2O2 aqueous solution were pumped into a micromixer at a flow rate of 0.25 mL / min. After thorough mixing, the mixture was introduced into a PFA tubular reactor with an inner diameter of 2 mm, a length of 10 m, and filled with 1.0 g of modified Sn-Beta molecular sieve. The reactor was placed in a constant temperature oil bath at 40℃, and the material was allowed to react for 5 h.
[0023] 4. The oxidation product intermediate fluid flowing out of the PFA tubular reactor is immediately pumped into an online NaOH aqueous solution at a flow rate of 0.15 mL / min for mixing, and then passed into a PFA capillary tube with an inner diameter of 1 mm and a length of 5 m (as a hydrolysis tubular reactor). The reactor is placed in a constant temperature water bath at 80℃, and the material is allowed to react for 15 min.
[0024] 5. Continuous separation and purification of the hydrolysis product reaction solution flowing out of the PFA capillary: First, the solution passes through a continuous separator to separate the organic phase; the organic phase is then passed into an evaporator to evaporate most of the solvent (for recycling); the residue is introduced into a continuous crystallizer and precipitated as a solid by programmed cooling (cooling down to 70°C at 18°C / h, holding for 1.2 h, then cooling down to 40°C at 6°C / h, holding for 1 h, and finally cooling down to room temperature at 11°C and stabilizing for 0.5 h). After continuous filtration and drying, white needle-like crystals of 4-phenoxyphenol are obtained.
[0025] According to high performance liquid chromatography (HPLC) analysis, the yield of 4-phenoxyphenol in this example was 88.9% and the purity was 99.7%, based on 4-phenoxybenzophenone.
[0026] Example 2 A method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology includes the following steps: 1. Dissolve 1.5 mmol of 4-phenoxybenzophenone in an appropriate amount of hexafluoroisopropanol (HFIP) to prepare a 0.05 mol / L solution, and place it in the first feed unit. Place a 15 wt.% H2O2 aqueous solution in the second feed unit. Place a 1 mol / L NaOH aqueous solution in the third feed unit.
[0027] 2. Take Sn-Beta molecular sieve (SiO2 / SnO2=100), immerse it in 0.5 mol / L ammonium nitrate solution at a solid-liquid ratio of 1:10, let it stand at 50℃ for 2 h, then centrifuge, wash and dry; immerse the activated molecular sieve in 0.2 mol / L sodium carbonate solution at a solid-liquid ratio of 1:5, sonicate at 30℃ for 10 min, centrifuge, wash and dry to obtain modified Sn-Beta molecular sieve.
[0028] 3. Using two precision syringe pumps, the 4-phenoxybenzophenone solution and the H2O2 aqueous solution were pumped into a micromixer at a flow rate of 0.25 mL / min. After thorough mixing, the mixture was introduced into a PFA tubular reactor with an inner diameter of 2 mm, a length of 10 m, and filled with 1.0 g of modified Sn-Beta molecular sieve. The reactor was placed in a constant temperature oil bath at 38℃, and the material was allowed to react for 6 h.
[0029] 4. The oxidation product intermediate fluid flowing out of the PFA tubular reactor is immediately pumped into an online NaOH aqueous solution at a flow rate of 0.15 mL / min for mixing, and then passed into a PFA capillary tube with an inner diameter of 1 mm and a length of 5 m (as a hydrolysis tubular reactor). The reactor is placed in a constant temperature water bath at 75℃, and the material is allowed to react for 20 min.
[0030] 5. Continuous separation and purification of the hydrolysis product reaction solution flowing out of the PFA capillary: First, the solution passes through a continuous separatory membrane to separate the organic phase; the organic phase is then passed into an evaporator to evaporate most of the solvent (for recycling); the residue is introduced into a continuous crystallizer and precipitated as a solid by programmed cooling (cooling down to 70°C at 15°C / h, holding for 1 h, then cooling down to 40°C at 3°C / h, holding for 0.5 h, and finally cooling down to room temperature at 10°C and stabilizing for 0.5 h). After continuous filtration and drying, white needle-like crystals of 4-phenoxyphenol are obtained.
[0031] According to high performance liquid chromatography (HPLC) analysis, the yield of 4-phenoxyphenol in this example was 85.1% and the purity was 99.2%, based on 4-phenoxybenzophenone.
[0032] Example 3 A method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology includes the following steps: 1. Dissolve 4-phenoxybenzophenone (4 mmol) in an appropriate amount of hexafluoroisopropanol (HFIP) to prepare a 0.2 mol / L solution, and place it in the first feed unit. Place a 30 wt.% H2O2 aqueous solution in the second feed unit. Place a 2 mol / L NaOH aqueous solution in the third feed unit.
[0033] 2. Take Sn-Beta molecular sieve (SiO2 / SnO2=100), immerse it in 0.5 mol / L ammonium nitrate solution at a solid-liquid ratio of 1:10, let it stand at 50℃ for 2 h, then centrifuge, wash and dry; immerse the activated molecular sieve in 0.2 mol / L sodium carbonate solution at a solid-liquid ratio of 1:5, sonicate at 30℃ for 10 min, centrifuge, wash and dry to obtain modified Sn-Beta molecular sieve.
[0034] 3. Using two precision syringe pumps, the 4-phenoxybenzophenone solution and the H2O2 aqueous solution were pumped into a micromixer at a flow rate of 0.25 mL / min. After thorough mixing, the mixture was introduced into a PFA tubular reactor with an inner diameter of 2 mm, a length of 10 m, and filled with 1.0 g of modified Sn-Beta molecular sieve. The reactor was placed in a constant temperature oil bath at 42℃, and the material was allowed to react for 4 h.
[0035] 4. The oxidation product intermediate fluid flowing out of the PFA tubular reactor is immediately pumped into an online NaOH aqueous solution at a flow rate of 0.15 mL / min for mixing, and then passed into a PFA capillary tube with an inner diameter of 1 mm and a length of 5 m (as a hydrolysis tubular reactor). The reactor is placed in a constant temperature water bath at 85℃, and the material is allowed to react for 10 min.
[0036] 5. Continuous separation and purification of the hydrolysis product reaction solution flowing out of the PFA capillary: First, the solution passes through a continuous separatory membrane to separate the organic phase; the organic phase is then passed into an evaporator to evaporate most of the solvent (for recycling); the residue is introduced into a continuous crystallizer and precipitated as a solid by programmed cooling (cooling down to 70°C at 20°C / h, holding for 1.5 h, then cooling down to 40°C at 8°C / h, holding for 1 h, and finally cooling down to room temperature at 12°C and stabilizing for 1 h). After continuous filtration and drying, white needle-like crystals of 4-phenoxyphenol are obtained.
[0037] According to high performance liquid chromatography (HPLC) analysis, the yield of 4-phenoxyphenol in this example was 86.3% and the purity was 99.4%, based on 4-phenoxybenzophenone.
[0038] Comparative Example 1 Control group of traditional concentrated sulfuric acid liquid catalyst.
[0039] According to high performance liquid chromatography (HPLC) analysis, the yield of 4-phenoxyphenol in this comparative example was 62.3% and the purity was 94.1%, based on 4-phenoxybenzophenone.
[0040] Comparative Example 2 The steps and parameters are the same as in Example 1, except that TS-1 molecular sieve is used instead of modified Sn-Beta molecular sieve as a solid catalyst.
[0041] According to high performance liquid chromatography (HPLC) analysis, the yield of 4-phenoxyphenol in this comparative example was 74.8% and the purity was 97.6%, based on 4-phenoxybenzophenone.
[0042] Comparative Example 3 The steps and parameters are the same as in Example 1, except that ordinary Sn-Beta molecular sieves are used instead of modified Sn-Beta molecular sieves as solid catalysts.
[0043] According to high performance liquid chromatography (HPLC) analysis, the yield of 4-phenoxyphenol in this comparative example was 72.0% and the purity was 96.4%, based on 4-phenoxybenzophenone.
[0044] The data above show that the continuous synthesis BV process of this invention can effectively improve the yield and purity of 4-phenoxyphenol (yield exceeds 85%, purity is greater than 99%), and the obtained 4-phenoxyphenol crystals have excellent quality, which is significantly better than traditional liquid acid catalysts and other solid catalysts.
[0045] The embodiments described above are merely preferred embodiments of the present invention, and while the descriptions are specific and detailed, they are not intended to limit the present invention. It should be noted that various changes and modifications can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the concept and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology, characterized in that, Includes the following steps: S1. Take hydrogen peroxide aqueous solution and 4-phenoxybenzophenone solution respectively and place them in the first and second feed units; S2. Hydrogen peroxide aqueous solution and 4-phenoxybenzophenone solution are pumped into a micro mixer by an injection pump and thoroughly mixed. Then, the mixture is passed into a tubular reactor filled with solid catalyst and kept in a constant temperature oil bath. S3. Place the sodium hydroxide aqueous solution in the third feed unit, pump the reaction product of S2 into the sodium hydroxide solution and mix thoroughly, then pass it into the hydrolysis tubular reactor and keep it in a constant temperature water bath. S4. The reaction product of S3 is continuously separated and purified, and the organic phase is separated, the solvent is evaporated, and the product is crystallized by temperature program to obtain 4-phenoxyphenol needle crystals.
2. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The concentration of the hydrogen peroxide aqueous solution in S1 is 15 wt.%-30 wt.%; the concentration of the 4-phenoxybenzophenone solution is 0.05-0.2 mol / L, and the solvent used is hexafluoroisopropanol or acetonitrile.
3. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The volume ratio of hydrogen peroxide aqueous solution to 4-phenoxybenzophenone solution in S2 is (1.02-1.05):
1.
4. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The solid catalyst described in S2 is a modified Sn-Beta molecular sieve with SiO2 / SnO2=100. The modification method is as follows: the Sn-Beta molecular sieve is first immersed in ammonium nitrate solution for activation, centrifuged, washed and dried, then immersed in sodium carbonate solution for ultrasonic treatment, centrifuged, washed and dried again to obtain the modified Sn-Beta molecular sieve.
5. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The constant temperature oil bath described in S2 is 38-42℃, and the time is 4-6 hours.
6. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The concentration of the sodium hydroxide aqueous solution described in S3 is 1-2 mol / L.
7. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The temperature of the constant temperature water bath described in S3 is 75-85℃, and the time is 10-20 min.
8. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The specific operation of continuous separation and purification in S4 is as follows: first, the organic phase is separated by a continuous separatory membrane, then the organic phase is passed into an evaporator to evaporate the solvent, and the residue is introduced into a continuous crystallizer. The solid is precipitated by programmed cooling, thus obtaining 4-phenoxyphenol crystals.
9. The method for synthesizing 4-phenoxyphenol by BV oxidation based on continuous flow technology according to claim 1, characterized in that, The parameters for the programmed cooling described in S4 are as follows: cooling to 70℃ at a rate of 15-20℃ / h, holding for 1-1.5 h, then cooling to 40℃ at a rate of 3-8℃ / h, holding for 0.5-1 h, and finally cooling to room temperature at a rate of 10-12℃ and stabilizing for 0.5-1 h.