Method for continuously synthesizing 4-bromo-3-methyl anisole

Abstract

The invention discloses a method for continuously synthesizing 4-bromine-3-methyl anisole, and belongs to the technical field of unsaturated halogenated hydrocarbon. Bromine and 3-methyl anisole are mixed through a micro-mixer and then enter a pipeline reactor to be subjected to bromination reaction, 4-bromine-3-methyl anisole is generated, and the 4-bromine-3-methyl anisole is continuously synthesized through the micro-mixer. The method specifically comprises the following steps: preparation of a composite catalyst, preparation of reaction materials, bromination reaction, online separation and catalyst recovery, and product refining. The bromination reaction method comprises the following steps: respectively conveying the material A and the material B to a micro-mixer, enabling reaction liquid fully mixed in the micro-mixer to enter a pipeline reactor, and carrying out bromination reaction at the reaction temperature of 4-8 DEG C under the control of a low-temperature circulating condensation bath for 20-30 minutes. The method provided by the invention solves the problems of the traditional kettle reaction and the existing continuous flow process, improves the conversion rate and selectivity of the target product, and reduces the generation of by-products.

Description

Technical Field

[0001] The present invention belongs to the technical field of unsaturated halogenated hydrocarbons, and particularly relates to a method for continuously synthesizing 4-bromo-3-methylanisole. Background Art

[0002] 4-Bromo-3-methylanisole is an important organic synthesis intermediate, which is widely used in the fields of medicine, pesticides and materials science. In the synthesis process of 4-bromo-3-methylanisole, 3-methylanisole is usually used as a substrate to carry out an electrophilic substitution reaction with bromine. Due to the synergistic effect of the methoxy group (strong ortho-para directing group) and the methyl group (weak ortho-para directing group) in the substrate molecule, there are competitive reactions at the bromination sites. In addition to the target 4-position product, the proportion of 5-position and 6-position isomer by-products often reaches 10-15%, and the dibrominated by-product is as high as 5-8%, resulting in a sharp increase in the cost of product separation and purification.

[0003] The traditional production method uses a kettle to dropwise add bromine and 3-methylanisole for reaction. Generally, the reaction temperature is controlled by the dropwise feeding method, that is, 3-methylanisole and part of hydrobromic acid are first added to the stirring kettle. When the temperature drops to 0-5 °C, the Br2-HBr solution is slowly dropped into the stirring kettle for reaction, and the dropping rate is determined according to the change of temperature. The reaction temperature needs to be maintained at 4-8 °C. The reaction efficiency of this batch operation process is extremely low, and due to the long residence time and serious backmixing, the occurrence of polybromination side reactions will be aggravated.

[0004] To improve the process efficiency, continuous flow bromination technology has been developed in recent years to enhance mass transfer and heat transfer through microreactors. However, the existing continuous schemes still have obvious defects such as insufficient catalyst stability, low two-phase mass transfer efficiency and waste of bromine resources: the acidic catalyst physically adsorbed and supported in such technologies is prone to elution of active components in the flowing system, and the single-cycle loss rate exceeds 10%, resulting in a rapid decline in the reaction rate and selectivity; in terms of the regulation of the two-phase reaction interface, it is difficult for hydrophobic aromatic ethers and aqueous bromine solutions to fully contact in the microchannel. Even if a phase transfer agent is added, the cross-phase transfer efficiency of bromide ions is still limited, resulting in uneven local bromine concentration. The mass transfer resistance of bromine causes overbromination side reactions and reduces selectivity; in terms of resource recycling, the by-product hydrobromic acid solution contains a lot of impurities and is difficult to remove. Generally, it is treated as hazardous waste, which not only increases the cost of hazardous waste disposal but also causes waste of raw materials, making the production cost relatively high.

[0005] Therefore, developing a continuous synthesis technology that can simultaneously solve the long-term stability of the catalyst, two-phase mass transfer efficiency, by-product inhibition and resource recycling has become the key to breaking through the industrialization bottleneck in this field. Summary of the Invention

[0006] Aiming at the deficiencies of the existing technologies, the present invention provides a method for continuously synthesizing 4-bromo-3-methylanisole. Through innovative reaction systems and process designs, the problems existing in traditional batch reactions and existing continuous flow processes are solved, the conversion rate and selectivity of the target product are improved, the generation of by-products is reduced, the closed-loop utilization of bromine elements is achieved, and continuous production is realized.

[0007] To solve the above technical problems, the technical solutions adopted by the present invention are as follows: A method for continuously synthesizing 4-bromo-3-methylanisole, in which bromine and 3-methylanisole are mixed through a micromixer and then enter a tubular reactor to undergo a bromination reaction to generate 4-bromo-3-methylanisole, specifically including the following steps: preparing a composite catalyst, preparing reaction materials, bromination reaction, online separation and catalyst recovery, and product refining.

[0008] The method for preparing the composite catalyst is as follows: Mesoporous silica is placed in an ethanol-water mixed solution, and 3-chloropropyltrimethoxysilane is added at the same time. After mixing evenly, it is refluxed at 80-90 °C for 4-6 h. After washing and drying, chloropropyl-functionalized silica is obtained. The chloropropyl-functionalized silica is dispersed in absolute ethanol, and a trimethylamine ethanol solution is added dropwise, and it is refluxed at 58-62 °C for 20-24 h. After the reaction is completed, it is washed and dried to obtain quaternary ammonium salt-functionalized silica; then the quaternary ammonium salt-functionalized silica is dispersed in DMF, 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate is added, and it is refluxed at 75-85 °C for 10-14 h. After washing and drying, a composite catalyst is obtained; The specific surface area of the mesoporous silica > 800 m 2 / g, and the pore diameter is 6-8 nm; The mass ratio of ethanol to water in the ethanol-water mixed solution is 100:20-40; The mass ratio of the mesoporous silica, 3-chloropropyltrimethoxysilane to the ethanol-water mixed solution is 10:0.8-1.2:8-12; The concentration of the trimethylamine ethanol solution is 15-25 wt%; The mass ratio of the chloropropyl-functionalized silica, trimethylamine ethanol solution, and absolute ethanol is 10:30-40:90-110; The mass ratio of the quaternary ammonium salt-functionalized silica, 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate, and DMF is 10:3-4:80-120.

[0009] The composite catalyst is fixed by chemical bonding. Trimethylamine attacks the chlorine atom of the chloropropyl group, and a Si-C-N + (CH3)3 bond is formed through nucleophilic substitution; the negative charge (-SO3 -) and the positively charged quaternary ammonium groups (-N + (CH3)3) forms a stable ion pair through ionic bonding, thereby anchoring 1-methyl-3-(3-sulfopropyl) imidazole hydrogen sulfate on the carrier surface; The composite catalyst has a sulfonic acid group loading of 0.80-1.13 mmol / g measured by acid-base titration, and a quaternary ammonium salt loading of 0.81-1.15 mmol / g calculated by measuring the nitrogen content in the catalyst; After 10 cycles of the composite catalyst, the loss rate of 1-methyl-3-(3-sulfonic acid propyl) imidazole hydrogen sulfate is less than 2%, and the loss rate of quaternary ammonium salt is less than 2%, and the composite catalyst has good stability.

[0010] The method for preparing the reaction materials includes the preparation of material A and the preparation of material B; Preparation of material A: dissolving bromine in aqueous hydrobromic acid to form a homogeneous solution material A; The concentration of the hydrobromic acid aqueous solution used in the material A is 25-35wt%; The mass ratio of bromine to hydrobromic acid aqueous solution in the material A is 16:90-110; Preparation of material B: adding the composite catalyst to 3-methylanisole, and then adding tetrabutylammonium bromide as a phase transfer aid, and dispersing uniformly to obtain material B; The mass ratio of 3-methylanisole, composite catalyst and tetrabutylammonium bromide in the material B is 100:0.1-0.2:0.5-1.

[0011] The bromination reaction method is as follows: material A and material B are respectively transported to a micro mixer, and the reaction solution after being fully mixed in the micro mixer enters a pipeline reactor for bromination reaction, the reaction temperature is 4-8°C, controlled by a low-temperature circulating condensation bath, the residence time is 20-30 minutes, and the solution flowing out after the reaction is completed is a crude product mixture; The mass ratio of material A to material B conveyed is 1:0.95-1.05; The pipeline reactor is internally filled with perfluorosulfonic acid resin filler.

[0012] The method for online separation and catalyst recovery is as follows: the crude mixed liquid flowing out of the reactor is directly introduced into a centrifugal separator; after centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid, the catalyst and the phase transfer agent; the aqueous phase is passed through a nanofiltration membrane to recover the catalyst and the phase transfer agent, and the recovered catalyst and the phase transfer agent are returned to the material B for recycling; the permeate is electrolytically regenerated to regenerate bromine and then returned to the material A system.

[0013] The method for refining the product is as follows: the separated organic phase is successively washed with an aqueous sodium bicarbonate solution to remove acid, washed with an aqueous sodium sulfite solution to remove residual bromine, and then anhydrous magnesium sulfate is added for drying and water removal to obtain the finished product of 4-bromo-3-methylanisole; The concentration of the aqueous sodium bicarbonate solution is 4-6 wt%; The concentration of the aqueous sodium sulfite solution is 8-12 wt%.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) In the step of preparing the composite catalyst of the present invention, the mesoporous silica support provides a large number of loading sites. 3-chloropropyltrimethoxysilane is used to load chloropropyl on the silica. Trimethylamine attacks the chlorine atom on the chloropropyl, and Si-C-N + (CH3)3 bond is formed through nucleophilic substitution; the negative charge (-SO3 - ) of 1-methyl-3-(3-sulfopropyl)imidazolium hydrogensulfate combines with the positive charge quaternary ammonium group (-N + (CH3)3) on the surface of quaternized silica through an ionic bond to form a stable ion pair, so that the surface of the composite catalyst is loaded with quaternary ammonium salt groups and sulfonic acid groups; The quaternary ammonium salt group carries a positive charge and combines with Br - or hydrogen bromide through ion pair action to form an ion pair [N + (CH3)3 - Br - , which is transferred to the organic phase (3-methylanisole), improves the effective concentration of bromine, promotes the bromination reaction, and reduces side reactions; at the same time, the positive charge of the quaternary ammonium salt attracts the negatively charged region on the benzene ring, such as the para position of the methoxy group, through electrostatic interaction, guiding the bromide ion to attack the para position directionally, and improving the selectivity of the target product; the sulfonic acid group provides a strong acidic environment, activates the benzene ring, especially the 4-position, promotes the electrophilic substitution reaction, and reduces the generation of by-products; The quaternary ammonium salt group and the sulfonic acid group on the catalyst surface act synergistically. The quaternary ammonium salt group is responsible for bromine activation and transfer, and the sulfonic acid group is responsible for benzene ring activation. The acidity of the sulfonic acid group and the phase transfer effect of the quaternary ammonium salt are synergistic, accelerating both the electrophilic substitution reaction and improving the selectivity of the reaction; The mesoporous structure of the support provides a confined environment, enabling the substrate and the catalyst active sites to contact efficiently at the nanoscale, further enhancing the catalytic efficiency.

[0015] (2) The composite catalyst of the present invention is fixed by chemical bonding, has strong binding firmness and stability, and the active groups are not easily shed. After 10 cycles of the composite catalyst, the loss of 1-methyl-3-(3-sulfopropyl)imidazolium hydrogensulfate is <2%, and the loss rate of the quaternary ammonium salt is <2%, showing good stability.

[0016] (3) In the present invention, the perfluorosulfonic acid resin filler in the tubular reactor serves as an additional acidic site, further enhancing the catalytic effect and improving the reaction rate and selectivity.

[0017] (4) In the present invention, instantaneously uniform mixing is achieved through a micromixer to avoid overbromination caused by excessive local bromine concentration; the plug flow characteristic of the tubular reactor reduces backmixing, ensuring a uniform reaction time and further improving selectivity.

[0018] (5) The 4-bromo-3-methylanisole synthesized by the method of the present invention has high selectivity, high yield and few by-products. In the prepared finished product, the concentration of 4-bromo-3-methylanisole is 98.03 - 98.19 mol%, the isomer is 1.35 - 1.42 mol%, the polybrominated product is 0.22 - 0.27 mol%, the conversion rate is 99.71 - 99.77%, and the selectivity is 98.32 - 98.43%. Specific Embodiments

[0019] In order to have a clearer understanding of the technical features, objectives and effects of the present invention, the specific embodiments of the present invention are now described.

[0020] Example 1 A method for continuously synthesizing 4-bromo-3-methylanisole, comprising the following steps: (1) Preparation of a composite catalyst Mesoporous silica is placed in an ethanol-water mixed solution, and 3-chloropropyltrimethoxysilane is added at the same time. After mixing evenly, it is refluxed at 85 °C for 5 h. After washing and drying, chloropropyl-functionalized silica is obtained. The chloropropyl-functionalized silica is dispersed in absolute ethanol, and a trimethylamine ethanol solution is added dropwise. It is refluxed at 60 °C for 22 h. After the reaction is completed, it is washed and dried to obtain quaternary ammonium salt-functionalized silica; the quaternary ammonium salt-functionalized silica is dispersed in DMF, and 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate is added. It is refluxed at 80 °C for 12 h. After washing and drying, a composite catalyst is obtained; The specific surface area of the mesoporous silica is 900 m 2 / g, and the pore diameter is 7 nm; The mass ratio of ethanol to water in the ethanol-water mixed solution is 100:30; The mass ratio of mesoporous silica, 3-chloropropyltrimethoxysilane to the ethanol-water mixed solution is 10:1:10; The concentration of the trimethylamine ethanol solution is 20 wt%; The mass ratio of chloropropyl-functionalized silica, trimethylamine ethanol solution and absolute ethanol is 10:35:100; The mass ratio of the quaternary ammonium salt silica, 1-methyl-3-(3-sulfonatepropyl) imidazole hydrogen sulfate and DMF is 10:3.5:100; The composite catalyst is fixed by chemical bonding, and trimethylamine attacks the chlorine atom of the chloropropyl group to form Si-CN by nucleophilic substitution. + (CH3)3 bond; negative charge of 1-methyl-3-(3-sulfopropyl) imidazole hydrogen sulfate (-SO3 - ) The positively charged quaternary ammonium groups (-N + (CH3)3) forms a stable ion pair through ionic bonding, thereby anchoring 1-methyl-3-(3-sulfopropyl) imidazole hydrogen sulfate on the carrier surface; The sulfonic acid group loading of the composite catalyst was measured by acid-base titration to be 1.02 mmol / g, and the quaternary ammonium salt loading was converted to 1.04 mmol / g by measuring the nitrogen content in the catalyst; After 10 cycles of the composite catalyst, the loss rate of 1-methyl-3-(3-sulfonic acid propyl) imidazole hydrogen sulfate is less than 2%, and the loss rate of quaternary ammonium salt is less than 2%, and the composite catalyst has good stability.

[0021] (2) Prepare reaction materials Material A: Dissolve bromine in aqueous hydrobromic acid to form a homogeneous solution material A; The concentration of the hydrobromic acid aqueous solution used in the material A is 30wt%; The mass ratio of bromine to hydrobromic acid aqueous solution in the material A is 16:100; Material B: Add the composite catalyst to 3-methylanisole, then add tetrabutylammonium bromide as a phase transfer aid, and disperse evenly to obtain material B; The mass ratio of 3-methylanisole, composite catalyst and tetrabutylammonium bromide in the material B is 100:0.15:0.8.

[0022] (3) Bromination reaction Material A and material B are transported to the micro mixer respectively. After being fully mixed in the micro mixer, the reaction liquid enters the pipeline reactor for bromination reaction. The reaction temperature is 6°C, which is controlled by a low-temperature circulating condensation bath. The residence time is 25 minutes. After the reaction is completed, the solution flowing out is the crude product mixture. The mass ratio of material A and material B conveyed is 1:1; The pipeline reactor is internally filled with perfluorosulfonic acid resin filler.

[0023] (4) Online separation and catalyst recovery The crude mixed solution flowing out of the reactor is directly introduced into a centrifugal separator. After centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid, catalyst and phase transfer agent; the aqueous phase recovers the catalyst and phase transfer agent through a nanofiltration membrane and returns to material B for recycling, and the permeate returns to the material A system after electrolytic regeneration of bromine.

[0024] (5) Product refinement The separated organic phase is successively washed with an aqueous sodium bicarbonate solution to remove acid, washed with an aqueous sodium sulfite solution to remove residual bromine, and then anhydrous magnesium sulfate is added for drying to remove water, obtaining the finished product of 4-bromo-3-methylanisole; The concentration of the aqueous sodium bicarbonate solution is 5 wt%; The concentration of the aqueous sodium sulfite solution is 10 wt%.

[0025] Example 2 A continuous method for synthesizing 4-bromo-3-methylanisole, comprising the following steps: (1) Preparation of a composite catalyst Mesoporous silica is placed in an ethanol-water mixed solution, and 3-chloropropyltrimethoxysilane is added at the same time. After mixing evenly, it is refluxed at 80 °C for 6 h. After washing and drying, chloropropyl-functionalized silica is obtained. The chloropropyl-functionalized silica is dispersed in absolute ethanol, and a trimethylamine ethanol solution is added dropwise, and it is refluxed at 58 °C for 24 h. After the reaction is completed, it is washed and dried to obtain quaternary ammonium salt-functionalized silica; the quaternary ammonium salt-functionalized silica is dispersed in DMF, 1-methyl-3-(3-sulfopropyl)imidazolium hydrogensulfate is added, and it is refluxed at 75 °C for 14 h. After washing and drying, a composite catalyst is obtained; The specific surface area of the mesoporous silica is 850 m 2 / g, and the pore diameter is 8 nm; The mass ratio of ethanol to water in the ethanol-water mixed solution is 100:20; The mass ratio of the mesoporous silica, 3-chloropropyltrimethoxysilane to the ethanol-water mixed solution is 10:0.8:8; The concentration of the trimethylamine ethanol solution is 15 wt%; The mass ratio of the chloropropyl-functionalized silica, trimethylamine ethanol solution and absolute ethanol is 10:30:90; The mass ratio of the quaternary ammonium salt-functionalized silica, 1-methyl-3-(3-sulfopropyl)imidazolium hydrogensulfate and DMF is 10:3:80; The composite catalyst is fixed by chemical bonding. Trimethylamine attacks the chlorine atom of chloropropyl, and forms a Si-C-N + (CH3)3 bond through nucleophilic substitution; the negative charge of 1-methyl-3-(3-sulfopropyl)imidazolium hydrogensulfate (-SO3 -) The positively charged quaternary ammonium groups (-N + (CH3)3) forms a stable ion pair through ionic bonding, thereby anchoring 1-methyl-3-(3-sulfopropyl) imidazole hydrogen sulfate on the carrier surface; The sulfonic acid group loading of the composite catalyst was measured by acid-base titration to be 0.80 mmol / g, and the quaternary ammonium salt loading was converted to 0.81 mmol / g by measuring the nitrogen content in the catalyst; After 10 cycles of the composite catalyst, the loss rate of 1-methyl-3-(3-sulfonic acid propyl) imidazole hydrogen sulfate is less than 2%, and the loss rate of quaternary ammonium salt is less than 2%, and the composite catalyst has good stability.

[0026] (2) Prepare reaction materials Material A: Dissolve bromine in aqueous hydrobromic acid to form a homogeneous solution material A; The concentration of the hydrobromic acid aqueous solution used in the material A is 25wt%; The mass ratio of bromine to hydrobromic acid aqueous solution in the material A is 16:90; Material B: Add the composite catalyst to 3-methylanisole, then add tetrabutylammonium bromide as a phase transfer aid, and disperse evenly to obtain material B; The mass ratio of 3-methylanisole, composite catalyst and tetrabutylammonium bromide in the material B is 100:0.1:0.5.

[0027] (3) Bromination reaction Material A and material B are transported to the micro mixer respectively. After being fully mixed in the micro mixer, the reaction liquid enters the pipeline reactor for bromination reaction. The reaction temperature is 4°C, which is controlled by a low-temperature circulating condensation bath. The residence time is 30 minutes. After the reaction is completed, the solution flowing out is the crude product mixture. The mass ratio of material A and material B conveyed is 1:0.95; The pipeline reactor is internally filled with perfluorosulfonic acid resin filler.

[0028] (4) Online separation and catalyst recovery The crude mixed liquid flowing out of the reactor is directly introduced into a centrifugal separator. After centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid, catalyst and phase transfer agent. The aqueous phase is passed through a nanofiltration membrane to recover the catalyst and phase transfer agent, which are returned to material B for recycling. The permeate is electrolytically regenerated to regenerate bromine and then returned to the material A system.

[0029] (5) Product refining The separated organic phase is washed with a sodium bicarbonate aqueous solution for deacidification, washed with a sodium sulfite aqueous solution to remove residual bromine, and then dried with anhydrous magnesium sulfate to obtain a finished 4-bromo-3-methylanisole product; The concentration of the sodium bicarbonate aqueous solution is 4 wt%; The concentration of the sodium sulfite aqueous solution is 8 wt%.

[0030] Example 3 A method for continuously synthesizing 4-bromo-3-methylanisole, comprising the following steps: (1) Preparation of a composite catalyst Put mesoporous silica into an ethanol-water mixture, and at the same time add 3-chloropropyltrimethoxysilane. After mixing evenly, reflux at 90 °C for 4 h. After washing and drying, chloropropyl-modified silica is obtained. Disperse the chloropropyl-modified silica in absolute ethanol, dropwise add a trimethylamine ethanol solution, and reflux at 62 °C for 20 h. After the reaction is completed, wash and dry to obtain quaternary ammonium salt-modified silica; Disperse the quaternary ammonium salt-modified silica in DMF, add 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate, and reflux at 85 °C for 14 h. After washing and drying, a composite catalyst is obtained; The specific surface area of the mesoporous silica is 1000 m 2 / g, and the pore diameter is 6 nm; The mass ratio of ethanol to water in the ethanol-water mixture is 100:40; The mass ratio of the mesoporous silica, 3-chloropropyltrimethoxysilane to the ethanol-water mixture is 10:1.2:12; The concentration of the trimethylamine ethanol solution is 25 wt%; The mass ratio of the chloropropyl-modified silica, trimethylamine ethanol solution, and absolute ethanol is 10:40:110; The mass ratio of the quaternary ammonium salt-modified silica, 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate, and DMF is 10:4:120; The composite catalyst is fixed by chemical bonding. Trimethylamine attacks the chlorine atom of chloropropyl, and forms a Si-C-N + (CH3)3 bond through nucleophilic substitution; the negative charge (-SO3 - ) of 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate and the positive charge quaternary ammonium group (-N + (CH3)3) on the surface of the quaternary ammonium salt-modified silica are combined by ionic bonds to form a stable ion pair, thereby anchoring 1-methyl-3-(3-sulfopropyl)imidazolium hydrogen sulfate on the surface of the carrier; The sulfonic acid group loading of the composite catalyst is measured to be 1.13 mmol / g by acid-base titration, and the quaternary ammonium salt loading is converted to be 1.15 mmol / g by measuring the nitrogen element content in the catalyst; After 10 cycles of the composite catalyst, the loss of 1-methyl-3-(3-sulfopropyl)imidazolium hydrogensulfate is <2%, and the loss rate of the quaternary ammonium salt is <2%, showing good stability.

[0031] (2)Prepare reaction materials Material A: Dissolve bromine in an aqueous hydrobromic acid solution to form a homogeneous solution, Material A. The concentration of the aqueous hydrobromic acid solution used for Material A is 35 wt%. The mass ratio of bromine to the aqueous hydrobromic acid solution in Material A is 16:110. Material B: Add the composite catalyst to 3-methylanisole, and then add tetrabutylammonium bromide as a phase transfer assistant, and disperse evenly to obtain Material B. The mass ratio of 3-methylanisole, the composite catalyst and tetrabutylammonium bromide in Material B is 100:0.2:1.

[0032] (3)Bromination reaction Material A and Material B are respectively transported to a micromixer. The reaction solution after sufficient mixing in the micromixer enters a tubular reactor for bromination reaction. The reaction temperature is 8 °C, controlled by a low-temperature circulating cooling bath, and the residence time is 20 min. The solution flowing out after the reaction is a crude product mixture. The mass ratio of the transportation of Material A and Material B is 1:1.05. The tubular reactor is internally filled with perfluorosulfonic acid resin packing.

[0033] (4)Online separation and catalyst recovery Directly introduce the crude product mixture flowing out of the reactor into a centrifuge separator. After centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid, the catalyst and the phase transfer agent; the aqueous phase recovers the catalyst and the phase transfer agent through a nanofiltration membrane and returns to Material B for recycling. The permeate is electrolyzed to regenerate bromine and then returns to the Material A system.

[0034] (5)Product purification Wash the separated organic phase successively with an aqueous sodium bicarbonate solution to remove acid, wash with an aqueous sodium sulfite solution to remove residual bromine, and then add anhydrous magnesium sulfate to dry and remove water to obtain the finished product of 4-bromo-3-methylanisole. The concentration of the aqueous sodium bicarbonate solution is 6 wt%. The concentration of the aqueous sodium sulfite solution is 12 wt%.

[0035] Example 4 A method for the continuous synthesis of 4-bromo-3-methylanisole, comprising the following steps: (1)Prepare reaction materials Material A: Dissolve bromine in an aqueous hydrobromic acid solution to form a homogeneous solution, Material A. The concentration of the aqueous hydrobromic acid solution used for the material A is 30 wt%. The mass ratio of bromine to the aqueous hydrobromic acid solution in the material A is 16:100. Material B: Tetrabutylammonium bromide is added to 3-methylanisole as a phase transfer assistant, and after being dispersed evenly, material B is obtained. The mass ratio of 3-methylanisole to tetrabutylammonium bromide in the material B is 100:0.8.

[0036] (2) Bromination reaction Material A and material B are respectively transported to a micro-mixer. The reaction solution after being fully mixed in the micro-mixer enters a tubular reactor to carry out the bromination reaction. The reaction temperature is 6 °C, which is controlled by a low-temperature circulating condensation bath. The residence time is 25 min. The solution flowing out after the reaction is a crude product mixture. The mass ratio of the transported material A and material B is 1:1. The tubular reactor is internally provided with perfluorosulfonic acid resin packing.

[0037] (3) Online separation and catalyst recovery The crude product mixture flowing out of the reactor is directly introduced into a centrifugal separator. After centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid and the phase transfer agent; the aqueous phase recovers the catalyst and the phase transfer agent through a nanofiltration membrane and returns to material B for recycling. The permeate is electrolyzed to regenerate bromine and then returns to the material A system.

[0038] (4) Product refinement The separated organic phase is successively washed with a 5 wt% aqueous sodium bicarbonate solution to remove acid, washed with a 10 wt% aqueous sodium sulfite solution to remove residual bromine, and then anhydrous magnesium sulfate is added for drying to remove water, obtaining the finished product of 4-bromo-3-methylanisole. The concentration of the aqueous sodium bicarbonate solution is 5 wt%. The concentration of the aqueous sodium sulfite solution is 10 wt%.

[0039] Example 5 A method for continuously synthesizing 4-bromo-3-methylanisole includes the following steps: (1) Preparation of a composite catalyst Mesoporous silica is placed in an ethanol-water mixed solution, and 3-chloropropyltrimethoxysilane is added simultaneously. After being mixed evenly, it is refluxed at 85 °C for 5 h. After washing and drying, chloropropyl-modified silica is obtained. The chloropropyl-modified silica is dispersed in absolute ethanol, and a trimethylamine ethanol solution is added dropwise. It is refluxed at 60 °C for 22 h. After the reaction ends, it is washed and dried to obtain the composite catalyst. The specific surface area of the mesoporous silica is 900 m 2 / g, and the pore diameter is 7 nm. The mass ratio of ethanol to water in the ethanol-water mixture is 100:30; The mass ratio of the mesoporous silica, 3-chloropropyltrimethoxysilane and ethanol-water mixture is 10:1:10; The concentration of the trimethylamine ethanol solution is 20wt%; The mass ratio of the chloropropylated silicon dioxide, trimethylamine ethanol solution and anhydrous ethanol is 10:35:100; The composite catalyst is fixed by chemical bonding, and trimethylamine attacks the chlorine atom of the chloropropyl group to form Si-CN by nucleophilic substitution. + (CH3)3 bond; The composite catalyst is converted into a quaternary ammonium salt loading of 1.05 mmol / g by measuring the nitrogen content in the catalyst; After 10 cycles, the composite catalyst has a quaternary ammonium salt loss rate of less than 2%, and has good stability.

[0040] (2) Prepare reaction materials Material A: Dissolve bromine in aqueous hydrobromic acid to form a homogeneous solution material A; The concentration of the hydrobromic acid aqueous solution used in the material A is 30wt%; The mass ratio of bromine to hydrobromic acid aqueous solution in the material A is 16:100; Material B: Add the composite catalyst to 3-methylanisole, then add tetrabutylammonium bromide as a phase transfer aid, and disperse evenly to obtain material B; The mass ratio of 3-methylanisole, composite catalyst and tetrabutylammonium bromide in the material B is 100:0.15:0.8.

[0041] (3) Bromination reaction Material A and material B are transported to the micro mixer respectively. After being fully mixed in the micro mixer, the reaction liquid enters the pipeline reactor for bromination reaction. The reaction temperature is 6°C, which is controlled by a low-temperature circulating condensation bath. The residence time is 25 minutes. After the reaction is completed, the solution flowing out is the crude product mixture. The mass ratio of material A and material B conveyed is 1:1; The pipeline reactor is internally filled with perfluorosulfonic acid resin filler.

[0042] (4) Online separation and catalyst recovery The crude mixed liquid flowing out of the reactor is directly introduced into a centrifugal separator. After centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid, catalyst and phase transfer agent. The aqueous phase is passed through a nanofiltration membrane to recover the catalyst and phase transfer agent, which are returned to material B for recycling. The permeate is electrolytically regenerated to regenerate bromine and then returned to the material A system.

[0043] (5) Product refining The separated organic phase was successively washed with an aqueous sodium bicarbonate solution to remove acid, washed with an aqueous sodium sulfite solution to remove residual bromine, and then anhydrous magnesium sulfate was added for drying to remove water, obtaining the finished product of 4-bromo-3-methylanisole; The concentration of the aqueous sodium bicarbonate solution was 5 wt%; The concentration of the aqueous sodium sulfite solution was 10 wt%.

[0044] Test Example For the finished products of 4-bromo-3-methylanisole prepared in Examples 1-5, quality inspection was carried out. Using gas chromatography analysis, the contents of 4-bromo-3-methylanisole, 3-methylanisole, isomers (the sum of 2-bromo-3-methylanisole, 5-bromo-3-methylanisole and 6-bromo-3-methylanisole), and polybromides (the sum of 2,6-dibromo-3-methylanisole, 2,4-dibromo-3-methylanisole, 4,6-dibromo-3-methylanisole and 2,4,6-tribromo-3-methylanisole) in the finished product of 4-bromo-3-methylanisole were detected. The conversion rate and selectivity of the product were calculated, and the measurement results are shown in Table 1.

[0045] Table 1 Product Quality Inspection Results

[0046] It can be seen from the above test results that for the finished products of 4-bromo-3-methylanisole prepared in Examples 1-3, the concentration of 4-bromo-3-methylanisole was 98.03-98.19 mol%, the conversion rate was 99.71-99.77%, and the selectivity was 98.32-98.43%. The prepared 4-bromo-3-methylanisole had high selectivity and high yield; In the bromination reaction of Example 4, no composite catalyst was added. In the finished product of 4-bromo-3-methylanisole prepared, the concentration of 4-bromo-3-methylanisole was 92.93 mol%, the conversion rate was 97.99, the selectivity was 94.84%, the isomers were 4.31%, and the polybromides were 1.55%. It can be seen that the concentration and selectivity of 4-bromo-3-methylanisole decreased significantly, the conversion rate decreased slightly, and the content of by-products increased; In Example 5, in the step of preparing the composite catalyst, only trimethylamine was loaded, and trimethylamine reacted with the chlorine atoms of chloropropyl to form a Si-C-N + (CH3)3 bond. Compared with Example 4, the concentration, conversion rate and selectivity of 4-bromo-3-methylanisole all decreased, and the contents of isomers and polybromide by-products increased. It shows that the composite catalyst loaded with quaternary ammonium salt can improve the concentration, conversion rate and selectivity of the product to a certain extent, reduce the content of by-products, and promote the reaction to proceed in the direction of the target product, but the effect indexes cannot reach the level of the present invention.

[0047] Finally, it should be noted that the above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for continuously synthesizing 4-bromo-3-methylanisole, characterized in that, Bromine and 3-methylanisole are mixed in a micro mixer and then enter a pipeline reactor for bromination reaction to generate 4-bromo-3-methylanisole. The specific preparation method includes the following steps: preparing a composite catalyst, preparing reaction materials, bromination reaction, online separation and catalyst recovery, and product refining; The method for preparing the composite catalyst comprises the following steps: placing mesoporous silica in an ethanol-water mixture, adding 3-chloropropyltrimethoxysilane, mixing evenly, refluxing at 80-90° C. for 4-6 hours, washing and drying to obtain chloropropylated silica; dispersing the chloropropylated silica in anhydrous ethanol, dripping trimethylamine ethanol solution, refluxing at 58-62° C. for 20-24 hours, washing and drying after the reaction to obtain quaternary ammonium salt silica; dispersing the quaternary ammonium salt silica in DMF, adding 1-methyl-3-(3-sulfonic acid propyl) imidazole hydrogen sulfate, refluxing at 75-85° C. for 10-14 hours, washing and drying to obtain the composite catalyst.

2. The method for continuously synthesizing 4-bromo-3-methylanisole according to claim 1, characterized in that, In the step of preparing the composite catalyst, The specific surface area of the mesoporous silica is > 800 m 2 / g, and the pore diameter is 6 - 8 nm; The mass ratio of ethanol to water in the ethanol-water mixture is 100:20-40; The mass ratio of the mesoporous silica, 3-chloropropyltrimethoxysilane and ethanol-water mixed liquid is 10:0.8-1.2:8-12.

3. The method for continuously synthesizing 4-bromo-3-methylanisole according to claim 1, wherein In the step of preparing the composite catalyst, The concentration of the trimethylamine ethanol solution is 15-25wt%; The mass ratio of the chloropropylated silicon dioxide, the trimethylamine ethanol solution and the anhydrous ethanol is 10:30-40:90-110; The mass ratio of the quaternary ammonium salt silicon dioxide, 1-methyl-3-(3-sulfonic acid propyl) imidazole hydrogen sulfate and DMF is 10:3-4:80-120.

4. A method for continuously synthesizing 4-bromo-3-methylanisole according to claim 1, characterized in that, The method for preparing the reaction materials includes the preparation of material A and the preparation of material B; Preparation of the material A: dissolving bromine in a hydrobromic acid aqueous solution to form a homogeneous solution material A; The preparation of the material B is as follows: the composite catalyst is added into 3-methylanisole, and then tetrabutylammonium bromide is added as a phase transfer aid, and the material B is obtained by uniformly dispersing the composite catalyst into 3-methylanisole.

5. A method for continuously synthesizing 4-bromo-3-methylanisole according to claim 4, characterized in that, In the step of preparing the reaction materials, The concentration of the hydrobromic acid aqueous solution used for the material A is 25-35wt%; The mass ratio of bromine to hydrobromic acid aqueous solution in the material A is 16:90-110; The mass ratio of 3-methylanisole, composite catalyst and tetrabutylammonium bromide in the material B is 100:0.1-0.2:0.5-1.

6. The method for continuously synthesizing 4-bromo-3-methylanisole according to claim 1, wherein The bromination reaction method is as follows: material A and material B are respectively transported to a micro mixer, and the reaction solution after being fully mixed in the micro mixer enters a pipeline reactor for bromination reaction. The reaction temperature is 4-8° C., which is controlled by a low-temperature circulating condensation bath, and the residence time is 20-30 minutes. After the reaction is completed, the solution flowing out is a crude mixed solution.

7. A method for continuously synthesizing 4-bromo-3-methylanisole according to claim 6, characterized in that, In the bromination step, The mass ratio of material A to material B conveyed is 1:0.95-1.05; The pipeline reactor is internally filled with perfluorosulfonic acid resin filler.

8. The method for continuously synthesizing 4-bromo-3-methylanisole according to claim 1, characterized in that, The method for on-line separation and catalyst recovery is as follows: the crude product mixture flowing out of the reactor is directly introduced into a centrifugal separator. After centrifugation, the upper organic phase contains the target product, and the lower aqueous phase contains hydrobromic acid, the catalyst and the phase transfer agent. The aqueous phase recovers the catalyst and the phase transfer agent through a nanofiltration membrane and returns to material B for recycling, and the permeate returns to the material A system after electrolytic regeneration of bromine.

9. The method for continuously synthesizing 4-bromo-3-methylanisole according to claim 1, characterized in that, The method for product purification is as follows: the separated organic phase is successively washed with an aqueous sodium bicarbonate solution to remove acid, washed with an aqueous sodium sulfite solution to remove residual bromine, and then anhydrous magnesium sulfate is added for drying and water removal to obtain the finished product of 4-bromo-3-methylanisole.

10. A method for continuously synthesizing 4-bromo-3-methylanisole according to claim 9, characterized in that, In the steps of the product purification, The concentration of the aqueous sodium bicarbonate solution is 4-6 wt%. The concentration of the aqueous sodium sulfite solution is 8-12 wt%.

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