Preparation method of p-tert-butoxystyrene

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of p-tert-butoxystyrene. According to the preparation method provided by the invention, the p-tert-butoxystyrene is prepared by utilizing the continuous flow microreactor, the operation is simple and safe, the efficiency is high, the reaction time is short, the temperature is low, expensive reagents are not used, the amplification effect does not exist, the prepared p-tert-butoxystyrene product is high in yield and purity and stable in quality, and the method is suitable for large-scale production and has wide application prospects. The production cost can be greatly reduced, and the production safety is improved.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing p-tert-butoxystyrene. Background Art

[0002] 4-tert-Butoxystyrene is a monomer raw material used to prepare polymers and copolymers. It is a derivative product of styrene and is mainly used in the production of coatings, unsaturated polyester resins, etc. Its polymer has a high glass transition temperature and is soluble in aliphatic hydrocarbons with low volatility. It has a wider range of applications than styrene and methyl styrene, making it important in the development of new materials, theoretical research, and dispersion polymerization. The product has broad application prospects. Although 4-tert-butoxystyrene is a niche chemical product, related research has been gradually increasing in recent years, and its market demand has also maintained a warming trend. In 2023, China's demand for tert-butoxystyrene products will be close to 10 million tons, and its share in the styrene derivative market will gradually increase.

[0003] At present, the method for synthesizing p-tert-butoxystyrene mainly uses metal-catalyzed suzuki coupling reaction. David M. Knapp et al. reported a method for synthesizing p-tert-butoxystyrene by suzuki coupling reaction in 2009, in which p-tert-butoxyhalobenzene and N-methyliminodiacetic acid (MIDA) borate react to synthesize p-tert-butoxystyrene. The metal-catalyzed suzuki coupling reaction can synthesize a series of styrene derivatives, but expensive precious metals are used as catalysts in the synthesis process, and the reaction temperature is high (above 90° C.), which is not only costly, but also has large energy consumption and high risk factor, and is not suitable for large-scale production. CN116969818A reports a method for synthesizing p-tert-butoxystyrene, in which vinyl magnesium chloride is first used to react with trimethyl borate under lithium chloride catalysis to generate vinyl boric acid, and then p-tert-butoxyhalobenzene is reacted under noble metal palladium catalysis to synthesize p-tert-butoxystyrene, the method has complex synthesis steps, needs to be divided into two stages, and the cost of using expensive catalysts is high, the reaction needs to be carried out under a certain pressure, there are potential safety hazards, low safety, and it is not easy to industrialize production.

[0004] Das, Santu et al. reported a method for synthesizing p-tert-butyloxystyrene by photochemical decarboxylation cross-coupling reaction in 2017. The method is to decarboxylate acrylic acid in the presence of ultraviolet light, and then react with p-tert-butyl iodobenzene under ultraviolet light with molybdenum-based polyoxometalate as a catalyst to synthesize p-tert-butyloxystyrene. Photochemical decarboxylation cross-coupling reaction can synthesize a series of ethylene derivatives, but the catalyst molybdenum-based polyoxometalate used in the synthesis process needs to be synthesized by itself and is difficult to recycle, and requires a long reaction time (36h), which is not suitable for large-scale continuous production. Hou, Liuzhen et al. reported a method for synthesizing p-tert-butyloxystyrene by Wittig reaction in the journal JACS in 2024. The method synthesizes p-tert-butyloxystyrene by reacting p-tert-butyloxybenzaldehyde and methyltriphenylphosphine bromide, but the synthesis route cost of the method is high, and the triphenylphosphine oxide produced during the reaction is not easy to remove, which affects the purification of the final product, and the yield is also low.

[0005] Therefore, it is hoped to provide a new method for preparing p-tert-butoxystyrene. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a method for preparing p-tert-butoxystyrene. The preparation method provided by the present invention uses a continuous flow microreactor to prepare p-tert-butoxystyrene, which is simple, safe, and efficient to operate, has a short reaction time and low temperature, does not use expensive reagents, does not have an amplification effect, and the prepared p-tert-butoxystyrene product has a high yield and purity and stable quality. The method of the present invention is suitable for large-scale production, can significantly reduce production costs, and improve production safety.

[0007] In a first aspect, the present invention provides a method for preparing tert-butoxystyrene, wherein the preparation method is carried out using a continuous flow microreactor, wherein the continuous flow microreactor comprises a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a back pressure regulating valve, a third cooling unit and a post-processing unit; or comprises a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a format unit, a first cooling unit and a second cooling unit, a preheating unit, a back pressure regulating valve and a post-processing unit;

[0008] The preparation method comprises:

[0009] (1) using a pumping unit to pump p-halophenol, isobutylene and sulfuric acid into a first mixing unit for mixing, and then passing them into an addition unit for addition reaction, and after the reaction is completed, flowing through a back pressure regulating valve into a post-processing unit for oil-water separation, and then taking the oil phase for concentration and purification to obtain p-tert-butyloxy halogenated benzene;

[0010] (2-1) using a pumping unit to pump the tert-butyloxy halogenated benzene, vinyl magnesium chloride, polymerization inhibitor and catalyst into a second mixing unit for mixing, and then passing them into a coupling unit for coupling reaction. After the reaction is completed, they flow through a back pressure regulating valve into a third cooling unit for cooling, and then pass them into a post-treatment unit for oil-water separation, and then take the oil phase for concentration and purification to obtain the tert-butyloxy styrene;

[0011] Or, (2-2) using a pumping unit to pump the tert-butoxy halogenated benzene and initiator into a preheating unit for preheating, then passing them into a format unit filled with magnesium powder for format reaction, and after the reaction is completed, passing them into a first cooling unit for cooling to obtain a tert-butoxyphenyl magnesium halide solution; using a pumping unit to pump the tert-butoxyphenyl magnesium halide solution, vinyl chloride, catalyst and inhibitor into a second mixing unit for mixing, and then passing them into a coupling unit for coupling reaction, after the reaction is completed, flowing through a back pressure regulating valve into a second cooling unit for cooling, and then passing them into a post-processing unit for oil-water separation, and then taking the oil phase for concentration and purification to obtain the tert-butoxystyrene.

[0012] The preparation method provided by the present invention utilizes a continuous flow microreactor to prepare p-tert-butoxystyrene, has the advantages of simple, safe and efficient operation, short reaction time, low temperature, no expensive reagents, no amplification effect, and high yield and purity of the prepared p-tert-butoxystyrene product, and stable quality. The method of the present invention is suitable for large-scale production, can significantly reduce production costs, and improve production safety. Specifically:

[0013] The preparation method provided by the present invention is carried out by using a continuous flow microreactor, and a continuous process is adopted in both the reaction stage and the post-processing stage, so the stability and reliability are good, and thus the product quality is stable and the reproducibility is good; moreover, the reaction temperature can be lowered, the expensive metal catalyst can be replaced, and the production cost can be reduced, and at the same time, there is no amplification effect, and when scaling up to pilot and industrialization, the tedious and complicated multiple step-by-step amplification and the adjustment and optimization of process conditions and parameters are omitted, which greatly saves manpower, material resources and project development time, can solve the amplification effect problem existing in industrialization, and greatly reduces the difficulty of industrial application; in addition, the product production scale can be flexibly changed, the flexibility is good, and the product quality is easy to control, which also greatly improves the safety of the production process.

[0014] As a preferred technical solution of the present invention, the molar ratio of isobutylene to p-halophenol is 2-4:1, such as 2:1, 3:1 or 4:1.

[0015] As a preferred technical solution of the present invention, the mass ratio of sulfuric acid to para-halophenol is 1:(5-10), for example, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc.

[0016] As a preferred technical solution of the present invention, the mass ratio of the polymerization inhibitor to p-tert-butoxyhalobenzene is 1:100.

[0017] As a preferred technical solution of the present invention, the mass ratio of the catalyst to p-tert-butoxyhalobenzene is 1:(100-1000), for example, 1:100, 1:200, 1:500, 1:800, 1:1000, etc.

[0018] As a preferred technical solution of the present invention, the molar ratio of the vinyl magnesium chloride to p-tert-butoxyhalobenzene is 1-1.3:1, for example, 1:1, 1.1:1, 1.2:1, 1.25:1, 1.3:1, etc.

[0019] As a preferred technical solution of the present invention, the mass ratio of the initiator to p-tert-butoxyhalobenzene is 2:100.

[0020] As a preferred technical solution of the present invention, the ratio of the amount of the magnesium powder to the total amount of p-tert-butoxyhalobenzene is 1.5:1.

[0021] As a preferred technical solution of the present invention, the molar ratio of vinyl chloride to p-tert-butoxyhalobenzene is 2.1-2.7:1, for example, 2.1:1, 2.2:1, 2.4:1, 2.6:1, 2.7:1, etc.

[0022] As a preferred technical solution of the present invention, the reaction temperature in the addition unit is -5°C, and the material residence time is 3.66-5.3 min, for example, 3.66 min, 4 min, 4.6 min, 5 min, 5.3 min, etc.

[0023] As a preferred technical solution of the present invention, the reaction temperature in the coupling unit is 40° C., and the material residence time is 2.74-3.5 min, for example, 2.74 min, 2.8 min, 3.0 min, 3.2 min, 3.5 min, etc.

[0024] As a preferred technical solution of the present invention, the reaction temperature in the format unit is 70° C., and the material residence time is 25-35 s, such as 25 s, 28 s, 30 s, 32 s, 35 s, etc.

[0025] As a preferred technical solution of the present invention, the temperature of the preheating unit is 70°C.

[0026] As a preferred technical solution of the present invention, the cooling temperature of the third cooling unit is 0-10°C, for example, 0°C, 2°C, 4°C, 6°C, 8°C, 10°C, etc.; or, the cooling temperature of the first cooling unit is 35°C, and the cooling temperature of the second cooling unit is 0-10°C, for example, 0°C, 2°C, 4°C, 6°C, 8°C, 10°C, etc.

[0027] As a preferred technical solution of the present invention, the p-halogenphenol is p-chlorophenol or p-bromophenol.

[0028] As a preferred technical solution of the present invention, the catalyst is Ni(dppp)Cl2 and / or Pd(dppf)Cl2.

[0029] As a preferred technical solution of the present invention, the polymerization inhibitor is phenothiazine.

[0030] As a preferred technical solution of the present invention, the initiator is ethyl bromide.

[0031] As a preferred technical solution of the present invention, the pumping unit is a diaphragm pump.

[0032] As a preferred technical solution of the present invention, the mixing units are all T-shaped mixers made of stainless steel.

[0033] As a preferred technical solution of the present invention, the channel diameter of the T-type mixer is 25 mm.

[0034] As a preferred technical solution of the present invention, the addition unit and the coupling unit each independently include at least one microreactor made of high borosilicate glass.

[0035] As a preferred technical solution of the present invention, the addition unit is composed of four microreactors made of high borosilicate glass connected in series.

[0036] As a preferred technical solution of the present invention, the coupling units in step (2-1) and step (2-2) are both composed of three borosilicate glass microreactors connected in series.

[0037] As a preferred technical solution of the present invention, the high borosilicate glass microreactor has a length of 100 mm, a width of 100 mm, a height of 48 mm, a liquid holding capacity of 8 mL, and its internal microtubes are a heart-shaped structure connected in series.

[0038] As a preferred technical solution of the present invention, the format unit is a cylindrical channel.

[0039] As a preferred technical solution of the present invention, the inner diameter of the cylindrical channel of the format unit is 5 mm and the length is 60 mm.

[0040] As a preferred technical solution of the present invention, the cooling units are all PFA tubular coolers that are completely immersed in a constant temperature oil bath.

[0041] As a preferred technical solution of the present invention, the coil length of the tubular cooler is 1 m and the inner diameter is 10 mm.

[0042] As a preferred technical solution of the present invention, the post-processing unit is a reactor with stirring and cooling, and the volume of the reactor is preferably 0.5-1L.

[0043] As a preferred technical solution of the present invention, the back pressure regulating valve pressure in step (1) is 1000 psi.

[0044] As a preferred technical solution of the present invention, the pressure of the back pressure regulating valve in step (2-1) is 1000-1100psi, for example, 1000psi, 1020psi, 1040psi, 1060psi, 1080psi, 1100psi, etc.; or, the pressure of the back pressure regulating valve in step (2-2) is 1000-1200psi, for example, 1000psi, 1050psi, 1100psi, 1150psi, 1200psi, etc.

[0045] As a preferred technical solution of the present invention, the purification method in step (1) is column chromatography.

[0046] As a preferred technical solution of the present invention, the purification methods in steps (2-1) and (2-2) are both column chromatography followed by vacuum distillation.

[0047] As a preferred technical solution of the present invention, the isobutylene in step (1) exists in the form of isobutylene gas or a dichloromethane or toluene solution of isobutylene.

[0048] As a preferred technical solution of the present invention, the p-halophenol and sulfuric acid in step (1) are in the form of a toluene solution of p-halophenol and sulfuric acid.

[0049] As a preferred technical solution of the present invention, the p-tert-butoxyhalobenzene, polymerization inhibitor and catalyst in step (2-1) are in the form of a tetrahydrofuran solution of tert-butoxyhalobenzene, polymerization inhibitor and catalyst.

[0050] As a preferred technical solution of the present invention, the p-tert-butoxyhalobenzene and the initiator in step (2-2) are in the form of a tetrahydrofuran solution of p-tert-butoxyhalobenzene and the initiator.

[0051] As a preferred technical solution of the present invention, the catalyst and the inhibitor in step (2-2) are added to the p-tert-butoxyphenylmagnesium halide solution and then pumped into the second mixing unit by a pumping unit.

[0052] As a preferred technical solution of the present invention, in step (1), the pumping flow rates of the toluene solution of p-halophenol and sulfuric acid and isobutylene are independently 2-5 mL / min.

[0053] As a preferred technical solution of the present invention, in step (1), the pumping flow rate of the toluene solution of p-halophenol and sulfuric acid is 3.75 mL / min, the pumping flow rate of the dichloromethane or toluene solution of isobutylene is 5 mL / min, and the pumping flow rate of the isobutylene gas is 2 mL / min.

[0054] As a preferred technical solution of the present invention, in step (2-1), the pumping flow rates of the p-tert-butoxyhalobenzene, the tetrahydrofuran solution of the polymerization inhibitor and the catalyst, and the vinyl magnesium chloride are independently 2.75-6 mL / min.

[0055] As a preferred technical solution of the present invention, in step (2-1), the pumping flow rate of the tetrahydrofuran solution of tert-butoxyhalobenzene, inhibitor and catalyst is 6 mL / min, and the pumping flow rate of vinyl magnesium chloride is 2.75-3.25 mL / min.

[0056] As a preferred technical solution of the present invention, the pumping flow rate of the tetrahydrofuran solution of tert-butoxyhalobenzene and initiator in step (2-2) is 3.5-4 mL / min.

[0057] As a preferred technical solution of the present invention, in step (2-2), the pumping flow rates of the p-tert-butoxyphenylmagnesium halide solution containing the catalyst and the inhibitor and the vinyl chloride are independently 0.8-6 mL / min.

[0058] As a preferred technical solution of the present invention, the pumping flow rate of the p-tert-butoxyphenylmagnesium halide solution containing the catalyst and the inhibitor is 6 mL / min, and the pumping flow rate of the vinyl chloride is 0.8 mL / min.

[0059] As a preferred technical solution of the present invention, the concentration of the p-halophenol in the solvent toluene is 1.16-1.93 mol / L.

[0060] As a preferred technical solution of the present invention, the concentration of isobutylene in the solvent dichloromethane or toluene is 2.89 mol / L.

[0061] As a preferred technical solution of the present invention, the concentration of the p-tert-butoxyhalobenzene in the solvent tetrahydrofuran is 0.87-1.08 mol / L.

[0062] As a preferred technical solution of the present invention, the vinyl magnesium chloride is a tetrahydrofuran solution of vinyl magnesium chloride, and the concentration of vinyl magnesium chloride in tetrahydrofuran is 2 mol / L.

[0063] The preparation method provided by the present invention, on the one hand, adopts a modular structure of the continuous flow reactor, and realizes the full continuous flow process by designing the organization mode of the modules and developing targeted process conditions and parameters, including the division of each zone and temperature setting, multi-stage oil-water separation and other factors acting synergistically; on the other hand, the present invention optimizes the reaction temperature, material concentration, material ratio and material flow rate, etc., so as to further combine it with the integrated full continuous flow reaction process, match each link and obtain better process effect.

[0064] The technical solution provided by the embodiment of the present invention has the following advantages compared with the prior art:

[0065] The preparation method provided by the present invention utilizes a continuous flow microreactor to prepare p-tert-butoxystyrene, has the advantages of simple, safe and efficient operation, short reaction time and low temperature, no expensive reagents are used, no amplification effect exists, the prepared p-tert-butoxystyrene product has high yield and purity and stable quality, and the method of the present invention is suitable for large-scale production, can greatly reduce production costs and improve production safety. DETAILED DESCRIPTION

[0066] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

[0067] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all of the embodiments.

[0068] Example 1

[0069] This embodiment provides a method for preparing p-tert-butoxystyrene, which is carried out using a continuous flow microreactor, wherein the continuous flow microreactor includes a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a back pressure regulating valve, a cooling unit and a post-processing unit, and specifically includes the following steps:

[0070] (1) The raw materials SM1 (p-bromophenol, 50 g, 289 mmol) and sulfuric acid (5 g, 10% wt) were dissolved in 150 mL of toluene to prepare a 1.93 M solution, which was cooled to -5°C in advance and pumped into the first mixing unit microchannel at a flow rate of 3.75 mL / min using a diaphragm pump. Another 200 mL of toluene was taken and cooled to -5°C and introduced into isobutylene (32.4 g, 578.0 mmol) to prepare a solution for use. The solution was pumped into the first mixing unit microchannel at a flow rate of 5 mL / min using a diaphragm pump, mixed, and the temperature was controlled at -5°C. Then, the addition unit was introduced for addition reaction (a total of 4 high borosilicate glass reaction plates, the size of each plate: 100 mm×100 mm×48 mm, the liquid holding capacity was 8 mL, and the microtube had a heart-shaped structure). The reaction temperature was -5°C and the residence time was 3.66 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1000 psi) and enters a post-treatment unit (1L reactor) containing 250 mL of NaOH (5% wt) aqueous solution for quenching, stirring and separation. After stirring for 10 min and standing for 30 min, the toluene phase is collected and the aqueous phase is discarded. The toluene phase is washed with 250 mL of water, dried over 20% wt anhydrous sodium sulfate, filtered, and the toluene phase is concentrated at 60° C. The concentrated crude product is dissolved in 200 mL of n-heptane and quickly purified by a 30% wt silica gel short column. The column liquid is concentrated to obtain a light yellow liquid product compound 1 (p-tert-butoxybromobenzene, 52 g). The purity is 99.1% as determined by GC, and the yield is 78.5%.

[0071] (2) Under nitrogen protection, phenothiazine (250 mg, 1% wt) and Ni(dppp)Cl2 (250 mg, 1% wt) or Pd(dppf)Cl2 (25 mg, 0.1% wt) were added to a solution of p-tert-butoxybromobenzene (25 g, 109.1 mmol) in tetrahydrofuran (150 mL). The mixture was stirred and dissolved for later use. The mixture was pumped into the microchannel of the second mixing unit at a flow rate of 6 mL / min using a diaphragm pump. A tetrahydrofuran solution of magnesium chloride (70.9 mL, 2 M, 141.9 mmol) was pumped into the microchannel of the second mixing unit at a flow rate of 2.75 mL / min using a diaphragm pump, mixed, and then introduced into the coupling unit for coupling reaction (a total of 3 high borosilicate glass reaction plates, single plate size: 100 mm × 100 mm × 48 mm, liquid holding volume 8 mL, heart-shaped microtube), reaction temperature 40 ° C, residence time 2.74 min, the reaction was completed After completion, the reaction solution flows through a back pressure regulating valve (pressure is 1100psi) into a cooling unit, the temperature drops to 10°C, and then the reaction solution enters a post-treatment unit (0.5L reactor) filled with 50mL of ethyl acetate and 150mL of saturated ammonium chloride aqueous solution for quenching, stirring and liquid separation (quenching temperature is controlled below 20°C), stirring for 10min, standing for 30min, collecting the organic phase, discarding the aqueous phase, washing the organic phase with 150mL of water, drying with 20%wt anhydrous sodium sulfate, filtering, and concentrating the organic phase at 50°C. The concentrated crude product is dissolved in 100mL of n-heptane, decolorized by passing through a 3.8g (15%wt) silica gel short column, and the column liquid is concentrated to obtain a colorless or light yellow liquid crude product. The crude product is purified by vacuum distillation with a 10cm thorn-type distillation column (vacuum degree -101Kpa, oil bath temperature 100°C) to obtain a colorless and transparent product of tert-butoxystyrene, 15.2g, with a purity of 99.5% and a yield of 79.3% as determined by GC.

[0072] Example 2

[0073] This embodiment provides a method for preparing p-tert-butoxystyrene, which is carried out using a continuous flow microreactor, wherein the continuous flow microreactor includes a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a back pressure regulating valve, a cooling unit and a post-processing unit, and specifically includes the following steps:

[0074] (1) The raw materials SM1 (p-bromophenol, 50 g, 289 mmol) and sulfuric acid (5 g, 10% wt) were dissolved in 250 mL of toluene to prepare a 1.16 M solution, which was cooled to -5°C in advance for use. The solution was pumped into the first mixing unit with a diaphragm pump at a flow rate of 5 mL / min, and isobutylene gas was pumped into the first mixing unit with a diaphragm pump at a flow rate of 2 mL / min. The continuous pumping time was about 1 h. The mixture was mixed in the microchannel of the first mixing unit and then introduced into the addition unit for addition reaction (a total of 4 high borosilicate glass reaction plates, the size of each plate: 100 mm × 100 mm × 48 mm, the liquid holding capacity 8 mL, heart-shaped microtube), the reaction temperature was -5°C, and the residence time was 4.6 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1000 psi) and enters a post-treatment unit (1L reactor) containing 250 mL of NaOH (5% wt) aqueous solution for quenching, stirring and separation. After stirring for 10 min and standing for 30 min, the toluene phase is collected and the aqueous phase is discarded. The toluene phase is washed with 250 mL of water, dried over 20% wt anhydrous sodium sulfate, filtered, and the toluene phase is concentrated at 60° C. The concentrated crude product is dissolved in 200 mL of n-heptane and quickly purified by a 30% wt silica gel short column. The column liquid is concentrated to obtain a light yellow liquid product compound 1 (p-tert-butoxybromobenzene, 62.3 g). The purity is 99.1% as determined by GC, and the yield is 94.0%.

[0075] (2) Under nitrogen protection, phenothiazine (500 mg, 1% wt) and Ni(dppp)Cl2 (500 mg, 1% wt) or Pd(dppf)Cl2 (50 mg, 0.1% wt) were added to a solution of p-tert-butoxybromobenzene (50 g, 218.2 mmol) in tetrahydrofuran (250 mL). The mixture was stirred and dissolved for later use. The mixture was pumped into the microchannel of the second mixing unit at a flow rate of 6 mL / min using a diaphragm pump. A tetrahydrofuran solution of magnesium chloride (137.5 mL, 2 M, 274.9 mmol) was pumped into the microchannel of the second mixing unit at a flow rate of 2.75 mL / min using a diaphragm pump, mixed, and then introduced into the coupling unit for coupling reaction (a total of 3 borosilicate glass reaction plates, single plate size: 100 mm × 100 mm × 48 mm, liquid holding volume 8 mL, heart-shaped microtube), reaction temperature 40 ° C, residence time 2.74 min, reaction After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1100psi) into a cooling unit, the temperature drops to 10°C, and then the reaction solution enters a post-treatment unit (1L reactor) equipped with 100mL of ethyl acetate and 250mL of saturated ammonium chloride aqueous solution for quenching, stirring and liquid separation (quenching temperature is controlled below 20°C), stirring for 10min, standing for 30min, collecting the organic phase, discarding the aqueous phase, washing the organic phase with 250mL of water, drying with 20%wt anhydrous sodium sulfate, filtering, and concentrating the organic phase at 50°C. The concentrated crude product is dissolved in 200mL of n-heptane, decolorized by passing through a 7.5g (15%wt) silica gel short column, and the column liquid is concentrated to obtain a colorless or light yellow liquid crude product. The crude product is purified by vacuum distillation with a 10cm thorn-type distillation column (vacuum degree -101Kpa, oil bath temperature 100°C) to obtain a colorless and transparent product of tert-butoxystyrene, 30g, with a purity of 99.6% and a yield of 78.0% as determined by GC.

[0076] Example 3

[0077] This embodiment provides a method for preparing p-tert-butoxystyrene, which is carried out using a continuous flow microreactor, wherein the continuous flow microreactor includes a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a back pressure regulating valve, a cooling unit and a post-processing unit, and specifically includes the following steps:

[0078] (1) The raw materials SM1 (p-chlorophenol, 50 g, 388.9 mmol) and sulfuric acid (5 g, 10% wt) were dissolved in 250 mL of toluene to prepare a 1.55 M solution, which was cooled to -5°C in advance for use. The solution was pumped into the first mixing unit with a diaphragm pump at a flow rate of 4 mL / min, and isobutylene gas was pumped into the first mixing unit with a diaphragm pump at a flow rate of 2 mL / min. The continuous pumping time was about 70 min. The mixture was mixed in the microchannel of the first mixing unit and then introduced into the addition unit for addition reaction (a total of 4 high borosilicate glass reaction plates, the size of each plate: 100 mm × 100 mm × 48 mm, the liquid holding capacity 8 mL, heart-shaped microtube), the reaction temperature was -5°C, and the residence time was 5.3 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1000 psi) and enters a post-treatment unit (1L reactor) containing 250 mL of NaOH (5% wt) aqueous solution for quenching, stirring and separation. After stirring for 10 min and standing for 30 min, the toluene phase is collected and the aqueous phase is discarded. The toluene phase is washed with 250 mL of water, dried over 20% wt anhydrous sodium sulfate, filtered, and the toluene phase is concentrated at 60° C. The concentrated crude product is dissolved in 200 mL of n-heptane and quickly purified by a 30% wt silica gel short column. The column liquid is concentrated to obtain a light yellow liquid product compound 1 (p-tert-butoxychlorobenzene, 65 g). The purity is 98.5% as determined by GC, and the yield is 90.5%.

[0079] (2) Under nitrogen protection, phenothiazine (500 mg, 1% wt) and Pd(dppf)Cl2 (50 mg, 0.1% wt) were added to a solution of p-tert-butoxychlorobenzene (50 g, 270.8 mmol) in tetrahydrofuran (250 mL), stirred and dissolved for later use, and then pumped into the microchannel of the second mixing unit with a diaphragm pump at a flow rate of 6 mL / min. A tetrahydrofuran solution of vinyl magnesium chloride (162.5 mL, 2 M, 324.9 mmol) was also taken and pumped into the microchannel of the second mixing unit with a diaphragm pump at a flow rate of 3.25 mL / min. After mixing, the coupling unit was introduced for coupling reaction (a total of 3 high borosilicate glass reaction plates, the size of each plate: 100 mm×100 mm×48 mm, the liquid holding capacity is 8 mL, and the heart-shaped microtube) at a reaction temperature of 40°C and a residence time of 2.74 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1100psi) into a cooling unit, the temperature is reduced to 10°C, and then the reaction solution enters a post-processing unit (1L reactor) equipped with 100mL ethyl acetate and 250mL saturated ammonium chloride aqueous solution for quenching, stirring and liquid separation (quenching temperature is controlled below 20°C), stirring for 10min, standing for 30min, collecting the organic phase, discarding the aqueous phase, washing the organic phase with 250mL water, drying with 20%wt anhydrous sodium sulfate, filtering, and concentrating the organic phase at 50°C. The concentrated crude product is dissolved in 200mL n-heptane, decolorized by passing through a 7.5g (15%wt) silica gel short column, and the column liquid is concentrated to obtain a colorless or light yellow liquid crude product. The crude product is purified by vacuum distillation with a 10cm thorn-type distillation column (vacuum degree -101Kpa, oil bath temperature 100°C) to obtain a colorless and transparent product of tert-butoxystyrene, 30g, with a GC purity of 99.5% and a yield of 78.0%.

[0080] The preparation process of p-tert-butoxystyrene described in Examples 1-3 is as follows:

[0081] Example 4

[0082] This embodiment provides a method for preparing p-tert-butoxystyrene, which is carried out using a continuous flow microreactor, wherein the continuous flow microreactor includes a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a format unit, a first cooling unit and a second cooling unit, a preheating unit, a back pressure regulating valve, and a post-processing unit; specifically, the following steps are included:

[0083] (1) The raw materials SM1 (p-bromophenol, 50 g, 289 mmol) and sulfuric acid (5 g, 10% wt) were dissolved in 250 mL of toluene to prepare a 1.16 M solution, which was cooled to -5°C in advance for use. The solution was pumped into the microchannel of the first mixing unit at a flow rate of 5 mL / min using a diaphragm pump, and isobutylene gas was pumped into the microchannel of the first mixing unit at a flow rate of 2 mL / min using a diaphragm pump. After mixing, the mixture was introduced into the addition unit for addition reaction (a total of 4 high borosilicate glass reaction plates, the size of each plate: 100 mm × 100 mm × 48 mm, the liquid holding capacity 8 mL, heart-shaped microtube), the reaction temperature was -5°C, and the residence time was 4.6 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1000 psi) and enters a post-treatment unit (1L reactor) containing 250 mL of NaOH (5% wt) aqueous solution for quenching, stirring and separation. After stirring for 10 min and standing for 30 min, the toluene phase is collected and the aqueous phase is discarded. The toluene phase is washed with 250 mL of water, dried over 20% wt anhydrous sodium sulfate, filtered, and the toluene phase is concentrated at 60° C. The concentrated crude product is dissolved in 200 mL of n-heptane and quickly purified by a 30% wt silica gel short column. The column liquid is concentrated to obtain a light yellow liquid product compound 1 (p-tert-butoxybromobenzene, 62 g). The purity is 99.0% and the yield is 93.6% as determined by GC.

[0084] (2) Compound 1 (p-tert-butoxy bromobenzene, 50 g, 218.2 mmol) and compound SM3 (ethyl bromide, 1 g, 2% wt) were dissolved in (250 mL) THF to prepare a 0.87 M mixed solution. The mixed solution was pumped into the preheating unit at a flow rate of 4 mL / min using a diaphragm pump, and the temperature was controlled at 70°C. The preheated mixed solution entered the format unit. The reaction section was a circular channel with an inner diameter of 5 mm and a length of 60 mm. The interior was filled with magnesium chips (7.9 g, 327.3 mmol, average particle size of 0.5 mm). The temperature was 70°C and the residence time was 25 s. The reacted material entered the first cooling unit, the temperature dropped to 35°C, and the obtained reaction solution entered a container with nitrogen protection facilities to obtain a gray THF solution of p-tert-butoxyphenylmagnesium bromide. 1 mL was taken and quenched with a saturated aqueous ammonium chloride solution. After GC detection, the remaining raw material was 0.1% and the product content was 98%. The obtained solution was directly used for the synthesis of p-tert-butoxystyrene.

[0085] (3) Under nitrogen protection, phenothiazine (500 mg, 1% wt) and Ni(dppp)Cl2 (500 mg, 1% wt) or Pd(dppf)Cl2 (50 mg, 0.1% wt) were added to the reaction output liquid of the previous step. After stirring and dissolving, the mixture was pumped into the second mixing unit at a flow rate of 6 mL / min using a diaphragm pump. The continuous pumping time was about 50 min. The temperature was controlled at 40°C. Vinyl chloride gas was pumped into the mixture at a flow rate of 0.8 mL / min using a diaphragm pump. After mixing, the mixture was introduced into the coupling unit for coupling reaction (a total of 3 high borosilicate glass reaction plates, the size of each plate: 100 mm × 100 mm × 48 mm, liquid holding capacity 8 mL, heart-shaped microtube). The reaction temperature was 40°C and the residence time was 3.5 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1100psi) into the second cooling unit, the temperature drops to 10°C, and then the reaction solution enters a post-processing unit (1L reactor) equipped with 100mL ethyl acetate and 250mL saturated ammonium chloride aqueous solution for quenching, stirring and liquid separation (quenching temperature is controlled below 20°C), stirring for 10min, standing for 30min, collecting the organic phase, discarding the aqueous phase, washing the organic phase with 250mL water, drying with 20%wt anhydrous sodium sulfate, filtering, and concentrating the organic phase at 50°C. The concentrated crude product is dissolved in 200mL n-heptane, decolorized by 7.5g (15%wt) silica gel short column, and the column liquid is concentrated to obtain a colorless or light yellow liquid crude product. The crude product is purified by vacuum distillation with a 10cm thorn-type distillation column (vacuum degree -101Kpa, oil bath temperature 100°C) to obtain a colorless and transparent product of tert-butoxystyrene, 34.5g, with a purity of 99.6% and a yield of 89.6% as determined by GC.

[0086] Example 5

[0087] This embodiment provides a method for preparing p-tert-butoxystyrene, which is carried out using a continuous flow microreactor, wherein the continuous flow microreactor includes a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a format unit, a first cooling unit and a second cooling unit, a preheating unit, a back pressure regulating valve, and a post-processing unit; specifically, the following steps are included:

[0088] (1) The raw materials SM1 (p-chlorophenol, 50 g, 388.9 mmol) and sulfuric acid (5 g, 10% wt) were dissolved in 250 mL of toluene to prepare a 1.55 M solution, which was cooled to -5°C in advance for use. The solution was pumped into the microchannel of the first mixing unit at a flow rate of 4 mL / min using a diaphragm pump, and isobutylene gas was pumped into the microchannel at a flow rate of 2 mL / min using a diaphragm pump. After mixing, the solution was introduced into the addition unit for addition reaction (a total of 4 high borosilicate glass reaction plates, the size of each plate: 100 mm × 100 mm × 48 mm, the liquid holding capacity 8 mL, heart-shaped microtube), the reaction temperature was -5°C, and the residence time was 5.3 min. After the reaction is completed, the reaction solution flows through a back pressure regulating valve (pressure is 1000 psi) and enters a post-treatment unit (1L reactor) containing 250 mL of NaOH (5% wt) aqueous solution for quenching, stirring and separation. After stirring for 10 min and standing for 30 min, the toluene phase is collected and the aqueous phase is discarded. The toluene phase is washed with 250 mL of water, dried over 20% wt anhydrous sodium sulfate, filtered, and the toluene phase is concentrated at 60° C. The concentrated crude product is dissolved in 200 mL of n-heptane and quickly purified by a 30% wt silica gel short column. The column liquid is concentrated to obtain a light yellow liquid product compound 1 (p-tert-butoxychlorobenzene, 65 g). The purity is 98.5% as determined by GC, and the yield is 90.5%.

[0089] (2) Compound 1 (p-tert-butoxychlorobenzene, 50 g, 270.8 mmol) and compound SM3 (ethyl bromide, 1 g, 2% wt) were dissolved in (250 mL) THF to prepare a 1.08 M mixed solution. The mixed solution was pumped into the preheating unit at a flow rate of 3.5 mL / min using a diaphragm pump, and the temperature was controlled at 70°C. The preheated mixed solution entered the format unit. The reaction section was a circular channel with an inner diameter of 5 mm and a length of 60 mm. The interior was filled with magnesium chips (9.8 g, 406.1 mmol, average particle size of 0.5 mm). The temperature was 70°C and the residence time was 35 s. The reacted material entered the first cooling unit, the temperature dropped to 35°C, and the obtained reaction solution entered a container with nitrogen protection facilities to obtain a THF gray solution of p-tert-butoxyphenylmagnesium chloride. 1 mL was taken and quenched with a saturated aqueous ammonium chloride solution. GC detection showed that the raw material remained 0.1% and the product content was 97.9%. The obtained solution was directly used for the synthesis of p-tert-butoxystyrene.

[0090] (3) Under nitrogen protection, phenothiazine (500 mg, 1% wt) and Ni(dppp)Cl2 (500 mg, 1% wt) or Pd(dppf)Cl2 (50 mg, 0.1% wt) were added to the reaction output liquid of the previous step. After stirring and dissolving, the mixture was pumped into the second mixing unit at a flow rate of 6 mL / min using a diaphragm pump. The continuous pumping time was about 50 min. The temperature was controlled at 40°C. Vinyl chloride gas was pumped into the mixture at a flow rate of 0.8 mL / min using a diaphragm pump. After mixing, the mixture was introduced into the coupling unit for coupling reaction (a total of 3 high borosilicate glass reaction plates, the size of each plate: 100 mm × 100 mm × 48 mm, liquid holding capacity 8 mL, heart-shaped microtube). The reaction temperature was 40°C and the residence time was 3.5 min. After the reaction is completed, the reaction solution flows through the back pressure regulating valve (pressure is 1100psi) into the second cooling unit, the temperature drops to 10°C, and then the reaction solution enters the post-processing unit (1L reactor) equipped with 100mL ethyl acetate and 250mL saturated ammonium chloride aqueous solution for quenching, stirring and liquid separation (quenching temperature is controlled below 20°C), stirring for 10min, standing for 30min, collecting the organic phase, discarding the aqueous phase, washing the organic phase with 250mL water, drying with 20%wt anhydrous sodium sulfate, filtering, and concentrating the organic phase at 50°C. The concentrated crude product is dissolved in 200mL n-heptane, decolorized by 7.5g (15%wt) silica gel short column, and the column liquid is concentrated to obtain a colorless or light yellow liquid crude product. The crude product is purified by vacuum distillation with a 10cm thorn-type distillation column (vacuum degree -101Kpa, oil bath temperature 100°C) to obtain a colorless and transparent product of tert-butoxystyrene, 40g, with a purity of 99.5% and a yield of 83.8% as determined by GC.

[0091] The preparation process of p-tert-butoxystyrene described in Examples 4 and 5 is as follows:

[0092]

[0093] It can be found that the preparation method provided by the present invention utilizes a continuous flow microreactor to prepare p-tert-butoxystyrene, which is simple, safe, and efficient to operate, has a short reaction time, a low temperature, does not use expensive reagents, and does not have an amplification effect. The prepared p-tert-butoxystyrene product has a high yield and purity and stable quality.

[0094] It should be noted that, in this article, relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0095] The above description is only a specific embodiment of the present invention, so that those skilled in the art can understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments described herein, but should conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing tert-butoxystyrene, characterized in that: The preparation method is carried out by using a continuous flow microreactor, which comprises a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a back pressure regulating valve, a third cooling unit and a post-processing unit; or comprises a pumping unit, a first mixing unit and a second mixing unit, an addition unit, a coupling unit, a format unit, a first cooling unit and a second cooling unit, a preheating unit, a back pressure regulating valve and a post-processing unit; The preparation method comprises: (1) using a pumping unit to pump p-halophenol, isobutylene and sulfuric acid into a first mixing unit for mixing, and then passing them into an addition unit for addition reaction, and after the reaction is completed, flowing through a back pressure regulating valve into a post-processing unit for oil-water separation, and then taking the oil phase for concentration and purification to obtain p-tert-butyloxy halogenated benzene; (2-1) using a pumping unit to pump the tert-butyloxy halogenated benzene, vinyl magnesium chloride, polymerization inhibitor and catalyst into a second mixing unit for mixing, and then passing them into a coupling unit for coupling reaction. After the reaction is completed, they flow through a back pressure regulating valve into a third cooling unit for cooling, and then pass them into a post-treatment unit for oil-water separation, and then take the oil phase for concentration and purification to obtain the tert-butyloxy styrene; Or, (2-2) using a pumping unit to pump the tert-butoxy halogenated benzene and initiator into a preheating unit for preheating, then passing them into a format unit filled with magnesium powder for format reaction, and after the reaction is completed, passing them into a first cooling unit for cooling to obtain a tert-butoxyphenyl magnesium halide solution; using a pumping unit to pump the tert-butoxyphenyl magnesium halide solution, vinyl chloride, catalyst and inhibitor into a second mixing unit for mixing, and then passing them into a coupling unit for coupling reaction, after the reaction is completed, flowing through a back pressure regulating valve into a second cooling unit for cooling, and then passing them into a post-processing unit for oil-water separation, and then taking the oil phase for concentration and purification to obtain the tert-butoxystyrene.

2. The preparation method according to claim 1, characterized in that: The molar ratio of isobutylene to para-halophenol is 2-4:1; And / or, the mass ratio of the sulfuric acid to the para-halophenol is 1:(5-10); And / or, the mass ratio of the polymerization inhibitor to p-tert-butoxyhalobenzene is 1:100; And / or, the mass ratio of the catalyst to p-tert-butoxyhalobenzene is 1:(100-1000); and / or, the molar ratio of the vinyl magnesium chloride to p-tert-butoxyhalobenzene is 1-1.3:1; And / or, the mass ratio of the initiator to p-tert-butoxyhalobenzene is 2:100; And / or, the ratio of the amount of the magnesium powder to the total amount of p-tert-butoxyhalobenzene is 1.5:1; And / or, the molar ratio of vinyl chloride to p-tert-butoxyhalobenzene is 2.1-2.7:

1.

3. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature in the addition unit is -5°C, and the material residence time is 3.66-5.3min; And / or, the reaction temperature in the coupling unit is 40° C., and the material residence time is 2.74-3.5 min; And / or, the reaction temperature in the format unit is 70°C and the material residence time is 25-35s; And / or, the temperature of the preheating unit is 70°C; And / or, the cooling temperature of the third cooling unit is 0-10°C; or, the cooling temperature of the first cooling unit is 35°C, and the cooling temperature of the second cooling unit is 0-10°C.

4. The preparation method according to any one of claims 1 to 3, characterized in that The p-halogenphenol is p-chlorophenol or p-bromophenol; And / or, the catalyst is Ni(dppp)Cl2 and / or Pd(dppf)Cl2; And / or, the inhibitor is phenothiazine; And / or, the initiator is ethyl bromide.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The pumping unit is a diaphragm pump; And / or, the mixing units are all T-shaped mixers made of stainless steel; And / or, the addition unit and the coupling unit each independently include at least one microreactor made of high borosilicate glass; And / or, the format unit is a cylindrical channel; And / or, the cooling units are all PFA tubular coolers completely immersed in a constant temperature oil bath.

6. The preparation method according to claim 5, characterized in that: The addition unit is composed of 4 microreactors made of high borosilicate glass connected in series; And / or, the coupling units in step (2-1) and step (2-2) are both composed of three borosilicate glass microreactors connected in series; And / or, the borosilicate glass microreactor has a length of 100 mm, a width of 100 mm, a height of 48 mm, a liquid holding capacity of 8 mL, and its internal microtubes are a heart-shaped structure connected in series; And / or, the channel diameter of the T-type mixer is 25 mm; And / or, the inner diameter of the cylindrical channel of the format unit is 5 mm and the length is 60 mm; And / or, the coil length of the tubular cooler is 1 m and the inner diameter is 10 mm; And / or, the pressure of the back pressure regulating valve in step (2-1) is 1000-1100 psi; or, the pressure of the back pressure regulating valve in step (2-2) is 1000-1200 psi.

7. The preparation method according to any one of claims 1 to 4, characterized in that: The isobutylene in step (1) is present in the form of isobutylene gas or a dichloromethane or toluene solution of isobutylene; And / or, the p-halophenol and sulfuric acid in step (1) are present in the form of a toluene solution of p-halophenol and sulfuric acid; And / or, the p-tert-butoxyhalobenzene, polymerization inhibitor and catalyst in step (2-1) are present in the form of a tetrahydrofuran solution of tert-butoxyhalobenzene, polymerization inhibitor and catalyst; Or, the p-tert-butoxyhalobenzene and the initiator in step (2-2) are present in the form of a tetrahydrofuran solution of p-tert-butoxyhalobenzene and the initiator; Alternatively, the catalyst and the inhibitor in step (2-2) are added to the p-tert-butoxyphenylmagnesium halide solution and then pumped into the second mixing unit using a pumping unit.

8. The preparation method according to claim 7, characterized in that: In step (1), the pumping flow rates of the toluene solution of p-halophenol and sulfuric acid and isobutylene are independently 2-5 mL / min; And / or, in step (2-1), the pumping flow rates of p-tert-butoxyhalobenzene, tetrahydrofuran solution of polymerization inhibitor and catalyst, and vinylmagnesium chloride are independently 2.75-6 mL / min.

9. The preparation method according to claim 7, characterized in that: In step (2-2), the pumping flow rate of the tetrahydrofuran solution of tert-butoxyhalobenzene and initiator is 3.5-4 mL / min; And / or, in step (2-2), the pumping flow rates of the p-tert-butoxyphenylmagnesium halide solution containing the catalyst and the inhibitor and the vinyl chloride are independently 0.8-6 mL / min.

10. The preparation method according to any one of claims 7 to 9, characterized in that: The concentration of the p-halogenphenol in the solvent toluene is 1.16-1.93 mol / L; And / or, the concentration of isobutylene in the solvent dichloromethane or toluene is 2.89 mol / L; And / or, the concentration of the p-tert-butoxyhalobenzene in the solvent tetrahydrofuran is 0.87-1.08 mol / L.

Images