Synthesis method of 3-n-propyl phenol

Abstract

The invention relates to the technical field of synthesis of organic compounds, in particular to a synthesis method of 3-n-propyl phenol, which comprises the following steps: (1) synthesis of 3-propenylphenol: taking m-hydroxybenzaldehyde as a raw material, reacting with ethyltriphenylphosphorus bromide (Wittig reagent) under the action of potassium tert-butoxide in a mixed solvent (with a volume ratio of 13: 3: 1) of petroleum ether / THF / ethylene glycol dimethyl ether (DME) to obtain 3-propenylphenol; after quenching with hydrochloric acid, purifying by using a ZnCl2-AlCl3 composite salt ethanol solution (with a molar ratio of 3: 1) to remove a by-product phosphorus oxytriphenolate so as to obtain 3-propenylphenol with the purity of greater than or equal to 98.5%, and rectifying a water phase to recover a solvent; (2) synthesis of 3-n-propyl phenol: 3-aminopropyltriethoxysilane modified mesoporous SiO2 loaded Raney nickel is taken as a catalyst, anhydrous sodium acetate is added as a cocatalyst, hydrogenation is carried out in ethanol at normal pressure and normal temperature, the catalyst can be repeatedly used for more than or equal to 5 times after washing, drying and hydrogen activation, and a product is subjected to reduced pressure distillation to obtain the 3-n-propyl phenol.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of organic compound synthesis, in particular to a synthesis method of 3-n-propylphenol. BACKGROUND

[0002] 3-n-propylphenol is an important aromatic compound. The synergistic effect of the phenolic hydroxyl group and the meta n-propyl group in the molecular structure of 3-n-propylphenol makes it have unique chemical properties. In the field of perfumes, the derivatives thereof can be used for synthesizing fragrances with floral or woody fragrance and are widely used in daily chemical products. In the field of high polymer materials, 3-n-propylphenol can be used as a monomer or a modifier of polyarylate and epoxy resin, and can significantly improve the heat resistance (the glass transition temperature is increased by 15-20 DEG C) and mechanical strength (the tensile strength is increased by 10-15 MPa) of the materials. In the field of medicine and pesticide, 3-n-propylphenol is a key building block for synthesizing beta-receptor blockers (such as propranolol) and fungicides (such as prothioconazole), and the antioxidant property of the phenolic hydroxyl group makes 3-n-propylphenol be used as an auxiliary antioxidant of high polymer materials to inhibit material aging.

[0003] However, the core challenge of the synthesis of 3-n-propylphenol lies in high regioselectivity. The hydroxyl group of phenol is a strong ortho-para directing group, and the conventional alkylation reaction is prone to preferentially generating ortho-n-propylphenol and para-n-propylphenol, and the proportion of the meta product is extremely low. In addition, the physical properties of the isomers are similar (for example, the boiling points of para-n-propylphenol and 3-n-propylphenol only differ by 3 DEG C), and the separation difficulty is extremely great. In the prior art, the synthesis routes of 3-n-propylphenol mainly have the following defects: Friedel-Crafts alkylation method: phenol and 1-chloropropane are used as raw materials, and the reaction is carried out under the catalysis of AlCl3. The method needs high temperature of 150-180 DEG C, and the strong corrosion of AlCl3 shortens the service life of the equipment (the service life of the stainless steel reaction kettle is only 6-8 months). In addition, the proportion of the ortho and para isomers in the product is more than 70%, the content of 3-n-propylphenol is less than 30%, and the product needs to be purified by multiple precise rectifications (the theoretical tray number is greater than or equal to 50) so that the energy consumption is high and the yield is only 25-30%, and the economic efficiency is poor.

[0004] Grignard reagent method: 3-bromophenol is used as a raw material, and n-propylmagnesium bromide is reacted in anhydrous ether. The method needs a low-temperature environment of-78 DEG C (depends on liquid nitrogen refrigeration, and the cost is high), and the Grignard reagent is easy to hydrolyze, so strict anhydrous conditions (the water content in the system is less than or equal to 0.01%) are needed. The operation difficulty is great. The magnesium salt impurities generated after the reaction are difficult to remove completely, the purity of the product is only 85-90%, the yield is about 45%, and the method is not suitable for large-scale production.

[0005] High temperature and high pressure hydrogenation method: 4-propyl-2-methoxyphenol as raw material, in n-cubebane / n-hexadecane mixed solvent, 2MPa hydrogen, 300℃ high temperature catalytic hydrogenation. This method needs special high temperature and high pressure reactor (equipment investment is 3-5 times of conventional reactor), 300℃ high temperature leads to easy carbonization of solvent (byproduct carbon black content is about 2%), 2MPa high pressure hydrogen exists leakage explosion risk; And the product still contains 5-8% p-n-propylphenol, needs to be separated by molecular distillation (vacuum degree 0.001MPa), the purification cost accounts for more than 30% of the total cost, the yield is only 59.5%.

[0006] In summary, the prior art or reaction condition is harsh, the safety risk is high, or the regioselectivity is poor, the purification is difficult, or the environmental protection is poor, and the cost is high. Therefore, developing a 3-n-propylphenol synthesis method with mild conditions, high selectivity, green environmental protection and low cost has become a technical problem to be solved in the field. SUMMARY

[0007] In view of the defects of the prior art, the application provides a synthesis method of 3-n-propylphenol.

[0008] The technical scheme adopted by the application to solve the technical problems is: a synthesis method of 3-n-propylphenol, comprising the following steps: (1) Synthesis of 3-propenylphenol: add mixed solvent to the reaction kettle, the mixed solvent is composed of petroleum ether (boiling range 60-90℃), tetrahydrofuran (THF, water content≤0.05%) and ethylene glycol dimethyl ether (DME, anhydrous) in a volume ratio of 13:3:1; add ethyl triphenyl phosphonium bromide (purity≥98%), stir to dissolve, then slowly drop potassium tert-butoxide (purity≥95%) at room temperature, stir for 40min; dissolve m-hydroxybenzaldehyde (purity≥99%) with the mixed solvent, drop into the reaction kettle at 30±2℃ under N2 protection (flow rate 0.5L / min), stir for 2h after dropping until TLC detection shows no raw material; quench with 1M hydrochloric acid to pH 6-7, filter the filter cake, wash with water, separate the upper organic phase, wash with brine, and concentrate to obtain the crude product; add the crude product to a 95% ethanol solution of ZnCl2-AlCl3 complex salt (complex salt concentration 0.15g / mL, molar ratio of ZnCl2 to AlCl3 3:1), stir for 1h, then filter, and concentrate the filtrate to obtain 3-propenylphenol; the water phase after quenching is subjected to rectification to recover petroleum ether, THF and DME; (2) Synthesis of 3-n-propylphenol: Into a three-neck flask was added a modified mesoporous SiO2 supported Raney nickel catalyst prepared from 3-aminopropyltriethoxysilane modified mesoporous SiO2 (pore size 20 nm) and Raney nickel at a mass ratio of 7:3, with a Raney nickel loading of 30 wt%; then a mixture solution of ethanol (95%) and 3-propenylphenol obtained in step (1) (ethanol:3-propenylphenol mass ratio of 5:1) and anhydrous sodium acetate promoter (molar ratio of 0.05:1 to 3-propenylphenol) was added; after 3 times of hydrogen replacement, stirring was performed at 10-40°C and 0.1-0.5 MPa until no raw material was detected by GC; ethanol was removed by rotary evaporation, and the catalyst was recovered by filtration after adding water; the filter cake was washed with dichloromethane and the aqueous phase was extracted, and the organic phases were combined and concentrated, followed by vacuum distillation (0.095 MPa, 120-125°C) to obtain 3-n-propylphenol; the recovered catalyst was washed with ethanol, vacuum dried at 80°C, and activated with hydrogen at 100°C, and could be reused.

[0009] Specifically, in step (1), the mass ratio of ethyltriphenylphosphonium bromide to m-hydroxybenzaldehyde was 3.65:1, and the mass ratio of potassium tert-butoxide to m-hydroxybenzaldehyde was 2:1.

[0010] Specifically, in step (1), the mass-volume ratio of the crude product to the ZnCl2-AlCl3 complex salt ethanol solution was 1:5 (g / mL).

[0011] Specifically, in step (1), the solvent recovered by rectification was dried (water content ≤0.05%) and reused for the preparation of the mixed solvent in step (1), and the solvent recovery rate was DME ≥88%, THF ≥86%, and petroleum ether ≥85%.

[0012] Specifically, in step (2), the mass ratio of the modified mesoporous SiO2 supported Raney nickel catalyst to 3-propenylphenol was 0.03:1.

[0013] Specifically, in step (2), after the catalyst was reused for 5 times, the catalytic activity remained more than 80% of the initial activity, and the corresponding 3-n-propylphenol yield was still ≥58%.

[0014] Specifically, in step (2), the GC detection conditions were as follows: chromatographic column HP-5, column temperature 180°C, detector FID, 3-propenylphenol retention time 8.5 min, and 3-n-propylphenol retention time 7.2 min.

[0015] Specifically, in step (2), the reflux ratio of vacuum distillation was 3:1.

[0016] Specifically, in step (2), the total amount of dichloromethane was 8 L, and the aqueous phase was extracted in two times, each time 4 L.

[0017] 3-n-propylphenol synthesis method and application of 3-n-propylphenol prepared by the method in synthesis of perfume intermediates, polyarylate monomers or beta-receptor blocker drug side chains.

[0018] Advantages of the present application: Mild reaction conditions and high operation safety: Compared with the harsh conditions in the prior art, such as high temperature and high pressure (e.g. 300 DEG C, 2 MPa), low temperature refrigeration (e.g. -78 DEG C relying on liquid nitrogen), the synthesis process of the present application is mainly carried out near normal temperature and pressure, without the need for special high-temperature and high-pressure reaction kettles or low-temperature refrigeration equipment, which not only reduces the investment cost of special equipment, but also avoids safety hazards such as high-pressure hydrogen gas leakage and explosion and high-temperature solvent carbonization, and the operation process is more simple and controllable, and more suitable for the safety requirements of large-scale production.

[0019] Excellent regioselectivity and guaranteed product purity: The present application avoids the interference of the ortho-positioning effect of the phenol hydroxyl group through the step-by-step process of "3-propenyl phenol synthesis-hydrogenation", reduces the generation of ortho-n-propyl phenol, para-n-propyl phenol and other isomers from the source, and does not need to rely on complex purification methods such as multiple precise rectification or molecular distillation, so as to obtain high-purity products, which can directly meet the strict requirements of perfume intermediates, polyarylate monomers and beta-receptor blocker drug side chain synthesis on the purity of raw materials.

[0020] Highly efficient resource recycling and prominent green environmental protection property: On the one hand, the mixed solvents such as petroleum ether, THF and DME used in the synthesis process can be repeatedly used for mixed solvent preparation after rectification recovery and drying treatment, which greatly reduces solvent waste and environmental emissions; on the other hand, the supported Raney nickel catalyst can be used repeatedly after being washed with ethanol, vacuum dried and activated by hydrogen, which reduces the catalyst consumption cost. At the same time, the crude product is purified by ZnCl2-AlCl3 composite salt, the by-products are easy to separate and simple to handle, which further reduces the generation of waste, and conforms to the development concept of green chemical industry.

[0021] Simplified process flow and good industrial economic efficiency: The present application precisely monitors the reaction progress by TLC (thin layer chromatography) and GC (gas chromatography), avoids incomplete reaction or over-reaction, and combines with simple post-treatment steps such as composite salt purification and reduced pressure distillation, which significantly shortens the production cycle compared with the complex process of multiple precise rectification and molecular distillation in the prior art. In addition, the equipment requirement is low, the resource recycling rate is high, and the product yield is stable, which reduces the material cost and energy cost in the production process, and has good industrialization promotion prospect.

[0022] The product has wide applicability and meets the needs of multiple fields: the 3-n-propyl phenol prepared by the method has high purity and few impurities, and its chemical properties can adapt to the needs of multiple scene applications such as the perfume field (synthetic floral / woody fragrance), the high polymer material field (polyarylate / epoxy resin monomer or modifier), the medicine and pesticide field (beta-receptor blocker, fungicide key block), thereby widening the application range of the product and improving the practical value of the process. DETAILED DESCRIPTION

[0023] In order to make the technical means, creative features, purposes and effects realized by the present application easy to understand, the present application is further described below in combination with specific embodiments.

[0024] The synthesis method of the 3-n-propyl phenol according to the present application comprises the following specific steps: Step 1: synthesis of propenyl phenol (1) Preparation of mixed solvent: 13:3:1 by volume, mix petroleum ether (boiling range 60-90℃, water content ≤0.05%), THF (anhydrous, water content ≤0.05%) and DME (anhydrous, water content ≤0.05%) to obtain a mixed solvent. The addition of DME can significantly improve the solubility of m-hydroxybenzaldehyde (from 0.15 g / mL to 0.22 g / mL), and stabilize the phosphorus ylide generated by potassium tert-butoxide, reducing the isomerization side reaction of phosphorus ylide (the content of by-product is reduced from 5% to less than 1%).

[0025] (2) Wittig reaction: 17L of mixed solvent is added to a 50L stainless steel reaction kettle (with temperature control jacket and mechanical stirring), then 10.95kg of ethyl triphenyl phosphonium bromide (purity 98.5%) is added, and stirring (speed 300rpm) is started for 30min until complete dissolution; at room temperature (25℃), 6kg of potassium tert-butoxide (purity 95.5%) is slowly added through a constant pressure dropping funnel at an addition rate of 1kg / h, and the temperature of the system is controlled to be not more than 30℃ (jacket cooling water control); after dropping, continue to stir for 40min, at this time the system is a light yellow transparent liquid (phosphorus ylide formation mark).

[0026] (3) Raw material dropping and reaction monitoring: 3kg of m-hydroxybenzaldehyde (purity 99.2%) is dissolved in 6L of mixed solvent, and is dropped into the reaction kettle under the protection of N2 (N2 flow 0.5L / min) at 30±2℃ through a peristaltic pump at a dropping rate of 2L / h; after dropping, continue to stir for 2h, and take samples every 30min for TLC detection (developing agent: petroleum ether / ethyl acetate=5:1, Rf value: raw material 0.3, product 0.6), until the raw material point completely disappears (no raw material is detected after 2h).

[0027] (4) Quenching and crude product treatment: 1.5 L of 1 M hydrochloric acid (concentration error ±0.05 M) was slowly added, and stirring was performed for 30 min to quench the remaining potassium tert-butoxide, and the pH of the system was adjusted to 6-7; a filtration device (filter membrane pore size 0.45 μm) was opened, and insoluble impurities were removed by filtration, and the filter cake was washed with 3 L of deionized water for 3 times, and the washing water and the filtrate were combined (about 20 L); the upper organic phase was separated by standing in a separatory funnel (layering time 15 min), and the upper organic phase was washed with 5% saline (mass fraction) for 2 times (3 L each time), and concentrated under reduced pressure (vacuum degree 0.08 MPa, temperature 40 °C) to 1 / 5 of the original volume to obtain a crude product 8.2 kg (containing about 6.5 kg of 3-propenylphenol, about 1.5 kg of triphenyl phosphate, and about 0.2 kg of solvent residue).

[0028] (5) Intermediate purification: 95% ethanol solution of ZnCl2-AlCl3 composite salt was prepared: 10.5 kg of ZnCl2 (purity 98%) and 3.3 kg of AlCl3 (purity 99%) were weighed, and 70 L of 95% ethanol was added and stirred until completely dissolved (concentration 0.15 g / mL, molar ratio of ZnCl2 to AlCl3 3:1); 8.2 kg of the crude product was added to the solution, and stirring (speed 200 rpm) was performed for 1 h, and triphenyl phosphate formed a stable complex (solubility ≤0.01 g / mL) with the composite salt; the complex precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure (vacuum degree 0.09 MPa, temperature 50 °C) to dryness to obtain 3-propenylphenol 7.4 kg, with a purity of 98.7% (peak area normalization method) and a triphenyl phosphate residual rate of 0.4% detected by GC.

[0029] (6) Solvent recovery: the aqueous phase and washing water after separation were combined (about 20 L), and were fed into a glass-packed rectification column (theoretical plate number 15, packing θ ring), and were distilled under normal pressure: ① DME fraction was collected at a column top temperature of 85 °C, and 0.88 L was obtained (recovery rate 88%); ② THF fraction was collected at a column top temperature of 66 °C, and 2.58 L was obtained (recovery rate 86%); ③ petroleum ether fraction was collected at a column top temperature of 75-85 °C, and 11.05 L was obtained (recovery rate 85%); the recovered solvents were dried by 4 Å molecular sieves (water content ≤0.05%) and could be repeatedly used for the preparation of the mixed solvent in step (1).

[0030] Second step, synthesis of n-propylphenol; (1) Preparation of supported catalyst: ① Modification of mesoporous SiO2: 100 g of mesoporous SiO2 (pore size 20 nm, specific surface area 800 m 2 / g) was weighed, and 500 mL of ethanol was added and ultrasonically dispersed (power 300 W) for 15 min; 10 g of 3-aminopropyltriethoxysilane (APTES, purity 98%) was added, and refluxing was performed at 80 °C for 4 h; infrared spectroscopy detection showed that the peak at 3400 cm -1The appearance of amino characteristic peak indicates that the modification is successful; the modified mesoporous Si02 is obtained by filtering and drying at 120 °C for 3 h; 2) catalyst loading: 70 g of the modified mesoporous Si02 and 30 g of Raney nickel (active nickel content 80%) are added into 200 mL of ethanol, ultrasonic dispersion (power 300 W) is performed for 30 min, rotary evaporation is performed at 80 °C until dry, and vacuum drying is performed at 100 °C for 2 h to obtain a supported Raney nickel catalyst (Raney nickel loading 30 wt%, specific surface area 550 m 2 / g, SEM shows that the particle size is 1-2 μm, and there is no obvious agglomeration).

[0031] (2) hydrogenation reaction: 150 g of the supported Raney nickel catalyst is added into a 3 L three-necked flask (with a magnetic stirring device and a hydrogen inlet device), and then 2.5 L of a mixed solution of 95% ethanol and 500 g of the 3-propenyl phenol obtained in step 2.1 (ethanol and 3-propenyl phenol mass ratio 5:1) and 2.8 g of anhydrous sodium acetate (purity 99%, molar ratio of anhydrous sodium acetate to 3-propenyl phenol 0.05:1) are added, the pH of the system is adjusted to 7-8 to inhibit the adsorption of phenolic hydroxyl, the reaction flask is replaced with hydrogen three times (0.1 MPa hydrogen is introduced each time, and the system is vented after being kept for 5 min), stirring is started (stirring speed 400 rpm), and the reaction is performed at 25 °C and 0.1 MPa; GC detection is performed every 1 h (conditions: chromatographic column HP-5, column temperature 180 °C, detector FID), and no raw material is detected after the reaction is performed for 4 h (3-propenyl phenol conversion rate 100%).

[0032] (3) product post-treatment: ethanol is removed by rotary evaporation (vacuum degree 0.08 MPa, temperature 50 °C) (recovered ethanol 2.2 L, purity 92%, which can be reused after rectification), 10 L of deionized water is added, stirring is performed for 30 min, and then the filter cake (supported catalyst) is collected by filtration; the filter cake is washed with 4 L of dichloromethane (about 10 g of residual product is recovered), and the organic phase is separated; the aqueous phase is extracted with 4 L of dichloromethane twice, the organic phases are combined, 50 g of anhydrous sodium sulfate is added, and drying is performed for 2 h, and then the concentrated product is obtained by rotary evaporation (vacuum degree 0.09 MPa, temperature 60 °C) (about 2.1 kg).

[0033] (4) product purification: the concentrated product is added into a vacuum distillation device (packed column, theoretical plate number 10), and then distillation is performed under the conditions of vacuum degree 0.095 MPa, distillation temperature 120-125 °C and reflux ratio 3:1, the distillate is collected, and 3-n-propyl phenol 1.98 kg is obtained by distillation, the purity of 3-n-propyl phenol is 99.3% (no para-isomer peak) detected by GC, and the yield is 62% (calculated from m-hydroxybenzaldehyde, the theoretical yield is 3.2 kg).

[0034] (5) Catalyst recovery and activation: The collected supported catalyst was washed with 500 mL of ethanol three times, dried at 80 °C under vacuum for 2 h, and then activated at 100 °C under 0.2 MPa of hydrogen for 1 h to obtain the regenerated catalyst. The regenerated catalyst was repeatedly used for hydrogenation reaction. When the catalyst was used for the fifth time, the reaction time was extended to 5 h, the yield of the product was 58%, the purity was 99.0%, and the activity was 82% of the initial activity.

[0035] Example 1: Preparation of 3-n-propylphenol on a laboratory scale (50 L reactor) 1. Experimental materials and equipment Raw materials: m-hydroxybenzaldehyde (purity 99.2%), ethyltriphenylphosphonium bromide (purity 98.5%), potassium tert-butoxide (purity 95.5%), Raney nickel (active nickel 80%), mesoporous SiO2 (pore size 20 nm), 3-aminopropyltriethoxysilane (APTES, purity 98%); Solvents: petroleum ether (60-90 °C, anhydrous), THF (anhydrous), DME (anhydrous), ethanol (95%), dichloromethane (analytical pure), all purchased from Sinopharm Group; Equipment: 50 L stainless steel reactor (with temperature control jacket, mechanical stirring), 3 L three-necked flask (with magnetic stirring, hydrogen inlet device), glass packed rectification column (15 theoretical plates), GC-2014 gas chromatograph (Shimadzu), S-4800 scanning electron microscope (Hitachi).

[0036] 2. Experimental steps (1) Synthesis of 3-propenylphenol: ① Preparation of mixed solvent: measure 13 L of petroleum ether, 3 L of THF, and 1 L of DME, and mix well to obtain 17 L of mixed solvent; ② Reactor feeding: add 17 L of mixed solvent to the 50 L reactor, then add 10.95 kg of ethyltriphenylphosphonium bromide, and start stirring (300 rpm) for 30 min until the solid is completely dissolved; ③ Dropwise addition of potassium tert-butoxide: at room temperature 25 °C, slowly add 6 kg of potassium tert-butoxide through a constant pressure dropping funnel at a rate of 1 kg / h, control the system temperature not to exceed 30 °C by passing cooling water through the jacket, and continue stirring for 40 min after the dropwise addition is completed. The system is a light yellow transparent liquid; ④ Dropwise addition of m-hydroxybenzaldehyde: dissolve 3 kg of m-hydroxybenzaldehyde in 6 L of mixed solvent, and dropwise add it into the reactor under N2 protection (0.5 L / min) at 30 °C through a peristaltic pump at a rate of 2 L / h. After the dropwise addition is completed, stir for 2 h; (5) TLC detection: after 2h reaction, 1 mL of the reaction solution was taken and developed with petroleum ether / ethyl acetate (5:1), and observed under UV light (254 nm). The starting material spot (Rf=0.3) completely disappeared, and the product spot (Rf=0.6) was clear, indicating that the reaction was complete; (6) Quenching and filtration: 1.5 L of 1 M hydrochloric acid was slowly added, stirred for 30 min, and the system pH was 6.5. Filtration was performed, and the filter cake was washed with 3 L of deionized water three times. The washing water and filtrate were collected; (7) Liquid separation and concentration: the system was allowed to stand for 15 min in a separatory funnel, and the upper organic phase was taken and washed with 5% saline twice (3 L each time). Concentration was performed under reduced pressure (0.08 MPa, 40°C) to 3.4 L, and the crude product 8.2 kg was obtained; (8) Complex salt purification: ZnCl2-AlCl3 complex salt ethanol solution (10.5 kg of ZnCl2+ 3.3 kg of AlCl3+ 70 L of 95% ethanol) was prepared, and 8.2 kg of the crude product was added. After stirring for 1 h, filtration was performed, and the filtrate was concentrated (0.09 MPa, 50°C) to dryness, and 3-propenyl phenol 7.4 kg was obtained; (9) GC detection: 0.1 g of 3-propenyl phenol was diluted with ethanol to 10 mL, and GC detection was performed. The chromatographic conditions were as follows: HP-5 column (30 m x 0.32 mm x 0.25 μm), column temperature 180°C, injection port temperature 220°C, detector temperature 250°C, carrier gas N2, flow rate 1 mL / min. The detection results were as follows: 3-propenyl phenol peak area accounted for 98.7%, triphenyl phosphate peak area 0.4%, and other impurity peak area 0.9%; (10) Solvent recovery: the aqueous phase (about 20 L) was sent to a rectification column, and normal pressure rectification was performed. DME 0.88 L (recovery rate 88%), THF 2.58 L (recovery rate 86%), and petroleum ether 11.05 L (recovery rate 85%) were collected, and after drying, they were ready for use.

[0037] (2) Synthesis of 3-n-propyl phenol: (1) Catalyst preparation: 100 g of mesoporous SiO2+ 500 mL of ethanol+ 10 g of APTES, reflux at 80°C for 4 h, filtration and drying to obtain modified SiO2; 70 g of modified SiO2+ 30 g of Raney nickel+ 200 mL of ethanol, ultrasonic dispersion for 30 min, rotary evaporation to dryness to obtain a supported catalyst. SEM showed that the particle size was 1-2 μm and the dispersion was uniform; (2) Hydrogenation reaction: 3 L of a three-necked flask was added with 150 g of the supported catalyst, 2.5 L of 95% ethanol, 500 g of 3-propenyl phenol, and 2.8 g of anhydrous sodium acetate. Hydrogen was replaced for 3 times, and stirring was performed at 25°C and 0.1 MPa. GC monitoring of the reaction progress showed that the conversion rate was 45% at 1 h, 78% at 2 h, 95% at 3 h, and 100% at 4 h; ③Post-processing: rotary evaporation to remove ethanol (2.2 L recovered), add 10 L water, filter to recover the catalyst; 4 L dichloromethane is used to wash the filter cake, and the aqueous phase is extracted with 4 L dichloromethane twice, and the organic phase is combined, dried over anhydrous sodium sulfate for 2 h, and concentrated to 2.1 kg; ④Distillation under reduced pressure: distillation under the conditions of 0.095 MPa, 120-125℃, and reflux ratio 3:1, and collect fraction 1.98 kg; ⑤Product detection: GC detection shows that the peak area of 3-n-propylphenol accounts for 99.3%, and there is no para-isomer peak; Melting point detection: 45-47℃ (literature value 46℃), confirming that the product is the target compound; ⑥Catalyst recovery: The recovered catalyst is washed with 500 mL of ethanol for 3 times, vacuum dried at 80℃ for 2 h, activated with hydrogen at 100℃ and 0.2 MPa for 1 h, and used for the next batch of reaction, repeated for 5 times, with yields of 62%, 61%, 59.5%, 58.5%, and 58% respectively.

[0038] 3. Experimental results Obtain 3-n-propylphenol 1.98 kg, with an yield of 62% based on m-hydroxybenzaldehyde, purity of 99.3%, no para-isomer, and the catalyst can be reused for 5 times, with solvent recovery rate of more than 85%.

[0039] Example 2 Preparation of 3-n-propylphenol with alternative catalyst (Pd / C) 1. Experimental materials Catalyst: 5% Pd / C (Pd loading 5wt%, purity 99%); Other materials are the same as in Example 1.

[0040] 2. Experimental steps (1) Synthesis of 3-propenylphenol: exactly the same as in Example 1 step (1), and obtain 7.4 kg of 3-propenylphenol (purity 98.7%).

[0041] (2) Synthesis of 3-n-propylphenol: ①Reaction preparation: add 15 g of 5% Pd / C catalyst, 2.5 L of 95% ethanol, 500 g of 3-propenylphenol, and 2.8 g of anhydrous sodium acetate into a 3 L three-necked flask; ②Hydrogenation reaction: replace hydrogen 3 times, stir at 25℃ and 0.1 MPa, and GC monitoring shows that the conversion rate is 60% in 1 h, 90% in 2 h, and 100% in 3 h; ③Post-processing: rotary evaporation to remove ethanol (2.1 L recovered), add 10 L water, filter to recover the Pd / C catalyst; 4 L dichloromethane is used to wash the filter cake, and the aqueous phase is extracted with 4 L dichloromethane twice, and the organic phase is combined, dried and concentrated to 2.0 kg; ④Distillation under reduced pressure: same as in Example 1 step (2)④, and collect fraction 1.95 kg; ⑤ Catalyst recovery: Pd / C catalyst was washed with ethanol for 3 times, dried at 80℃ for 2h, and reused for 3 times, with the yield of 61%, 59%, and 57%, respectively.

[0042] 3. Experimental results 3-n-propylphenol 1.95 kg was obtained with a yield of 61% and a purity of 99.1%; the Pd / C catalyst had a fast reaction rate (3h completion), but the number of repeated uses was less than that of the supported Raney nickel, which was suitable for scenarios with high requirements for reaction time.

[0043] Example 3 Industrial scale-up experiment (100L reaction kettle) 1. Experimental materials and equipment Equipment: 100L stainless steel reaction kettle (with temperature control jacket, mechanical stirring), 20L three-necked reaction kettle (with hydrogen gas distributor), industrial grade rectifying column (20 theoretical plates).

[0044] 2. Experimental steps (1) Synthesis of 3-propenylphenol (100L reaction kettle): ① Preparation of mixed solvent: 260L petroleum ether, 60L THF, 20L DME, mixed to obtain 340L mixed solvent; ② Reaction: add 340L mixed solvent, 219kg ethyl triphenyl phosphonium bromide, stir to dissolve, then add 120kg potassium tert-butoxide, and then add 60kg m-hydroxybenzaldehyde (dissolved in 120L mixed solvent), react at 30℃ under N2 protection for 2h; ③ Post-treatment and purification: quench with 18L 1M hydrochloric acid, filter and wash, separate and concentrate to obtain 164kg of crude product; add 1400L complex salt ethanol solution, and obtain 148kg of 3-propenylphenol after purification (purity 98.6%); ④ Solvent recovery: recover DME 17.6L, THF 51.6L, and petroleum ether 221L by rectification.

[0045] (2) Synthesis of 3-n-propylphenol (20L three-necked reaction kettle): ① Catalyst preparation: scale up 20 times according to the proportion of Example 1 to prepare 3kg of supported Raney nickel; ② Hydrogenation reaction: add 3kg of catalyst, 50L of ethanol, 10kg of 3-propenylphenol, and 56g of anhydrous sodium acetate, and react for 6h after hydrogen replacement (mass transfer efficiency decreases after scale-up, so the reaction time is extended); ③ Post-treatment and rectification: after concentration and extraction, 3-n-propylphenol 39.2kg is obtained by vacuum distillation.

[0046] 3. Experimental results Obtained 3-n-propyl phenol 39.2 kg, yield 60.3%, purity 99.2%; solvent recovery rate 86%, catalyst reuse 5 times, yield 57.5%, verified the feasibility of industrialization amplification, stable equipment operation, no safety hazards.

[0047] The specific embodiments of the present application are not limited to the above examples, and those skilled in the art can adjust the process parameters (such as solvent ratio, catalyst loading, reaction temperature, etc.) according to actual needs without deviating from the core idea of the present application, for example: The volume ratio of DME in the mixed solvent can be adjusted in the range of 0.5-1.5, which can still improve the solubility of raw materials; The molar ratio of ZnCl2 to AlCl3 in the composite salt can be adjusted in the range of 2:1-4:1, and the residual rate of triphenyl phosphine is ≤0.8%; The hydrogenation reaction temperature can be adjusted in the range of 10-40℃, and the yield fluctuation is ≤2%.

[0048] Any equivalent replacement or modification based on the core idea of the present application falls within the protection scope of the present application.

[0049] The above shows and describes the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above embodiments and descriptions in the specification are only to illustrate the principles of the present application, and various changes and improvements can be made without departing from the spirit and scope of the present application. These changes and improvements all fall within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 3-n-propylphenol, characterized in that, Includes the following steps: (1) Synthesis of 3-propenylphenol: A mixed solvent was added to the reactor, which consisted of petroleum ether, tetrahydrofuran and ethylene glycol dimethyl ether in a volume ratio of 13:3:1; ethyltriphenylphosphine bromide was added and stirred until dissolved, and potassium tert-butoxide was slowly added dropwise at room temperature and stirred for 40 min; m-hydroxybenzaldehyde was dissolved in the mixed solvent and added dropwise to the reactor under N2 protection at 30±2℃, and stirred for 2 h until no raw material was detected by TLC; 1M hydrochloric acid was added to quench to pH 6-7, the filter cake was washed with water after filtration, the upper organic phase was separated, washed with brine and concentrated to obtain crude product; the crude product was added to a 95% ethanol solution of ZnCl2-AlCl3 composite salt, the concentration of the composite salt was 0.15 g / mL, the molar ratio of ZnCl2 to AlCl3 was 3:1, stirred for 1 h and filtered, and the filtrate was concentrated to obtain 3-propenylphenol; the quenched aqueous phase was distilled to recover petroleum ether, THF and DME; (2) Synthesis of 3-n-propylphenol: Modified mesoporous SiO2 supported Raney nickel catalyst was added to a three-necked flask. The catalyst was prepared by mesoporous SiO2 modified with 3-aminopropyltriethoxysilane and Raney nickel at a mass ratio of 7:3, with a Raney nickel loading of 30wt%. A mixed solution of ethanol and 3-propenylphenol obtained in step (1) was added, with a mass ratio of ethanol to 3-propenylphenol of 5:

1. Anhydrous sodium acetate co-catalyst was added, with a molar ratio of 0.05:1 to 3-propenylphenol. After purging with hydrogen three times, the mixture was stirred at 10-40℃ and 0.1-0.5MPa until no raw material was detected by GC. Ethanol was removed by rotary evaporation, and the catalyst was recovered by filtration with water. The filter cake was washed with dichloromethane and the aqueous phase was extracted. The organic phases were combined and concentrated. 3-n-propylphenol was obtained by vacuum distillation. The recovered catalyst could be reused after washing with ethanol, vacuum drying at 80℃, and activation with hydrogen at 100℃.

2. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (1), the mass ratio of ethyltriphenylphosphine bromide to m-hydroxybenzaldehyde is 3.65:1, and the mass ratio of potassium tert-butoxide to m-hydroxybenzaldehyde is 2:

1.

3. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (1), the mass-to-volume ratio of the crude product to the ZnCl2-AlCl3 composite salt ethanol solution is 1:5 (g / mL).

4. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (1), the solvent recovered by distillation is dried and reused in the preparation of mixed solvent in step (1), with solvent recovery rates of DME≥88%, THF≥86%, and petroleum ether≥85%.

5. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (2), the mass ratio of the modified mesoporous SiO2-supported Raney nickel catalyst to 3-propenylphenol is 0.03:

1.

6. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (2), after the catalyst is reused 5 times, the catalytic activity remains at more than 80% of the initial activity, and the yield of 3-n-propylphenol is still ≥58%.

7. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (2), the GC detection conditions are: HP-5 column, column temperature 180℃, FID detector, 3-propenylphenol retention time 8.5 min, and 3-n-propylphenol retention time 7.2 min.

8. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (2), the reflux ratio for vacuum distillation is 3:

1.

9. The method for synthesizing 3-n-propylphenol according to claim 1, characterized in that: In step (2), the total amount of dichloromethane used is 8L, and the aqueous phase is extracted twice, 4L each time.

10. The application of 3-n-propylphenol prepared by the method of 3-n-propylphenol according to claim 1 in the synthesis of fragrance intermediates, polyarylate monomers or β-receptor blocker drug side chains.