Preparation method of 2-methyl-4-acetylbenzoic acid

Abstract

The invention discloses a preparation method of 2-methyl-4-acetylbenzoic acid, and relates to the technical field of production of 2-methyl-4-acetylbenzoic acid. 1-(4-fluoro-3-methylphenyl) ethanone is obtained from o-fluorotoluene and acetyl chloride under the catalytic action of AlCl and sulfonic acid functionalized mesoporous silica; the preparation method comprises the following steps: preparing 4-acetylbenzonitrile from 4-methylbenzonitrile under the action of a supported metal catalyst, then obtaining 4-acetyl-2-methylbenzonitrile under the action of 15-crown ether-5, PEG-400 and acetone cyanohydrin matched with CuI, and finally obtaining 2-methyl-4-acetylbenzoic acid under the action of oxygen and the supported metal catalyst. And the product has high yield and purity and is environment-friendly.

Description

Technical Field

[0001] The present invention relates to the technical field of the production of 2-methyl-4-acetylbenzoic acid, and specifically relates to a preparation method of 2-methyl-4-acetylbenzoic acid. Background Art

[0002] 2-Methyl-4-acetylbenzoic acid is the core intermediate of fluralaner. As a γ-aminobutyric acid-gated chloride channel disruptor, fluralaner has high insecticidal activity against pests such as ticks, fleas, and lice, and has no significant cross-resistance with existing insecticides. It is widely used in the veterinary and agricultural fields. Its derivatives have also been found to have potential for antioxidant and anti-tumor effects, further expanding the application scenarios. The industrialization routes of 2-methyl-4-acetylbenzoic acid include the oxidation method (oxidation of 3,4-dimethylacetophenone), the Friedel-Crafts acylation-carbonylation method (o-bromotoluene route), the diazotization-Sandmeyer method (4-amino-3-methylbenzoic acid route), and the cyanide hydrolysis route (o-fluorotoluene route). Among them, in the cyanide hydrolysis route (o-fluorotoluene route), the three-step reactions of o-fluorotoluene through Friedel-Crafts acylation, substitution of fluorine with sodium cyanide, and hydrolysis to generate the target product are all controllable reactions. The technical route is clear and well supported by the literature, meeting the requirements of large-scale production and being widely used. However, there are still problems such as a large amount of three wastes, low yield, and low purity. Summary of the Invention

[0003] The technical problem to be solved by the present invention is: aiming at the deficiencies existing in the prior art, to provide a preparation method of 2-methyl-4-acetylbenzoic acid with high product yield and purity and being environmentally friendly.

[0004] To solve the above technical problem, the technical solution of the present invention is: A preparation method of 2-methyl-4-acetylbenzoic acid, comprising the following steps: A: Add a mixed solvent of 1,2-dichloroethane and cyclopentyl methyl ether to a reaction kettle. After cooling to -5 - 0 °C, add AlCl3 and sulfonic acid-functionalized mesoporous silica to the system, and then dropwise add a mixed solution of o-fluorotoluene and acetyl chloride. React at 30 - 40 °C for 1 - 1.5 h. After quenching the reaction solution, wash it with water, remove the solvent, and distill the crude product under reduced pressure to obtain 1-(4-fluoro-3-methylphenyl)ethanone; B: Add 1-(4-fluoro-3-methylphenyl)ethanone to a reactor, and then add a mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide, as well as 15-crown-5 and PEG-400 as a mixed phase transfer catalyst, and acetone cyanohydrin complexed with CuI as a catalyst. React at 110 - 150 °C for 3 - 5 h. Cool the reaction solution to room temperature, add ethanol, stir evenly, then continue to dropwise add deionized water, stir for 0.5 - 1 h, continue to cool to 0 - 5 °C, and filter to obtain 4-acetyl-2-methylbenzonitrile; C: 4-Acetyl-2-methylbenzonitrile is added to purified water, and the temperature is raised to 75 - 80 °C. Then, oxygen is introduced, and under the action of a supported metal catalyst, the temperature is raised to 80 - 85 °C for reaction for 4 - 5 h. Then, the temperature is lowered to 10 - 15 °C for suction filtration to obtain 2-methyl-4-acetylbenzoic acid.

[0005] Preferably, in step A, the mass ratio of o-fluorotoluene to the volume of the mixed solvent of 1,2-dichloroethane and cyclopentyl methyl ether is 1 g : 5 - 6 ml, and the volume ratio of dichloroethane to cyclopentyl methyl ether is 1.5 - 2 : 1.

[0006] Preferably, in step A, the addition amount of AlCl3 accounts for 1 - 2% w / w of the mass of o-fluorotoluene, and the addition amount of sulfonic acid-functionalized mesoporous silica accounts for 10% w / w of the mass of o-fluorotoluene; The molar ratio of o-fluorotoluene to acetyl chloride is 1 : 1.1 - 1.2; The reaction solution is quenched to pH 7 - 8 with saturated sodium bicarbonate solution, and then washed 2 - 3 times with saturated sodium chloride solution. During the vacuum distillation of the crude product, the top temperature is controlled at 80 - 85 °C.

[0007] The preparation method of sulfonic acid-functionalized mesoporous silica is as follows: Cetyltrimethylammonium bromide is dissolved in deionized water at 60 °C, stirred until clear, and 25wt% ammonia water is added dropwise to adjust the pH to 10.0 - 11.0 to obtain a dissolution solution; At room temperature, tetraethyl orthosilicate is added dropwise to the dissolution solution, and the stirring rate is maintained at 250 - 400 rpm for reaction for 1 - 3 h to form a transparent sol; The sol is crystallized at a constant temperature of 110 - 115 °C for 24 - 30 h, cooled and then filtered, washed with deionized water until neutral, and dried at 60 °C for 10 - 12 h; The above-mentioned dried filter cake is added to a mixed solution of ethanol and hydrochloric acid, refluxed at 80 °C for 24 h, filtered, washed with water until neutral, filtered and dried to obtain mesoporous silica; Mesoporous silica, 3-chloropropyltrimethoxysilane, toluene, and FeCl3 are added to a reactor, refluxed at 110 °C for 24 h under nitrogen protection. After the reaction is completed, it is filtered, washed 3 times each with toluene and ethanol, and vacuum dried at 60 °C for 12 h to obtain an intermediate; The intermediate is added to concentrated sulfuric acid in an ice bath, stirred and reacted for 8 h. During the reaction, the temperature is controlled ≤ 30 °C. The reaction solution is poured into ice water for quenching, filtered, washed with deionized water until the filtrate pH = 7, and vacuum dried at 80 °C for 24 h to obtain sulfonic acid-functionalized mesoporous silica.

[0008] Among them, the molar ratio of cetyltrimethylammonium bromide, tetraethyl orthosilicate, and deionized water is 1 : 2 - 4 : 500 - 800; The mass ratio of mesoporous silica, 3-chloropropyltrimethoxysilane, toluene and FeCl3 is 1: 1.5 - 2: 20 - 30: 0.05 - 0.1; The addition ratio of the intermediate (chloropropyl-SiO2) to 98% concentrated sulfuric acid is 1 g: 5 - 10 mL.

[0009] Preferably, in step B, the mass of 1-(4-fluoro-3-methylphenyl)ethanone to the volume ratio of the mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide is 1 g: 2.5 - 3 ml, and the volume ratio of dimethyl sulfoxide to N,N-dimethylformamide is 1.5 - 2: 1; The molar ratio of 15-crown-5 to 1-(4-fluoro-3-methylphenyl)ethanone is 0.02 - 0.03: 1; The mass ratio of PEG-400 to 1-(4-fluoro-3-methylphenyl)ethanone is 1: 10 - 20; The molar ratio of 1-(4-fluoro-3-methylphenyl)ethanone to acetone cyanohydrin and CuI is 1: 0.3 - 0.4: 0.01 - 0.05.

[0010] Preferably, in step B, the material is first heated to 110 - 120 °C at a rate of 2 - 3 °C / min, reacted at this temperature for 1 - 2 h, and then heated to 130 - 150 °C at a rate of 3 - 4 °C / min and reacted for 2 - 3 h.

[0011] Preferably, 4-acetyl-2-methylbenzonitrile in step B is dissolved in an ethanol-water mixed solvent and refluxed at 75 - 80 °C, then hot filtered at 60 - 65 °C, and the filtrate is cooled to 0 - 5 °C at a rate of 2 - 3 °C / min and maintained for 1.5 - 2 h, and the crystals are collected to obtain purified 4-acetyl-2-methylbenzonitrile, where the amount of the ethanol-water mixed solvent used is 5 - 10 times the mass of 4-acetyl-2-methylbenzonitrile, and the volume ratio of ethanol to water is 7 - 8: 2.

[0012] Preferably, the addition amount of ethanol in step B is 1 - 2 times the volume of the reaction solution, the addition amount of deionized water is 0.5 - 1 times the volume of ethanol, the stirring speed during the reaction is 200 - 400 rpm, the reaction solution is cooled to room temperature at a speed of 200 - 300 rpm, and finally cooled to 0 - 5 °C at a speed of 150 - 250 rpm.

[0013] Preferably, in step C, the mass of 4-acetyl-2-methylbenzonitrile to the volume ratio of purified water is 1: 5 - 6 g / ml, and the oxygen flow rate is 50 - 100 mL / min.

[0014] Preferably, the added mass of the supported metal catalyst in step C accounts for 5-10 w / w of the mass of 4-acetyl-2-methylbenzonitrile. The supported metal catalyst is a palladium catalyst supported on activated carbon, and the mass ratio of palladium to activated carbon is 1-5:100.

[0015] The preparation method of the palladium catalyst supported on activated carbon is as follows: Add activated carbon into 10wt% HNO3 solution, stir at 80°C for 2h, filter, wash with water until neutral, and vacuum dry at 110°C for 12h to obtain pretreated activated carbon; Dissolve PdCl2 in 37wt% concentrated hydrochloric acid, then add deionized water, assist dissolution with ultrasound, and then adjust the pH to 2-3 with 10-15wt% sodium hydroxide solution to obtain H2PdCl4 solution; Add the pretreated activated carbon into the H2PdCl4 solution, stir at room temperature and 150-200 rpm for 2-4h to ensure that Pd 2+ is evenly adsorbed; Cool the impregnated activated carbon slurry to 0-5°C, slowly add a NaBH4 solution with a concentration of 0.5% - 2% g / ml, stir for 30min, filter with suction, and wash with deionized water until there is no Cl - , and vacuum dry at 60°C for 12h to obtain the palladium catalyst supported on activated carbon.

[0016] Among them, the specific surface area of the activated carbon is ≥800m² / g, the particle size is 100-200 mesh, and the Pd loading amount in the palladium catalyst supported on activated carbon is 1-5% w / w.

[0017] Preferably, the 2-methyl-4-acetylbenzoic acid in step C is used to remove pigment impurities by the combined technology of activated carbon adsorption - ethanol hot dissolution, and then recrystallized with ethyl acetate - n-heptane to obtain purified 2-methyl-4-acetylbenzoic acid, wherein the added amount of activated carbon accounts for 5-10% w / w of the mass of 2-methyl-4-acetylbenzoic acid; The addition ratio of 4-acetyl-2-methylbenzonitrile to ethyl acetate - n-heptane is 1 g:1.5-2 ml, and the volume ratio of ethyl acetate to n-heptane is 1:2-3.

[0018] Due to the adoption of the above technical solutions, the beneficial effects of the present invention are as follows: 1. Co-dropping of o-fluorotoluene and acetyl chloride can prevent the excessive aggregation of acetyl chloride, reduce the occurrence of side reactions, and improve the purity of the product.

[0019] 2. AlCl3 can activate acetyl chloride to form acyl cations (RCO +),(sulfonic acid-functionalized mesoporous silica provides Brønsted acidic sites to stabilize reaction intermediates. Meanwhile, its mesoporous structure enhances mass transfer efficiency and shortens the reaction time. Under the synergistic catalysis of AlCl3 and sulfonic acid-functionalized mesoporous silica, regioselective acetylation is promoted, facilitating the formation of the target 4-position acetylated product. The feeding environment at -5-0 °C greatly avoids the inactivation of AlCl3 or the decomposition of the product, improving the catalytic efficiency.

[0020] 3. Dimethyl sulfoxide (DMSO) has a relatively strong polarity, which is conducive to the homogeneous progress of the reaction. N,N-Dimethylformamide (DMF) assists in dissolving the intermediate to prevent precipitation. At the same time, the high boiling points of the two solvents allow high-temperature reactions (110-150 °C), promoting the nucleophilic substitution of fluoride by cyanide (-CN).

[0021] 4. The hydrophobic outer shell of 15-crown-5 can transfer CN⁻ from the aqueous phase (or polar solvent phase) to the organic phase (DMSO / DMF mixed solvent), promoting its contact with the substrate (fluoroarene) and avoiding the solvation and encapsulation of CN⁻ by cations, increasing the reaction activity by 3-5 times; the long-chain ether structure of PEG-400 can wind around the liquid-liquid or solid-liquid interface, making it easier for CN⁻ to transfer from the polar phase to the reaction phase. At the same time, the ether oxygen atoms form weak hydrogen bonds with CN⁻ to temporarily stabilize the active intermediate. The two work together to construct a biphasic transfer channel, covering a wider mass transfer path and reducing the diffusion resistance of CN⁻. 15-crown-5 dominates the activation at low temperatures, and PEG-400 maintains stability at high temperatures to meet the requirements of gradient temperature increase. The combination of the rigid ring of 15-crown-5 and the flexible chain of PEG-400 prevents the catalyst from agglomerating and deactivating at high temperatures, greatly improving the conversion efficiency. The precise cation complexation of 15-crown-5 reduces the additional electrophilic attack of free metal ions on the aromatic ring (such as over-cyanation), and the interfacial isolation effect of PEG-400 reduces the local concentration of CN⁻, avoiding the formation of polysubstitution by-products. The synergistic effect enables CN⁻ to preferentially attack the 4-position substituted by fluorine (rather than the ortho-position of the methyl group), and the selectivity of the target product (4-acetyl-2-methylbenzonitrile) is >90%.

[0022] 5. CuI preferentially coordinates with the fluorine atom of the substrate (4-fluoro-3-methylacetophenone) to form an aryl-Cu complex, enhancing the polarity of the C-F bond. CuI reduces the energy barrier of nucleophilic aromatic substitution by 40 - 50%. The CN⁻ released by acetone cyanohydrin is captured by Cu⁺ to generate the active species Cu(CN)₂⁻, which has less steric hindrance and is more likely to attack the aromatic ring, avoiding side reactions of free CN⁻ (such as dimerization to form (CN)₂) and improving the purity of the product. At the same time, the aryl-Cu-CN intermediate generates the target nitrile through reductive elimination, and regenerates the CuI catalyst. The recycling of CuI reduces the catalyst dosage to as low as 0.01 - 0.05 equivalents. The coordination of CuI guides the precise attack of CN⁻ on the fluorine-substituted 4-position, and the by-products (such as 3-position cyanated products) are <5%.

[0023] 6. Pd nanoparticles adsorb O₂ and dissociate it into atomic oxygen. At the same time, water molecules dissociate on the Pd surface to provide protons (H⁺), forming the active intermediate Pd-OOH (peroxo-hydroxy). Pd / C reduces the activation energy of O₂ by 60 - 70%. The d electron orbit of Pd interacts with the nitrile π * orbital to directionally activate the C≡N bond. Pd-OOH attacks the carbon atom of the nitrile group (-CN) to generate an amide intermediate (-CONH₂), further oxidatively cleaves the C-N bond, and finally generates a carboxylic acid (-COOH). In addition, the hydrophobicity of the Pd / C surface inhibits over-oxidation (such as acetyl group removal), preferentially retains the target functional group, and improves the purity of the product. The mesoporous structure of activated carbon promotes the diffusion of O₂ and the substrate, greatly shortening the reaction time.

[0024] 7. In the synthesis of 4-acetyl-2-methylbenzonitrile, a staged gradient temperature control method is adopted. The low temperature section of 110 - 120 °C ensures that CN⁻ preferentially attacks the C-F bond with higher activity on the aromatic ring (rather than the acetyl or methyl sites), avoiding the generation of multi-substituted by-products. At this time, the HCN release rate of acetone cyanohydrin is moderate, preventing side reactions of dicyanation or polymerization caused by excessive local CN⁻ concentration. The high temperature section of 130 - 150 °C increases the temperature to accelerate the electronic reorganization of the aromatic ring, ensuring that the cyano group is finally located at the 4-position, and the product selectivity is >90%. In addition, the high temperature can decompose the possible imine intermediate (such as Ar-C=N-OH), promoting the reaction to convert to the target product. The low temperature section of 1 - 2 h ensures that fluorine is completely substituted (conversion rate >95%). The high temperature section of 2 - 3 h shortens the subsequent aromatic ring rearrangement time, and the total reaction time is shortened by 1 h compared with the constant temperature method. And 15-crown-5 plays a major role in the low temperature section, and PEG-400 maintains interfacial mass transfer in the high temperature section. The active windows of the two are complementary, and the crystal size of the generated product is more uniform, and the yield of subsequent ethanol-water recrystallization is improved. Description of the Drawings

[0025] Figure 1It is the liquid chromatography diagram of purifying 2-methyl-4-acetylbenzoic acid in Example 1 of the present invention; Figure 2 It is the liquid chromatography diagram of purifying 2-methyl-4-acetylbenzoic acid in Example 2 of the present invention. Specific embodiments

[0026] The present invention will be further described below in conjunction with embodiments. Example 1

[0027] A preparation method of 2-methyl-4-acetylbenzoic acid includes the following steps: A: Add 300 ml of 1,2-dichloroethane and 200 ml of cyclopentyl methyl ether into the reaction kettle. After cooling to -5°C, add 1 g of AlCl3 and 10 g of sulfonic acid-functionalized mesoporous silica into the system respectively, and then dropwise add a mixed solution of 100 g of o-fluorotoluene and 76.9 g of acetyl chloride. React at 30°C for 1 h. Quench the reaction solution to pH 7 with saturated sodium bicarbonate solution, and then wash it twice with saturated sodium chloride solution. Control the top temperature at 80°C during the vacuum distillation of the crude product to obtain 1-(4-fluoro-3-methylphenyl)ethanone 131.2 g, with a yield of 95%; B: Add 1-(4-fluoro-3-methylphenyl)ethanone into the reactor, and then add a mixed solvent of 197 ml of dimethyl sulfoxide and 131 ml of N,N-dimethylformamide, 5.81 g of 15-crown-5 and 13.1 g of PEG-400 as a mixed phase transfer catalyst, 21.8 g of acetone cyanohydrin and 1.63 g of CuI as a catalyst. The stirring speed during the reaction is 200 rpm. The material is first heated to 110°C at a rate of 2°C / min and reacted at this temperature for 1 h, and then heated to 130°C at a rate of 3°C / min and reacted for 2 h. The reaction solution is cooled to room temperature at a speed of 200 rpm, add 240 ml of ethanol, which is 1 time the volume of the reaction solution, stir evenly, and then continue to drop 120 ml of deionized water, which is 0.5 times the volume of ethanol, stir for 0.5 h, and filter to obtain 4-acetyl-2-methylbenzonitrile. 4-acetyl-2-methylbenzonitrile is dissolved in 633 g of ethanol-water mixed solvent (560 ml of ethanol, 240 ml of water), refluxed at 75°C, then hot filtered at 60°C. The filtrate is cooled to 0°C at a rate of 2°C / min and 150 rpm and maintained for 1.5 h. Collect the crystals to obtain purified 4-acetyl-2-methylbenzonitrile, 126.6 g, with a yield of 92.3%; C: Add 633 ml of purified water to the purified 4-acetyl-2-methylbenzonitrile, heat up to 75 °C, then introduce oxygen at a flow rate of 50 mL / min, and under the action of 6.33 g of supported metal catalyst (0.0633 g of palladium), heat up to 80 °C and react for 4 h, then cool down to 10 °C and filter by suction to obtain 2-methyl-4-acetylbenzoic acid. 2-Methyl-4-acetylbenzoic acid removes pigment impurities through the combined technology of activated carbon adsorption - ethanol hot dissolution, and then is recrystallized with 760 ml of ethyl acetate - n-heptane (190 ml of ethyl acetate, 570 ml of n-heptane) to obtain purified 2-methyl-4-acetylbenzoic acid, 134.2 g, with a yield of 94.7% and a purity of 99.485%. Example 2

[0028] A preparation method of 2-methyl-4-acetylbenzoic acid, comprising the following steps: A: Add 350 ml of 1,2-dichloroethane and 200 ml of cyclopentyl methyl ether mixed solvent to the reaction kettle, cool down to -2.5 °C, then add 1.5 g of AlCl3 and 10 g of sulfonic acid-functionalized mesoporous silica to the system, and then dropwise add a mixed solution of 100 g of o-fluorotoluene and 82 g of acetyl chloride, react at 35 °C for 1.25 h, quench the reaction solution to pH 8 with saturated sodium bicarbonate solution, and then wash with saturated sodium chloride solution 3 times. Control the top temperature of the crude product during vacuum distillation at 82.5 °C to obtain 1-(4-fluoro-3-methylphenyl)ethanone, 130.9 g, with a yield of 94.8%; B: Add 1-(4-fluoro-3-methylphenyl)ethanone to the reactor, and then add a mixed solvent of 235.6 ml of dimethyl sulfoxide and 130.9 ml of N,N-dimethylformamide, as well as 7.27 g of 15-crown-5 and 8.73 g of PEG-400 as a mixed phase transfer catalyst, 25.3 g of acetone cyanohydrin and 4.91 g of CuI as a catalyst. The stirring speed during the reaction is 300 rpm. The material is first heated to 115 °C at a rate of 2.5 °C / min, react at this temperature for 1.5 h, and then heated to 140 °C at a rate of 3.5 °C / min and react for 2.5 h. The reaction solution is cooled to room temperature at a speed of 250 rpm, add 360 ml of ethanol, stir evenly and then continue to drop 270 ml of deionized water, stir for 0.75 h, filter by suction to obtain 4-acetyl-2-methylbenzonitrile. 4-Acetyl-2-methylbenzonitrile is dissolved with 956 g of ethanol - water mixed solvent (906 ml of ethanol, 240 ml of water) and refluxed at 78 °C, then hot filtered at 62 °C. The filtrate is cooled to 3 °C at a rate of 2.5 °C / min and 200 rpm and maintained for 1.8 h. Collect the crystals to obtain purified 4-acetyl-2-methylbenzonitrile, 127.5 g, with a yield of 93.1%; C: 701 ml of purified water was added to 4-acetyl-2-methylbenzonitrile, and the temperature was raised to 78 °C. Then, oxygen with a flow rate of 75 mL / min was introduced. Under the action of 9.56 g of supported metal catalyst (0.287 g of palladium), the temperature was raised to 83 °C and the reaction was carried out for 4.5 h. Then, the temperature was lowered to 12 °C and suction filtration was performed to obtain 2-methyl-4-acetylbenzoic acid. 2-Methyl-4-acetylbenzoic acid was decolorized and removed of impurity pigments by the combined technology of activated carbon adsorption - ethanol hot dissolution. Then, it was recrystallized with 781 ml of ethyl acetate - n-heptane (223 ml of ethyl acetate, 558 ml of n-heptane) to obtain 135.8 g of purified 2-methyl-4-acetylbenzoic acid, with a yield of 95.2% and a purity of 99.581%. Example 3

[0029] A preparation method of 2-methyl-4-acetylbenzoic acid, comprising the following steps: A: 400 ml of 1,2-dichloroethane and 200 ml of cyclopentyl methyl ether were added to a reaction kettle as a mixed solvent. After cooling to 0 °C, 2 g of AlCl3 and 10 g of sulfonic acid-functionalized mesoporous silica were added to the system respectively. Then, a mixed solution of 100 g of o-fluorotoluene and 85.6 g of acetyl chloride was added dropwise. The reaction was carried out at 40 °C for 1.5 h. The reaction solution was quenched to pH 8 with saturated sodium bicarbonate solution, and then washed 3 times with saturated sodium chloride solution. During the vacuum distillation of the crude product, the top temperature of the column was controlled at 85 °C to obtain 130.8 g of 1-(4-fluoro-3-methylphenyl)ethanone, with a yield of 94.7%; B: 1-(4-fluoro-3-methylphenyl)ethanone was added to a reactor, and then a mixed solvent of 261.6 ml of dimethyl sulfoxide and 130.8 ml of N,N-dimethylformamide, 8.73 g of 15-crown-5 and 6.54 g of PEG-400 were added as a mixed phase transfer catalyst. 28.9 g of acetone cyanohydrin and 8.19 g of CuI were used as catalysts. The stirring speed during the reaction was 400 rpm. The material was first heated to 120 °C at a rate of 3 °C / min and reacted at this temperature for 2 h. Then, it was heated to 150 °C at a rate of 4 °C / min and reacted for 3 h. The reaction solution was cooled to room temperature at a speed of 300 rpm, 480 ml of ethanol was added, and after stirring evenly, 480 ml of deionized water was continuously added dropwise. After stirring for 1 h, suction filtration was performed to obtain 4-acetyl-2-methylbenzonitrile. 4-Acetyl-2-methylbenzonitrile was dissolved in 1266 g of ethanol - water mixed solvent (1282 ml of ethanol, 253 ml of water) and refluxed at 80 °C, then hot filtered at 65 °C. The filtrate was cooled to 5 °C at a rate of 3 °C / min and 250 rpm and maintained for 2 h. The crystals were collected to obtain 126.6 g of purified 4-acetyl-2-methylbenzonitrile, with a yield of 92.5%; C: 760 ml of purified water was added to 4-acetyl-2-methylbenzonitrile, and the temperature was raised to 80 °C. Then, oxygen with a flow rate of 100 mL / min was introduced. Under the action of 12.66 g of supported metal catalyst (0.633 g of palladium), the temperature was raised to 85 °C and reacted for 5 h. Then, the temperature was lowered to 15 °C and filtered by suction to obtain 2-methyl-4-acetylbenzoic acid. 2-Methyl-4-acetylbenzoic acid was decolorized and purified by activated carbon adsorption-ethanol hot dissolution combined technology, and then recrystallized with 1012 ml of ethyl acetate-n-heptane (253 ml of ethyl acetate, 759 ml of n-heptane) to obtain 135.7 g of purified 2-methyl-4-acetylbenzoic acid, with a yield of 95.8% and a purity of 99.520%. Example 4

[0030] The preparation method of the sulfonic acid-functionalized mesoporous silica in Examples 1-3 is as follows: 36.4 g of cetyltrimethylammonium bromide was dissolved in 900 g of deionized water at 60 °C, stirred until clear, and 25 wt% ammonia water was added dropwise to adjust the pH to 10.0 to obtain a solution; 41.6 g of tetraethyl orthosilicate was added dropwise to the solution at room temperature, and the stirring rate was maintained at 250 rpm. The reaction was carried out for 1 h to form a transparent sol; The sol was crystallized at a constant temperature of 110 °C for 24 h, cooled and filtered, washed with deionized water until neutral, and dried at 60 °C for 10 h; The above dried filter cake was added to a mixed solution of ethanol and hydrochloric acid (volume ratio 1:1), refluxed at 80 °C for 24 h, filtered, washed with water until neutral, filtered and dried to obtain 30 g of mesoporous silica; 30 g of mesoporous silica, 45 g of 3-chloropropyltrimethoxysilane, 600 ml of toluene, and 1.5 g of FeCl3 were added to a reactor, and refluxed at 110 °C for 24 h under nitrogen protection. After the reaction, it was filtered, washed 3 times with toluene and ethanol respectively, and vacuum dried at 60 °C for 12 h to obtain 38 g of intermediate; The intermediate was added to 300 ml of 98% concentrated sulfuric acid in an ice bath, stirred and reacted for 8 h. During the reaction, the temperature was controlled ≤30 °C. The reaction solution was poured into ice water for quenching, filtered, washed with deionized water until the filtrate pH = 7, and vacuum dried at 80 °C for 24 h to obtain 42 g of sulfonic acid-functionalized mesoporous silica.

[0031] The preparation method of the palladium catalyst supported on activated carbon in Examples 1-3 is as follows: (1) Pretreatment of activated carbon 10 g of activated carbon was added to 100 ml of 10 wt% HNO3 solution, stirred at 80 °C for 2 h, filtered, washed with water until neutral, and vacuum dried at 110 °C for 12 h to obtain pretreated activated carbon.

[0032] (2) Preparation of Palladium Precursor Solution Dissolve 0.85 g of PdCl2 in 2 ml of concentrated hydrochloric acid with a concentration of 37 wt%. Then add 50 ml of deionized water and assist dissolution with ultrasound for 30 min. Then adjust the pH to 2 - 3 with 10 - 15 wt% sodium hydroxide solution to obtain H2PdCl4 solution.

[0033] (3) Equal - volume Impregnation Method Add the pretreated activated carbon into the H2PdCl4 solution, stir at room temperature for 4 h, and the stirring speed is 200 rpm.

[0034] (4) Reduction Process Cool the impregnated activated carbon slurry to 0 - 5 °C, slowly add NaBH4 solution (0.2 g of NaBH4 dissolved in 10 ml of deionized water), and stir for 30 min.

[0035] (5) Post - treatment Filter with a Buchner funnel and wash with deionized water until there is no Cl - , and dry in vacuum at 60 °C for 12 h to obtain 10.5 g of palladium catalyst supported on activated carbon.

[0036] It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A preparation method of 2-methyl-4-acetylbenzoic acid, characterized in that It includes the following steps: A: Add a mixed solvent of 1,2-dichloroethane and cyclopentyl methyl ether into the reaction kettle. After cooling to -5 - 0 °C, add AlCl3 and sulfonic acid-functionalized mesoporous silica into the system respectively, and then dropwise add a mixed solution of o-fluorotoluene and acetyl chloride. React at 30 - 40 °C for 1 - 1.5 h. After quenching the reaction solution, wash it with water, remove the solvent, and distill the crude product under reduced pressure to obtain 1-(4-fluoro-3-methylphenyl)ethanone; B: Add 1-(4-fluoro-3-methylphenyl)ethanone into the reactor, and then add a mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide and 15-crown-5 and PEG-400 as a mixed phase transfer catalyst, acetone cyanohydrin coordinated with CuI as a catalyst. React at 110 - 150 °C for 3 - 5 h. Cool the reaction solution to room temperature, add ethanol, stir evenly, then continue to dropwise add deionized water, stir for 0.5 - 1 h, continue to cool to 0 - 5 °C, and filter to obtain 4-acetyl-2-methylbenzonitrile; C: Add purified water to 4-acetyl-2-methylbenzonitrile, heat up to 75 - 80 °C, then introduce oxygen, and react at 80 - 85 °C for 4 - 5 h under the action of a supported metal catalyst. Then cool to 10 - 15 °C and filter to obtain 2-methyl-4-acetylbenzoic acid.

2. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: In step A, the mass ratio of o-fluorotoluene to the volume of the mixed solvent of 1,2-dichloroethane and cyclopentyl methyl ether is 1 g : 5 - 6 ml, and the volume ratio of dichloroethane to cyclopentyl methyl ether is 1.5 - 2 :

1.

3. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: In step A, the addition amount of AlCl3 accounts for 1 - 2% w / w of the mass of o-fluorotoluene, and the addition amount of sulfonic acid-functionalized mesoporous silica accounts for 10% w / w of the mass of o-fluorotoluene; The molar ratio of o-fluorotoluene to acetyl chloride is 1 : 1.1 - 1.2; Quench the reaction solution with saturated sodium bicarbonate solution to pH 7 - 8, then wash it with saturated sodium chloride solution 2 - 3 times. Control the top temperature at 80 - 85 °C during the reduced pressure distillation of the crude product.

4. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, wherein: In step B, the mass ratio of 1-(4-fluoro-3-methylphenyl)ethanone to the volume of the mixed solvent of dimethyl sulfoxide and N,N-dimethylformamide is 1 : 2.5 - 3 g / ml, and the volume ratio of dimethyl sulfoxide to N,N-dimethylformamide is 1.5 - 2 : 1; The molar ratio of 15-crown-5 to 1-(4-fluoro-3-methylphenyl)ethanone is 0.02 - 0.03 : 1; The mass ratio of PEG-400 to 1-(4-fluoro-3-methylphenyl)ethanone is 1 : 10 - 20; The molar ratio of 1-(4-fluoro-3-methylphenyl)ethanone to acetone cyanohydrin and CuI is 1 : 0.3 - 0.4 : 0.01 - 0.

05.

5. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: In step B, the materials are first heated to 110 - 120 °C at a rate of 2 - 3 °C / min, react at this temperature for 1 - 2 h, and then heated to 130 - 150 °C at a rate of 3 - 4 °C / min and react for 2 - 3 h.

6. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: The 4-acetyl-2-methylbenzonitrile in step B is dissolved in an ethanol-water mixed solvent and refluxed at 75 - 80 °C, then hot filtered at 60 - 65 °C. The filtrate is cooled to 0 - 5 °C at a rate of 2 - 3 °C / min and maintained for 1.5 - 2 h, and the crystals are collected to obtain purified 4-acetyl-2-methylbenzonitrile. The amount of the ethanol-water mixed solvent used is 5 - 10 times the mass of 4-acetyl-2-methylbenzonitrile, and the volume ratio of ethanol to water is 7 - 8:

2.

7. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: In step B, the addition amount of ethanol is 1 - 2 times the volume of the reaction solution, the addition amount of deionized water is 0.5 - 1 times the volume of ethanol, the stirring speed during the reaction is 200 - 400 rpm, the reaction solution is cooled to room temperature at a speed of 200 - 300 rpm, and finally cooled to 0 - 5 °C at a speed of 150 - 250 rpm.

8. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: In step C, the mass ratio of 4-acetyl-2-methylbenzonitrile to the volume of purified water is 1 g:5 - 6 ml, and the oxygen flow rate is 50 - 100 mL / min.

9. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, wherein: In step C, the added mass of the supported metal catalyst accounts for 5 - 10 w / w of the mass of 4-acetyl-2-methylbenzonitrile. The supported metal catalyst is a palladium catalyst supported on activated carbon, and the mass ratio of palladium to activated carbon is 1 - 5:

100.

10. The preparation method of 2-methyl-4-acetylbenzoic acid according to claim 1, characterized in that: In step C, the 2-methyl-4-acetylbenzoic acid removes pigment impurities through the combined technology of activated carbon adsorption - ethanol hot dissolution, and then is recrystallized with ethyl acetate - n-heptane to obtain purified 2-methyl-4-acetylbenzoic acid. The addition amount of activated carbon accounts for 5 - 10% w / w of the mass of 2-methyl-4-acetylbenzoic acid; The addition amount ratio of 4-acetyl-2-methylbenzonitrile to ethyl acetate - n-heptane is 1 g:1.5 - 2 ml, and the volume ratio of ethyl acetate to n-heptane is 1:2 - 3.

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