Preparation process of 2-methyl-4-acetylbenzoic acid

Abstract

The invention provides a preparation process of 2-methyl-4-acetylbenzoic acid, and provides a novel synthesis method of 2-methyl-4-acetylbenzoic acid, 2-chloro-4-aminotoluene is used as a raw material, and the final product is obtained through bromination, diazotization, formatting, carbonyl protection, formatting and acidolysis. The method disclosed by the invention has the characteristics of low cost, high safety, high yield and suitability for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, and specifically relates to a preparation process of 2-methyl-4-acetylbenzoic acid. Background Technology

[0002] 2-Methyl-4-acetylbenzoic acid is a key intermediate in the preparation of the veterinary drug fluranaridine, with CAS number 55860-35-0. The synthesis of this compound belongs to the field of pharmaceutical technology. The existing technologies for synthesizing 2-methyl-4-acetylbenzoic acid mainly include the following six methods:

[0003] 1) Patent EP2172462A1 discloses two synthetic methods. One method uses N-(4-acetyl-2-methylphenyl)acetamide as the starting material, followed by amino deprotection, diazotization bromination, and palladium-catalyzed carbon monoxide direct carbonylation to obtain the target product. In this method, the initial starting material N-(4-acetyl-2-methylphenyl)acetamide is difficult to obtain, requiring multiple reaction steps. Furthermore, the route uses sodium nitrite, posing a risk of nitrosamine formation. The carbon monoxide reaction requires high temperature and pressure, and carbon monoxide is colorless, odorless, and highly toxic, increasing the reaction risk. The other method requires 4-bromo-2-methylbenzoic acid, which is also difficult to obtain. The other starting material, n-butyl vinyl ether, is a highly flammable liquid, and the reaction conditions are similar to those in method one, posing a significant risk and making it unsuitable for industrial application. The specific route is shown below. Figure 1 .

[0004] 2) Patent WO2011104089A1 mentions a synthetic method. Using o-fluorotoluene as the starting material, the product is obtained through Friedel-Crafts acylation, cyanation, and cyanohydrolysis. The sodium cyanide used in the reaction is highly toxic, and the yield of the hydrolyzed product is low, therefore it is not suitable for large-scale industrial production. The specific process route is as follows. Figure 2 3) Patent CN109553528A mentions a synthesis method. Potassium ferrocyanide is used instead of the highly toxic sodium cyanide to avoid the use of such a poison. However, after repeated experiments by professional technicians, it was found that the cyanidation yield was extremely low after changing the raw materials, making it unsuitable for industrial application. The specific process route is as follows. Figure 2 .

[0005] 4) Publication No. CN115477577A mentions a synthetic method. Starting with 5-carbonylphthalide or 5-formylchlorophthalide, it undergoes a nucleophilic substitution reaction on the acyl carbon with a malonic ester compound, followed by decarboxylation to generate an acetyl group, and finally ring-opening via palladium-carbon hydrogenation to obtain the product. However, 5-carbonylphthalide is difficult to obtain in this reaction, and the condensing agent EDCI used in the reaction is expensive; furthermore, the decarboxylation after condensation with a malonic ester compound does not meet atom economy requirements; overall, the analytical experimental cost is high, making it unsuitable for industrialization. The specific process route is as follows. Figure 3 .

[0006] 5) Patent CN1183264623 mentions a synthesis method. Using o-bromotoluene as a raw material, Friedel-Crafts acylation yields the intermediate 4-bromo-3-methylacetophenone. This intermediate, under the action of a catalyst and ligand, undergoes a carbonylation reaction using carbon monoxide. Compared to method 1), the raw materials are readily available, and carbon monoxide is not used directly, making it safer. However, the indirect carbon dioxide production reaction has two disadvantages: first, the carbon monoxide production is not timely, resulting in a longer carbonylation reaction time and potentially incomplete reaction; second, carbon dioxide is generated during carbon monoxide production, and the reaction is under high pressure, requiring exhaust to control the pressure, leading to carbon monoxide loss and potential safety hazards due to insufficient carbon monoxide absorption. Furthermore, the overall reaction yield is low, making it unsuitable for industrial production. The specific process route is as follows. Figure 4 .

[0007] 6) Patent CN118561677 mentions a synthetic method. Using 4-amino-3-methylbenzoic acid as a raw material, the final product is obtained through diazotization and Sandmeier reaction, acylation, nucleophilic substitution, decarboxylation, and carbonyl insertion. This method suffers from the same cost disadvantages as method 4) and the same safety hazards as method 5), making it unsuitable for industrial production. The specific process route is shown below. Figure 5 .

[0008] Existing synthesis methods have been found to have many drawbacks, such as difficulty in obtaining raw materials, high costs, highly toxic materials, and significant process risks.

[0009] Therefore, it is extremely important to develop a low-cost, safe process route that is suitable for large-scale production. Summary of the Invention

[0010] The purpose of this invention is to provide a low-cost, safe process route that is suitable for large-scale production.

[0011] In a first aspect, the present invention provides a method for preparing 2-methyl-4-acetylbenzoic acid, comprising the following steps:

[0012]

[0013] (a) Compound 2 was obtained by bromination of 2-chloro-4-aminotoluene as a raw material;

[0014] (b) Compound 2 was subjected to a diazotization reaction and deamination reduction to obtain compound 3;

[0015] (c) Compound 3 was subjected to a Grignard reaction to give compound 4;

[0016] (d) Compound 4 was mixed with a protecting agent and dehydrated under the action of a catalyst to obtain compound 5;

[0017] (e) Compound 5 was hydrolyzed under acidic conditions via a Grignard reaction to give 2-methyl-4-acetylbenzoic acid.

[0018] In another preferred embodiment, in step (a), bromination system is added dropwise under heating conditions using 2-chloro-4-aminotoluene as a raw material to obtain compound 2.

[0019] In another preferred embodiment, the bromination system comprises a combination of a reaction solvent and a brominating agent, preferably including dichloromethane / bromine, hydrobromic acid / hydrogen peroxide, DMF / N-bromosuccinimide, DMF / dibromohydantoin, DMSO / hydrobromic acid, and more preferably DMSO / hydrobromic acid.

[0020] In another preferred embodiment, the molar ratio of hydrobromic acid to 2-chloro-4-aminotoluene is 1-5:1, more preferably (2.0-2.5):1, and even more preferably 2.05:1.

[0021] In another preferred embodiment, the mass ratio of DMSO to 2-chloro-4-aminotoluene is (1-5:1), preferably 3:1.

[0022] In another preferred embodiment, in step (a), the reaction temperature of the heating condition is 60-80°C, preferably 70-75°C.

[0023] In another preferred embodiment, step (b) includes step (b1): mixing water and compound 2, and diazotizing by adding an aqueous sodium nitrite solution dropwise under acidic conditions at low temperature;

[0024] Step (b2): Use a reducing agent as a base, heat to reflux, and add the diazonium salt dropwise to the reducing agent to reduce it to obtain compound 3.

[0025] In another preferred embodiment, in step (b1), the acidic conditions are provided by an inorganic acid, including hydrochloric acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid or hydrochloric acid.

[0026] In another preferred embodiment, in step (b1), the molar ratio of the inorganic acid to compound 2 is (1-4):1, preferably 1.25:1.

[0027] In another preferred embodiment, in step (b1), the low temperature condition is 0-10°C, preferably 0-5°C.

[0028] In another preferred embodiment, in step (b1), the mass ratio of water to compound 2 is 1-10:1, more preferably 2-6:1, and most preferably 4:1.

[0029] In another preferred embodiment, the molar ratio of sodium nitrite to compound 2 is 1-1.5:1, preferably 1.05:1.

[0030] In another preferred embodiment, in step (b2), the reducing agent includes methanol, ethanol, isopropanol, hypophosphite, sodium borohydride, preferably ethanol.

[0031] In another preferred embodiment, the molar ratio of the reducing agent to compound 2 is (3-8):1, more preferably 3-5:1, and most preferably 4:1.

[0032] In another preferred embodiment, step (c) includes step (c1): under nitrogen protection, solvent, compound 3 and magnesium shavings are mixed at room temperature to react and obtain Grignard reagent;

[0033] Step (c2): Under a nitrogen atmosphere, the generated Grignard reagent is added dropwise to the acetylation reagent to generate compound 4.

[0034] In another preferred embodiment, in step (c1), the solvent includes tetrahydrofuran, dimethyltetrahydrofuran, a mixture of toluene and tetrahydrofuran, a mixture of toluene and dimethyltetrahydrofuran, preferably tetrahydrofuran; or a mixture of toluene and tetrahydrofuran.

[0035] In another preferred embodiment, the mass ratio of solvent to compound 3 is 1-8:1, more preferably 3-5:1, and most preferably 4:1.

[0036] In another preferred embodiment, the mass ratio of toluene:tetrahydrofuran:compound 3 is 1-3:1-3:1, preferably 2:2:1.

[0037] In another preferred embodiment, the molar ratio of magnesium shavings to compound 3 is (1-3):1, preferably (1-2):1, and more preferably 1.3:1.

[0038] In another preferred embodiment, in step (c1), the reaction temperature is 20-40°C, preferably 25-30°C.

[0039] In another preferred embodiment, in step (c2), the acetylation agent includes acetic anhydride, 4-acetylmorpholine, preferably acetic anhydride.

[0040] In another preferred embodiment, the molar ratio of the acetylation reagent to compound 3 is 1-3:1, more preferably (1-1.5):1, and most preferably 1.1:1.

[0041] In another preferred embodiment, in step (c2), the acetylation temperature is -10-10°C, more preferably -5-5°C, and most preferably -5-0°C.

[0042] In another preferred embodiment, in step (d), compound 4, solvent, and protective agent are mixed and refluxed under the action of a catalyst to generate compound 5.

[0043] In another preferred embodiment, in step (d), the solvent includes benzene, toluene, dichloroethane, cyclohexane, preferably cyclohexane or 1,2-dichloroethane.

[0044] In another preferred embodiment, the mass ratio of solvent to compound 4 is (3-10):1, more preferably 4-6:1, and most preferably 5:1.

[0045] In another preferred embodiment, in step (d), the protective agent includes ethylene glycol, propylene glycol, and butanediol, preferably ethylene glycol.

[0046] In another preferred embodiment, the molar ratio of the protective agent to compound 4 is (1-2):1, preferably 1.15:1.

[0047] In another preferred embodiment, in step (d), the catalyst comprises sodium hydroxide, potassium hydroxide, anhydrous phosphoric acid, and p-toluenesulfonic acid, preferably p-toluenesulfonic acid.

[0048] In another preferred embodiment, the molar ratio of catalyst to compound 4 is (0.001-0.005):1, preferably 0.002:1.

[0049] In another preferred embodiment, step (e) includes step (e1): under nitrogen protection, solvent, compound 5 and magnesium shavings are mixed and heated to react and obtain Grignard reagent;

[0050] Step (e2): Carbon dioxide is passed through to generate a carboxylate, which is then hydrolyzed under acidic conditions to generate 2-methyl-4-acetylbenzoic acid.

[0051] In another preferred embodiment, in step (e1), the solvent includes tetrahydrofuran, dimethyltetrahydrofuran, a mixture of toluene and tetrahydrofuran, a mixture of toluene and dimethyltetrahydrofuran, preferably a mixture of toluene and tetrahydrofuran.

[0052] In another preferred embodiment, the mass ratio of solvent to compound 5 is 1-8:1, more preferably 3-5:1, and most preferably 4:1.

[0053] In another preferred embodiment, the mass ratio of toluene:tetrahydrofuran:compound 5 is 1-3:1-3:1, preferably 2:2:1.

[0054] In another preferred embodiment, in step (e1), the molar ratio of magnesium shavings to compound 5 is (1-3):1, preferably 1.15:1.

[0055] In another preferred embodiment, in step (e1), the reaction temperature (Greek temperature) is 60-90°C, more preferably 70-80°C, and most preferably 75-80°C.

[0056] In another preferred embodiment, in step (e2), the acidic condition is an inorganic acid, including hydrochloric acid or sulfuric acid, preferably hydrochloric acid.

[0057] In another preferred embodiment, the molar ratio of the inorganic acid to compound 5 is (2.0-3.0):1, preferably 2.15:1.

[0058] In another preferred embodiment, in step (e2), the hydrolysis temperature is 60-80°C, preferably 65-70°C.

[0059] In another preferred embodiment, in step (e2), the temperature at which carbon dioxide is introduced (i.e., the gas temperature) is -5 to 20°C, more preferably -5 to 5°C, and most preferably -5 to 0°C.

[0060] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0061] The following figures are used to illustrate specific embodiments of the present invention and are not intended to limit the scope of the invention as defined by the claims.

[0062] Figure 1 The specific process route of patent EP2172462A1 is shown.

[0063] Figure 2 The specific process routes of patents WO2011104089A1 and CN109553528A are shown.

[0064] Figure 3 The specific process route of patent CN115477577A is shown.

[0065] Figure 4 The specific process route of patent CN1183264623 is shown.

[0066] Figure 5 The specific process route of patent CN118561677 is shown. Detailed Implementation

[0067] Through extensive and in-depth research, the inventors have developed a novel synthetic method for 2-methyl-4-acetylbenzoic acid, solving the problems mentioned in the background section. This invention uses 2-chloro-4-aminotoluene as a raw material, and proceeds through bromination, diazotization, Grignard oxidation, carbonyl protection, Grignard oxidation, and acid hydrolysis to obtain the final product. The method of this invention is characterized by low cost, high safety, high yield, and suitability for large-scale industrial production. Based on this, the invention was completed.

[0068] Before describing this invention, it should be understood that the invention is not limited to the specific methods and experimental conditions described, as such methods and conditions can be varied. It should also be understood that the terminology used herein is intended only to describe particular embodiments and is not intended to be limiting; the scope of the invention will be limited only by the appended claims.

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. As used herein, when referring to a specifically enumerated numerical value, the term “about” means that the value can vary from the enumerated value by no more than 1%. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0070] While any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention, preferred methods and materials are exemplified herein.

[0071] Method for preparing 2-methyl-4-acetylbenzoic acid

[0072] This invention provides a method for preparing 2-methyl-4-acetylbenzoic acid, comprising the following steps:

[0073]

[0074] (a) Compound 2 was obtained by bromination of 2-chloro-4-aminotoluene as a raw material;

[0075] (b) Compound 2 was subjected to a diazotization reaction and deamination reduction to obtain compound 3;

[0076] (c) Compound 3 was subjected to a Grignard reaction to give compound 4;

[0077] (d) Compound 4 was mixed with a protecting agent and dehydrated under the action of a catalyst to obtain compound 5;

[0078] (e) Compound 5 was hydrolyzed under acidic conditions via a Grignard reaction to give 2-methyl-4-acetylbenzoic acid.

[0079] In a preferred embodiment, the method of the present invention includes:

[0080] Step 1: 2-Chloro-4-aminotoluene undergoes a bromination reaction to yield compound 2;

[0081] Step 2: Compound 2 is reduced by diazotization to obtain compound 3.

[0082] Step 3: Compound 3 undergoes a Grignard reaction to acquire an acetyl group, yielding compound 4;

[0083] Step 4: Compound 4 is dehydrated with ethylene glycol to protect the acetyl group, yielding compound 5;

[0084] Step 5: Compound 5 undergoes Grignard reaction, followed by hydrochloric acid hydrolysis to obtain the final product 2-methyl-4-acetylbenzoic acid.

[0085] In a preferred embodiment, the specific operation steps of the method of the present invention are as follows:

[0086] S1 is specifically obtained by mixing 2-chloro-4-aminotoluene as a raw material and a solvent, and then adding a brominating agent dropwise under heating conditions to obtain compound 2;

[0087] The above bromination system can use dichloromethane / bromine, hydrobromic acid / hydrogen peroxide, DMF / NBS, DMF / dibromohydantoin, DMSO / hydrobromic acid, etc. From the perspective of safety and economy, DMSO / hydrobromic acid is preferred, the molar ratio of hydrobromic acid to raw material is (2.0-2.5):1, more preferably 2.05:1, and the mass ratio of DMSO to raw material is (1-5:1), preferably 3:1.

[0088] The reaction temperature is 60-80℃, preferably 70-75℃.

[0089] S2 specifically consists of: S2-1: water is used as a solvent to mix with compound 2, and sodium nitrite aqueous solution is added dropwise at low temperature for diazotization under acidic conditions; S2-2: a reducing agent is used as a base, the mixture is heated to reflux, and the diazonium salt is added dropwise to the reducing agent for reduction to obtain compound 3;

[0090] In S2-1 above, water is used as the solvent, and the mass ratio of water to compound 2 is 4:1.

[0091] The acidic conditions in S2-1 above are provided by an inorganic acid, which is either hydrochloric acid or sulfuric acid, preferably sulfuric acid. The molar ratio of sulfuric acid to compound 2 is (1-4):1, preferably 1.25:1.

[0092] The low temperature condition in S2-1 above is 0-10℃, more preferably 0-5℃.

[0093] The molar ratio of sodium nitrite and the compound in S2-1 above is 1-1.5:1, preferably 1.05:1.

[0094] The reducing agent used in S2-2 above is one of methanol, ethanol, isopropanol, hypophosphite, sodium borohydride, etc., preferably ethanol, and the molar ratio of ethanol to compound 2 is (3-8):1, more preferably 4:1.

[0095] S3 specifically consists of: S3-1: Under nitrogen protection, solvent, compound 3, and magnesium shavings are mixed at room temperature to react and obtain a Grignard reagent; S3-2: Under a nitrogen atmosphere, the generated Grignard reagent is added dropwise to an acetylation reagent to generate compound 4;

[0096] The solvent in S3-1 above is one of tetrahydrofuran, dimethyltetrahydrofuran, a mixture of toluene and tetrahydrofuran, or a mixture of toluene and dimethyltetrahydrofuran, preferably a mixture of toluene and tetrahydrofuran, with a mass ratio of toluene:tetrahydrofuran:raw material of 2:2:1.

[0097] The molar ratio of magnesium shavings and compound 3 in S3-1 above is (1-3):1, preferably 1.3:1.

[0098] The reaction temperature in S3-1 above is 20-40℃, more preferably 25-30℃.

[0099] The acetylation reagent in S3-2 above is one of acetic anhydride and 4-acetylmorpholine, preferably acetic anhydride, and the molar ratio of acetic anhydride and compound 3 is (1-1.5):1, preferably 1.1:1.

[0100] The acetylation temperature in S3-2 above is -5-5℃, preferably -5-0℃.

[0101] S4 is specifically: compound 4, solvent, and protective agent are mixed and refluxed under the action of a catalyst to generate compound 5;

[0102] The solvent is one of benzene, toluene, 1,2-dichloroethane, cyclohexane, etc., preferably cyclohexane, and the mass ratio of cyclohexane and compound 4 is (3-10):1, preferably 5:1.

[0103] The above-mentioned protective reagent is one of ethylene glycol, propylene glycol, butanediol, etc., preferably ethylene glycol, and the molar ratio of ethylene glycol to compound 4 is (1-2):1, preferably 1.15:1.

[0104] The dehydration catalyst mentioned above is one of potassium hydroxide, sodium hydroxide, anhydrous boric acid, and p-toluenesulfonic acid, preferably p-toluenesulfonic acid. The molar ratio of p-toluenesulfonic acid and compound 4 is (0.001-0.005):1, preferably 0.002:1.

[0105] S5 specifically consists of: S5-1: Under nitrogen protection, the solvent, compound 3, and magnesium shavings are mixed and heated to produce the Grignard reagent; S5-2: Carbon dioxide is passed through to generate a carboxylate, which is then hydrolyzed under acidic conditions to produce the target compound.

[0106] The solvent in S5-1 above is one of tetrahydrofuran, dimethyltetrahydrofuran, a mixture of toluene and tetrahydrofuran, or a mixture of toluene and dimethyltetrahydrofuran, preferably a mixture of toluene and tetrahydrofuran, with a mass ratio of toluene:tetrahydrofuran:raw material of 2:2:1.

[0107] The molar ratio of magnesium shavings and compound 3 in S5-1 above is (1-3):1, preferably 1.15:1.

[0108] The reaction temperature in S5-1 above is 60-90℃, more preferably 75-80℃.

[0109] The temperature at which carbon dioxide is introduced in S5-2 is -5 to 20°C, more preferably 0 to 5°C.

[0110] In the above S5-2, the acidic condition is hydrochloric acid or sulfuric acid, preferably hydrochloric acid, and the molar ratio of hydrochloric acid to raw material is (2.0-3.0):1, preferably 2.15:1.

[0111] The hydrolysis temperature in S5-2 above is 60-80℃, preferably 65℃-70℃.

[0112] The advantages of this invention include:

[0113] (1) This invention is the first to develop a novel synthetic method for 2-methyl-4-acetylbenzoic acid, solving the problems mentioned in the background art. This invention uses 2-chloro-4-aminotoluene as a raw material, and obtains the final product through bromination, diazotization, Grignard oxidation, carbonyl protection, Grignard oxidation, and acid hydrolysis. The method of this invention is characterized by low cost, high safety, high yield, and suitability for large-scale industrial production.

[0114] (2) The raw materials of this invention are readily available, inexpensive, and have low cost.

[0115] (3) This invention does not use highly toxic carbon monoxide, and is therefore safe.

[0116] (4) This invention does not use high temperature and high pressure, the reaction conditions are mild and easy to operate.

[0117] (5) The present invention has a high yield and is suitable for large-scale industrial production.

[0118] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0119] Unless otherwise specified, all materials and reagents used in the examples are commercially available products.

[0120] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0121] Example 1:

[0122] S1: In a dry 500mL three-necked flask, add 212.4g of dimethyl sulfoxide and 70.8g of 2-chloro-4-aminotoluene sequentially. Heat to 70℃ and add 172.78g of 48% hydrobromic acid aqueous solution dropwise over approximately 3 hours. After the addition, maintain the temperature for 3-4 hours until the reaction is complete. Cool down and add 10% sodium hydroxide aqueous solution dropwise to adjust the pH of the reaction solution to 8-9. Extract three times with 50g of dichloromethane. Recover dichloromethane by atmospheric distillation and recover dimethyl sulfoxide by vacuum distillation to obtain compound 2: 105.40g, purity >98%, yield: 95.60%.

[0123] S2: In a dry 1000mL three-necked flask, add water (400g), concentrated sulfuric acid (56.25g), and compound 2 (99.23g) in sequence to an ice-water bath. Stir until homogeneous, lower the internal temperature to 0℃, and add sodium nitrite aqueous solution (30%) (108.6g) dropwise at a controlled temperature of 0-5℃. Keep the temperature and stir until the reaction is complete. Prepare another dry 1000mL three-necked flask, add ethanol (82.8g), heat to reflux, add the prepared diazonium salt dropwise, keep the temperature until the reaction is complete, recover the ethanol by distillation at atmospheric pressure, cool and separate the layers to obtain an oil layer. Wash the oil layer with sodium bicarbonate aqueous solution until neutral to obtain the crude product. Distill the crude product to obtain compound 3 (85.16g), purity >98%, yield: 92.09%.

[0124] S3: In a dry 500mL three-necked flask under a nitrogen atmosphere, add 164g of toluene, 164g of tetrahydrofuran, and 12.50g of magnesium shavings. Add 8.3g of compound 3 (approximately 10% of the total amount) dropwise and stir to initiate the reaction. After initiation, slowly add the remaining 73.9g of compound 3 dropwise over approximately 3 hours, maintaining the temperature at 25-30℃ and stirring until the reaction is complete. Separately, in a dry 500mL three-necked flask under a nitrogen atmosphere, add 44.92g of acetic anhydride. Cool to 0℃ and, while maintaining 0℃, add the prepared Grignard reagent dropwise over approximately 2 hours, maintaining the temperature until the reaction is complete. After the reaction is complete, quench the reaction mixture in 48.67g of cooled concentrated hydrochloric acid. Separately extract the mixture into layers. Extract twice with 30g of toluene. Distill the mixed organic phases to recover the solvent, yielding 62.93g of compound 4 with a purity >98% and a yield of 93.30%.

[0125] S4: In a dry 500mL three-necked flask, add 300g of cyclohexane, 59.02g of compound 4, 24.98g of ethylene glycol, and 0.12g of p-toluenesulfonic acid in sequence. Under a nitrogen atmosphere, heat and reflux to separate water. Maintain reflux for about 5 hours until the reaction is complete. Distill to recover the solvent, and obtain compound 5: 73.3g, purity >98%, yield: 98.50%.

[0126] S5: Toluene: 136g, tetrahydrofuran: 136g, and magnesium shavings: 8.84g were added sequentially to a dry 500mL three-necked flask. The mixture was heated to 50℃, and compound 5: 6.8g (approximately 10% of the total mass) was added dropwise. The mixture was stirred to initiate the reaction. After the temperature stabilized, the temperature was raised to 75℃ and the remaining compound 5: 61.24g was added dropwise over approximately 3 hours. The mixture was kept at this temperature and stirred until the reaction was complete. The temperature was lowered to 0℃ and carbon dioxide was introduced. After the reaction was complete, the reaction solution was quenched in cooled concentrated hydrochloric acid: 69.8g. The temperature was then raised to 65℃ and stirred for 2 hours. The mixture was separated into layers, and the solvent was recovered by distillation. Recrystallization from methanol yielded a white product: 51.94g, with a purity >99% and a yield of 91.09%.

[0127] Example 2: In this example, the preparation method is roughly the same as in Example 1, except that the bromination system in S1 is different. The specific preparation method in this example is as follows:

[0128] S1: In a dry 500mL three-necked flask, 212.4g of dichloromethane and 70.8g of 2-chloro-4-aminotoluene were added sequentially. Bromine (42g) was then added dropwise at room temperature over approximately 3 hours. After the addition, the mixture was kept at this temperature for 10 hours until the reaction was complete. The mixture was washed twice with 100g of 10% sodium bicarbonate aqueous solution and once with 100g of water. 30g of dichloromethane was used to extract the aqueous phase twice. The combined organic phases were then distilled at atmospheric pressure to recover the dichloromethane, yielding compound 2 (63.57g), with a purity >98% and a yield of 57.66%.

[0129] Steps S2-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0130] Example 3: In this example, the preparation method is roughly the same as in Example 1, except that the solvent used in S1 is different. The specific preparation method in this example is as follows:

[0131] S1: In a dry 500mL three-necked flask, add water (212.4g), 2-chloro-4-aminotoluene (70.8g), and 48% hydrobromic acid aqueous solution (172.18g) sequentially. Then, add hydrogen peroxide (35%) (53.4g) dropwise at 25℃ over approximately 3 hours. After the addition, maintain the temperature for 8 hours until the reaction is complete. Cool the flask and add 10% sodium hydroxide aqueous solution dropwise to adjust the pH of the reaction solution to 8-9. Extract the solution three times with 100g of dichloromethane. Recover the dichloromethane by distillation under normal pressure to obtain compound 2 (67.32g), with a purity >98% and a yield of 61.06%.

[0132] Steps S2-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0133] Example 4: In this example, the preparation method is roughly the same as in Example 1, except that the solvent used in S1 is different. The specific preparation method in this example is as follows:

[0134] S1: DMF: 70g and 2-chloro-4-aminotoluene: 70.8g were added sequentially to a dry 500mL three-necked flask. The temperature was raised to 80℃ and NBS: 93.44g + DMF: 150g solution was added dropwise under controlled temperature for about 3 hours. After the addition, the mixture was kept at the temperature for 8 hours until the reaction was complete. DMF was recovered under reduced pressure. After cooling, the mixture was diluted with dichloromethane. The solid was filtered, and the solvent was recovered from the filtrate to obtain compound 2: 58.95g, purity >98%, yield: 53.47%.

[0135] Steps S2-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0136] Example 5: In this example, the preparation method is roughly the same as in Example 1, except that the solvent used in S1 is different. The specific preparation method in this example is as follows:

[0137] S1: DMF: 70g and 2-chloro-4-aminotoluene: 70.8g were added sequentially to a dry 500mL three-necked flask. The temperature was raised to 80℃ and a solution of dibromohydantoin: 75.05g + DMF: 150g was added dropwise under controlled temperature over approximately 3 hours. After the addition, the mixture was kept at this temperature for 9 hours until the reaction was complete. DMF was recovered under reduced pressure, and the mixture was cooled and diluted with dichloromethane. The solid was filtered, and the solvent was recovered from the filtrate to obtain compound 2: 61.22g, purity >98%, yield: 55.53%.

[0138] Steps S2-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0139] The results of Examples 1 to 5 are summarized in Table 1.

[0140] Table 1

[0141]

[0142] Example 6: In this example, the preparation method is roughly the same as in Example 1, except that the S2 reaction temperature is different. The specific preparation method in this example is as follows:

[0143] S1 is the same as in Example 1.

[0144] S2: In a dry 1000mL three-necked flask, add water (400g), concentrated sulfuric acid (56.25g), and compound 2 (99.23g) in sequence to an ice-water bath. Stir until homogeneous, and add sodium nitrite aqueous solution (30%) (108.6g) dropwise while maintaining the temperature at 15-20℃. Stir until the reaction is complete. Prepare another dry 1000mL three-necked flask, add ethanol (82.8g), heat to reflux, add the prepared diazonium salt dropwise, and maintain the temperature until the reaction is complete. Distill at atmospheric pressure to recover the ethanol, cool to separate the layers, and obtain an oil layer. Wash the oil layer with sodium bicarbonate aqueous solution until neutral to obtain the crude product. Distill the crude product to obtain compound 3 (55.62g), purity >98%, yield: 60.15%.

[0145] Steps S3-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0146] Example 7: In this example, the preparation method is roughly the same as in Example 1, except that the acidic environment of S2 is different. The specific preparation method in this example is as follows:

[0147] S1 is the same as in Example 1.

[0148] S2: In a dry 1000mL three-necked flask, add water (400g), concentrated hydrochloric acid (57.03g), and compound 2 (99.23g) in sequence to an ice-water bath. Stir until homogeneous, and add sodium nitrite aqueous solution (30%) (108.6g) dropwise while maintaining the temperature at 0-5℃. Stir until the reaction is complete. Prepare another dry 1000mL three-necked flask, add ethanol (82.8g), heat to reflux, add the prepared diazonium salt dropwise, and maintain the temperature until the reaction is complete. Distill at atmospheric pressure to recover ethanol, cool to separate the layers, and obtain an oil layer. Wash the oil layer with sodium bicarbonate aqueous solution until neutral to obtain the crude product. Distill the crude product to obtain compound 3 (78.53g), purity >98%, yield: 84.92%.

[0149] Steps S3-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0150] Example 8: In this example, the preparation method is roughly the same as in Example 1, except that the S2 reducing reagent is different. The specific preparation method in this example is as follows:

[0151] S1 is the same as in Example 1.

[0152] S2: In a dry 1000mL three-necked flask, add water (400g), concentrated sulfuric acid (56.25g), and compound 2 (99.23g) in sequence to an ice-water bath. Stir until homogeneous, and add sodium nitrite aqueous solution (30%) (108.6g) dropwise while maintaining the temperature at 0-5℃. Stir until the reaction is complete. Prepare another dry 1000mL three-necked flask, add methanol (57.67g), heat to reflux, add the prepared diazonium salt dropwise, and maintain the temperature until the reaction is complete. Distill at atmospheric pressure to recover ethanol, cool to separate the layers, and obtain an oil layer. Wash the oil layer with sodium bicarbonate aqueous solution until neutral to obtain the crude product. Distill the crude product to obtain compound 3 (73.29g), purity >98%, yield: 79.26%.

[0153] Steps S3-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0154] Example 9: In this example, the preparation method is roughly the same as in Example 1, except that the S2 reducing reagent is different. The specific preparation method in this example is as follows:

[0155] S1 is the same as in Example 1.

[0156] S2: In a dry 1000mL three-necked flask, add water (400g), concentrated sulfuric acid (56.25g), and compound 2 (99.23g) in sequence to an ice-water bath. Stir until homogeneous, and add sodium nitrite aqueous solution (30%) (108.6g) dropwise while maintaining the temperature at 0-5℃. Stir until the reaction is complete. Prepare another dry 1000mL three-necked flask, add hypophosphoric acid (115.3g), heat to reflux, add the prepared diazonium salt dropwise, and maintain the temperature until the reaction is complete. Distill at atmospheric pressure to recover ethanol, cool to separate the layers, and obtain an oil layer. Wash the oil layer with sodium bicarbonate aqueous solution until neutral to obtain the crude product. Distill the crude product to obtain compound 3 (62.78g), purity >98%, yield: 67.89%.

[0157] Steps S3-S5 are largely the same as in Example 1, and the results are also largely the same as in Example 1.

[0158] The results of Examples 6 to 9 are summarized in Table 2.

[0159] Table 2

[0160]

[0161] Example 10: In this example, the preparation method is roughly the same as in Example 1, except that the Grignard reaction solvent in S3 is different. The specific preparation method in this example is as follows:

[0162] S1-S2 are the same as in Example 1.

[0163] S3: In a dry 500mL three-necked flask under a nitrogen atmosphere, add 330g of tetrahydrofuran and 12.50g of magnesium shavings. Then, add 8.3g of compound 3 (approximately 10% of the total amount) dropwise and stir to initiate the reaction. After initiation, slowly add the remaining 73.9g of compound 3 dropwise at 25-30℃ over approximately 3 hours, maintaining the temperature and stirring until the reaction is complete. Separately, in a dry 500mL three-necked flask under a nitrogen atmosphere, add 44.92g of acetic anhydride. Cool to 0℃ and, while maintaining 0℃, add the prepared Grignard reagent dropwise over approximately 2 hours, maintaining the temperature until the reaction is complete. After the reaction is complete, quench the reaction mixture in 48.67g of cooled concentrated hydrochloric acid. The mixture is separated into layers, extracted twice with 30g of toluene, and the solvent is recovered by distillation of the mixed organic phases, yielding 62.91g of compound 4 with a purity >98% and a yield of 93.27%.

[0164] S4-S5 are the same as in Example 1.

[0165] Example 11: In this example, the preparation method is roughly the same as in Example 1, except that the Grignard reaction solvent in S3 is different. The specific preparation method in this example is as follows:

[0166] S1-S2 are the same as in Example 1.

[0167] S3: In a dry 500mL three-necked flask under a nitrogen atmosphere, add 330g of dimethyltetrahydrofuran and 12.50g of magnesium shavings. Then, add 8.3g of compound 3 (approximately 10% of the total amount) dropwise and stir to initiate the reaction. After initiation, slowly add the remaining 73.9g of compound 3 dropwise at 25-30℃ over approximately 3 hours, maintaining the temperature and stirring until the reaction is complete. Separately, in a dry 500mL three-necked flask under a nitrogen atmosphere, add 44.92g of acetic anhydride. Cool to 0℃ and, while maintaining 0℃, add the prepared Grignard reagent dropwise over approximately 2 hours, maintaining the temperature until the reaction is complete. After the reaction is complete, quench the reaction mixture in 48.67g of cooled concentrated hydrochloric acid. The mixture is separated into layers, extracted twice with 30g of toluene, and the solvent is recovered by distillation of the mixed organic phases, yielding 47.21g of compound 4 with a purity >98% and a yield of 69.99%.

[0168] S4-S5 are the same as in Example 1.

[0169] Example 12:

[0170] In this embodiment, the preparation method is roughly the same as in Example 1, except that the amount of magnesium chips used in S3 is different. The specific preparation method in this embodiment is as follows:

[0171] S1-S2 are the same as in Example 1.

[0172] S3: In a dry 500mL three-necked flask under a nitrogen atmosphere, add 164g of toluene, 164g of tetrahydrofuran, and 19.23g of magnesium filings. Add 8.3g of compound 3 (approximately 10% of the total amount) dropwise and stir to initiate the reaction. After initiation, slowly add the remaining 73.9g of compound 3 dropwise over approximately 3 hours, maintaining the temperature at 25-30℃ and stirring until the reaction is complete. Separately, in a dry 500mL three-necked flask under a nitrogen atmosphere, add 44.92g of acetic anhydride. Cool to 0℃ and, while maintaining 0℃, add the prepared Grignard reagent dropwise over approximately 2 hours, maintaining the temperature until the reaction is complete. After the reaction is complete, quench the reaction mixture in 48.67g of cooled concentrated hydrochloric acid. Separately extract the mixture into layers. Extract twice with 30g of toluene. Distill the mixed organic phases to recover the solvent, yielding 58.67g of compound 4 with a purity >98% and a yield of 86.98%.

[0173] S4-S5 are the same as in Example 1.

[0174] Example 13: In this example, the preparation method is roughly the same as in Example 1, except that the acylation temperature in S3 is different. The specific preparation method in this example is as follows:

[0175] S1-S2 are the same as in Example 1.

[0176] S3: In a dry 500mL three-necked flask under a nitrogen atmosphere, add 164g of toluene, 164g of tetrahydrofuran, and 12.50g of magnesium shavings. Add 8.3g of compound 3 (approximately 10% of the total amount) dropwise and stir to initiate the reaction. After initiation, slowly add the remaining 73.9g of compound 3 dropwise over approximately 3 hours, maintaining the temperature at 25-30℃ and stirring until the reaction is complete. Separately, in a dry 500mL three-necked flask under a nitrogen atmosphere, add 44.92g of acetic anhydride. Cool to 20℃ and maintain the temperature at 20℃ while adding the prepared Grignard reagent dropwise over approximately 2 hours, maintaining the temperature until the reaction is complete. After the reaction is complete, quench the reaction mixture in 48.67g of cooled concentrated hydrochloric acid. Separately extract the mixture into layers. Extract twice with 30g of toluene. Distill the mixed organic phases to recover the solvent, yielding 36.32g of compound 4 with a purity >98% and a yield of 53.85%.

[0177] S4-S5 are the same as in Example 1.

[0178] The results of Examples 10 to 13 are summarized in Table 3.

[0179] Table 3

[0180]

[0181] Example 14: In this example, the preparation method is roughly the same as in Example 1, except that the solvent in S4 is different. The specific preparation method in this example is as follows:

[0182] S1-S3 are the same as in Example 1.

[0183] S3: In a dry 500mL three-necked flask, add 300g of 1,2-dichloroethane, 59.02g of compound 4, 24.98g of ethylene glycol, and 0.12g of p-toluenesulfonic acid in sequence. Under a nitrogen atmosphere, heat and reflux to remove water, and maintain the reflux for about 5 hours until the reaction is complete. Distill to recover the solvent, and obtain compound 5: 59.87g, purity >98%, yield: 80.45%.

[0184] S5 is the same as in Example 1.

[0185] Example 15: In this example, the preparation method is roughly the same as in Example 1, except that the solvent in S4 is different. The specific preparation method in this example is as follows:

[0186] S1-S3 are the same as in Example 1.

[0187] S3: In a dry 500mL three-necked flask, add benzene: 300g, compound 4: 59.02g, ethylene glycol: 24.98g, and p-toluenesulfonic acid: 0.12g in sequence. Under a nitrogen atmosphere, heat and reflux to separate water. Maintain reflux for about 5 hours until the reaction is complete. Distill to recover the solvent, and obtain compound 5: 53.98g with a purity >98% and a yield of 72.53%.

[0188] S5 is the same as in Example 1.

[0189] Example 16: In this example, the preparation method is roughly the same as in Example 1, except that the solvent in S4 is different. The specific preparation method in this example is as follows:

[0190] S1-S3 are the same as in Example 1.

[0191] S3: Toluene: 300g, compound 4: 59.02g, ethylene glycol: 24.98g, p-toluenesulfonic acid: 0.12g were added sequentially to a dry 500mL three-necked flask. Under a nitrogen atmosphere, the mixture was heated to reflux to remove water. The mixture was kept at reflux for about 5 hours until the reaction was complete. The solvent was recovered by distillation to obtain compound 5: 55.79g, with a purity >98% and a yield of 74.97%.

[0192] S5 is the same as in Example 1.

[0193] The results of Examples 14 to 16 are summarized in Table 4.

[0194] Table 4

[0195] solvent Yield of compound 5 Example 1 Cyclohexane 98.50％ Example 14 1,2-Dichloroethane 80.45％ Example 15 benzene 72.53％ Example 16 Toluene 74.97％

[0196] Example 17: In this example, the preparation method is roughly the same as in Example 1, except that the grading temperature is different in S5. The specific preparation method in this example is as follows:

[0197] S1-S4 are the same as in Example 1.

[0198] S5: Toluene: 136g, tetrahydrofuran: 136g, and magnesium shavings: 8.84g were added sequentially to a dry 500mL three-necked flask. The mixture was heated to 50℃, and compound 5: 6.8g (approximately 10% of the total mass) was added dropwise. The mixture was stirred to initiate the reaction. After the temperature stabilized, the temperature was raised to 50℃ and the remaining compound 5: 61.24g was added dropwise over approximately 3 hours. The mixture was kept at this temperature and stirred until the reaction was complete. The temperature was lowered to 0℃ and carbon dioxide was introduced. After the reaction was complete, the reaction solution was quenched in cooled concentrated hydrochloric acid: 69.8g. The temperature was then raised to 65℃ and stirred for 2 hours. The mixture was separated into layers, and the solvent was recovered by distillation. Recrystallization from methanol yielded a white product: 37.85g, purity >99%, yield: 66.38%.

[0199] Example 18: In this example, the preparation method is roughly the same as in Example 1, except that the grading temperature is different in S5. The specific preparation method in this example is as follows:

[0200] S1-S4 are the same as in Example 1.

[0201] S5: Toluene: 136g, tetrahydrofuran: 136g, and magnesium shavings: 8.84g were added sequentially to a dry 500mL three-necked flask. The mixture was heated to 50℃, and compound 5: 6.8g (approximately 10% of the total mass) was added dropwise. The mixture was stirred to initiate the reaction. After the temperature stabilized, the temperature was raised to 60℃ and the remaining compound 5: 61.24g was added dropwise over approximately 3 hours. The mixture was kept at this temperature and stirred until the reaction was complete. The temperature was lowered to 0℃ and carbon dioxide was introduced. After the reaction was complete, the reaction solution was quenched in cooled concentrated hydrochloric acid: 69.8g. The temperature was then raised to 65℃ and stirred for 2 hours. The mixture was separated into layers, and the solvent was recovered by distillation. Recrystallization from methanol yielded a white product: 43.20g, purity >99%, yield: 75.76%.

[0202] Example 19: In this example, the preparation method is roughly the same as in Example 1, except that the grading temperature is different in S5. The specific preparation method in this example is as follows:

[0203] S1-S4 are the same as in Example 1.

[0204] S5: Toluene: 136g, tetrahydrofuran: 136g, and magnesium shavings: 8.84g were added sequentially to a dry 500mL three-necked flask. The mixture was heated to 50℃, and compound 5: 6.8g (approximately 10% of the total mass) was added dropwise. The mixture was stirred to initiate the reaction. After the temperature stabilized, the temperature was raised to 90℃ and the remaining compound 5: 61.24g was added dropwise over approximately 3 hours. The mixture was kept at this temperature and stirred until the reaction was complete. The temperature was lowered to 0℃ and carbon dioxide was introduced. After the reaction was complete, the reaction solution was quenched in cooled concentrated hydrochloric acid: 69.8g. The temperature was then raised to 65℃ and stirred for 2 hours. The mixture was separated into layers, and the solvent was recovered by distillation. Recrystallization from methanol yielded a white product: 39.53g, purity >99%, yield: 69.33%.

[0205] Example 20: In this example, the preparation method is roughly the same as in Example 1, except that the carbon dioxide temperature in S5 is different. The specific preparation method in this example is as follows:

[0206] S1-S4 are the same as in Example 1.

[0207] S5: Toluene: 136g, tetrahydrofuran: 136g, and magnesium shavings: 8.84g were added sequentially to a dry 500mL three-necked flask. The mixture was heated to 50℃, and compound 5: 6.8g (approximately 10% of the total mass) was added dropwise. The mixture was stirred to initiate the reaction. After the temperature stabilized, the temperature was raised to 75℃ and the remaining compound 5: 61.24g was added dropwise over approximately 3 hours. The mixture was kept at this temperature and stirred until the reaction was complete. The temperature was lowered to 30℃ and carbon dioxide was introduced. After the reaction was complete, the reaction solution was quenched in cooled concentrated hydrochloric acid: 69.8g. The temperature was then raised to 65℃ and stirred for 2 hours. The mixture was separated into layers, and the solvent was recovered by distillation. Recrystallization from methanol yielded a white product: 32.56g, purity >99%, yield: 57.10%.

[0208] The results of Examples 17 to 20 are summarized in Table 5.

[0209] Table 5

[0210] Format temperature Ventilation temperature Product yield Example 1 75℃ 0℃ 91.09％ Example 17 50℃ 0℃ 66.38％ Example 18 60℃ 0℃ 75.76％ Example 19 90℃ 0℃ 69.33％ Example 20 75℃ 30℃ 57.10％

[0211] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing 2-methyl-4-acetylbenzoic acid, characterized in that, Includes the following steps: (a) Compound 2 was obtained by bromination of 2-chloro-4-aminotoluene as a raw material; (b) Compound 2 was subjected to a diazotization reaction and deamination reduction to obtain compound 3; (c) Compound 3 was subjected to a Grignard reaction to give compound 4; (d) Compound 4 was mixed with a protecting agent and dehydrated under the action of a catalyst to obtain compound 5; (e) Compound 5 was hydrolyzed under acidic conditions via a Grignard reaction to give 2-methyl-4-acetylbenzoic acid.

2. The preparation method according to claim 1, characterized in that, In step (a), 2-chloro-4-aminotoluene is used as a raw material, and a bromination system is added dropwise under heating conditions to obtain compound 2; preferably, the bromination system includes a combination of a reaction solvent and a brominating reagent, preferably including dichloromethane / bromine, hydrobromic acid / hydrogen peroxide, DMF / N-bromosuccinimide, DMF / dibromohydantoin, DMSO / hydrobromic acid, and more preferably DMSO / hydrobromic acid.

3. The preparation method according to claim 1, characterized in that, Step (b) includes step (b1): mixing water and compound 2, and diazotizing by adding sodium nitrite aqueous solution dropwise at low temperature under acidic conditions; preferably, the acidic conditions are provided by an inorganic acid, including hydrochloric acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid or hydrochloric acid; Step (b2): Apply a reducing agent as a base, heat to reflux, and add the diazonium salt dropwise to the reducing agent to reduce it to obtain compound 3; preferably, the reducing agent includes methanol, ethanol, isopropanol, hypophosphite, sodium borohydride, and preferably ethanol.

4. The preparation method according to claim 3, characterized in that, In step (b1), the low temperature condition is 0-10℃, preferably 0-5℃.

5. The preparation method according to claim 1, characterized in that, Step (c) includes step (c1): under nitrogen protection, solvent, compound 3 and magnesium shavings are mixed at room temperature to react and obtain Grignard reagent; preferably, the solvent includes tetrahydrofuran, dimethyltetrahydrofuran, a mixture of toluene and tetrahydrofuran, a mixture of toluene and dimethyltetrahydrofuran, preferably tetrahydrofuran; or a mixture of toluene and tetrahydrofuran; Step (c2): Under a nitrogen atmosphere, the generated Grignard reagent is added dropwise to the acetylation reagent to generate compound 4; preferably, the acetylation temperature is -10-10℃, more preferably -5-5℃, and most preferably -5-0℃.

6. The preparation method according to claim 1, characterized in that, In step (d), compound 4, solvent, and protective agent are mixed and refluxed under the action of a catalyst to generate compound 5.

7. The preparation method according to claim 6, characterized in that, In step (d), the solvent includes benzene, toluene, dichloroethane, cyclohexane, preferably cyclohexane or 1,2-dichloroethane.

8. The preparation method according to claim 6, characterized in that, In step (d), the protective agent includes ethylene glycol, propylene glycol, and butanediol, preferably ethylene glycol.

9. The preparation method according to claim 1, characterized in that, Step (e) includes step (e1): under nitrogen protection, solvent, compound 5 and magnesium shavings are mixed and heated to obtain Grignard reagent; preferably, the solvent includes tetrahydrofuran, dimethyltetrahydrofuran, a mixture of toluene and tetrahydrofuran, a mixture of toluene and dimethyltetrahydrofuran, and more preferably a mixture of toluene and tetrahydrofuran; preferably, the reaction temperature (Grenfell temperature) is 60-90°C, more preferably 70-80°C, and more preferably 75-80°C; Step (e2): Carbon dioxide is passed through to generate a carboxylate, which is then hydrolyzed under acidic conditions to generate 2-methyl-4-acetylbenzoic acid; preferably, the temperature at which carbon dioxide is passed through (i.e., the gas temperature) is -5 to 20°C, more preferably -5 to 5°C, and most preferably -5 to 0°C.

10. The preparation method according to claim 9, characterized in that, Solvent: The mass ratio of compound 5 is 1-8:1, preferably 3-5:1, and most preferably 4:1.

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