Method for preparing 2-methyl-4-acetylbenzoic acid

Abstract

The invention relates to the field of pharmaceutical chemicals, and discloses a method for preparing 2-methyl-4-acetylbenzoic acid. The method comprises the following steps: by taking 4-nitro-o-xylene as a raw material, carrying out oxidation reaction to obtain 4-nitro-2-methyl benzoic acid, then carrying out reduction reaction to obtain 4-amino-2-methyl benzoic acid, and then carrying out diazotization, coupling and hydrolysis reaction to obtain the 2-methyl-4-acetyl benzoic acid. The method is mild in reaction condition, high in yield and purity, green, environmentally friendly and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemicals, and in particular to a method for preparing 2-methyl-4-acetylbenzoic acid. Background Art

[0002] Fluerana is a broad-spectrum isoxazoline insecticide that has good insecticidal effects on pests such as Acarida, Ovoidea, Hemiptera, Diptera, and Lepidoptera. Compared with other insecticides on the market, Fluerana has comparable or higher insecticidal activity. Fluerana not only has no significant cross-resistance with existing insecticides, but also has good insecticidal activity against some resistant pests. Therefore, Fluerana is expected to be developed as a pesticide for the prevention and control of agricultural pests. As an important intermediate for the synthesis of Fluerana, 2-methyl-4-acetylbenzoic acid has high economic value and commercial prospects.

[0003] At present, the synthesis methods of 2-methyl-4-acetylbenzoic acid mainly include the following:

[0004] EP2172462A1 discloses a method for preparing 2-methyl-4-acetylbenzoic acid, using 4-bromo-3-methylacetophenone as a raw material, 1,3-diphenylphosphine propane and palladium carbon as catalysts, and carbon monoxide pressurized to 0.8Mpa / 120°C to react to obtain 2-methyl-4-acetylbenzoic acid. The synthesis route is as follows:

[0005]

[0006] However, the carbon monoxide used in this method is a highly toxic gas. Using it under high temperature and high pressure conditions is highly corrosive to equipment and poses a high safety risk. In addition, the catalyst used is expensive, which increases the preparation cost.

[0007] CN109553528A discloses a method for preparing 2-methyl-4-acetylbenzoic acid, using 2-fluorotoluene as a raw material, and obtaining 2-methyl-4-acetylbenzoic acid through acetylation reaction, cyanation reaction and hydrolysis reaction. The synthesis route is as follows:

[0008]

[0009] However, this method has many reaction steps, hydrolysis will produce a large amount of acidic wastewater, the yield is not high, and the raw materials are expensive.

[0010] CN114315748A discloses a method for preparing 4-acetyl-2-methylbenzoic acid, using 4-bromo-2-methylbenzoic acid as a raw material, and obtaining 4-acetyl-2-methylbenzoic acid through Suzuki coupling reaction. The synthetic route is as follows:

[0011]

[0012] However, when this method is applied to format reactions, the format reactions in the process are difficult to control, have a high risk factor, demanding process conditions, low reaction yields, and high costs.

[0013] Therefore, it is urgent to develop a preparation method of 2-methyl-4-acetylbenzoic acid with mild process conditions, high purity and high yield to meet the requirements of industrial production. Summary of the invention

[0014] The purpose of the present invention is to overcome the problems of harsh preparation process conditions and low yield of 2-methyl-4-acetylbenzoic acid in the prior art, and to provide a method for preparing 2-methyl-4-acetylbenzoic acid. The method has mild reaction conditions, high yield and purity, low cost, is more environmentally friendly, and is suitable for industrial production.

[0015] In order to achieve the above object, the present invention provides a method for preparing 2-methyl-4-acetylbenzoic acid, wherein the method comprises: using 4-nitro-o-xylene as a raw material, obtaining 4-nitro-2-methylbenzoic acid through an oxidation reaction, then obtaining 4-amino-2-methylbenzoic acid through a reduction reaction, and then obtaining 2-methyl-4-acetylbenzoic acid through diazotization, coupling and hydrolysis reactions.

[0016] Through the above technical solution, the present invention can achieve the following technical effects:

[0017] (1) The method for preparing 2-methyl-4-acetylbenzoic acid provided by the present invention uses 4-nitro-o-xylene as a starting material and undergoes oxidation, reduction, diazotization, coupling and hydrolysis reactions to finally prepare 2-methyl-4-acetylbenzoic acid, wherein the starting material is cheap and readily available, the conditions in the entire process are mild, the reaction is easy to control, the raw material conversion rate is high, the by-products are small, and the product purity is high;

[0018] (2) The method for preparing 2-methyl-4-acetylbenzoic acid provided by the present invention avoids the dangers of highly toxic gases, highly toxic cyanides, and high-temperature and high-pressure oxidation operations that may be involved in the prior art process, thereby greatly improving the safety of production;

[0019] (3) The method for preparing 2-methyl-4-acetylbenzoic acid provided by the present invention can continuously feed the diazotization, coupling and hydrolysis reactions, shortening the reaction time of the entire process, reducing the post-processing time cost and the intermediate loss of the target product, and improving the yield;

[0020] (4) The method for preparing 2-methyl-4-acetylbenzoic acid provided by the present invention is simple to operate, has low requirements on production equipment, significantly reduces the amount of three wastes generated, fundamentally reduces pollution to the environment, has broad application prospects, and is conducive to industrialization. DETAILED DESCRIPTION

[0021] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0022] The invention provides a method for preparing 2-methyl-4-acetylbenzoic acid, wherein the method comprises: using 4-nitro-o-xylene as a raw material, performing an oxidation reaction to obtain 4-nitro-2-methylbenzoic acid, performing a reduction reaction to obtain 4-amino-2-methylbenzoic acid, and then performing diazotization, coupling and hydrolysis reactions to obtain 2-methyl-4-acetylbenzoic acid.

[0023] In the present invention, the compound 4-nitro-o-xylene is used as a raw material, and 2-methyl-4-acetylbenzoic acid is finally prepared by oxidation, reduction, diazotization, coupling and hydrolysis reactions. In the preparation process of 2-methyl-4-acetylbenzoic acid, diazotization, coupling and hydrolysis reactions can be continuously fed, shortening the reaction time of the entire process, reducing the time cost of post-processing and the intermediate loss of the target product, having a good yield, mild reaction conditions, simple operation, and cheap and easily available starting raw materials. No highly toxic carbon monoxide or cyanide is needed in the process, and the method is suitable for industrialized scale-up production.

[0024] The route of preparing 2-methyl-4-acetylbenzoic acid of the present invention is as follows:

[0025]

[0026] In some embodiments of the present invention, preferably, the specific step of the oxidation reaction includes: in the presence of a first catalyst and a first solvent, subjecting 4-nitro-o-xylene to an oxidation reaction to obtain 4-nitro-2-methylbenzoic acid.

[0027] In some embodiments of the present invention, preferably, relative to 1 mol of 4-nitro-o-xylene, the amount of the first catalyst is 0.01-0.2 mol, for example, 0.01 mol, 0.025 mol, 0.05 mol, 0.75 mol, 0.1 mol, 0.125 mol, 0.15 mol, 0.175 mol, 0.2 mol, and any value in the range consisting of any two numerical values, preferably 0.02-0.05 mol; the amount of the first solvent is 6.5-8.5 mol, for example, 6.5 mol, 7 mol, 7.5 mol, 8 mol, 8.5 mol, and any value in the range consisting of any two numerical values, preferably 7-8 mol.

[0028] In some embodiments of the present invention, preferably, the first catalyst is a metal catalyst, preferably at least one selected from cobalt chloride, copper chloride, zinc chloride and tin chloride, more preferably cobalt chloride.

[0029] In some embodiments of the present invention, preferably, the first solvent is an organic solvent, preferably selected from monocarboxylic acids, more preferably selected from at least one of acetic acid, propionic acid and butyric acid, and further preferably acetic acid.

[0030] In some embodiments of the present invention, preferably, the conditions of the oxidation reaction include: in the presence of oxygen, the reaction temperature is 40-200°C, preferably 80-160°C; the reaction pressure is 0.5-4.5MPa, preferably 2-4MPa; the reaction time is 5-10h, preferably 6-8h. The preferred conditions are more conducive to improving the purity and yield of 2-methyl-4-acetylbenzoic acid.

[0031] In the present invention, in the oxidation reaction, after the 4-nitro-o-xylene has reacted completely, the reaction is stopped.

[0032] In some embodiments of the present invention, preferably, the specific step of the reduction reaction comprises: in the presence of a second catalyst and a second solvent, subjecting 4-nitro-2-methylbenzoic acid to a reduction reaction to obtain 4-amino-2-methylbenzoic acid.

[0033] In some embodiments of the present invention, preferably, relative to 1 mol of 4-nitro-2-methylbenzoic acid, the amount of the second catalyst is 0.01-0.2 mol, for example, 0.01 mol, 0.025 mol, 0.05 mol, 0.75 mol, 0.1 mol, 0.125 mol, 0.15 mol, 0.175 mol, 0.2 mol, and any value in the range consisting of any two numerical values, preferably 0.05-0.1 mol; the amount of the second solvent is 15.5-18 mol, for example, 15.5 mol, 16 mol, 16.5 mol, 17.5 mol, 18 mol, and any value in the range consisting of any two numerical values, preferably 16-17.5 mol.

[0034] In some embodiments of the present invention, preferably, the second catalyst is a palladium catalyst, preferably palladium carbon.

[0035] In some embodiments of the present invention, preferably, the second solvent is selected from at least one of ethanol, methanol, isopropanol and acetonitrile, preferably methanol.

[0036] In some embodiments of the present invention, preferably, the reduction reaction conditions include: in the presence of hydrogen, the reaction temperature is 20-60°C, preferably 30-60°C; the reaction pressure is 0.5-4.5MPa, preferably 2-4MPa; the reaction time is 2-10h, preferably 3-8h. The preferred conditions are more conducive to improving the purity and yield of 2-methyl-4-acetylbenzoic acid.

[0037] In the present invention, in the reduction reaction, after 4-nitro-2-methylbenzoic acid is produced, the reaction is stopped.

[0038] In some embodiments of the present invention, preferably, the diazotization reaction process comprises: under acidic conditions, diazotizing 4-amino-2-methylbenzoic acid with a diazotization reagent to obtain a clear diazonium salt solution.

[0039] In the present invention, the specific steps of the diazotization reaction include: under acidic conditions and at a temperature of 0-5°C, adding a diazotization reagent into a four-necked bottle containing 4-amino-2-methylbenzoic acid, and stirring the mixture for 0.5-1.5 hours after the addition to obtain a light yellow diazonium salt clear liquid.

[0040] In some embodiments of the present invention, preferably, the acidic condition is provided by an inorganic acid, preferably the inorganic acid is selected from hydrochloric acid and / or sulfuric acid, preferably sulfuric acid. The inorganic acid is conducive to dissolving 4-amino-2-methylbenzoic acid, producing nitric acid, and maintaining the strong acidity of the reaction medium.

[0041] In the present invention, the inorganic acid is present in the form of an inorganic acid aqueous solution, preferably, the concentration of the inorganic acid aqueous solution is 18-25wt%, preferably 20-22wt%. When the concentration of the inorganic acid aqueous solution is less than 18wt%, the concentration of the acid is low, the rate at which 4-amino-2-methylbenzoic acid is converted into ammonium salt by the action of the inorganic acid is low, and the diazotization reaction time is long; when the concentration of the inorganic acid aqueous solution is greater than 25wt%, the concentration of the acid is high, which is not conducive to the hydrolysis of the ammonium salt into free 4-amino-2-methylbenzoic acid, so that the concentration of the free 4-amino-2-methylbenzoic acid participating in the diazotization reaction is significantly reduced, resulting in a decrease in the diazotization reaction rate and an increase in the reaction time.

[0042] In some embodiments of the present invention, preferably, the diazotization agent is selected from nitrites, preferably sodium nitrite and / or potassium nitrite, more preferably sodium nitrite.

[0043] In some embodiments of the present invention, preferably, relative to 1 mol of 4-amino-2-methylbenzoic acid, the amount of the inorganic acid used is 1.75-3 mol, for example, 1.75 mol, 2 mol, 2.25 mol, 2.5 mol, 2.75 mol, 3 mol, and any value in the range consisting of any two values, preferably 2-2.5 mol.

[0044] In the present invention, the amount of the inorganic acid used is less than 1.75 mol relative to 1 mol of 4-amino-2-methylbenzoic acid, the acid amount is insufficient, and the generated diazonium salt is easy to self-couple with the unreacted 4-amino-2-methylbenzoic acid to generate a large amount of diazoamino compounds; the amount of the inorganic acid used is greater than 3 mol relative to 1 mol of 4-amino-2-methylbenzoic acid, and the excessive acid causes waste; the amount of the inorganic acid used is 1.75-3 mol relative to 1 mol of 4-amino-2-methylbenzoic acid, which is conducive to making the reaction have a higher conversion rate and yield, and the effect is better within the preferred range.

[0045] In some embodiments of the present invention, preferably, the amount of the diazotization reagent used is 1.05-1.2 mol relative to 1 mol of 4-amino-2-methylbenzoic acid.

[0046] In the present invention, the amount of the diazotization reagent used is less than 1.05 mol relative to 1 mol of 4-amino-2-methylbenzoic acid, and self-coupling is likely to occur to produce a diazoamino compound; relative to 1 mol of 4-amino-2-methylbenzoic acid, the amount of the diazotization reagent used is greater than 1.2 mol, and the diazotization reagent is excessive, so that the diazotization reagent will induce a series of side reactions, resulting in a low yield of the next coupling reaction.

[0047] In the present invention, preferably, the feeding time of the diazotizing agent is 2-3h. If the feeding is too slow, the unreacted 4-amino-2-methylbenzoic acid will react with the diazonium salt to produce a yellow precipitate of diazoamino; if the feeding is too fast, it will cause a local excess of the diazotizing agent, excessive heat release, and difficulty in control. At the same time, the nitrous acid production rate exceeds the consumption rate of the diazotization reaction, resulting in partial decomposition loss of nitrous acid, resulting in a waste of raw materials and the generation of toxic gases.

[0048] In some embodiments of the present invention, preferably, the conditions of the diazotization reaction include: reaction temperature of 0-5°C, reaction time of 3-10h.

[0049] In the present invention, the temperature of the diazotization reaction is not higher than 5°C. Most diazonium salts are unstable and easily decomposed under conditions higher than 5°C.

[0050] In some embodiments of the present invention, preferably, the coupling reaction process comprises: subjecting the diazonium salt clear solution obtained by the diazotization reaction to a coupling reaction in the presence of a catalyst and a solution containing acetaldehyde oxime to obtain an organic phase.

[0051] In the present invention, the coupling reaction process may further include standing the mixture obtained by the coupling reaction for stratification, and washing the obtained organic phase with an alkaline aqueous solution. Preferably, the obtained organic phase is washed with an alkaline aqueous solution until it becomes neutral.

[0052] In the present invention, the alkali is selected from at least one of aqueous ammonia, sodium bicarbonate, sodium bicarbonate, potassium bicarbonate and potassium carbonate, preferably aqueous ammonia. The concentration of the aqueous alkali solution is not particularly limited, preferably 4-8wt%, more preferably 5wt%.

[0053] In some embodiments of the present invention, preferably, the catalyst for the coupling reaction is a copper salt, preferably at least one of copper sulfate, copper acetate, cupric chloride and cuprous chloride.

[0054] In some embodiments of the present invention, preferably, the acidic condition is provided by an organic acid, preferably the organic acid is a monocarboxylic acid, more preferably at least one selected from acetic acid, propionic acid and butyric acid, and further preferably acetic acid. In the present invention, the role of the monocarboxylic acid is to generate sodium carboxylate as a buffer for the reaction system during the reaction.

[0055] In some embodiments of the present invention, preferably, the acetaldehyde oxime is present in the form of an acetaldehyde oxime aqueous solution. In the present invention, preferably, the concentration of the acetaldehyde oxime aqueous solution is 45-55wt%, more preferably 50wt%.

[0056] In some embodiments of the present invention, preferably, the solvent in the solution is an inert organic solvent, preferably at least one selected from toluene, o-xylene, m-xylene and p-xylene, preferably toluene.

[0057] In the present invention, preferably, the amount of the solvent is 3-10 mol relative to 1 mol of 4-amino-2-methylbenzoic acid. The function of the solvent is to extract the generated 2-methyl-4-acetylbenzoic acid oxime intermediate in time to prevent it from continuing to have other side reactions in the system.

[0058] In some embodiments of the present invention, preferably, relative to 1 mol 4-amino-2-methylbenzoic acid, the amount of the catalyst is 0.04-0.16 mol, for example, 0.04 mol, 0.05 mol, 0.08 mol, 0.1 mol, 0.12 mol, 0.14 mol, 0.16 mol, and any value in the range composed of any two numerical values, preferably 0.05-0.1 mol; the amount of acetaldehyde oxime is 1-5 mol, for example, 1 mol, 1.1 mol, 1.5 mol, 2 mol, 2.5 mol, 3 mol, 3.5 mol, 4 mol, 4.5 mol, 5 mol, and any value in the range composed of any two numerical values, preferably 1.1-1.5 mol; the amount of the organic acid is 0.1-2 mol, for example, 0.1 mol, 0.2 mol, 0.5 mol, 0.8 mol, 1.1 mol, 1.4 mol, 1.7 mol, 2 mol, and any value in the range composed of any two numerical values, preferably 0.2-1.1 mol.

[0059] In some embodiments of the present invention, preferably, during the reaction of adding the diazonium salt in the coupling reaction, the pH of the reaction system is controlled to be 4-4.5 and the temperature of the reaction system is controlled to be 0-5°C.

[0060] In the present invention, during the reaction of adding diazonium salt in the coupling reaction, the pH of the reaction system is controlled to be 4-4.5 by dripping liquid caustic soda, preferably, the concentration of the liquid caustic soda is 30wt%. Controlling the pH of the reaction system in the coupling reaction within the above range is conducive to improving the reaction yield.

[0061] In the present invention, the temperature of the reaction system during the coupling reaction is controlled by an ice-salt bath, and the reaction temperature is not higher than 5°C, preferably 0-5°C.

[0062] In the present invention, in the coupling reaction, the reaction is stopped after the diazonium salt clear solution (ammonium salt) has reacted completely.

[0063] In some embodiments of the present invention, preferably, the hydrolysis reaction process comprises: subjecting the organic phase obtained by the diazotization reaction to a hydrolysis reaction under acidic conditions to obtain 2-methyl-4-acetylbenzoic acid.

[0064] In some embodiments of the present invention, preferably, the acidic condition is provided by an inorganic acid, preferably the inorganic acid is selected from hydrochloric acid and / or sulfuric acid, preferably hydrochloric acid.

[0065] In the present invention, the inorganic acid is present in the form of an inorganic acid aqueous solution, preferably, the concentration of the inorganic acid aqueous solution is 15-22wt%, preferably 18-20wt%. The concentration of the inorganic acid aqueous solution is less than 15wt%, and too low a concentration results in a long hydrolysis reaction time, while the concentration of the inorganic acid aqueous solution is greater than 22wt%, and too high a concentration results in a decrease in reaction yield.

[0066] In some embodiments of the present invention, preferably, relative to 1 mol of 4-amino-2-methylbenzoic acid, the amount of the inorganic acid used is 0.05-2 mol, preferably 0.0.8-2 mol.

[0067] In some embodiments of the present invention, preferably, the conditions of the hydrolysis reaction include: reaction temperature of 20-100° C., and reaction time of 3-6 h.

[0068] In the present invention, in the hydrolysis reaction, after the methyl-4-acetylbenzoic acid intermediate reacts completely, the reaction is stopped. In the present invention, the hydrolysis reaction process may also include standing and stratifying the mixture obtained by the hydrolysis reaction, washing the obtained organic phase with an alkaline aqueous solution, drying, desolventizing and recrystallizing to obtain a white solid, that is, obtaining 2-methyl-4-acetylbenzoic acid.

[0069] In the present invention, the alkali is selected from at least one of ammonia water, sodium bicarbonate, sodium bicarbonate, potassium bicarbonate and potassium carbonate, and more preferably sodium carbonate and / or sodium bicarbonate. The concentration of the aqueous alkali solution is not particularly limited, and preferably the concentration is 4-8wt%, more preferably 5wt%. Preferably, the obtained organic phase is washed with an aqueous alkali solution until it is neutral.

[0070] In the present invention, the drying method is to use a desiccant for drying, and the desiccant is preferably anhydrous sodium sulfate.

[0071] In the present invention, the diazotization, coupling and hydrolysis reactions are consecutive steps, which shortens the reaction time of the entire process, reduces the time cost of post-treatment and the intermediate loss of the target compound, improves the reaction yield, and is suitable for industrial production.

[0072] In the present invention, room temperature refers to "25° C." unless otherwise specified.

[0073] The present invention will be described in detail below through examples.

[0074] In the following examples, unless otherwise specified, all raw materials used were commercially available.

[0075] The contents (purity) of reactants and products were measured by liquid chromatography (Agilent HPLC 1260).

[0076] The conversion and selectivity of the reaction were calculated by the following formula:

[0077] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0078] Yield = actual mass of target product / theoretical mass of target product × 100%.

[0079] Example 1

[0080] (1) Oxidation reaction: At room temperature, 45 g of acetic acid, 15.1 g (0.1 mol) of 4-nitro-o-xylene and 0.75 g of cobalt chloride were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and stirred. Nitrogen was introduced for replacement three times, and oxygen was introduced to 4 MPa. The temperature was raised to 140-160° C. and the reaction was carried out for 8 h. The reaction was tracked by HPLC. When the percentage of 4-nitro-o-xylene in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., zirconium oxide was filtered, and acetic acid was recovered under reduced pressure to obtain 4-nitro-2-methylbenzoic acid with a purity of 95% and a yield of 85% (based on 4-nitro-o-xylene);

[0081] (2) Reduction reaction: at room temperature, 54 g of methanol, 18.1 g (0.1 mol) of 4-nitro-2-methylbenzoic acid and 0.9 g of palladium carbon were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and nitrogen was introduced for replacement three times. Hydrogen was introduced to 4 MPa, and the temperature was raised to 50-60° C. for reaction for 6 h. The reaction was followed by HPLC. When the percentage of 4-nitro-2-methylbenzoic acid in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., the palladium carbon was filtered, and the solvent was evaporated under reduced pressure to recover methanol to obtain 4-amino-2-methylbenzoic acid with a purity of 96% and a yield of 95% (based on 4-nitro-2-methylbenzoic acid);

[0082] (3) Diazotization reaction: At room temperature, 100 g of sulfuric acid aqueous solution (20 wt%) and 15.1 g (0.1 mol) of 4-amino-2-methylbenzoic acid were added in sequence to a 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser. After cooling to 0° C., 25.3 g of NaNO2 aqueous solution (30 wt%) was added dropwise, and the temperature during the addition was controlled at 0-5° C. The addition was completed after 3 h, and the mixture was stirred at 0-5° C. for 1 h to obtain a light yellow diazonium salt clear solution, which was kept warm for later use.

[0083] Coupling reaction: add 1.51g of copper sulfate, 2.62g of acetic acid, 16.4g of acetaldehyde oxime aqueous solution (50wt%) and 30mL of toluene to a 500mL four-necked bottle, stir and cool to below 5°C, add the diazonium salt clarified solution, and simultaneously dropwise add liquid caustic soda (30wt%), control the pH at 4-4.5, the temperature at 0-5°C, add dropwise for 3h, heat to 15°C and stir for 1h, track the reaction by HPLC, stop the reaction after the percentage of the ammonium salt peak area to the total peak area is less than 0.5%, let stand for stratification, and wash the obtained organic phase with aqueous ammonia (5wt%) until neutral;

[0084] Hydrolysis reaction: 30 mL (20 wt%) of hydrochloric acid was added to the organic phase, heated and stirred under reflux for 3 h, and the reaction was tracked by HPLC. When the peak area of ​​the methyl-4-acetylbenzoic acid intermediate accounted for less than 0.5% of the total peak area, the reaction was stopped, and the phase was allowed to stand for stratification. The organic phase was washed with a sodium bicarbonate aqueous solution (5 wt%) until neutral, dried over anhydrous sodium sulfate, and recrystallized after desolventization to obtain a white solid, i.e., 2-methyl-4-acetylbenzoic acid, with a purity of 99.6% and a yield of 75%;

[0085] The total yield of the above steps (1)-(3) is 60.56%.

[0086] Example 2

[0087] (1) Oxidation reaction: At room temperature, 45 g of acetic acid, 15.1 g (0.1 mol) of 4-nitro-o-xylene and 0.75 g of cobalt chloride were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and stirred. Nitrogen was introduced for replacement three times, and oxygen was introduced to 3.5 MPa. The temperature was raised to 140-160° C. and the reaction was carried out for 8 h. The reaction was tracked by HPLC. When the percentage of 4-nitro-o-xylene in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., zirconium oxide was filtered, and acetic acid was recovered under reduced pressure to obtain 4-nitro-2-methylbenzoic acid with a purity of 95% and a yield of 83% (based on 4-nitro-o-xylene);

[0088] (2) Reduction reaction: at room temperature, 54 g of methanol, 18.1 g (0.1 mol) of 4-nitro-2-methylbenzoic acid and 0.9 g of palladium carbon were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and nitrogen was introduced for replacement three times. Hydrogen was introduced to 4 MPa, and the temperature was raised to 50-60° C. for reaction for 7 h. The reaction was followed by HPLC. When the percentage of 4-nitro-2-methylbenzoic acid in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., the palladium carbon was filtered, and the solvent was evaporated under reduced pressure to recover methanol to obtain 4-amino-2-methylbenzoic acid with a purity of 96% and a yield of 94% (based on 4-nitro-2-methylbenzoic acid);

[0089] (3) Diazotization reaction: At room temperature, 100 g of sulfuric acid aqueous solution (20 wt%) and 15.1 g (0.1 mol) of 4-amino-2-methylbenzoic acid were added in sequence to a 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser. After cooling to 0° C., 25.3 g of NaNO2 aqueous solution (30 wt%) was added dropwise, and the temperature during the addition was controlled at 0-5° C. The addition was completed after 3 h, and the mixture was stirred at 0-5° C. for 1 h to obtain a light yellow diazonium salt clear solution, which was kept warm for later use.

[0090] Coupling reaction: add 1.08g of copper chloride, 2.93g of acetic acid, 15.3g of acetaldehyde oxime aqueous solution (50wt%) and 30mL of toluene to a 500mL four-necked flask, stir and cool to below 5°C, add the diazonium salt clarified solution, and simultaneously dropwise add liquid caustic soda (30wt%), control the pH at 4-4.5, the temperature at 0-5°C, add dropwise for 3h, heat to 15°C and stir for 1h, track the reaction by HPLC, stop the reaction when the percentage of the ammonium salt peak area to the total peak area is less than 0.5%, let stand for stratification, and wash the obtained organic phase with aqueous ammonia (5wt%) until neutral;

[0091] Hydrolysis reaction: 30 mL (20 wt%) of hydrochloric acid was added to the organic phase, heated and stirred under reflux for 3 h, and the reaction was tracked by HPLC. When the peak area of ​​the methyl-4-acetylbenzoic acid intermediate accounted for less than 0.5% of the total peak area, the reaction was stopped, and the phase was allowed to stand for stratification. The organic phase was washed with a sodium bicarbonate aqueous solution (5 wt%) until neutral, dried over anhydrous sodium sulfate, and recrystallized after desolventization to obtain a white solid, i.e., 2-methyl-4-acetylbenzoic acid, with a purity of 99.6% and a yield of 74%;

[0092] The total yield of the above steps (1)-(3) is 58.62%.

[0093] Example 3

[0094] (1) Oxidation reaction: At room temperature, 45 g of acetic acid, 15.1 g (0.1 mol) of 4-nitro-o-xylene and 0.75 g of cobalt chloride were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and stirred. Nitrogen was introduced for replacement three times, and oxygen was introduced to 3 MPa. The temperature was raised to 120-140° C. and the reaction was carried out for 10 h. The reaction was followed by HPLC. When the percentage of 4-nitro-o-xylene in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., zirconium oxide was filtered, and acetic acid was recovered under reduced pressure to obtain 4-nitro-2-methylbenzoic acid with a purity of 95% and a yield of 75% (based on 4-nitro-o-xylene);

[0095] (2) Reduction reaction: at room temperature, 54 g of methanol, 18.1 g (0.1 mol) of 4-nitro-2-methylbenzoic acid and 0.9 g of palladium carbon were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and nitrogen was introduced for replacement three times. Hydrogen was introduced to 3 MPa, and the temperature was raised to 50-60° C. for reaction for 10 h. The reaction was tracked by HPLC. When the percentage of 4-nitro-2-methylbenzoic acid in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., the palladium carbon was filtered, and the solvent was evaporated under reduced pressure to recover methanol to obtain 4-amino-2-methylbenzoic acid with a purity of 96% and a yield of 85% (based on 4-nitro-2-methylbenzoic acid);

[0096] (3) Diazotization reaction: At room temperature, 100 g of sulfuric acid aqueous solution (20 wt%) and 15.1 g (0.1 mol) of 4-amino-2-methylbenzoic acid were added in sequence to a 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser. After cooling to 0° C., 25.3 g of NaNO2 aqueous solution (30 wt%) was added dropwise, and the temperature during the addition was controlled at 0-5° C. The addition was completed after 3 h, and the mixture was stirred at 0-5° C. for 1 h to obtain a light yellow diazonium salt clear solution, which was kept warm for later use.

[0097] Coupling reaction: add 2.8g of copper acetate, 1.7g of acetic acid, 15g of acetaldehyde oxime aqueous solution (50wt%) and 30mL of toluene to a 500mL four-necked bottle, stir and cool to below 5°C, add the diazonium salt clarified solution, and simultaneously dropwise add liquid caustic soda (30wt%), control the pH at 4-4.5, the temperature at 0-5°C, and complete the dropwise addition in 3h, raise the temperature to 15°C and stir for 1h, track the reaction by HPLC, stop the reaction when the peak area of ​​the ammonium salt accounts for less than 0.5% of the total peak area, let stand for stratification, and wash the obtained organic phase with aqueous ammonia (5wt%) until neutral;

[0098] Hydrolysis reaction: 30 mL (20 wt%) of hydrochloric acid was added to the organic phase, heated and stirred under reflux for 5 h, and the reaction was tracked by HPLC. When the peak area of ​​the methyl-4-acetylbenzoic acid intermediate accounted for less than 0.5% of the total peak area, the reaction was stopped, and the phase was allowed to stand for stratification. The organic phase was washed with a sodium bicarbonate aqueous solution (5 wt%) until neutral, dried over anhydrous sodium sulfate, and recrystallized after desolventization to obtain a white solid, i.e., 2-methyl-4-acetylbenzoic acid, with a purity of 99.5% and a yield of 73%;

[0099] The total yield of the above steps (1)-(3) is 46.53%.

[0100] Example 4

[0101] (1) Oxidation reaction: At room temperature, 45 g of acetic acid, 15.1 g (0.1 mol) of 4-nitro-o-xylene and 0.75 g of cobalt chloride were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and stirred. Nitrogen was introduced for replacement three times, and oxygen was introduced to 2 MPa. The temperature was raised to 160-180° C. and the reaction was carried out for 8 h. The reaction was tracked by HPLC. When the percentage of 4-nitro-o-xylene in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., zirconium oxide was filtered, and acetic acid was recovered under reduced pressure to obtain 4-nitro-2-methylbenzoic acid with a purity of 92% and a yield of 70% (based on 4-nitro-o-xylene);

[0102] (2) Reduction reaction: at room temperature, 54 g of methanol, 18.1 g (0.1 mol) of 4-nitro-2-methylbenzoic acid and 0.9 g of palladium carbon were added to a 500 mL autoclave equipped with a mechanical stirrer, a thermometer and a condenser, and nitrogen was introduced for replacement three times. Hydrogen was introduced to 2 MPa, and the temperature was raised to 50-60° C. for reaction for 10 h. The reaction was tracked by HPLC. When the percentage of 4-nitro-2-methylbenzoic acid in all peak areas was less than 0.2%, the reaction was stopped, the temperature was lowered to 20-30° C., the palladium carbon was filtered, and the solvent was evaporated under reduced pressure to recover methanol to obtain 4-amino-2-methylbenzoic acid with a purity of 96% and a yield of 80% (based on 4-nitro-2-methylbenzoic acid);

[0103] (3) Diazotization reaction: At room temperature, 100 g of sulfuric acid aqueous solution (20 wt%) and 15.1 g (0.1 mol) of 4-amino-2-methylbenzoic acid were added in sequence to a 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser. After cooling to 0° C., 25.3 g of NaNO2 aqueous solution (30 wt%) was added dropwise, and the temperature during the addition was controlled at 0-5° C. The addition was completed after 2 h, and the mixture was stirred at 0-5° C. for 1 h to obtain a light yellow diazonium salt clarified liquid, which was kept warm for later use.

[0104] Coupling reaction: add 1.37g of cuprous chloride, 3.34g of acetic acid, 16.57g of acetaldehyde oxime aqueous solution (50wt%) and 30mL of toluene to a 500mL four-necked bottle, stir and cool to below 5°C, add the diazonium salt clarified solution, and simultaneously dropwise add liquid caustic soda (30wt%), control the pH at 4-4.5, the temperature at 0-5°C, add dropwise for 2h, heat to 15°C and stir for 2h, track the reaction by HPLC, stop the reaction when the peak area of ​​the ammonium salt accounts for less than 0.5% of the total peak area, let stand for stratification, and wash the obtained organic phase with aqueous ammonia (5wt%) until neutral;

[0105] Hydrolysis reaction: 30 mL (20 wt%) of hydrochloric acid was added to the organic phase, heated and stirred under reflux for 3 h, and the reaction was tracked by HPLC. After the peak area of ​​the 2-methyl-4-acetylbenzoic acid intermediate accounted for less than 0.5% of the total peak area, the reaction was stopped, and the phase was allowed to stand for stratification. The organic phase was washed with a sodium bicarbonate aqueous solution (5 wt%) until neutral, dried over anhydrous sodium sulfate, and recrystallized after desolventization to obtain a white solid, i.e., 2-methyl-4-acetylbenzoic acid, with a purity of 99.3% and a yield of 70%;

[0106] The total yield of the above steps (1)-(3) is 39.2%.

[0107] It can be seen from the above Examples 1-4 that the method provided by the present invention, i.e., using 4-nitro-o-xylene as a starting material, undergoing oxidation, reduction, diazotization, coupling and hydrolysis reactions, and finally obtaining the target product 2-methyl-4-acetylbenzoic acid, avoids the defects of harsh reaction conditions and high cost, and has the advantages of mild conditions, high reaction yield and purity, and low cost.

[0108] Compared with Example 1, in Example 3 and Example 4, the purity and yield of the obtained 2-methyl-4-acetylbenzoic acid were slightly reduced, and the total yield of the reaction was slightly reduced because the preferred conditions of the present invention were not fully adopted in the reactions involved in steps (1) to (3).

[0109] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing 2-methyl-4-acetylbenzoic acid, characterized in that: The method comprises: using 4-nitro-o-xylene as a raw material, performing an oxidation reaction to obtain 4-nitro-2-methylbenzoic acid, performing a reduction reaction to obtain 4-amino-2-methylbenzoic acid, and then performing diazotization, coupling and hydrolysis reactions to obtain 2-methyl-4-acetylbenzoic acid.

2. The method according to claim 1, wherein: The specific steps of the oxidation reaction include: in the presence of a first catalyst and a first solvent, causing 4-nitro-o-xylene to undergo an oxidation reaction to obtain 4-nitro-2-methylbenzoic acid; Preferably, relative to 1 mol of 4-nitro-o-xylene, the amount of the first catalyst is 0.01-0.2 mol, preferably 0.02-0.05 mol; the amount of the first solvent is 6.5-8.5 mol, preferably 7-8 mol; Preferably, the first catalyst is a metal catalyst, preferably at least one selected from cobalt chloride, copper chloride, zinc chloride and tin chloride, more preferably cobalt chloride; Preferably, the first solvent is an organic solvent, preferably selected from monocarboxylic acids, more preferably selected from at least one of acetic acid, propionic acid and butyric acid, and further preferably acetic acid.

3. The method according to claim 2, wherein: The conditions of the oxidation reaction include: in the presence of oxygen, the reaction temperature is 40-200° C., preferably 80-160° C.; the reaction pressure is 0.5-4.5 MPa, preferably 2-4 MPa; the reaction time is 5-10 h, preferably 6-8 h.

4. The method according to any one of claims 1 to 3, wherein: The specific steps of the reduction reaction include: in the presence of a second catalyst and a second solvent, causing 4-nitro-2-methylbenzoic acid to undergo a reduction reaction to obtain 4-amino-2-methylbenzoic acid; Preferably, relative to 1 mol of 4-nitro-2-methylbenzoic acid, the amount of the second catalyst is 0.01-0.2 mol, preferably 0.05-0.1 mol; the amount of the second solvent is 15.5-18 mol, preferably 16-17.5 mol; Preferably, the second catalyst is a palladium catalyst, preferably palladium on carbon; Preferably, the second solvent is selected from at least one of ethanol, methanol, isopropanol and acetonitrile, preferably methanol.

5. The method according to claim 4, wherein: The reduction reaction conditions include: in the presence of hydrogen, the reaction temperature is 20-60° C., preferably 30-60° C.; the reaction pressure is 0.5-4.5 MPa, preferably 2-4 MPa; the reaction time is 2-10 h, preferably 3-8 h.

6. The method according to any one of claims 1 to 5, wherein: The diazotization reaction process comprises: under acidic conditions, diazotizing 4-amino-2-methylbenzoic acid with a diazotization reagent to obtain a clear diazonium salt solution; Preferably, the acidic condition is provided by an inorganic acid, preferably the inorganic acid is selected from hydrochloric acid and / or sulfuric acid, preferably sulfuric acid; Preferably, the diazotizing agent is selected from nitrites, preferably selected from sodium nitrite and / or potassium nitrite, more preferably sodium nitrite; Preferably, relative to 1 mol of 4-amino-2-methylbenzoic acid, the amount of the inorganic acid used is 1.75-3 mol; and the amount of the diazotizing agent used is 1.05-1.2 mol.

7. The method according to claim 6, wherein: The conditions of the diazotization reaction include: reaction temperature of 0-5°C and reaction time of 3-10h.

8. The method according to any one of claims 1 to 7, wherein: The coupling reaction process comprises: in the presence of a catalyst and an acidic condition, in the presence of a solution containing acetaldehyde oxime, subjecting the diazonium salt clear solution obtained by the diazotization reaction to a coupling reaction to obtain an organic phase; Preferably, the catalyst for the coupling reaction is a copper salt, preferably at least one of copper sulfate, copper acetate, copper chloride and cuprous chloride; Preferably, the acidic condition is provided by an organic acid, preferably the organic acid is a monocarboxylic acid, more preferably at least one selected from acetic acid, propionic acid and butyric acid, further preferably acetic acid; Preferably, the acetaldehyde oxime is present in the form of an acetaldehyde oxime aqueous solution; Preferably, the solvent in the solution is an inert organic solvent, preferably at least one selected from toluene, o-xylene, m-xylene and p-xylene, preferably toluene; Preferably, relative to 1 mol of 4-amino-2-methylbenzoic acid, the amount of the catalyst is 0.04-0.16 mol, preferably 0.05-0.1 mol; the amount of acetaldehyde oxime is 1-5 mol, preferably 1.1-1.5 mol; the amount of the organic acid is 0.1-2 mol, preferably 0.2-1.1 mol.

9. The method according to claim 8, wherein: In the coupling reaction, during the reaction of adding the diazonium salt, the pH of the reaction system is controlled to be 4-4.5, the temperature of the reaction system is controlled to be 0-5° C., and the reaction time is controlled to be 3-8 hours.

10. The method according to any one of claims 1 to 9, wherein: The hydrolysis reaction process comprises: under acidic conditions, hydrolyzing the organic phase obtained by the diazotization reaction to obtain 2-methyl-4-acetylbenzoic acid; Preferably, the acidic condition is provided by an inorganic acid, preferably the inorganic acid is selected from hydrochloric acid and / or sulfuric acid, preferably hydrochloric acid; Preferably, relative to 1 mol of 4-amino-2-methylbenzoic acid, the amount of the inorganic acid is 0.1-2.1 mol, preferably 0.8-2 mol; Preferably, the conditions of the hydrolysis reaction include: reaction temperature of 20-100° C., and reaction time of 3-6 h.

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