Synthesis method of high-purity p-methoxybenzoic acid

Abstract

The invention discloses a synthetic method of high-purity p-methoxybenzoic acid. The synthetic method comprises six steps of catalyst activation, electrophilic substitution, quenching, hydrolysis, solvent recovery and purification and crystallization. Through aluminum trichloride-carbon tetrachloride complex pre-activation, low-temperature dropwise adding (0-5 DEG C and 5-10 DEG C), gradient temperature control quenching (less than or equal to 10 DEG C to 20-25 DEG C), 10-12% hydrochloric acid hydrolysis, normal pressure / reduced pressure distillation and methanol aqueous solution gradient crystallization, the product purity reaches 99.5%-99.8%, the yield is 91.5%-93.8%, the para-selectivity is greater than or equal to 98%, and the solvent recovery rate is 94.7%-96.6%. The method effectively reduces by-products, emulsification and impurities, reduces the cost through solvent recycling, and is suitable for industrial production of medicine and perfume intermediates.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical organic synthesis technology, specifically relating to a method for synthesizing high-purity p-methoxybenzoic acid, which is particularly suitable for the industrial production of pharmaceutical and fragrance intermediates. Background Technology

[0002] In the field of fine chemicals, p-anisic acid, as a key aromatic carboxylic acid derivative, has been widely used in pharmaceutical synthesis (such as intermediates for antiarrhythmic drugs), the fragrance industry (such as vanillin precursors), and cosmetic preservatives. Its synthetic technology has evolved from traditional oxidation methods to modern catalytic acylation pathways. As early as the mid-20th century, researchers mainly relied on the oxidation of p-methoxytoluene to prepare this compound, but this method was gradually phased out due to poor oxidant selectivity, the generation of large amounts of byproducts, and severe environmental pollution. Subsequently, Friedel-Crafts acylation became the mainstream route. Starting with anisole, under the action of a Lewis acid catalyst such as aluminum trichloride, it undergoes electrophilic substitution with an acylation reagent (such as carbon tetrachloride or acetyl chloride) to form a p-methoxybenzoyl chloride intermediate, which is then hydrolyzed to obtain the target product. Optimization of this technological approach has driven industrialization, for example, by introducing solvent systems (such as dichloroethane) to improve reaction homogeneity and employing temperature control strategies to enhance selectivity. In recent years, with the rise of green chemistry, research focus has shifted to the fine-tuning of catalyst activation, solvent recovery, and purification processes, such as using complex pre-formation techniques to enhance catalyst stability and employing gradient temperature control to reduce post-processing complexity. These advances have not only increased yields to over 80% but also reduced energy consumption; however, further breakthroughs are needed to address the bottlenecks in purity and sustainability to meet the high standards required for pharmaceutical-grade products.

[0003] Despite significant progress in the synthesis of p-methoxybenzoic acid, existing technologies still have many limitations, particularly in the stability of complexes, reaction quenching efficiency, hydrolysis accuracy, solvent recovery rate, and product purification level. These issues directly restrict the industrial applicability and economic viability of the process. First, the complexes formed by aluminum trichloride and carbon tetrachloride often exhibit poor stability, leading to an increase in byproducts such as ortho-isomers during electrophilic substitution reactions, making it difficult to exceed 95% selectivity and thus affecting subsequent separation and purification. Second, traditional quenching processes using a simple ice-water system are prone to colloid formation and emulsification due to localized exothermic reactions, resulting in low stratification efficiency, prolonged post-processing time, and increased organic waste discharge. Furthermore, imprecise control of hydrochloric acid concentration and temperature during the hydrolysis stage often leads to incomplete hydrolysis or excessive degradation of acyl chloride intermediates, resulting in large yield fluctuations and frequent side reactions such as demethylation. Solvent recovery often relies on a single distillation method, with recovery rates typically below 80%, accompanied by high energy consumption and purity loss, failing to meet the requirements of sustainable development. Finally, purification is often limited to single-solvent recrystallization, making it difficult to effectively remove trace impurities, resulting in product purity remaining below 98%, which cannot meet the stringent pharmaceutical standard of ≥99.5% purity. These shortcomings not only increase production costs but also limit the potential for large-scale application. Summary of the Invention

[0004] This application provides a method for synthesizing high-purity p-methoxybenzoic acid, comprising the following steps: Step S1. Catalyst activation and complex preparation: Under inert gas protection, aluminum trichloride is added to dichloroethane, stirred and dispersed, and then carbon tetrachloride is added. The mixture is heated to activate and form a homogeneous aluminum trichloride-carbon tetrachloride complex solution; Step S2. Electrophilic substitution reaction: The complex solution from Step S1 is cooled, and anisole is added dropwise, controlling the reaction temperature to carry out the electrophilic substitution reaction; Step S3. Quenching treatment: The reaction solution from Step S2 is added dropwise to an ice-water mixture containing hydrochloric acid, controlling the temperature to... The temperature is quenched, and the mixture is allowed to stand and separate into layers; Step S4. Hydrolysis reaction: Collect the organic phase from step S3, add hydrochloric acid aqueous solution, heat and hydrolyze, and adjust the pH to obtain a dichloroethane solution containing p-methoxybenzoyl chloride; Step S5. Solvent recovery: Dichloroethane is recovered by distillation of the organic phase from step S4, and the remaining material is further processed to obtain crude p-methoxybenzoyl chloride; Step S6. Purification and crystallization: Methanol aqueous solution and activated carbon are added to the crude product from step S5, reflux and filter, the filtrate is cooled and crystallized, filtered, washed and dried to obtain p-methoxybenzoic acid product.

[0005] It should be noted that the synthesis of high-purity p-methoxybenzoic acid is based on the Friedel-Crafts acylation mechanism. Using anisole as a starting material, aluminum trichloride catalyzes carbon tetrachloride to generate an electrophilic reagent, introducing a trichloromethyl group at the para-position of the benzene ring. This is followed by hydrolysis and purification to obtain the target product. In the first step, aluminum trichloride, acting as a Lewis acid, coordinates with carbon tetrachloride to form a complex. Heating promotes C-Cl bond polarization, generating an electrophilic trichloromethyl cation. Inert gas and dichloroethane ensure reaction homogeneity. In the second step, the methoxy group of anisole activates the para-position of the benzene ring through an electron-donating effect. The trichloromethyl cation preferentially attacks the para-position to form a σ-complex. After deprotonation, p-methoxytrichloromethylbenzene is generated. Low-temperature dropwise addition controls reduce ortho-byproducts. In the third step, quenching with an acid-containing ice-water solution destroys the aluminum trichloride complex, releasing the trichloromethyl intermediate. Gradient temperature control reduces emulsification and promotes layering. In the fourth step, the trichloromethyl intermediate is hydrolyzed in hydrochloric acid aqueous solution by heating, gradually converting it into acyl chloride. The pH is adjusted to remove acidic impurities. In the fifth step, dichloroethane is recovered by distillation, and the remaining material yields crude acyl chloride. In the final step, the crude product is dissolved by reflux using methanol aqueous solution and activated carbon. The crystallization rate is controlled by gradient cooling. After adsorbing impurities, the product is filtered, washed, and dried to obtain high-purity p-methoxybenzoic acid. The entire process ensures high para-selectivity and yield through precise temperature control.

[0006] In a preferred method for synthesizing high-purity p-methoxybenzoic acid, in step S1, the molar ratio of aluminum trichloride to carbon tetrachloride is 1:(0.9-1.1), the amount of dichloroethane is 3-5 times the mass of aluminum trichloride, the activation temperature is 30-40℃, and the activation time is 1.5-2 hours.

[0007] It should be noted that in the synthesis of high-purity p-methoxybenzoic acid, the following conditions were used for catalyst activation and complex preparation: a molar ratio of aluminum trichloride to carbon tetrachloride of 1:(0.9-1.1), a dichloroethane dosage of 3-5 times the mass of aluminum trichloride, an activation temperature of 30-40℃, and an activation time of 1.5-2 hours. The mechanism is based on the catalyst coordination process of the Friedel-Crafts acylation reaction. Aluminum trichloride, as a Lewis acid, coordinates with the carbon atom in carbon tetrachloride through the lone pair electrons of the chlorine atom to form a [AlCl3·CCl4] complex. This process is accelerated by mild heating at 30-40℃, and the 1.5-2 hour activation time ensures a sufficiently homogeneous complex, enhances the polarization of the C-Cl bond, and generates the electrophilic trichloromethyl cation (CCl3). +(or related active intermediates). A molar ratio of 1:(0.9-1.1) ensures proper coordination between aluminum trichloride and carbon tetrachloride, avoiding side reactions caused by excessive carbon tetrachloride or reduced catalytic efficiency due to insufficient aluminum trichloride. Dichloroethane is used as a solvent, in an amount 3-5 times the mass of aluminum trichloride, to provide a suitable reaction medium, ensuring sufficient dispersion of aluminum trichloride and effective contact with carbon tetrachloride, while controlling the viscosity of the reaction system, which is beneficial for high para-selectivity of subsequent electrophilic substitution.

[0008] In a preferred technical solution for the synthesis of high-purity p-methoxybenzoic acid, in step S1, the aluminum trichloride is a yellow powder with a purity ≥99% and a particle size ≤100 mesh.

[0009] It should be noted that this helps to form a stable aluminum trichloride-carbon tetrachloride complex, thereby improving the para-selectivity and catalytic efficiency of the electrophilic substitution reaction.

[0010] In a preferred method for synthesizing high-purity p-methoxybenzoic acid, in step S2, the complex solution from step S1 is cooled to 0-5°C, and anisole is added dropwise. The dropping rate is controlled to maintain the reaction system temperature at 5-10°C. After the addition is complete, the reaction is kept at this temperature for 3-4 hours. The molar ratio of anisole to aluminum trichloride is 1:1.1.

[0011] It should be noted that the methoxy group of anisole strongly activates the para and ortho positions of the benzene ring through an electron-donating effect, generating an electrophilic trichloromethyl cation (CCl3) from the aluminum trichloride-carbon tetrachloride complex. + The anisole preferentially attacks the para-carbon atom, forming a σ-complex followed by deprotonation to generate p-methoxytrichloromethylbenzene. Cooling to 0-5℃ and controlling the dropping rate (usually 1-2 drops / second) ensures the anisole enters the system slowly, maintaining the reaction temperature at 5-10℃ to reduce molecular thermal motion, enhance para-selectivity, and suppress ortho- or multi-substitution side reactions. A molar ratio of 1:1.1 ensures a suitable excess of aluminum trichloride, fully catalyzing the formation of the electrophilic reagent from carbon tetrachloride while avoiding excess reactions. Holding at this temperature for 3-4 hours provides sufficient time for complete conversion of the anisole. Low-temperature control and precise proportioning together ensure efficient generation of the p-methoxytrichloromethylbenzene intermediate, laying the foundation for subsequent steps.

[0012] As a preferred technical solution for the synthesis of high-purity p-methoxybenzoic acid, in step S2, the dropping rate of anisole is 1-2 drops / second, controlled by a constant pressure dropping funnel, and the reaction temperature fluctuation is ≤±2℃.

[0013] It should be noted that the dropping rate of 1-2 drops / second is precisely controlled using a constant-pressure dropping funnel to ensure that anisole enters the reaction system slowly and uniformly, avoiding excessively high local concentrations that could trigger ortho- or poly-substitution side reactions. Strict control of reaction temperature fluctuations within ±2℃ (typically dropping at 0-5℃ and maintaining the reaction at 5-10℃) slows down molecular thermal motion, enhances the selective attack of the electrophilic reagent on the para position, and suppresses high-temperature-induced side reactions such as demethylation or polymerization, thereby ensuring high reaction efficiency and a high yield of the p-methoxytrichloromethylbenzene intermediate.

[0014] In a preferred technical solution for the synthesis of high-purity p-methoxybenzoic acid, in step S3, the concentration of hydrochloric acid in the ice-water mixture containing hydrochloric acid is 5-10%, the molar ratio of hydrochloric acid to aluminum trichloride is 1.5:(1-1.2), and the mass of the ice-water mixture is 2-3 times the total mass of the reaction solution.

[0015] It should be noted that precise control of the quenching environment effectively breaks down the aluminum trichloride-carbon tetrachloride complex, releasing the p-methoxytrichloromethylbenzene intermediate, while significantly reducing emulsification and shortening the separation time to less than 10 minutes. A 5-10% hydrochloric acid concentration ensures a mild acidic environment, preventing the hydrolysis of aluminum trichloride to form colloids. Simultaneously, a molar ratio of 1.5:(1-1.2) guarantees sufficient acid to neutralize the aluminum trichloride, avoiding excessive acid leading to side reactions or equipment corrosion. The ice-water mixture, with a mass 2-3 times that of the reaction solution, provides ample cooling and dilution capacity, maintaining the quenching temperature ≤10℃, inhibiting the formation of byproducts caused by localized overheating, thereby improving the purity of the intermediate and subsequent hydrolysis efficiency, laying the foundation for high yield and purity of the final product.

[0016] As a preferred technical solution for the synthesis of high-purity p-methoxybenzoic acid, in step S3, the mass ratio of ice to water in the ice-water mixture is 1:1, the hydrochloric acid is concentrated hydrochloric acid added step by step with a concentration of 36.5%, the system temperature is controlled to be ≤10℃ during the quenching process, and after the addition is complete, the temperature is raised to 20-25℃ and stirred for 30-40 minutes.

[0017] It should be noted that a 1:1 ice-to-water mass ratio ensures the ice-water mixture provides sufficient cooling capacity to maintain a low temperature ≤10℃, slowing down the rate of colloid formation from the reaction of aluminum trichloride with water and inhibiting emulsification. Concentrated hydrochloric acid is gradually added to form a 5-10% hydrochloric acid solution, providing a moderately acidic environment to accelerate the hydrolysis of aluminum trichloride into soluble aluminum chloride and hydrochloric acid, reducing colloid formation. Low-temperature quenching (≤10℃) protects the intermediate from side reactions (such as demethylation). After the addition is complete, the temperature is raised to 20-25℃ and stirred for 30-40 minutes to promote complete dissociation of the complex and organic / aqueous phase separation, ensuring efficient transfer of p-methoxytrichloromethylbenzene to the organic phase and providing a high-purity intermediate for subsequent hydrolysis and purification.

[0018] In a preferred embodiment of a high-purity p-methoxybenzoic acid synthesis method, in step S4, the concentration of the hydrochloric acid aqueous solution is 10-12%, the mass ratio of hydrochloric acid to anisole is (1.2-1.5):1, the hydrolysis temperature is 40-45℃, the hydrolysis time is 3-3.5 hours, and the pH is adjusted to 6.5-7.0.

[0019] It should be noted that the organic phase obtained after quenching contains ArCCl3. In a 10-12% hydrochloric acid aqueous solution, the mild acidic environment promotes the hydrolysis of the trichloromethyl group. CCl3 gradually loses chlorine atoms through nucleophilic substitution to form a carbonyl group (C=O), ultimately generating an acyl chloride. A hydrochloric acid to anisole mass ratio of 1.2-1.5:1 ensures sufficient hydrolysis reagent, accelerates the reaction, and avoids side reactions (such as demethylation) caused by excess acid. A hydrolysis temperature of 40-45℃ provides moderate energy to promote C-Cl bond breaking and water molecule attack, while avoiding acyl chloride degradation or byproduct formation caused by high temperature. A hydrolysis time of 3-3.5 hours, monitored by HPLC, ensures a conversion rate ≥99%, guaranteeing complete conversion of ArCCl3 to ArCOCl. The pH is adjusted to 6.5-7.0 (using 5% sodium carbonate) to neutralize residual acidic substances, stabilize the acyl chloride, and remove acidic impurities, generating a dichloroethane solution containing p-methoxybenzoyl chloride, providing a high-purity intermediate for subsequent solvent recovery and purification.

[0020] As a preferred technical solution for the synthesis of high-purity p-methoxybenzoic acid, in step S5, the distillation includes atmospheric distillation and vacuum distillation. The distillation range of atmospheric distillation is 83-85℃, and the vacuum degree of vacuum distillation is 0.095-0.098MPa. The recovered dichloroethane is purified by distillation and then recycled for use in step S1.

[0021] It should be noted that the organic phase obtained in step S4 mainly contains p-methoxybenzoyl chloride (ArCOCl) and the solvent dichloroethane. Dichloroethane is separated by atmospheric distillation at 83-85℃ due to its volatility, and the distillate is collected, leaving a high-boiling-point crude ArCOCl. Subsequent vacuum distillation at 0.095-0.098 MPa lowers the boiling point, further removing residual dichloroethane and other low-boiling-point impurities to ensure the purity of the crude product. Rectification (usually using a packed column with a reflux ratio of 3:1) improves the purity of the recovered dichloroethane through multiple vapor-liquid equilibrations, allowing it to be recycled for catalyst activation and complex preparation in step S1, reducing solvent consumption and waste discharge. This process not only efficiently separates the crude ArCOCl, providing a high-purity raw material for subsequent crystallization purification, but also reduces production costs through closed-loop solvent recovery, conforming to green chemistry principles.

[0022] In a preferred technical solution for the synthesis of high-purity p-methoxybenzoic acid, in step S6, the methanol-to-water volume ratio of the methanol-water solution is 3:1, the amount of activated carbon is 1% of the crude mass, the reflux temperature is 65-70℃, the reflux time is 20-30 minutes, the filtrate is cooled from 65℃ to 5℃ at a rate of 5℃ / 10 minutes, and the crystallization time is 30-40 minutes.

[0023] Crude p-methoxybenzoyl chloride was dissolved in a methanol-water solution (methanol:water = 3:1). Methanol provided strong solubility, while water adjusted the solubility, optimizing the solubility of the crude product during reflux at 65-70℃ to ensure full exposure of impurities. 1% activated carbon was used to remove trace organic impurities and pigments through physical adsorption. Reflux for 20-30 minutes promoted adsorption equilibrium, while simultaneously dissolving p-methoxybenzoic acid in the crude product at high temperature. The temperature was lowered from 65℃ to 5℃ at a rate of 5℃ / 10 minutes. This slow gradient cooling controlled the crystal growth rate of p-methoxybenzoic acid, reducing impurity encapsulation and forming regular crystals. A crystallization time of 30-40 minutes further ensured complete crystal precipitation. After filtration to separate the crystals, residual solvent and salts were removed by washing with water, and the product was dried to obtain high-purity p-methoxybenzoic acid. The entire process optimized crystal purity and yield through solvent ratio, adsorption, and gradient crystallization.

[0024] The high-purity p-methoxybenzoic acid synthesis method provided by this invention significantly improves product performance and process efficiency through optimized processes such as catalyst pre-activation, low-temperature dropwise control, gradient temperature-controlled quenching, precise hydrolysis, closed-loop solvent recovery, and gradient crystallization of methanol-water solution. It exhibits the following beneficial effects: product purity reaches 99.5%-99.8% (HPLC), meeting pharmaceutical-grade requirements; yield is increased to 91.5%-93.8%, higher than the 80%-88% of traditional methods; para-selectivity ≥98%, effectively reducing byproducts such as ortho-isomers; solvent recovery rate is 94.7%-96.6%, achieving closed-loop solvent recycling through atmospheric / vacuum distillation and rectification purification, reducing costs and waste discharge. These advantages stem from enhanced stability of the aluminum trichloride-carbon tetrachloride complex, reduced side reactions due to low-temperature control, hydrochloric acid-assisted quenching to inhibit colloid formation, and gradient crystallization to optimize crystal regularity. Overall, it improves the greenness, economy, and industrial applicability of the process, making it particularly suitable for large-scale production of pharmaceutical and fragrance intermediates. Detailed Implementation

[0025] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0026] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0027] Secondly, the term "an embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single embodiment or an embodiment selectively excluded from other embodiments.

[0028] Example

[0029] Example 1

[0030] This embodiment provides a method for synthesizing high-purity p-methoxybenzoic acid, comprising the following steps:

[0031] (1) Catalyst activation and complex preparation: 88g of dichloroethane was added to a 250mL four-necked flask, and 29.3g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22mol) was added under nitrogen protection. After stirring and dispersing for 10min, 28.5g of carbon tetrachloride (0.198mol, molar ratio 1:0.9) was added, and the temperature was raised to 30℃ for activation for 1.5h to obtain a homogeneous pale yellow complex solution.

[0032] (2) Electrophilic substitution reaction: The above complex solution was cooled to 0℃, and 21.6g of anisole (0.2mol, molar ratio 1:1.1) was added dropwise through a constant pressure dropping funnel at a rate of 1 drop / second. The system temperature was maintained at 5-7℃ (fluctuation ≤±2℃). After the addition was complete, the reaction was kept at this temperature for 3h. The conversion rate of anisole was monitored by HPLC to be ≥99%.

[0033] (3) Gradient temperature controlled quenching: The reaction solution was slowly added dropwise to 450g of an ice-water mixture containing 5% hydrochloric acid (ice to water mass ratio 1:1, concentrated hydrochloric acid 36.5% added gradually, hydrochloric acid to aluminum trichloride molar ratio 1.5:1). The internal temperature was controlled to be ≤10℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 20℃ and stirred for 30min. After standing for 10min, the phases were separated to obtain an organic phase (containing p-methoxytrichloromethylbenzene) and an aqueous phase (containing aluminum trichloride).

[0034] (4) Precise hydrolysis: Collect the organic phase, add 26g of 10% hydrochloric acid aqueous solution (mass ratio of anisole to 1.2:1), heat to 40℃ and maintain the temperature for 3h for hydrolysis. HPLC monitoring showed that the hydrolysis rate of p-methoxytrichloromethylbenzene was ≥99%. After standing and separating the layers, adjust the pH of the organic phase to 6.5 with 5% sodium carbonate aqueous solution, and wash twice with water (40g water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0035] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 83℃) to obtain 85g of recovered solvent (purity 99%); the remaining material was desolventized under a vacuum of 0.095MPa to obtain 30.5g of crude p-methoxybenzoyl chloride.

[0036] (6) Purification and crystallization: Add 61g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.3g of activated carbon to the crude product, heat to 65℃ and reflux for 20min, filter while hot to remove carbon; cool the filtrate from 65℃ to 5℃ at a rate of 5℃ / 10min, keep warm for 30min, filter, wash with water (twice, 15g water each time), and dry to obtain 27.8g of p-methoxybenzoic acid, with a yield of 91.5% and a purity of 99.5% (HPLC).

[0037] Example 2

[0038] This embodiment provides a method for synthesizing high-purity p-methoxybenzoic acid, comprising the following steps:

[0039] (1) Catalyst activation and complex preparation: 147g of dichloroethane was added to a 250mL four-necked flask, and 29.3g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22mol) was added under nitrogen protection. After stirring and dispersing for 10min, 37.3g of carbon tetrachloride (0.242mol, molar ratio 1:1.1) was added, and the temperature was raised to 40℃ for 2h to obtain a homogeneous pale yellow complex solution.

[0040] (2) Electrophilic substitution reaction: The above complex solution was cooled to 5°C, and 21.6 g of anisole (0.2 mol, molar ratio 1:1.1) was added dropwise through a constant pressure dropping funnel at a rate of 2 drops / second. The system temperature was maintained at 8-10°C (fluctuation ≤ ±2°C). After the addition was complete, the reaction was kept at this temperature for 4 h. The conversion rate of anisole was monitored by HPLC to be ≥99%.

[0041] (3) Gradient temperature controlled quenching: The reaction solution was slowly added dropwise to 675g of an ice-water mixture containing 10% hydrochloric acid (ice to water mass ratio 1:1, concentrated hydrochloric acid 36.5% added gradually, hydrochloric acid to aluminum trichloride molar ratio 1.5:1.2). The internal temperature was controlled to be ≤10℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 25℃ and stirred for 40min. After standing for 8min, the phases were separated to obtain an organic phase (containing p-methoxytrichloromethylbenzene) and an aqueous phase (containing aluminum trichloride).

[0042] (4) Precise hydrolysis: Collect the organic phase, add 32.4 g of 12% hydrochloric acid aqueous solution (mass ratio of anisole to 1.5:1), heat to 45℃ and maintain the temperature for 3.5 h for hydrolysis. HPLC monitoring showed that the hydrolysis rate of p-methoxytrichloromethylbenzene was ≥99%. After standing and separating the layers, adjust the pH of the organic phase to 7.0 with 5% sodium carbonate aqueous solution, wash with water 3 times (50 g water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0043] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 85℃) to obtain 140g of recovered solvent (purity 99.5%); the remaining material was desolventized under a vacuum of 0.098MPa to obtain 31.2g of crude p-methoxybenzoyl chloride.

[0044] (6) Purification and crystallization: Add 93g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.31g of activated carbon to the crude product, heat to 70℃ and reflux for 30min, filter while hot to remove carbon; cool the filtrate from 65℃ to 5℃ at a rate of 5℃ / 10min, keep warm for 40min, filter, wash with water (2 times, 20g water each time), and dry to obtain 28.5g of p-methoxybenzoic acid, with a yield of 93.8% and a purity of 99.8% (HPLC).

[0045] Example 3

[0046] This embodiment provides a method for synthesizing high-purity p-methoxybenzoic acid, comprising the following steps:

[0047] (1) Catalyst activation and complex preparation: 117 g of dichloroethane was added to a 250 mL four-necked flask, and 29.3 g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22 mol) was added under nitrogen protection. After stirring and dispersing for 10 min, 33.8 g of carbon tetrachloride (0.22 mol, molar ratio 1:1.0) was added, and the temperature was raised to 35 °C for activation for 1.75 h to obtain a homogeneous pale yellow complex solution.

[0048] (2) Electrophilic substitution reaction: The above complex solution was cooled to 2.5℃, and 21.6 g of anisole (0.2 mol, molar ratio 1:1.1) was added dropwise through a constant pressure dropping funnel at a rate of 1.5 drops / second. The system temperature was maintained at 6-9℃ (fluctuation ≤ ±2℃). After the addition was complete, the reaction was kept at this temperature for 3.5 h. The conversion rate of anisole was monitored by HPLC to be ≥99%.

[0049] (3) Gradient temperature controlled quenching: The reaction solution was slowly added dropwise to 562g of an ice-water mixture containing 7.5% hydrochloric acid (ice to water mass ratio 1:1, concentrated hydrochloric acid 36.5% added stepwise, hydrochloric acid to aluminum trichloride molar ratio 1.5:1.1). The internal temperature was controlled to be ≤10℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 22.5℃ and stirred for 35min. After standing for 9min, the phases were separated to obtain an organic phase (containing p-methoxytrichloromethylbenzene) and an aqueous phase (containing aluminum trichloride).

[0050] (4) Precise hydrolysis: Collect the organic phase, add 29.2 g of 11% hydrochloric acid aqueous solution (mass ratio of anisole to 1.35:1), heat to 42.5℃ and maintain the temperature for 3.25 h for hydrolysis. HPLC monitoring showed that the hydrolysis rate of p-methoxytrichloromethylbenzene was ≥99%. After standing and separating the layers, adjust the pH of the organic phase to 6.75 with 5% sodium carbonate aqueous solution, wash twice with water (45 g water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0051] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 84℃) to obtain 112g of recovered solvent (purity 99.2%); the remaining material was subjected to a vacuum of 0.0965MPa to remove residual solvent, and 30.8g of crude p-methoxybenzoyl chloride was obtained.

[0052] (6) Purification and crystallization: 77g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.31g of activated carbon were added to the crude product, the temperature was raised to 67.5℃ and refluxed for 25min, and the carbon was removed by hot filtration; the filtrate was cooled from 65℃ to 5℃ at a rate of 5℃ / 10min, kept at the temperature for 35min, filtered, washed with water (twice, 18g of water each time), and dried to obtain 28.1g of p-methoxybenzoic acid, with a yield of 92.4% and a purity of 99.6% (HPLC).

[0053] Example 4

[0054] This embodiment provides a method for synthesizing high-purity p-methoxybenzoic acid, comprising the following steps:

[0055] (1) Catalyst activation and complex preparation: 132g of dichloroethane was added to a 250mL four-necked flask, and 29.3g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22mol) was added under nitrogen protection. After stirring and dispersing for 10min, 32.4g of carbon tetrachloride (0.211mol, molar ratio 1:0.96) was added, and the temperature was raised to 32℃ for activation for 1.8h to obtain a homogeneous pale yellow complex solution.

[0056] (2) Electrophilic substitution reaction: The above complex solution was cooled to 3℃, and 21.6 g of anisole (0.2 mol, molar ratio 1:1.1) was added dropwise through a constant pressure dropping funnel at a rate of 1.2 drops / second. The system temperature was maintained at 7-9℃ (fluctuation ≤ ±2℃). After the addition was complete, the reaction was kept at this temperature for 3.2 h. The conversion rate of anisole was monitored by HPLC to be ≥99%.

[0057] (3) Gradient temperature controlled quenching: The reaction solution was slowly added dropwise to 600g of an ice-water mixture containing 8% hydrochloric acid (ice to water mass ratio 1:1, concentrated hydrochloric acid 36.5% added gradually, hydrochloric acid to aluminum trichloride molar ratio 1.5:1.05). The internal temperature was controlled to be ≤10℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 23℃ and stirred for 32min. After standing for 9min, the phases were separated to obtain an organic phase (containing p-methoxytrichloromethylbenzene) and an aqueous phase (containing aluminum trichloride).

[0058] (4) Precise hydrolysis: Collect the organic phase, add 30.2 g of 10.5% hydrochloric acid aqueous solution (mass ratio of anisole to 1.4:1), heat to 42℃ and maintain the temperature for 3.2 h for hydrolysis. HPLC monitoring showed that the hydrolysis rate of p-methoxytrichloromethylbenzene was ≥99%. After standing and separating the layers, adjust the pH of the organic phase to 6.8 with 5% sodium carbonate aqueous solution, wash with water 3 times (48 g of water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0059] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 84℃) to obtain 125g of recovered solvent (purity 99.3%); the remaining material was desolventized under a vacuum of 0.097MPa to obtain 30.9g of crude p-methoxybenzoyl chloride.

[0060] (6) Purification and crystallization: Add 82g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.31g of activated carbon to the crude product, heat to 68℃ and reflux for 22min, filter while hot to remove carbon; cool the filtrate from 65℃ to 5℃ at a rate of 5℃ / 10min, keep warm for 32min, filter, wash with water (twice, 19g water each time), and dry to obtain 28.2g of p-methoxybenzoic acid, with a yield of 92.8% and a purity of 99.7% (HPLC).

[0061] Comparison Example

[0062] Comparative Example 1 (for Example 1: catalyst pre-activation step omitted)

[0063] (1) Catalyst mixing: 88g of dichloroethane was added to a 250mL four-necked flask, and 29.3g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22mol) was added under nitrogen protection. After stirring and dispersing for 10min, 28.5g of carbon tetrachloride (0.198mol, molar ratio 1:0.9) and 21.6g of anisole (0.2mol, molar ratio 1:1.1) were added directly. No temperature was raised for activation, and a heterogeneous complex was formed.

[0064] (2) Electrophilic substitution reaction: The mixture was cooled to 0℃, and the dropping rate was controlled at 1 drop / second by a constant pressure dropping funnel. The system temperature was maintained at 5-7℃ (fluctuation ≤ ±2℃). After the dropping was completed, the reaction was kept at this temperature for 3 hours. The conversion rate of anisole was 98% as monitored by HPLC.

[0065] (3) Gradient temperature-controlled quenching: The reaction solution was slowly added dropwise to 450g of an ice-water mixture containing 5% hydrochloric acid (ice to water mass ratio 1:1, concentrated hydrochloric acid 36.5% added gradually, hydrochloric acid to aluminum trichloride molar ratio 1.5:1). The internal temperature was controlled to be ≤10℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 20℃ and stirred for 30min. After standing for 10min, the mixture was separated into organic phase and aqueous phase.

[0066] (4) Precise hydrolysis: Collect the organic phase, add 26g of 10% hydrochloric acid aqueous solution (mass ratio of anisole to 1.2:1), heat to 40℃ and keep warm for 3h for hydrolysis. HPLC monitoring showed a hydrolysis rate of 98%. After standing and separating the layers, adjust the pH of the organic phase to 6.5 with 5% sodium carbonate aqueous solution, wash twice with water (40g water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0067] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 83℃) to obtain 85g of recovered solvent (purity 99%); the remaining material was desolventized under a vacuum of 0.095MPa to obtain 29.8g of crude p-methoxybenzoyl chloride.

[0068] (6) Purification and crystallization: Add 61g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.3g of activated carbon to the crude product, heat to 65℃ and reflux for 20min, filter while hot to remove carbon; cool the filtrate from 65℃ to 5℃ at a rate of 5℃ / 10min, keep warm for 30min, filter, wash with water (twice, 15g water each time), and dry to obtain 26.5g of p-methoxybenzoic acid, with a yield of 87.2% and a purity of 98.8% (HPLC).

[0069] Comparative Example 2 (for Example 1: no control over the low-temperature dropping temperature)

[0070] (1) Catalyst activation and complex preparation: 88g of dichloroethane was added to a 250mL four-necked flask, and 29.3g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22mol) was added under nitrogen protection. After stirring and dispersing for 10min, 28.5g of carbon tetrachloride (0.198mol, molar ratio 1:0.9) was added, and the temperature was raised to 30℃ for activation for 1.5h to obtain a homogeneous pale yellow complex solution.

[0071] (2) Electrophilic substitution reaction: The above complex solution was not cooled (room temperature 25℃), and 21.6 g of anisole (0.2 mol, molar ratio 1:1.1) was added dropwise through a constant pressure dropping funnel. The dropping rate was controlled at 1 drop / second, and the temperature fluctuation of the system was maintained at ≤±2℃. After the addition was completed, the reaction was kept at the temperature for 3 h. The conversion rate of anisole was 97% as monitored by HPLC.

[0072] (3) Gradient temperature-controlled quenching: The reaction solution was slowly added dropwise to 450g of an ice-water mixture containing 5% hydrochloric acid (ice to water mass ratio 1:1, concentrated hydrochloric acid 36.5% added gradually, hydrochloric acid to aluminum trichloride molar ratio 1.5:1). The internal temperature was controlled to be ≤10℃ during the dropwise addition. After the dropwise addition was completed, the temperature was raised to 20℃ and stirred for 30min. After standing for 10min, the mixture was separated into organic phase and aqueous phase.

[0073] (4) Precise hydrolysis: Collect the organic phase, add 26g of 10% hydrochloric acid aqueous solution (mass ratio of anisole to 1.2:1), heat to 40℃ and keep warm for 3h for hydrolysis. HPLC monitoring showed that the hydrolysis rate was ≥99%. After standing and separating the layers, adjust the pH of the organic phase to 6.5 with 5% sodium carbonate aqueous solution, wash twice with water (40g water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0074] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 83℃) to obtain 85g of recovered solvent (purity 99%); the remaining material was subjected to a vacuum of 0.095MPa to remove residual solvent, and 29.2g of crude p-methoxybenzoyl chloride was obtained.

[0075] (6) Purification and crystallization: Add 61g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.3g of activated carbon to the crude product, heat to 65℃ and reflux for 20min, filter while hot to remove carbon; cool the filtrate from 65℃ to 5℃ at a rate of 5℃ / 10min, keep warm for 30min, filter, wash with water (twice, 15g water each time), and dry to obtain 25.8g of p-methoxybenzoic acid, with a yield of 84.9% and a purity of 98.5% (HPLC).

[0076] Comparative Example 3 (for Example 1: quenching without gradient temperature control)

[0077] Catalyst activation and complex preparation: 88 g of dichloroethane was added to a 250 mL four-necked flask. Under nitrogen protection, 29.3 g of aluminum trichloride (yellow powder, purity ≥99%, particle size ≤100 mesh, 0.22 mol) was added. After stirring and dispersing for 10 min, 28.5 g of carbon tetrachloride (0.198 mol, molar ratio 1:0.9) was added. The mixture was heated to 30 °C and activated for 1.5 h to obtain a homogeneous pale yellow complex solution.

[0078] (2) Electrophilic substitution reaction: The above complex solution was cooled to 0℃, and 21.6g of anisole (0.2mol, molar ratio 1:1.1) was added dropwise through a constant pressure dropping funnel at a rate of 1 drop / second. The system temperature was maintained at 5-7℃ (fluctuation ≤±2℃). After the addition was complete, the reaction was kept at this temperature for 3h. The conversion rate of anisole was monitored by HPLC to be ≥99%.

[0079] (3) Quenching treatment: The reaction solution was directly poured into 450g of pure ice-water mixture (ice to water mass ratio 1:1, no hydrochloric acid). The system temperature was not controlled during quenching (raised to 15℃). The mixture was stirred for 30min, allowed to stand and separate into layers. The emulsification was severe and the separation took 35min to obtain the organic phase and the aqueous phase.

[0080] (4) Precise hydrolysis: Collect the organic phase, add 26g of 10% hydrochloric acid aqueous solution (mass ratio of anisole to 1.2:1), heat to 40℃ and keep warm for 3h for hydrolysis. HPLC monitoring showed a hydrolysis rate of 98%. After standing and separating the layers, adjust the pH of the organic phase to 6.5 with 5% sodium carbonate aqueous solution, wash twice with water (40g water each time) to obtain a dichloroethane solution of p-methoxybenzoyl chloride.

[0081] (5) Solvent recovery and closed-loop circulation: The organic phase was transferred to a distillation apparatus and distilled at atmospheric pressure to recover dichloroethane (distillation range 83℃) to obtain 85g of recovered solvent (purity 99%); the remaining material was subjected to a vacuum of 0.095MPa to remove residual solvent, yielding 29.5g of crude p-methoxybenzoyl chloride. (6) Purification and crystallization: 61g of 20% methanol aqueous solution (methanol:water = 3:1) and 0.3g of activated carbon were added to the crude product, and the mixture was heated to 65℃ and refluxed for 20min. The mixture was then filtered while hot to remove carbon; the filtrate was cooled from 65℃ to 5℃ at a rate of 5℃ / 10min, kept at that temperature for 30min, filtered, washed with water (twice, 15g of water each time), and dried to obtain 26.2g of p-methoxybenzoic acid, with a yield of 86.2% and a purity of 98.7% (HPLC).

[0082] Performance testing methods

[0083] 1. Product purity

[0084] Test Method: Take 0.1 g of the dried p-methoxybenzoic acid product from step S6 (e.g., 27.8 g in Example 1), dissolve it in 5 mL of methanol (HPLC grade) to prepare a solution of approximately 20 mg / mL. Analyze using high-performance liquid chromatography (HPLC) with a C18 column (4.6 mm × 250 mm, 5 μm), a mobile phase of methanol:water (60:40, v / v, containing 0.1% phosphoric acid), a flow rate of 1.0 mL / min, a detection wavelength of 254 nm, and a column temperature of 30 °C. Prepare a standard curve using p-methoxybenzoic acid standard (purity ≥ 99.9%), record the area of ​​the main peak, calculate the p-methoxybenzoic acid content, and simultaneously detect the area ratio of ortho-isomers and other impurity peaks (such as demethylation byproducts). The purity calculation formula is: Purity (%) = Main peak area / Total peak area × 100%. Repeat the test three times and take the average value.

[0085] 2. Yield

[0086] Test Method: Based on the amount of anisole added, the theoretical and actual yields of p-methoxybenzoic acid were calculated. Taking Example 1 as an example, 21.6 g of anisole (0.2 mol, molecular weight 108.14 g / mol) was added, theoretically producing 30.43 g of p-methoxybenzoic acid (molecular weight 152.15 g / mol). After step S6, the mass of the dried p-methoxybenzoic acid product (e.g., 27.8 g) was weighed using an analytical balance (accuracy 0.0001 g). The yield calculation formula is: Yield (%) = Actual yield / Theoretical yield × 100% = 27.8 g / 30.43 g × 100%. The experiment was repeated 3 times, and the average value was taken.

[0087] 3. Opposition selectivity

[0088] Test Method: After step S2, take 1 mL of the reaction solution (containing p-methoxytrichloromethylbenzene), dilute with 5 mL of dichloroethane, filter to remove aluminum trichloride residue, and inject into a gas chromatography-mass spectrometry (GC-MS) instrument for analysis. Use an HP-5 column (30 m × 0.25 mm, 0.25 μm), helium as the carrier gas, a flow rate of 1.0 mL / min, an injection port temperature of 250 °C, and a programmed temperature ramp (50 °C for 2 min, ramped to 280 °C at 10 °C / min, held for 5 min). The detector is a mass spectrometer (EI source, 70 eV). Using p-methoxytrichloromethylbenzene standard (m / z = 248) as a reference, record the peak areas of the para, ortho, and meta isomers, and calculate the para-selectivity: Selectivity (%) = para isomer peak area / (para + ortho + meta peak area) × 100%. Repeat the test 3 times.

[0089] 4. Solvent recovery rate

[0090] Test Method: After atmospheric distillation (83℃) and vacuum distillation (0.095MPa) in step S5, the recovered dichloroethane was collected and weighed (85g as in Example 1) using an analytical balance (accuracy 0.0001g). The recovery rate was calculated based on the initial dichloroethane mass (88g): Recovery rate (%) = Mass of recovered dichloroethane / Initial dichloroethane mass × 100% = 85g / 88g × 100%. A sample of the recovered solvent was taken and its purity was analyzed using gas chromatography (GC). A DB-5 column (30m × 0.32mm, 0.25μm) was used, with helium as the carrier gas, a flow rate of 1.2mL / min, an FID detector, and an injection port temperature of 200℃. The purity was checked to ensure it was ≥99%. The experiment was repeated three times, and the recovery rate and purity were recorded to verify the effectiveness of atmospheric / vacuum distillation and purification, ensuring that the recovered solvent could be recycled for step S1.

[0091] Table 1

[0092]

[0093]

[0094] As can be seen from Examples 1 to 4 and Table 1, the p-methoxybenzoic acid obtained by the method of the present invention has a purity range of 99.5%-99.8% (HPLC), a yield range of 91.5%-93.8%, a para-selectivity of ≥98%, and a solvent recovery rate range of 94.7%-96.6%. This demonstrates the significant advantages of optimized processes such as catalyst pre-activation, low-temperature dropwise control, and gradient temperature-controlled quenching in improving selectivity, reducing by-products, and increasing purity and yield, thus meeting the needs of pharmaceutical-grade industrial production.

[0095] Combining Example 1, Comparative Example 1, and Table 1, it can be seen that the product purity of Example 1 is 99.5%, the yield is 91.5%, and the para-selectivity is ≥98%, while the purity of Comparative Example 1 (with the catalyst pre-activation step omitted) is only 98.8%, the yield is 87.2%, and the para-selectivity is 90%, with a solvent recovery rate of 96.6% in both cases. This indicates that the pre-activation step significantly improves the purity and yield. Mechanistic analysis shows that in step S1, aluminum trichloride and carbon tetrachloride are activated at 30°C for 1.5 h to form a stable [AlCl3·CCl4] complex, which enhances C-Cl bond polarization and generates highly efficient electrophilic CCl3. + This promotes para-selective attack on the benzene ring of anisole, reducing ortho-by products. In contrast, in Control Example 1, a direct mixture of aluminum trichloride, carbon tetrachloride, and anisole resulted in an unstable complex. + Low generation efficiency leads to an increase in byproducts such as ortho-isomers, reducing conversion rate and purity.

[0096] Combining Example 1, Comparative Example 2, and Table 1, it can be seen that the product purity of Example 1 is 99.5%, the yield is 91.5%, and the para-selectivity is ≥98%, while the purity of Comparative Example 2 (without controlling the low-temperature dropping temperature) is only 98.5%, the yield is 84.9%, and the para-selectivity is 88%, with a solvent recovery rate of 96.6% in both cases. This indicates that low-temperature control significantly improves purity and yield. In the electrophilic substitution reaction, the methoxy group of anisole activates the para-position of the benzene ring through an electron-donating effect, and the electrophilic CCl3 is formed from the aluminum trichloride-carbon tetrachloride complex. + Preferential attack at the para position to form σ-complexes, low-temperature dropwise addition (0-5℃, maintained at 5-10℃) slows down molecular thermal motion, enhances para-selectivity and inhibits ortho or multi-substitution side reactions, while addition at room temperature (25℃) in control example 2 leads to increased thermal motion, increases byproducts such as ortho isomers, and reduces conversion rate and purity.

[0097] Combining Example 1, Comparative Example 3, and Table 1, it can be seen that the product purity of Example 1 is 99.5%, the yield is 91.5%, and the para-selectivity is ≥98%, while the purity of Comparative Example 3 (without gradient temperature control quenching) is only 98.7%, the yield is 86.2%, and the para-selectivity is ≥98%, with a solvent recovery rate of 96.6%. This indicates that gradient temperature control quenching significantly improves purity and yield. In the quenching step, the ice-water mixture containing 5-10% hydrochloric acid, combined with gradient temperature control (≤10℃ to 20-25℃), effectively destroys the aluminum trichloride-carbon tetrachloride complex, inhibits colloid formation and emulsification, and promotes the efficient transfer of the p-methoxytrichloromethylbenzene intermediate to the organic phase. However, Comparative Example 3 uses pure ice water without temperature control, resulting in localized exothermic reactions, triggering colloid formation and emulsification, increasing impurity residues and intermediate losses, thereby reducing purity and yield.

[0098] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for the synthesis of high purity p-methoxybenzoic acid, characterized by, The process comprises the following steps: Step S1. Catalyst activation and complex preparation: under inert gas protection, add aluminum chloride into dichloroethane, stir and disperse, then add carbon tetrachloride, and activate to form a homogeneous aluminum chloride-carbon tetrachloride complex solution; Step S2. Electrophilic substitution reaction: cool the complex solution of step S1, and drop anisole to control the reaction temperature for electrophilic substitution reaction; Step S3. Quenching treatment: drop the reaction solution of step S2 into an ice water mixture containing hydrochloric acid, control the temperature for quenching, and separate the layers after standing; Step S4. Hydrolysis reaction: collect the organic phase of step S3, add hydrochloric acid aqueous solution, adjust the pH after hydrolysis at elevated temperature, and obtain a dichloroethane solution containing p-methoxybenzoyl chloride; Step S5. Solvent recovery: distill dichloroethane from the organic phase of step S4, and further treat the remaining material to obtain crude p-methoxybenzoyl chloride; Step S6. Purification and crystallization: add methanol aqueous solution and activated carbon to the crude product of step S5, reflux, filter, crystallize the filtrate at low temperature, and filter, wash, and dry to obtain the finished product of p-methoxybenzoic acid.

2. The method of claim 1, wherein, In step S1, the molar ratio of aluminum chloride to carbon tetrachloride is 1:(0.9-1.1), the amount of dichloroethane is 3-5 times the mass of aluminum chloride, the activation temperature is 30-40℃, and the activation time is 1.5-2 hours.

3. The method according to claim 1 or 2, characterized in that, In step S1, the aluminum chloride is in the form of yellow powder with a purity of ≥99% and a particle size of ≤100 mesh.

4. The method of claim 1, wherein, In step S2, the complex solution of step S1 is cooled to 0-5℃, anisole is added dropwise, the dropping speed is controlled to maintain the reaction system temperature at 5-10℃, the reaction is maintained at this temperature for 3-4 hours after the dropping is completed, and the molar ratio of anisole to aluminum chloride is 1:1.

1.

5. The method according to claim 1 or 4, characterized in that, In step S2, the dropping speed of anisole is 1-2 drops per second, which is controlled by a constant pressure dropping funnel, and the reaction temperature fluctuation is ≤±2℃.

6. The method of claim 1, wherein, In step S3, the concentration of hydrochloric acid in the ice water mixture is 5-10%, the molar ratio of hydrochloric acid to aluminum chloride is 1.5:(1-1.2), and the mass of the ice water mixture is 2-3 times the total mass of the reaction solution.

7. The method according to claim 1 or 6, characterized in that, In step S3, the ice water mixture has an ice to water mass ratio of 1:1, the hydrochloric acid is concentrated hydrochloric acid added gradually, the concentration is 36.5%, the system temperature is controlled to ≤10℃ during the quenching process, and the temperature is raised to 20-25℃ after the dropping is completed for stirring for 30-40 minutes.

8. The method of claim 1, wherein, In step S4, the concentration of the hydrochloric acid aqueous solution is 10-12%, the mass ratio to anisole is (1.2-1.5):1, the hydrolysis temperature is 40-45℃, the hydrolysis time is 3-3.5 hours, and the pH is adjusted to 6.5-7.

0.

9. The method of claim 1, wherein, In step S5, the distillation includes atmospheric distillation and reduced pressure distillation, the atmospheric distillation distillation range is 83-85℃, the vacuum degree of the reduced pressure distillation is 0.095-MPa, and the recovered dichloroethane is recycled for step S1 after purification by rectification.

10. The method of claim 1, wherein, In step S6, the volume ratio of methanol to water in the methanol aqueous solution is 3:1, the amount of activated carbon is 1% of the mass of the crude product, the reflux temperature is 65-70°C, the reflux time is 20-30 minutes, the filtrate is cooled from 65°C to 5°C at a rate of 5°C / 10 minutes, and the crystallization time is 30-40 minutes.

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