Continuous flow synthesis of benorylate

Abstract

This invention relates to the field of compound synthesis technology, specifically to a continuous flow synthesis method for benorilate. The preparation is carried out in a microchannel continuous flow reactor. S1: A salicylic acid solution and an acetic anhydride solution are mixed at the same flow rate and then reacted in a first reaction unit to obtain acetylsalicylic acid. S2: An acetylsalicylic acid solution and a sulfoxide solution are mixed at the same flow rate and then reacted in a second reaction unit to obtain acetylsalicyl chloride. S3: A p-aminophenol solution and an acetic anhydride solution are mixed at the same flow rate and then reacted in a third reaction unit to obtain p-acetaminophen. S4: A p-acetaminophen solution and an alkaline solution are mixed at the same flow rate and then reacted in a fourth reaction unit. The outflowing reactants are then mixed with an acetylsalicyl chloride solution at the same flow rate and then reacted in a fifth reaction unit. After purification, benorilate is obtained. This four-step reaction has high yield and short reaction time, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and more specifically to a continuous flow synthesis method for benorilates. Background Technology

[0002] Benorilates are primarily used to prepare formulations that relieve symptoms such as colds and toothaches. Benorilates are synthesized through the esterification of acetaminophen and aspirin, aiming to reduce gastrointestinal irritation and achieve synergistic therapeutic effects. The synthesis of benorilates mainly falls into two categories: one is the classic two-step aspirinyl chloride method, which is a milder process but initially suffered from low yields and easy hydrolysis; the other is the direct esterification method, which, although shorter, requires the use of a condensing agent.

[0003] In recent years, technological advancements have focused on process optimization and green chemistry. Research directions include developing highly efficient catalysts to achieve one-step synthesis and avoid the use of harmful reagents such as thionyl chloride, significantly improving the safety and environmental friendliness of the reaction. Simultaneously, process analysis techniques (such as infrared and Raman spectroscopy) have been introduced for online monitoring of reaction progress to achieve precise control. Furthermore, research has expanded to the control and removal of impurities during the production process to ensure pharmaceutical quality.

[0004] Although existing benorilate synthesis processes have improved in safety and efficiency, the reactor-based production model still has inherent limitations, such as low material addition precision, uneven heat transfer, and difficulty in continuous large-scale production. The current technology for benorilate synthesis is as follows: ① Acyl chloride synthesis method: CN101560168A improves the two-step method for aspirin acyl chloride, using toluene or tetrahydrofuran as solvent and DMF as catalyst. First, acetylsalicylic acid is reacted with bis(trichloromethyl) carbonate to generate acetylsalicylic acid chloride, which is then reacted with sodium acetaminophen at room temperature under the action of polyethylene glycol-6000 phase transfer catalyst to obtain benorilate. However, the CN101560168A patent process uses large amounts of polyethylene glycol and toluene, resulting in complicated post-processing and hindering environmental protection. Furthermore, this reaction requires low-temperature control, leading to high energy consumption. CN101844997A uses 4-dimethylaminopyridine as an ultra-efficient catalyst, feeding aspirin acyl chloride and acetaminophen at a ratio of 0.95–1.20:1.00, adding an inorganic base as an acid-binding agent, and reacting at 0–20℃ for 10 minutes to 3 hours. This route offers high yield, good quality, low cost, less waste, and easier production control. However, patent CN101844997A uses a DCC / DMAP catalytic system. DCC is expensive and easily produces the difficult-to-separate byproduct dicyclohexylurea, leading to complex post-treatment. The DMAP catalyst is also expensive, hindering cost control in industrial production. The "Optimization of Benorilate Synthesis Process" uses Vilsmeier reagent / triethylamine instead of traditional chlorination reagents, with DMF as the solvent, achieving an overall yield of 80.4% in a two-step reaction. This route has a low odor, simple equipment, requires no tail gas absorption, produces less wastewater and waste gas, and has milder reaction conditions, making it safer and more environmentally friendly. However, this process uses a thionyl chloride / pyridine chlorination system, which has the problems of a strong irritating odor and high environmental pressure; the overall yield is only 69%, which is relatively low; and the reaction temperature requires precise control, demanding high operational standards.

[0005] ② One-step condensation green method: "4-Dimethylaminopyridine-catalyzed synthesis of benorilates" uses 4-dimethylaminopyridine (DMAP) as a catalyst and dicyclohexylcarbodiimide (DCC) as a condensing agent. Single-factor experiments were conducted to explore the optimal conditions for synthesizing benorilates, including reaction temperature, time, and reactant ratios. This route avoids the harmful gases generated by thionyl chloride used in traditional methods, allowing for one-step synthesis, making it green, efficient, and significantly safer. However, the raw material used, m-diisopropylbenzene, has a complex preparation process, limited availability, and high cost. The reaction must be carried out in a high-pressure reactor under heating conditions, requiring high pressure resistance from the equipment. The use of dilute acid and the oxidative cracking process easily generate byproducts, increasing the difficulty of product separation and purification.

[0006] ③ Microwave Synthesis Method: "Application of Microwave Synthesis Technology in Benorilate Preparation and Structural Analysis of Byproducts" This method uses microwave synthesis technology, with aspirin and paracetamol as raw materials, to prepare benorilate through a one-step condensation under microwave irradiation. The advantages of this route are short reaction time, simple operation, low energy consumption, and effective improvement of reaction efficiency and selectivity. However, although microwave synthesis in this literature results in a rapid reaction, microwave equipment is difficult to scale up industrially and is not suitable for mass production.

[0007] Existing processes or reagents used are toxic or harmful, have high requirements for equipment and operating environment, are cumbersome in post-processing, or have high energy consumption, long reaction time, and low reaction yield. Therefore, a benorilate process that balances environmental protection requirements with improved production efficiency and increased reaction yield urgently needs to be developed. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides a continuous flow synthesis method for benorilates. This invention integrates the preparation of acetylsalicylic acid, acetylsalicylic acid chloride, acetaminophen, and benorilates into a single process using a microchannel continuous flow apparatus. The four-step reaction achieves high yields, simple separation, and short reaction times, making it suitable for large-scale industrial production.

[0009] To achieve the above objectives, the present invention is implemented through the following technical solution: The continuous flow synthesis method for benorilates includes the following steps: The preparation is carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. S1. After mixing the salicylic acid solution and the first acetic anhydride solution at the same flow rate, the mixture enters the first reaction unit to carry out the first reaction. After collecting the first reaction material, it is concentrated, pulped and dried to obtain acetylsalicylic acid. S2. The acetylsalicylic acid is formed into an acetylsalicylic acid solution, which is then mixed with a thionyl chloride solution at the same flow rate and introduced into the second reaction unit for a second reaction. The second reaction material is collected and concentrated to remove the solvent, thereby obtaining acetylsalicyl chloride. The acetylsalicyl chloride is then formed into an acetylsalicyl chloride solution for later use. S3. Simultaneously, the p-aminophenol solution and the second acetic anhydride solution are mixed at the same flow rate and then introduced into the third reaction unit to carry out the third reaction. After collecting the third reaction material, it is concentrated, pulped and dried to obtain p-acetaminophenol. S4. The acetaminophen is mixed with an alkaline solution at the same flow rate and then enters the fourth reaction unit for the fourth reaction. The outflowing fourth reaction material is mixed with the acetylsalicylic acid chloride solution at the same flow rate and then enters the fifth reaction unit for the fifth reaction. The fifth reaction material is collected, concentrated, washed, and recrystallized to obtain benorilate.

[0010] Furthermore, the salicylic acid solution in S1 contains salicylic acid, pyridine, and an alcohol solvent, the concentration of salicylic acid in the salicylic acid solution is 0.2-0.6 mol / L, and the amount of pyridine used is 0.2-0.5 times the molar amount of salicylic acid; the first acetic anhydride solution contains acetic anhydride and an alcohol solvent, and the molar concentration of the first acetic anhydride solution is 1.05-1.3 times the molar concentration of salicylic acid.

[0011] Furthermore, in S1, the temperature of the first reaction is 20-60°C, and the residence time of the material in the first reaction unit is 25-80 seconds.

[0012] Furthermore, the acetylsalicylic acid solution in S2 contains acetylsalicylic acid, N,N-dimethylformamide, and a polar organic solvent. The concentration of acetylsalicylic acid in the acetylsalicylic acid solution is 0.05-0.2 mol / L, and the amount of N,N-dimethylformamide is 0.03-0.06 times the molar amount of acetylsalicylic acid. The thionyl chloride solution contains thionyl chloride and a polar organic solvent, and the molar concentration of the thionyl chloride solution is 1.8-2.3 times the molar concentration of acetylsalicylic acid.

[0013] Furthermore, in S2, the temperature of the second reaction is 20-25°C, and the residence time of the material in the second reaction unit is 10-18 minutes.

[0014] Furthermore, the p-aminophenol solution in S3 contains p-aminophenol and an alcohol solvent, and the concentration of p-aminophenol in the p-aminophenol solution is 0.05-0.12 mol / L; The second acetic anhydride solution contains acetic anhydride and an alcohol solvent, and the molar concentration of the second acetic anhydride solution is 1-1.2 times the molar concentration of the p-aminophenol solution.

[0015] Furthermore, the temperature of the third reaction in S3 is 25-40°C, and the residence time of the material in the third reaction unit is 10-20 seconds.

[0016] Furthermore, the acetaminophen solution in S4 contains acetaminophen and a polar organic solvent, and the concentration of acetaminophen in the acetaminophen solution is 0.08-0.15 mol / L; The alkaline solution is an aqueous solution of sodium hydroxide, wherein the mass percentage of sodium hydroxide is 6%-10%. The acetylsalicylic acid chloride solution contains acetylsalicylic acid chloride prepared by S2 and a polar organic solvent, and the concentration of the acetylsalicylic acid chloride solution is 0.1-0.4 mol / L.

[0017] Furthermore, the temperature of the fourth reaction is 25-35°C, and the residence time of the material in the fourth reaction unit is 1-3 minutes; The temperature of the fifth reaction is 25-35℃, and the residence time of the material in the fifth reaction unit is 7-20 minutes.

[0018] Furthermore, the alcohol solvents used in the salicylic acid solution, acetic anhydride solution, and p-aminophenol solution are each selected from one or more of ethanol and methanol; the polar organic solvents used in the acetylsalicylic acid chloride solution, the sulfonyl chloride solution, and the p-aminophenol solution are selected from one or more of dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, and acetone.

[0019] Furthermore, the flow rate of a single solution stream entering the first reaction unit is 0.45-3 mL / min; The single-stream solution flow rate entering the second reaction unit is 1-3 mL / min; The single-stream solution flow rate entering the third reaction unit is 3-10 mL / min; The single-stream solution flow rate entering the fourth reaction unit is 0.5-2 mL / min; The flow rate of a single solution entering the fifth reaction unit is 0.05-1.8 mL / min.

[0020] Beneficial technical effects: This invention employs a microchannel continuous flow process to prepare benorilates, effectively improving reaction efficiency while simultaneously enhancing the reaction yield and product purity of the benorilate product. The space-time yield of the benorilate product is 1300-2200 g·L⁻¹. -1 ·h -1 Within this range, the product purity is at least 84%, which greatly shortens the reaction time. Attached Figure Description

[0021] Figure 1 This is a flowchart illustrating the synthesis process of benorilate in this invention. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] Unless otherwise specifically stated, the numerical values ​​set forth in these embodiments do not limit the scope of the invention. Techniques and methods known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques and methods should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values. It should be noted that values ​​expressed, for example, as "within the range of ab" or "between the range of ab," do not include the endpoint values ​​a and b; values ​​expressed as "for ab," "is ab," or "ab" include the endpoint values ​​a and b.

[0024] Furthermore, it should be noted that the use of terms such as "first" and "second" to define the relevant solutions and reaction units is merely for the purpose of distinguishing the raw materials and reaction units. Unless otherwise stated, the above terms have no special meaning and therefore should not be construed as limiting the scope of protection of this invention.

[0025] Experimental methods not specified in the following examples are generally performed according to national standards; if there is no corresponding national standard, they are performed according to general standard requirements or general methods.

[0026] Retention time refers to the time required for a material to pass through a continuous flow reactor. The specific calculation method is as follows: Retention time = liquid holding volume × (60 s / min) / total volumetric flow rate; The liquid holding volume is the capacity of the continuous flow reaction unit, which is a fixed value of 100 mL. Total volumetric flow rate = flow rate of syringe pump ① + flow rate of reaction unit.

[0027] Space-time yield = Product mass ÷ (Reaction unit volume × Time)

[0028] Example 1

[0029] The continuous flow synthesis method for benorilates includes the following steps: The preparation is carried out in a microchannel continuous flow reactor, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The reaction coil of the first reaction unit has an inner diameter of 0.8 mm and a length of 3 m; the reaction coil of the second reaction unit has an inner diameter of 0.8 mm and a length of 3 m; the reaction coil of the third reaction unit has an inner diameter of 0.8 mm and a length of 3 m; the reaction coil of the fourth reaction unit has an inner diameter of 0.8 mm and a length of 3 m; and the reaction coil of the fifth reaction unit has an inner diameter of 0.8 mm and a length of 3 m. For the specific process route, please refer to... Figure 1 ; S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.2 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 25°C. After the mixture remained in the first reaction unit for 30 seconds, the reaction mixture flowed out of the first reaction unit. The first reaction material was collected continuously for 5 min. The first reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol was added in an amount equal to the weight of the solid, and the mixture was stirred. The mixture was filtered and dried at 40°C to obtain 9.71 g of acetylsalicylic acid as a white solid (space-time yield 4850 g·L⁻¹). -1 ·h -1 (Purity 99.37wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.3 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.1 mol / L. Acetic anhydride was dissolved in ethanol to prepare a 0.11 mol / L component F. The amount of acetic anhydride used was 1.1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then introduced into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 25°C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, with a weight ratio of 1:1 (based on the solid weight), was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 5.18 g of white acetaminophen solid (space-time yield 2590 g·L⁻¹). -1 ·h -1 (Purity 100wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 25°C. The mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.2 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 25°C. The mixture was held in the fifth reaction unit for 7.5 min and then flowed out of the fifth reaction unit. The mixture was continuously collected for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 51.32 g of white benorilate crystals (space-time yield 2137.5 g·L⁻¹). -1 ·h -1 (Purity 98.25wt%).

[0030] Example 2

[0031] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.3 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 25°C. After the mixture remained in the first reaction unit for 30 seconds, the reaction mixture flowed out of the first reaction unit and was continuously collected for 5 min to obtain the first reaction material. The first reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol was added in an amount equal to the weight of the solid, and the mixture was stirred. The mixture was filtered and dried at 40°C to obtain 9.22 g of acetylsalicylic acid as a white solid (space-time yield 4718 g·L⁻¹). -1 ·h -1 (Purity 99.10wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.2 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.08 mol / L. Acetic anhydride was dissolved in ethanol to prepare component F with a concentration of 0.088 mol / L. The amount of acetic anhydride used was 1.1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then introduced into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 25°C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, with a weight ratio of 1:1 (based on the solid weight), was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 5.01 g of white acetaminophen solid (space-time yield 2460 g·L⁻¹). -1 ·h -1 (Purity 98.99wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 25°C, and the mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.2 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 25°C, and the mixture was held in the fifth reaction unit for 7.5 min. The mixture was then discharged from the fifth reaction unit and collected continuously for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 33.43 g of white benorilate crystals (space-time yield 1315 g·L⁻¹). -1 ·h -1 (Purity 84.81wt%).

[0032] Example 3

[0033] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.5 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 25°C. After the mixture remained in the first reaction unit for 30 seconds, the reaction mixture flowed out of the first reaction unit. The first reaction material was collected continuously for 5 min and then concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, at a weight ratio of 1, was added and the mixture was stirred. The mixture was then filtered and dried at 40°C to obtain 8.63 g of acetylsalicylic acid as a white solid (space-time yield 4613 g·L⁻¹). -1 ·h -1 (Purity 98.67wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.15 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.06 mol / L. Acetic anhydride was dissolved in ethanol to prepare component F with a concentration of 0.066 mol / L. The amount of acetic anhydride used was 1.1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then introduced into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 25°C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, with a weight ratio equal to that of the solid, was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 4.92 g of white acetaminophen solid (space-time yield 2412 g·L⁻¹). -1 ·h -1 (Purity 98.82wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 25°C, and the mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.2 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 25°C, and the mixture was held in the fifth reaction unit for 7.5 min. The mixture was then discharged from the fifth reaction unit and collected continuously for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 41.21 g of white benorilate crystals (space-time yield 1678 g·L⁻¹). -1 ·h -1 (Purity 90.16wt%).

[0034] Example 4

[0035] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.5 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 20 °C. After the mixture remained in the first reaction unit for 30 seconds, the reaction mixture flowed out of the first reaction unit and was continuously collected for 5 min to obtain the first reaction material. The first reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50 °C) to obtain a white or brown solid. Anhydrous ethanol was added in an amount equal to the weight of the solid and the mixture was stirred. The mixture was filtered and dried at 40 °C to obtain 8.4 g of acetylsalicylic acid as a white solid (space-time yield 4589 g·L⁻¹). -1 ·h -1 (Purity 98.43wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.1 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.1 mol / L. Acetic anhydride was dissolved in ethanol to prepare a 0.12 mol / L component F. The amount of acetic anhydride used was 1.2 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then fed into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 25°C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, at a weight ratio of 1, was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 4.76 g of white acetaminophen solid (space-time yield 2381 g·L⁻¹). -1 ·h -1 (Purity 98.31wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 25°C. The mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.2 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 25°C. The mixture was held in the fifth reaction unit for 7.5 min and then flowed out of the fifth reaction unit. The mixture was continuously collected for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 31.72 g of white benorilate crystals (space-time yield 1206 g·L⁻¹). -1 ·h -1 (Purity 82.31wt%).

[0036] Example 5

[0037] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.5 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 40 °C. After the mixture remained in the first reaction unit for 30 seconds, the reaction mixture flowed out of the first reaction unit. The first reactant was collected continuously for 5 min and then concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50 °C) to obtain a white or brown solid. Anhydrous ethanol, at a weight ratio of 1, was added and the mixture was stirred. The mixture was then filtered and dried at 40 °C to obtain 8.52 g of acetylsalicylic acid as a white solid (space-time yield 4601 g·L⁻¹). -1 ·h -1 (Purity 98.51wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.3 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.1 mol / L. Acetic anhydride was dissolved in ethanol to prepare a 0.1 mol / L component F, with the amount of acetic anhydride being 1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then fed into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 25°C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, at a weight ratio of 1, was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 5.08 g of white acetaminophen solid (space-time yield 2517 g·L⁻¹). -1 ·h -1 (Purity 99.17wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 30°C. The mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.2 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 30°C. The mixture was held in the fifth reaction unit for 7.5 min and then flowed out of the fifth reaction unit. The mixture was continuously collected for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 46.11 g of white benorilate crystals (space-time yield 1987 g·L⁻¹). -1 ·h -1 (Purity 94.78wt%).

[0038] Example 6

[0039] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.5 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 50°C. After the mixture remained in the first reaction unit for 30 seconds, the reaction mixture flowed out of the first reaction unit. The first reaction material was collected continuously for 5 min. The first reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol was added in an amount equal to the weight of the solid and the mixture was stirred. The mixture was filtered and dried at 40°C to obtain 8.54 g of acetylsalicylic acid as a white solid (space-time yield 4606 g·L⁻¹). -1 ·h -1 (Purity 98.55wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.3 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.1 mol / L. Acetic anhydride was dissolved in ethanol to prepare a 0.11 mol / L component F. The amount of acetic anhydride used was 1.1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (4.5 mL / min) and then introduced into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 25°C. After the mixture remained in the third reaction unit for 20 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, with a weight ratio of 1:1 (based on the solid weight), was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 5.18 g of white acetaminophen solid (space-time yield 2577 g·L⁻¹). -1 ·h -1 (Purity 100wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 35°C. The mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.1 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 35°C. The mixture was held in the fifth reaction unit for 7.5 min and then flowed out of the fifth reaction unit. The mixture was continuously collected for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 36.67 g of white benorilate crystals (space-time yield 1498 g·L⁻¹). -1 ·h -1 (Purity 87.34wt%).

[0040] Example 7

[0041] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.5 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (1.8 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 25°C. After the mixture remained in the first reaction unit for 50 seconds, the reaction mixture flowed out of the first reaction unit. The first reaction material was collected continuously for 5 min and then concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol was added in an amount equal to the weight of the solid and the mixture was stirred. The mixture was filtered and dried at 40°C to obtain 8.48 g of acetylsalicylic acid as a white solid (space-time yield 4607 g·L⁻¹). -1 ·h -1 (Purity 98.55wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.1 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.1 mol / L. Acetic anhydride was dissolved in ethanol to prepare a 0.11 mol / L component F. The amount of acetic anhydride used was 1.1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then fed into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 30°C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol, at a weight ratio of 1, was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 5.18 g of white acetaminophen solid (space-time yield 2588 g·L⁻¹). -1 ·h -1 (Purity 100wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (0.75 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 25°C. The mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.05 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 25°C. The mixture was held in the fifth reaction unit for 15 min and then discharged from the fifth reaction unit. The mixture was continuously collected for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 30.13 g of white benorilate crystals (space-time yield 1116 g·L⁻¹). -1 ·h -1 (Purity 81.13wt%).

[0042] Example 8

[0043] The continuous flow synthesis method for benorilates includes the following steps: The preparation was carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. The equipment used is the same as in Example 1. S1. Dissolve salicylic acid and pyridine in ethanol to prepare component A, which contains 0.5 mol / L salicylic acid and the amount of pyridine is 0.5 times the molar amount of salicylic acid. Acetic anhydride was dissolved in ethanol to prepare component B at a concentration of 0.6 mol / L, wherein the amount of acetic anhydride used was 1.2 times the molar amount of salicylic acid. Component A and component B were mixed at the same flow rate (1.3 mL / min) and then fed into the first reaction unit for the first reaction. The temperature of the first reaction was controlled at 25°C. After the mixture remained in the first reaction unit for 70 seconds, the reaction mixture flowed out of the first reaction unit and was continuously collected for 5 min to obtain the first reaction material. The first reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50°C) to obtain a white or brown solid. Anhydrous ethanol was added in an amount equal to the weight of the solid, and the mixture was stirred. The mixture was filtered and dried at 40°C to obtain 8.39 g of acetylsalicylic acid as a white solid (space-time yield 4581 g·L⁻¹). -1 ·h -1 (Purity 98.41wt%) S2. Acetylsalicylic acid was dissolved in anhydrous dichloromethane, and DMF was added to prepare component C, which contained 0.1 mol / L acetylsalicylic acid. The amount of DMF used was 0.05 times the molar amount of acetylsalicylic acid. Thionyl chloride was dissolved in anhydrous dichloromethane to prepare component D at a concentration of 0.2 mol / L, wherein the amount of thionyl chloride used was twice the molar amount of acetylsalicylic acid. Component C and component D were mixed at the same flow rate (2 mL / min) and then fed into the second reaction unit for the second reaction. The temperature of the second reaction was controlled at room temperature. After the mixture was kept in the second reaction unit for 15 min, the reaction mixture flowed out of the second reaction unit and the second reaction material was collected. It was then concentrated under vacuum (vacuum degree 80 mbar, concentration temperature 35℃) to obtain the intermediate light yellow liquid acetylsalicylic acid chloride. Acetylsalicylic acid chloride was dissolved in tetrahydrofuran to prepare component I at a concentration of 0.1 mol / L for later use. S3. Simultaneously, the reaction raw material p-aminophenol was dissolved in ethanol to prepare component E with a concentration of 0.1 mol / L. Acetic anhydride was dissolved in ethanol to prepare a 0.11 mol / L component F. The amount of acetic anhydride used was 1.1 times the molar amount of p-aminophenol. Component E and component F were mixed at the same flow rate (9 mL / min) and then fed into the third reaction unit for the third reaction. The temperature of the third reaction was controlled at 40 °C. After the mixture remained in the third reaction unit for 10 s, the reaction mixture flowed out of the third reaction unit and was continuously collected for 5 min to obtain the third reaction material. The third reaction material was concentrated under vacuum (vacuum degree 20 mbar, concentration temperature 50 °C) to obtain a white or brown solid. Anhydrous ethanol, at a weight ratio of 1, was added and stirred for 2 h. The mixture was then filtered and vacuum dried to obtain 5.17 g of white acetaminophen solid (space-time yield 2588 g·L⁻¹). -1 ·h -1 (Purity 100wt%) S4. Prepare a 0.1 mol / L component G by dissolving acetaminophen in tetrahydrofuran; Sodium hydroxide was mixed with water to form an alkaline solution, and a 7wt% component H was prepared. Component G and component H were mixed at the same flow rate (1 mL / min) and then fed into the fourth reaction unit for the fourth reaction. The temperature of the fourth reaction was controlled at 25°C. The mixture was held in the fourth reaction unit for 2 min. The outflowing fourth reaction material was mixed with component I in S2 at the same flow rate (0.5 mL / min) and then fed into the fifth reaction unit for the fifth reaction. The temperature of the fifth reaction was controlled at 25°C. The mixture was held in the fifth reaction unit for 30 min and then flowed out of the fifth reaction unit. The mixture was continuously collected for 1 h to obtain the fifth reaction material. The fifth reaction material was evaporated to dryness with tetrahydrofuran, filtered, and washed with cold water until neutral to obtain a white crude benorilate. It was recrystallized with 95 wt% ethanol and dried to obtain 14.76 g of white benorilate crystals (space-time yield 546 g·L⁻¹). -1 ·h -1 (Purity 41.39wt%).

[0044] The parameters and results for each step in the above cases are shown in Table 1 below.

[0045] Table 1. Parameters and results for each step in each case.

[0046] As shown above, the variable amount of pyridine, the first reaction temperature, and the residence time in the first reaction unit in step S1 have little effect on the yield and purity of the acetylsalicylic acid product. The space-time yield of the product is 4580-4850 g / (L·h), and the product purity is between 98-99.5%. In step S3, reducing the concentration of p-aminophenol leads to a decrease in the space-time yield of p-acetaminophen, but has little effect on the purity of p-acetaminophen. In S4, in Examples 1-4, the yield and purity of benorilate decrease with the decrease of acetylsalicylic acid chloride concentration; in Examples 4, 7, and 8, increasing the temperature leads to an increase in side reactions and a decrease in purity. At relatively low acetylsalicylic acid chloride concentrations, the purity and yield of benorilate decrease significantly with the extension of reaction time. It can be seen that a higher acyl chloride concentration is beneficial to promoting the forward condensation reaction and improving the reaction rate and conversion rate. Comparing Examples 1 and 5 / 6, increasing the reaction temperature at higher acyl chloride concentrations may lead to side reactions. Therefore, the purity of the final products in Examples 5 and 6 is slightly lower than that in Example 1, indicating that room temperature is more favorable for benorilate synthesis. The optimal reaction scheme for benorilate synthesis is high concentration, short reaction time, and room temperature reaction.

[0047] The four-step reaction of this invention is carried out in microchannels, which can yield high-purity benorilate in a short time, demonstrating the great advantages of continuous flow technology in handling rapid, exothermic or unstable intermediate reactions.

[0048] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A continuous flow synthesis method for benorilates, characterized in that, Includes the following steps: The preparation is carried out in a microchannel continuous flow reaction apparatus, which includes a first reaction unit, a second reaction unit, a third reaction unit, and a fourth reaction unit and a fifth reaction unit connected in series. S1. After mixing the salicylic acid solution and the first acetic anhydride solution at the same flow rate, the mixture enters the first reaction unit to carry out the first reaction. After collecting the first reaction material, it is concentrated, pulped and dried to obtain acetylsalicylic acid. S2. The acetylsalicylic acid is formed into an acetylsalicylic acid solution, which is then mixed with a thionyl chloride solution at the same flow rate and introduced into the second reaction unit for a second reaction. The second reaction material is collected and concentrated to remove the solvent, thereby obtaining acetylsalicyl chloride. The acetylsalicyl chloride is then formed into an acetylsalicyl chloride solution for later use. S3. Simultaneously, the p-aminophenol solution and the second acetic anhydride solution are mixed at the same flow rate and then introduced into the third reaction unit to carry out the third reaction. After collecting the third reaction material, it is concentrated, pulped and dried to obtain p-acetaminophenol. S4. The acetaminophen is mixed with an alkaline solution at the same flow rate and then enters the fourth reaction unit for the fourth reaction. The outflowing fourth reaction material is mixed with the acetylsalicylic acid chloride solution at the same flow rate and then enters the fifth reaction unit for the fifth reaction. The fifth reaction material is collected, concentrated, washed, and recrystallized to obtain benorilate.

2. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The salicylic acid solution in S1 contains salicylic acid, pyridine, and an alcohol solvent. The concentration of salicylic acid in the salicylic acid solution is 0.2-0.6 mol / L, and the amount of pyridine used is 0.2-0.5 times the molar amount of salicylic acid. The first acetic anhydride solution contains acetic anhydride and an alcohol solvent. The molar concentration of the first acetic anhydride solution is 1.05-1.3 times the molar concentration of salicylic acid.

3. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The flow rate of a single solution entering the first reaction unit is 0.45-3 mL / min; the temperature of the first reaction in S1 is 20-60℃, and the residence time of the material in the first reaction unit is 25-80 seconds.

4. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The acetylsalicylic acid solution in S2 contains acetylsalicylic acid, N,N-dimethylformamide, and a polar organic solvent. The concentration of acetylsalicylic acid in the acetylsalicylic acid solution is 0.05-0.2 mol / L, and the amount of N,N-dimethylformamide is 0.03-0.06 times the molar amount of acetylsalicylic acid. The thionyl chloride solution contains thionyl chloride and a polar organic solvent, and the molar concentration of the thionyl chloride solution is 1.8-2.3 times the molar concentration of acetylsalicylic acid.

5. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The flow rate of the single solution entering the second reaction unit is 1-3 mL / min; the temperature of the second reaction in S2 is 20-25℃, and the residence time of the material in the second reaction unit is 10-18 minutes.

6. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The p-aminophenol solution described in S3 contains p-aminophenol and an alcohol solvent, and the concentration of p-aminophenol in the p-aminophenol solution is 0.05-0.12 mol / L; The second acetic anhydride solution contains acetic anhydride and an alcohol solvent, and the molar concentration of the second acetic anhydride solution is 1-1.2 times the molar concentration of the p-aminophenol solution.

7. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The flow rate of the single solution entering the third reaction unit is 3-10 mL / min; the temperature of the third reaction in S3 is 25-40℃, and the residence time of the material in the third reaction unit is 10-20 seconds.

8. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The acetaminophen solution described in S4 contains acetaminophen and a polar organic solvent, and the concentration of acetaminophen in the acetaminophen solution is 0.08-0.15 mol / L; The alkaline solution is an aqueous solution of sodium hydroxide, wherein the mass percentage of sodium hydroxide is 6%-10%. The acetylsalicylic acid chloride solution contains acetylsalicylic acid chloride prepared by S2 and a polar organic solvent, and the concentration of the acetylsalicylic acid chloride solution is 0.1-0.4 mol / L.

9. The continuous flow synthesis method for benorilate according to claim 1, characterized in that, The single-stream solution flow rate entering the fourth reaction unit is 0.5-2 mL / min; the temperature of the fourth reaction is 25-35℃; and the residence time of the material in the fourth reaction unit is 1-3 minutes. The single-stream solution flow rate entering the fifth reaction unit is 0.05-1.8 mL / min; the temperature of the fifth reaction is 25-35℃; and the residence time of the material in the fifth reaction unit is 7-20 minutes.

10. The continuous flow synthesis method for benorilate according to any one of claims 2-9, characterized in that, The alcohol solvents used in the salicylic acid solution, acetic anhydride solution, and p-aminophenol solution are selected from one or more of ethanol and methanol, respectively; the polar organic solvents used in the acetylsalicylic acid chloride solution, the sulfonyl chloride solution, and the p-aminophenol solution are selected from one or more of dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, dioxane, acetonitrile, and acetone.

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