A method for the selective nitration of 4-acetamidobenzoic anisole in a continuous flow microchannel reactor

Abstract

This invention relates to a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, belonging to the field of compound synthesis. The method includes: mixing 4-acetamidoanisole with a solvent to obtain feed solution A; using nitric acid as feed solution B; washing the microchannel reaction system with a solvent; pumping feed solution A and feed solution B separately into the microchannel reactor using metering pumps; after the reaction is complete, the product flows out from the outlet of the microchannel reactor, and the reaction solution is collected; diluting the reaction solution with ice water, precipitating the product, filtering, washing, and drying to obtain 4-acetamido-2-nitroanisole, or separating the reaction solution by washing with water, distilling under reduced pressure, and drying to obtain 4-methoxy-2-nitroacetanilide. This method only requires changing the solvent system of one feed solution to obtain two isomers with excellent selectivity. It features high reaction safety, short reaction time, simple post-processing, avoids the dangers of batch nitration reactions, and significantly reduces economic costs.

Description

Technical Field

[0001] This invention relates to a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, belonging to the field of compound synthesis. Background Technology

[0002] The compound 4-acetamidoanisole has two nitration products: 4-acetamido-2-nitroanisole and 4-methoxy-2-nitroacetanilide, both of which have a certain market demand. 4-acetamido-2-nitroanisole is an important intermediate for 2-amino-4-acetamidoanisole and is mainly used in the synthesis of disperse dyes. It can be used to prepare more than twenty varieties of blue disperse dyes, such as CI Disperse Blue 79, CI Disperse Blue 291, and CI Disperse Blue 58. Disperse dyes using the reducing agent as the coupling component are stable in quality, have high color intensity, good dye application performance, and are in high market demand. They are mainly used as color developers in cosmetic hair dyeing and can also be used for dyeing wool, fur, etc.

[0003] 4-Methoxy-2-nitroacetanilide is an important intermediate in dye production and in the drug omeprazole (OPZ). OPZ was the first proton pump inhibitor, marketed in 1988. Due to its high efficacy, it has become the drug of choice for treating acid-related disorders. OPZ selectively and non-competitively inhibits the activity of the proton pump (H+ / K+-ATP) in the secretory membrane of parietal cells and has a strong, long-term inhibitory effect on gastric acid secretion. It is commonly used to treat gastroesophageal reflux disease (GERD), peptic ulcers, duodenal ulcers, and other conditions.

[0004] Current research on continuous flow nitration technology for 4-acetaminophen ether, such as CN113527126A, describes the nitration of 4-acetaminophen ether using a tubular reactor to obtain 2-nitro-4-acetaminophen ether. However, this requires a large excess of nitrifying agent, resulting in a significant amount of residual nitric acid and the potential generation of polynitration byproducts, posing safety hazards. Another example is the continuous flow nitration step in CN111704555A, which requires a mixed acid system of concentrated sulfuric acid and concentrated nitric acid as the nitrifying agent to obtain 4-methoxy-2-nitroacetanilide. However, using a mixed acid system as the nitrifying agent presents problems such as preparation hazards, sulfuric acid waste, large volumes of wastewater and waste acid requiring treatment, and the potential for isomer formation. Summary of the Invention

[0005] To address the problems of existing nitration technologies for 4-acetaminophen, such as safety hazards, purification difficulties, poor selectivity, high production costs, and environmental pollution, this invention provides a method for selectively nitrating 4-acetaminophen using a continuous flow microchannel reactor. This method only requires changing the solvent system of one raw material to obtain two isomers with excellent selectivity.

[0006] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: A method for selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0007] 1) Mix 4-acetaminophen with a solvent and stir until dissolved to obtain raw material solution A, wherein the solvent is concentrated sulfuric acid or dichloromethane, the molar ratio of concentrated sulfuric acid to 4-acetaminophen is 5 to 7.9:1, and the concentration of 4-acetaminophen in dichloromethane is 0.1 to 2 mol / L;

[0008] Take nitric acid with a concentration of 65%–98% as raw material solution B;

[0009] 2) Clean the microchannel reaction system with the solvent. The microchannel reaction system includes a microchannel reactor and two metering pumps connected to it. Ensure that there is no water or air in the pipeline. Then replace the solvent in the two metering pumps with raw material solution A and raw material solution B, respectively.

[0010] 3) Set the reaction temperature of the microchannel reactor to 0-25℃ using a high-low temperature integrated machine. Pump raw material solution A and raw material solution B into the microchannel reactor through metering pumps respectively. After the reaction is completed, the product flows out from the outlet of the microchannel reactor and the reaction solution is collected.

[0011] Wherein, the molar ratio of 4-acetaminophen to nitric acid is 1:1 to 2, the flow rate of the metering pump pumping into raw material solution A is 1 to 30 mL / min, the flow rate of the metering pump pumping into raw material solution B is 0.1 to 10 mL / min, and the mixing and residence time of raw material solution A and raw material solution B in the microchannel reactor is 0.5 to 5 min.

[0012] 4) Dilute the reaction solution obtained in 3) with ice water, the product precipitates, filter, wash, and dry to obtain 4-acetamido-2-nitroanisole, or wash the reaction solution obtained in 3) with water, separate the layers, distill under reduced pressure, and dry to obtain 4-methoxy-2-nitroacetanilide.

[0013] Based on the above technical solution, the present invention can be further improved as follows.

[0014] Furthermore, in 1), the concentration of the concentrated sulfuric acid is 80% to 98%.

[0015] Furthermore, in 2), the metering pump is a high-pressure plunger pump.

[0016] Furthermore, in step 2), the microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a single plate holding capacity of 10 mL. Both the microchannel reactor and the high-pressure plunger pump used in this invention are commercially available products, and their heart-shaped internal structure is as follows... Figure 4, Figure 5 As shown.

[0017] Furthermore, in 3), the flow rate ratio of the metering pump pumping in raw material liquid A to the metering pump pumping in raw material liquid B is 4 to 8:1.

[0018] Furthermore, in step 4), the drying temperature is 60°C and the drying time is 12 hours.

[0019] The reaction equation for the selective nitration of 4-acetamidoanisole in this invention is shown below, and the process flow diagram is as follows. Figure 1 As shown:

[0020]

[0021] The beneficial effects of this invention are:

[0022] This invention discloses a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, which can selectively synthesize 4-acetamido-2-nitroanisole and 4-methoxy-2-nitroacetanilide. Compared with existing technologies, this method uses the cheapest and most readily available concentrated nitric acid as the nitrating agent, and the amount of nitrating agent used for both isomers does not exceed 2 equivalents. While keeping the reaction apparatus, reaction temperature, and nitrating agent constant, only the solvent system of the other feedstock needs to be changed to obtain the two isomers with excellent selectivity. Furthermore, this method can effectively control the amount of nitric acid used, reducing environmental pollution and lowering risks. Attached Figure Description

[0023] Figure 1 This is a process flow diagram of the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor according to the present invention;

[0024] Figure 2 The process flow diagram for the selective nitration preparation of 4-acetamido-2-nitroanisole using a continuous flow microchannel reactor according to the present invention is shown below.

[0025] Figure 3 The process flow diagram for the selective nitration preparation of 4-methoxy-2-nitroacetanilide using a continuous flow microchannel reactor according to the present invention is shown below;

[0026] Figure 4 This is a schematic diagram of the heart-shaped internal structure of the microchannel reactor used in this invention;

[0027] Figure 5 This is a photograph of the heart-shaped internal structure of the microchannel reactor used in this invention. Detailed Implementation

[0028] The principles and features of the present invention are described below with reference to the accompanying drawings. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0029] Example 1

[0030] This embodiment describes a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0031] Step 1: Pour 40g of 98% concentrated sulfuric acid and 10g of 4-acetaminophen into beaker A and stir until dissolved to obtain raw material solution A. Pour 60mL of 65% nitric acid into beaker B to obtain raw material solution B.

[0032] Step 2: First, clean the entire microchannel reaction system with 98% concentrated sulfuric acid. The microchannel reaction system includes a microchannel reactor and two connected high-pressure plunger pumps, ensuring that there is no water or air in the pipeline. Then, replace the concentrated sulfuric acid in the two high-pressure plunger pumps with feed solution A and feed solution B, respectively. The microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

[0033] Step 3: Feed solution A and feed solution B are pumped into the microchannel reactor at flow rates of 4.5 mL / min and 1 mL / min, respectively, using a high-pressure plunger pump. At this time, the molar ratio of 4-acetaminophen to nitric acid is 1:1.2. The reaction temperature is controlled at 10℃ using a high-low temperature integrated machine, and the residence time is 2 minutes. After the reaction is completed, the product flows out from the outlet of the microchannel reactor, and the resulting reaction solution is collected.

[0034] Step 4: The reaction solution was diluted with ice water, the product precipitated, filtered, washed, and dried at 60℃ for 12 h to obtain crude 4-acetamido-2-nitrobenzene ether with a separation yield of 89%. The process flow diagram is shown below. Figure 2 As shown.

[0035] Example 2

[0036] This embodiment describes a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0037] Step 1: Pour 50g of 92% concentrated sulfuric acid and 10g of 4-acetaminophen into beaker A and stir until dissolved to obtain raw material solution A. Pour 60mL of 70% nitric acid into beaker B to obtain raw material solution B.

[0038] Step 2: First, clean the entire microchannel reaction system with 92% concentrated sulfuric acid. The microchannel reaction system includes a microchannel reactor and two connected high-pressure plunger pumps, ensuring that there is no water or air in the pipeline. Then, replace the concentrated sulfuric acid in the two high-pressure plunger pumps with feed solution A and feed solution B, respectively. The microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

[0039] Step 3: Feed solution A and feed solution B are pumped into the microchannel reactor at flow rates of 14 mL / min and 3 mL / min, respectively, using a high-pressure plunger pump. At this time, the molar ratio of 4-acetaminophen to nitric acid is 1:1.5. The reaction temperature is controlled at 0℃ using a high-low temperature integrated machine, and the residence time is 1.25 minutes. After the reaction is completed, the product flows out from the outlet of the microchannel reactor, and the resulting reaction solution is collected.

[0040] Step 4: The reaction solution was diluted with ice water, the product precipitated, filtered, washed, and dried at 60℃ for 12 h to obtain crude 4-acetamido-2-nitrobenzene ether with a separation yield of 94%.

[0041] Example 3

[0042] This embodiment describes a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0043] Step 1: Pour 40g of 80% concentrated sulfuric acid and 10g of 4-acetaminophen into beaker A and stir until dissolved to obtain raw material solution A. Pour 60mL of 98% nitric acid into beaker B to obtain raw material solution B.

[0044] Step 2: First, clean the entire microchannel reaction system with 80% concentrated sulfuric acid. The microchannel reaction system includes a microchannel reactor and two connected high-pressure plunger pumps, ensuring that there is no water or air in the pipeline. Then, replace the concentrated sulfuric acid in the two high-pressure plunger pumps with feed solution A and feed solution B, respectively. The microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

[0045] Step 3: Feed solution A and feed solution B are pumped into the microchannel reactor at flow rates of 5 mL / min and 1 mL / min, respectively, using a high-pressure plunger pump. At this time, the molar ratio of 4-acetaminophen to nitric acid is 1:1.2. The reaction temperature is controlled at 20℃ using a high-low temperature integrated machine, and the residence time is 4 minutes. After the reaction is completed, the product flows out from the outlet of the microchannel reactor, and the resulting reaction solution is collected.

[0046] Step 4: The reaction solution was diluted with ice water, the product precipitated, filtered, washed, and dried at 60℃ for 12 h to obtain crude 4-acetamido-2-nitrobenzene ether with a separation yield of 80%.

[0047] Example 4

[0048] This embodiment describes a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0049] Step 1: Pour 100 mL of dichloromethane and 3.3 g of 4-acetaminophen into beaker A and stir until dissolved to obtain raw material solution A. Pour 60 mL of 65% nitric acid into beaker B to obtain raw material solution B.

[0050] Step 2: First, clean the entire microchannel reaction system with dichloromethane. The microchannel reaction system includes a microchannel reactor and two connected high-pressure plunger pumps, ensuring that there is no water or air in the pipeline. Then, replace the dichloromethane in the two high-pressure plunger pumps with feed solution A and feed solution B, respectively. The microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

[0051] Step 3: Feed solution A and feed solution B are pumped into the microchannel reactor at flow rates of 10 mL / min and 0.2 mL / min respectively using a high-pressure plunger pump. At this time, the molar ratio of 4-acetaminophen to nitric acid is 1:1.3. The reaction temperature is controlled at 20℃ using a high-low temperature integrated machine, and the residence time is 2 minutes. After the reaction is completed, the product flows out from the outlet of the microchannel reactor, and the reaction solution is collected.

[0052] Step 4: The reaction solution was washed with water and separated, then distilled under reduced pressure and dried at 60℃ for 12 hours to obtain crude 4-methoxy-2-nitroacetanilide with a yield of 84%. The process flow diagram is shown below. Figure 3 As shown.

[0053] Example 5

[0054] This embodiment describes a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0055] Step 1: Pour 100 mL of dichloromethane and 8.3 g of 4-acetaminophen into beaker A and stir until dissolved to obtain raw material solution A. Pour 60 mL of 80% nitric acid into beaker B to obtain raw material solution B.

[0056] Step 2: First, clean the entire microchannel reaction system with dichloromethane. The microchannel reaction system includes a microchannel reactor and two connected high-pressure plunger pumps, ensuring that there is no water or air in the pipeline. Then, replace the dichloromethane in the two high-pressure plunger pumps with feed solution A and feed solution B, respectively. The microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

[0057] Step 3: Feed solution A and feed solution B are pumped into the microchannel reactor at flow rates of 10 mL / min and 0.75 mL / min respectively using a high-pressure plunger pump. At this time, the molar ratio of 4-acetaminophen to nitric acid is 1:2. The reaction temperature is controlled at 10℃ using a high-low temperature integrated machine, and the residence time is 2 minutes. After the reaction is completed, the product flows out from the outlet of the microchannel reactor, and the resulting reaction solution is collected.

[0058] Step 4: The reaction solution was washed with water and separated, then distilled under reduced pressure and dried at 60°C for 12 hours to obtain crude 4-methoxy-2-nitroacetanilide with a separation yield of 89%.

[0059] Example 6

[0060] This embodiment describes a method for the selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, comprising:

[0061] Step 1: Pour 100 mL of dichloromethane and 33 g of 4-acetaminophen into beaker A and stir until dissolved to obtain raw material solution A. Pour 60 mL of 98% nitric acid into beaker B to obtain raw material solution B.

[0062] Step 2: First, clean the entire microchannel reaction system with dichloromethane. The microchannel reaction system includes a microchannel reactor and two connected high-pressure plunger pumps, ensuring that there is no water or air in the pipeline. Then, replace the dichloromethane in the two high-pressure plunger pumps with feed solution A and feed solution B, respectively. The microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

[0063] Step 3: Feed solution A and feed solution B are pumped into the microchannel reactor at flow rates of 10 mL / min and 2.2 mL / min respectively using a high-pressure plunger pump. At this time, the molar ratio of 4-acetaminophen to nitric acid is 1:1.5. The reaction temperature is controlled at 15℃ using a high-low temperature integrated machine, and the residence time is 1.6 min. After the reaction is completed, the product flows out from the outlet of the microchannel reactor, and the resulting reaction solution is collected.

[0064] Step 4: The reaction solution was washed with water and separated, then distilled under reduced pressure and dried at 60°C for 12 hours to obtain crude 4-methoxy-2-nitroacetanilide with a separation yield of 95%.

[0065] The 4-acetamido-2-nitroanisole prepared in Examples 1-3 and the 4-methoxy-2-nitroacetanilide prepared in Examples 4-6 have the following 1H and 1C NMR spectra data. After verification, they are consistent with the data in existing literature, and it can be confirmed that the obtained products are all target products.

[0066] Compound structure characterization:

[0067] 4-Acetamido-2-nitrobenzyl ether:

[0068] 1 H NMR (400MHz CDCl3) δ7.97 (s, 1H), 7.80 (d, J=9.0Hz, 1H), 7.56 (s, 1H), 7.27 (s, 1H), 7.05 (d, J=9.0Hz, 1H), 3.95 (s, 3H), 2.19 (s, 54H).

[0069] 13 C NMR (100MHz, CDCl3) δ168.69, 149.65, 130.82, 126.28, 117.46, 114.09, 56.80, 24.32.

[0070] 4-Methoxy-2-nitroacetanilide:

[0071] 1 H NMR (400MHz CDCl3) δ10.05 (s, 1H), 8.63 (d, J=9.3Hz, 1H), 7.66 (s, 1H), 7.25 (dd, J=9.8, 8.3Hz, 1H), 3.86 (s, 2H), 2.27 (s, 2H).

[0072] 13 C NMR (100MHz, CDCl3) δ168.79, 154.96, 137.06, 128.50, 123.87, 123.39, 108.51, 55.90, 25.42.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. 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 selective nitration of 4-acetamidoanisole using a continuous flow microchannel reactor, characterized in that, include: 1) Mix 4-acetaminophen with a solvent and stir until dissolved to obtain raw material solution A, wherein the solvent is concentrated sulfuric acid or dichloromethane, the molar ratio of concentrated sulfuric acid to 4-acetaminophen is 5 to 7.9:1, and the concentration of 4-acetaminophen in dichloromethane is 0.1 to 2 mol / L; Take nitric acid with a concentration of 65%–98% as raw material solution B; 2) Clean the microchannel reaction system with the solvent. The microchannel reaction system includes a microchannel reactor and two metering pumps connected to it. Ensure that there is no water or air in the pipeline. Then replace the solvent in the two metering pumps with raw material solution A and raw material solution B, respectively. 3) Set the reaction temperature of the microchannel reactor to 0-25℃ using a high-low temperature integrated machine. Pump raw material solution A and raw material solution B into the microchannel reactor through metering pumps respectively. After the reaction is completed, the product flows out from the outlet of the microchannel reactor and the reaction solution is collected. Wherein, the molar ratio of 4-acetaminophen to nitric acid is 1:1 to 2, the flow rate of the metering pump pumping into raw material solution A is 1 to 30 mL / min, the flow rate of the metering pump pumping into raw material solution B is 0.1 to 10 mL / min, and the mixing and residence time of raw material solution A and raw material solution B in the microchannel reactor is 0.5 to 5 min. 4) Dilute the reaction solution obtained in 3) with ice water, the product precipitates, filter, wash, and dry to obtain 4-acetamido-2-nitroanisole, or wash the reaction solution obtained in 3) with water, separate the layers, distill under reduced pressure, and dry to obtain 4-methoxy-2-nitroacetanilide.

2. The method according to claim 1, characterized in that, In 1), the concentration of the concentrated sulfuric acid is 80% to 98%.

3. The method according to claim 1, characterized in that, In 2), the metering pump is a high-pressure plunger pump.

4. The method according to claim 1, characterized in that, In 2), the microchannel reactor is a plate-type microchannel reactor made of silicon carbide, with a heart-shaped internal structure and a liquid holding capacity of 10 mL per plate.

5. The method according to claim 1, characterized in that, In 3), the flow rate ratio of the metering pump pumping in raw material liquid A to the metering pump pumping in raw material liquid B is 4 to 8:

1.

6. The method according to claim 1, characterized in that, In step 4), the drying temperature is 60°C and the drying time is 12 hours.

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