Method and system for continuously synthesizing 2, 3-dimethyl-4-nitropyridine-N-oxide based on microchannel

Abstract

The invention discloses a method and a system for continuously synthesizing 2, 3-dimethyl-4-nitropyridine-N-oxide based on a microchannel, and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) carrying out oxidation reaction on 2, 3-dimethyl pyridine, hydrogen peroxide and acetic acid in a first micro-channel reactor, and introducing a formaldehyde aqueous solution from an inlet in the last plate of the first micro-channel reactor for quenching to obtain an oxidation reaction solution; (2) feeding the oxidation reaction liquid to a concentration device, separating formaldehyde, part of water and part of acetic acid, and reducing the content of acetic acid to 15 wt% or below; (3) reacting the concentrated reaction solution, concentrated sulfuric acid and nitric acid in a second microchannel reactor to obtain a nitration reaction solution; and (4) carrying out post-treatment on the nitration reaction liquid to obtain the product. According to the method, the crude product can be directly precipitated, the yield of the crude product is 82% or above, and the purity of the crude product is 96% or above. The method significantly reduces the consumption of sulfuric acid, and is safe and suitable for industrial amplification.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method and system for the continuous synthesis of 2,3-dimethyl-4-nitropyridine-N-oxide based on microchannels. Background Technology

[0002] 2,3-Dimethyl-4-nitropyridine-N-oxide is an important pharmaceutical intermediate used in the synthesis of lansoprazole and rabeprazole. Starting with 2,3-dimethylpyridine, hydrogen peroxide and a suitable catalyst are added to oxidize it to obtain 2,3-dimethylpyridine-N-oxide. Then, concentrated nitric acid / sulfuric acid or fuming nitric acid / sulfuric acid is used as a mixed acid nitrating agent to prepare 2,3-dimethyl-4-nitropyridine-N-oxide.

[0003] For example, patent application number CN201310476334.1 discloses a method for synthesizing a chloromethylpyridine derivative, an intermediate in proton pump inhibitors. The method uses compound 1-2,3-dimethylpyridine as a starting material and prepares the derivative through oxidation, nitration, substitution, alcoholysis, and chloromethylation. The reactants, processes, and conditions are as follows: (1) Oxidation: Compound 1 was added to a certain amount of glacial acetic acid and a catalytic amount of concentrated sulfuric acid under stirring conditions, heated to 80-110℃, and H2O2 with a mass concentration of 30±2% was added dropwise. The reaction was kept at this temperature until the reaction was completely converted as detected by TLC. A reducing agent was added to decompose the excess H2O2. The amount of reducing agent was determined by detecting the reaction with starch-potassium iodide paper until it no longer turned blue. Acetic acid and water were removed by vacuum distillation to obtain compound 2—2,3-dimethylpyridine-N-oxide. The volume of glacial acetic acid was 2-4 times that of compound 1, the amount of hydrogen peroxide was 1.25-1.75 times the molar amount of compound 1, and the amount of concentrated sulfuric acid was 3-5% of the mass of compound 1.

[0004] (2) Nitration: Under ice-water bath, add an appropriate amount of concentrated H2SO4 to compound 2, stir and heat to 80-90℃, slowly add a mixed acid consisting of 98% concentrated H2SO4 and 63-67% concentrated HNO3, absorb the tail gas with alkaline solution, keep the reaction at the temperature until the reaction is detected by TLC; after cooling the reaction solution, pour it into crushed ice, neutralize it with supersaturated Na2CO3 solution to pH = 8-10, a yellow solid precipitates out, extract with chloroform, dry, filter, and evaporate to dryness to obtain a yellow solid, recrystallize with a small amount of ethanol to obtain high purity compound 3-4-nitro-2,3-dimethylpyridine-N-oxide; the volume ratio of concentrated H2SO4 to concentrated HNO3 in the mixed acid is 2.8-3.3:1.

[0005] For example, patent application number CN201310476356.8 discloses an industrial production method for chloromethylpyridine derivatives, which uses the following raw materials and process flow: 1) Oxidation reaction: Dilute 2,3-dimethylpyridine with acetic acid, add a certain amount of concentrated sulfuric acid, heat to 80-100℃, add hydrogen peroxide with a mass concentration of 28-32%, keep the reaction at the temperature for 4-5 hours after the addition is complete, quench with a reducing agent, recover the solvent by vacuum distillation, and the residual liquid—pyridine nitrogen oxides—is directly used for the next step of the reaction; the distilled acetic acid and water are separated by azeotropic distillation, and the obtained acetic acid is reused.

[0006] 2) Nitration reaction: The pyridine nitrogen oxides obtained from the oxidation reaction are added to concentrated sulfuric acid at a temperature <10℃, and then the temperature is raised to 80-90℃. A mixed acid of concentrated sulfuric acid and concentrated nitric acid in a volume ratio of 2.5-3.5:1 is slowly added dropwise. In this reaction step, a NO2 tail gas absorption device should be added to facilitate environmental protection. After the addition is completed, the reaction is kept at a constant temperature for 4-8 hours, preferably 6 hours, and the endpoint is controlled midway. After the reaction is completed, the reaction solution is cooled and poured into ice water. It is then neutralized with alkali to pH=8-10 with stirring. Ethyl acetate or other organic solvents suitable for industrial use are added to extract and separate the organic phase. The organic phase is dried and evaporated under reduced pressure to obtain a yellow solid crude product. It is recrystallized with ethanol to obtain pure 2,3-dimethyl-4-nitropyridine-N-oxide. The extractant can be reused by vacuum distillation. The aqueous phase is further treated to obtain Na2SO4, NaNO3 and other inorganic salts.

[0007] In the prior art, oxidation reactions can also be carried out using microchannel reactors. For example, patent application number CN202310915997.2 discloses a continuous flow process for a key intermediate of p-prazole, including: mixing 2,3-dimethylpyridine, 30% hydrogen peroxide, and acetic acid solution and placing them in a storage bottle; pumping the material in the storage bottle into a microreactor at a certain flow rate using a plunger metering pump; setting the reaction temperature and residence time in the microreactor; monitoring the reaction to completion by HPLC; and allowing the reaction solution to flow out and enter a post-processing system for post-processing to obtain compound 2. The specified flow rate is 0.1 ml / min-5 ml / min; the reaction temperature in the microreactor is 120℃-150℃; and the residence time is 10 seconds to 120 minutes.

[0008] In nitration reactions, concentrated sulfuric acid acts as a catalyst and dehydrates the nitrifying agent. When using 65%-68% concentrated nitric acid as the nitrating agent, the high water content of the concentrated nitric acid affects the reaction in its presence, leading to a decrease in yield and a slower reaction rate. To improve the yield and accelerate the reaction rate, a large amount of sulfuric acid is often added, typically in a volume ratio of 2.5-3.5:1 between concentrated sulfuric acid and concentrated nitric acid. While using fuming nitric acid can increase the rate, the amount of sulfuric acid used is still relatively large. The use of large amounts of sulfuric acid presents the following problems: (1) It will generate a large amount of waste salt (nitrates, sulfates, etc.); (2) If more concentrated sulfuric acid is required, more alkali will be needed in the subsequent treatment. More concentrated sulfuric acid and more alkali will lead to higher costs. (3) A large amount of concentrated sulfuric acid will generate a lot of heat when the reactants are added. In the existing technology, it is usually added at low temperature or in an ice-water bath, which is not only demanding but also difficult to operate. If the concentrated sulfuric acid is added too quickly, it may boil over.

[0009] In addition, the existing technology takes a long time for the entire production process, usually exceeding 24 hours. Summary of the Invention

[0010] On one hand, embodiments of the present invention provide a method for the continuous synthesis of 2,3-dimethyl-4-nitropyridine-N-oxide based on microchannels, the method comprising: (1) 2,3-Dimethylpyridine, hydrogen peroxide and acetic acid undergo an oxidation reaction in the first microchannel reactor. Formaldehyde aqueous solution is introduced into the inlet of the last plate (specifically the fourth plate) of the first microchannel reactor to quench the oxidation reaction solution.

[0011] (2) The oxidation reaction solution is sent to a concentration unit to separate formaldehyde, the reaction product formic acid, a portion of water (most of it, with minimal residue), and a portion of acetic acid, reducing the acetic acid content to below 15 wt% (specifically 5 wt%-15 wt%). In this step, step (1) achieves safe online quenching without generating waste salt; after concentration, water, formaldehyde, and a portion of acetic acid are removed, allowing the solution to directly enter the next reactor for further reaction.

[0012] (3) The concentrated reaction solution, concentrated sulfuric acid, and nitric acid react in a second microchannel reactor to obtain a nitration reaction solution. The concentrated reaction solution is mixed with concentrated sulfuric acid and introduced through one inlet of the second microchannel reactor, while nitric acid is introduced through the other inlet; or the concentrated reaction solution is introduced through one inlet of the second microchannel reactor, and the mixed acid of concentrated sulfuric acid and nitric acid is introduced through the other inlet; or the concentrated reaction solution, concentrated sulfuric acid, and nitric acid are mixed and introduced through one inlet of the second microchannel reactor. The nitric acid is concentrated nitric acid or fuming nitric acid; the volume ratio of the concentrated reaction solution to concentrated sulfuric acid is 1:0.8-1.5. The amount of concentrated sulfuric acid used in this patent is approximately 25%-46% of that used in the prior art, which correspondingly reduces the amount of alkali used in the post-treatment, thereby reducing the amount of waste salt generated. A comparison of concentrated sulfuric acid and nitric acid provides a more intuitive understanding; in this patent, the volume ratio of concentrated sulfuric acid to nitric acid is approximately 1.12:1, while in the prior art it is approximately 3.2:1.

[0013] (4) The nitration reaction solution is post-processed to obtain the product.

[0014] The reaction conditions for step (1) are as follows: the volume ratio of acetic acid to 2,3-dimethylpyridine is 1-4:1; the molar ratio of hydrogen peroxide to 2,3-dimethylpyridine is 1-2:1; the molar ratio of formaldehyde to 2,3-dimethylpyridine is 0.1-1:1; the concentration of hydrogen peroxide is 30-40 wt% (specifically 40 wt%); the concentration of formaldehyde aqueous solution is 18-55 wt% (specifically 37 wt%); the reaction temperature is 120-150℃; the quenching temperature is 30-70℃; the reaction pressure is 1.0-4.0 MPa; and the residence time is 5-40 min. Preferably, the reaction temperature is 110-120℃, the reaction pressure is 0.7-1.2 MPa, and the residence time is 15-20 min.

[0015] In step (1), 2,3-dimethylpyridine, hydrogen peroxide and acetic acid are mixed and introduced into the inlet of the first microchannel reactor; or 2,3-dimethylpyridine and acetic acid are mixed and introduced into one inlet of the first microchannel reactor, and hydrogen peroxide is introduced into the other inlet of the first microchannel reactor.

[0016] In step (3), the reaction temperature is 100-130℃ (preferably around 115℃), the reaction pressure is 0.5-3.0 MPa, and the residence time is 10-60 min. The molar amount of nitric acid is similar to that in existing technologies. Preferably, in step (3), the nitric acid is fuming nitric acid. In step (3), the concentrated reaction solution is mixed with concentrated sulfuric acid and introduced through one inlet of the second microchannel reactor, while the fuming nitric acid is introduced through the other inlet of the second microchannel reactor; or the concentrated reaction solution, concentrated sulfuric acid, and fuming nitric acid are mixed and introduced through one inlet of the second microchannel reactor. The volumetric flow rate ratio of the concentrated reaction solution, concentrated sulfuric acid, and fuming nitric acid is 1:0.8-1.5:0.6-1.0.

[0017] In step (4), the nitration reaction solution is quenched with ice water, and the pH value is adjusted to 6-7 by adding alkali. After standing (e.g., standing for 12 hours), the product is precipitated. The alkali can be a sodium hydroxide solution; specifically, the alkali is a 30wt% sodium hydroxide solution.

[0018] Specifically, the method for continuous synthesis of 2,3-dimethyl-4-nitropyridine-N-oxide based on microchannels provided in this embodiment of the invention includes: (1) 2,3-Dimethylpyridine, hydrogen peroxide, and acetic acid undergo an oxidation reaction in the first microchannel reactor. Formaldehyde aqueous solution is introduced into the inlet of the last plate of the first microchannel reactor for quenching to obtain the oxidation reaction solution. 2,3-Dimethylpyridine, hydrogen peroxide, and acetic acid are mixed and introduced into the inlet of the first microchannel reactor; or 2,3-Dimethylpyridine and acetic acid are mixed and introduced into one inlet of the first microchannel reactor, and hydrogen peroxide is introduced into the other inlet of the first microchannel reactor.

[0019] The volume ratio of acetic acid to 2,3-dimethylpyridine is 1-4:1, the molar ratio of hydrogen peroxide to 2,3-dimethylpyridine is 1-2:1, and the molar ratio of formaldehyde to 2,3-dimethylpyridine is 0.1-1:1; the concentration of hydrogen peroxide is 30-40 wt%, the concentration of formaldehyde aqueous solution is 18-55 wt%, the reaction temperature is 120-150℃, the quenching temperature is 30-70℃, the reaction pressure is 1.0-4.0 MPa, and the residence time is 5-40 min.

[0020] (2) The oxidation reaction solution is sent to a concentration device to separate formaldehyde, some water and some acetic acid, and reduce the content of acetic acid to below 15wt%.

[0021] (3) The concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid are reacted in a microchannel reactor to obtain a nitration reaction solution; wherein, the concentrated reaction solution and concentrated sulfuric acid are mixed and introduced into one inlet of the second microchannel reactor, and the fuming nitric acid is introduced into the other inlet of the second microchannel reactor; or the concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid are mixed and introduced into one inlet of the second microchannel reactor, the volume flow ratio of the concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid is 1:0.8-1.5:0.6-1.0, the reaction temperature is 100-130℃, the reaction pressure is 0.5-3.0Mpa, and the residence time is 10-60min.

[0022] (4) The nitration reaction solution is quenched with ice water, and the pH value is adjusted to 6-7 by adding alkali. After standing, the product is precipitated.

[0023] On the other hand, embodiments of the present invention also provide a system for the continuous synthesis of 2,3-dimethyl-4-nitropyridine-N-oxide based on microchannels, the system comprising: The first microchannel reactor is used for the oxidation reaction of 2,3-dimethylpyridine, hydrogen peroxide and acetic acid, and is quenched by the formaldehyde aqueous solution introduced through the inlet on the last plate to obtain the oxidation reaction solution.

[0024] The concentration unit is used to concentrate the oxidation reaction solution, separating formaldehyde, some water and some acetic acid, reducing the acetic acid content to below 15 wt%.

[0025] The second microchannel reactor is used to react the concentrated reaction solution, concentrated sulfuric acid, and nitric acid to obtain a nitration reaction solution. The concentrated reaction solution is mixed with concentrated sulfuric acid and introduced into the second microchannel reactor through one inlet, while nitric acid is introduced through the other inlet. Alternatively, the concentrated reaction solution is introduced into the second microchannel reactor through one inlet, while the mixed acid of concentrated sulfuric acid and nitric acid is introduced through the other inlet. Or, the concentrated reaction solution, concentrated sulfuric acid, and nitric acid are mixed and introduced into the second microchannel reactor through one inlet.

[0026] The reaction vessel is used to quench the nitration reaction solution with ice water, add alkali to adjust the pH value to 6-7, and let it stand.

[0027] A separation device used to separate the obtained products.

[0028] The first microchannel reactor, the second microchannel reactor, and the reaction vessel are connected sequentially by pipelines, with buffer containers installed between adjacent structures as needed. Pumps, flow meters, and / or valves are installed on the pipelines as needed. The inlet of the first microchannel reactor is connected to the supply structure of the corresponding raw material through pipelines, and part of the inlet of the second microchannel reactor is connected to the supply structure of the corresponding raw material (concentrated sulfuric acid, nitric acid) through pipelines.

[0029] Preferably, the first and second microchannel reactors can be common microchannel reactors, with silicon carbide microchannel reactors being more preferred. The first microchannel reactor has two or three inlets, one of which (for formaldehyde solution) is located on the last plate, and the remaining inlets (for 2,3-dimethylpyridine, hydrogen peroxide, and acetic acid) are located at the beginning. The second microchannel reactor has one or two inlets (both at the beginning) for introducing the concentrated reaction solution, concentrated sulfuric acid, and fuming nitric acid. Further, the reaction streams output from the first and second microchannel reactors pass through a three-way valve, one side connected to the reaction solution collection area and the other side connected to the sample collection area. The component levels of the reaction solution are detected by TLC or HPLC, and the flow immediately switches to the reaction solution collection area after sample collection.

[0030] This invention achieves efficient preparation of the target product through a continuous "oxidation-distillation-nitration" process. The method includes: completing the oxidation reaction of 2,3-dimethylpyridine in a continuous flow microchannel reactor, removing formaldehyde, most of the water, and excess acetic acid from the reaction solution, controlling the residual acetic acid in the mixture to less than 15%; subsequently, the concentrated reaction solution undergoes nitration in the continuous flow microchannel reactor, and after quenching with ice water and adjusting the pH, the crude product can be directly precipitated, with a yield of over 82% and a purity of over 96%. This invention significantly reduces the amount of sulfuric acid used, is safe, and suitable for industrial scale-up. Detailed Implementation

[0031] The invention will be further described below through specific embodiments. However, it should be noted that these embodiments are merely illustrative and do not limit the scope of the invention.

[0032] Example 1 (single-strand oxidation + single-strand nitration, 300g grade) 1. Oxidation reaction: Feeding: 300g of 2,3-dimethylpyridine + 600ml of acetic acid + 408g of 30wt% hydrogen peroxide; Quenching: 91g of 37wt% formaldehyde aqueous solution.

[0033] Reaction conditions: Raw material feed rate of 5 ml / min using a single pump, reaction temperature of 140-145℃, reaction pressure of 1.4 MPa, and residence time of 13 min. Formaldehyde feed rate of 0.28 ml / min.

[0034] Product: After concentration and separation, a mixed solution of 368g was obtained (containing 5.17wt% acetic acid, with 628g concentrated sulfuric acid and 454g fuming nitric acid added as a single stream of nitration reactants).

[0035] 2. Nitrification reaction (single feed): Feed parameters: 5 ml / min (containing 347.0 g of effective raw material), the volume ratio of concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid is 1:0.93:0.86; Reaction conditions: reaction temperature 114℃, reaction pressure 0.85MPa, residence time 17min.

[0036] 3. Post-processing: The reaction solution was quenched in 600 ml of ice water, and after adjusting the pH with 30 wt% sodium hydroxide solution, 85% crude product (purity 96.5%) was precipitated. After crystallization, the purity was 98.5%.

[0037] 4. Results: The total reaction time was 31 min, the yield was 83.1%, and the amount of waste salt was 5.76 tons / ton of product (a reduction of 60.8% compared to the existing technology (based on the amount of concentrated H2SO4 being 3 times the volume of the reaction raw materials).

[0038] Example 2 (Dual oxidation + dual nitration, 300g grade) 1. Oxidation reaction: Feeding: A-share (300g raw material + 600ml acetic acid), B-share (408g 30wt% hydrogen peroxide), quenching: 91g 37wt% formaldehyde aqueous solution, dual-pump feeding; Product: 411g of mixed liquid was obtained by gas-liquid separation (containing 14.8wt% acetic acid, and 822g of concentrated sulfuric acid was added as A-shares).

[0039] 2. Nitration reaction (two feed streams): Feed parameters: A stream (concentrated reaction solution + 822g sulfuric acid), 4.7ml / min; B stream 1.5ml / min (370g fuming nitric acid, approximately 245.0ml); The volume ratio of concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid is 1:1.08:0.60.

[0040] Reaction conditions: reaction temperature 116℃, reaction pressure 1.1MPa, residence time 17min.

[0041] 3. Post-processing: Same as in Example 1, 86% crude product (purity 96.2%) was precipitated, and the purity after crystallization was 97.8%.

[0042] 4. Results: Conversion rate 97%, total reaction time 32 min, waste salt volume 6.33 tons / ton of product (57% reduction compared to existing technology (based on the amount of concentrated H2SO4 being 3 times the volume of the reaction raw materials)).

[0043] Example 3 (single-stream oxidation + two-stream nitration, 700g grade) 1. Oxidation reaction: Feeding: 700g raw material + 2100ml acetic acid + 959g 30wt% hydrogen peroxide; Quenching: 212.05g 37wt% formaldehyde aqueous solution; Single pump feeding. Product: 840g of mixed liquid was obtained by gas-liquid separation (containing 14.9wt% acetic acid, 1920g of concentrated sulfuric acid was added as A-shares).

[0044] 2. Nitration reaction (two feed streams): Feed parameters: A stream 4.7 ml / min, B stream 1.51 ml / min (907.7 g fuming nitric acid), the volume ratio of concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid is 1:1.23:0.71.

[0045] Reaction conditions: Same as in Example 1, stay for 17 min.

[0046] 3. Post-processing: Same as in Example 1, 85.5% crude product (purity 96.3%) was precipitated.

[0047] A comparison of the method of this patent with the prior art (using CN201310476334.1 as the prior art) is shown in Table 1: Table 1

[0048] The amount of sulfuric acid used is based on the raw materials used in the nitration reaction (the main component is pyridine nitrogen oxides, and a small amount of acetic acid).

[0049] As can be seen from Table 1, the method of this patent has the following advantages: (1) Short reaction time; (2) If less sulfuric acid is used, less alkali is used, and consequently less waste salt is produced; (3) The purity is similar to that of existing technologies, but the yield is higher than that of existing technologies; (4) Continuous flow production is suitable for industrial production; (5) The product is directly extracted without extraction, which not only simplifies the process and reduces costs, but also reduces pollution; (6) After the oxidation reaction, there is no need for separate quenching, which reduces the risk of post-processing. Simple concentration simplifies the process and reduces energy consumption.

[0050] 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 the continuous synthesis of 2,3-dimethyl-4-nitropyridine-N-oxide based on microchannels, characterized in that, The method includes: (1) 2,3-Dimethylpyridine, hydrogen peroxide and acetic acid undergo an oxidation reaction in the first microchannel reactor. Formaldehyde aqueous solution is introduced into the inlet of the last plate of the first microchannel reactor to quench the oxidation reaction solution. (2) The oxidation reaction solution is sent to a concentration device to separate formaldehyde, some water and some acetic acid, and reduce the content of acetic acid to below 15 wt%. (3) The concentrated reaction solution, concentrated sulfuric acid and nitric acid react in the second microchannel reactor to obtain the nitration reaction solution; The concentrated reaction solution is mixed with concentrated sulfuric acid and introduced into one inlet of the second microchannel reactor, while nitric acid is introduced into the other inlet of the second microchannel reactor; or the concentrated reaction solution is introduced into one inlet of the second microchannel reactor, while the mixed acid of concentrated sulfuric acid and nitric acid is introduced into the other inlet of the second microchannel reactor; or the concentrated reaction solution, concentrated sulfuric acid, and nitric acid are mixed and introduced into one inlet of the second microchannel reactor. The nitric acid used is concentrated nitric acid or fuming nitric acid, and the volume ratio of the concentrated reaction solution to concentrated sulfuric acid is 1:0.8-1.

5. (4) The nitration reaction solution is post-processed to obtain the product.

2. The method according to claim 1, characterized in that, The reaction conditions for step (1) are as follows: the volume ratio of acetic acid to 2,3-dimethylpyridine is 1-4:1, the molar ratio of hydrogen peroxide to 2,3-dimethylpyridine is 1-2:1, the molar ratio of formaldehyde to 2,3-dimethylpyridine is 0.1-1:1; the concentration of hydrogen peroxide is 30-40wt%, the concentration of formaldehyde aqueous solution is 18-55wt%; the reaction temperature is 120-150℃, the quenching temperature is 30-70℃, the reaction pressure is 1.0-4.0MPa, and the residence time is 5-40min.

3. The method according to claim 1, characterized in that, In step (1), 2,3-dimethylpyridine, hydrogen peroxide and acetic acid are mixed and introduced into the inlet of the first microchannel reactor; or 2,3-dimethylpyridine and acetic acid are mixed and introduced into one inlet of the first microchannel reactor, and hydrogen peroxide is introduced into the other inlet of the first microchannel reactor.

4. The method according to claim 1, characterized in that, In step (3), the reaction temperature is 100-130℃, the reaction pressure is 0.5-3.0MPa, and the residence time is 10-60min.

5. The method according to claim 1, characterized in that, In step (3), the nitric acid is fuming nitric acid.

6. The method according to claim 5, characterized in that, In step (3), the concentrated reaction solution is mixed with concentrated sulfuric acid and introduced through one inlet of the second microchannel reactor, while fuming nitric acid is introduced through the other inlet of the second microchannel reactor. Alternatively, the concentrated reaction solution, concentrated sulfuric acid, and fuming nitric acid can be mixed and introduced into one inlet of the second microchannel reactor; the volume flow rate ratio of the concentrated reaction solution, concentrated sulfuric acid, and fuming nitric acid is 1:0.8-1.5:0.6-1.

0.

7. The method according to claim 1, characterized in that, In step (4), the nitration reaction solution is quenched with ice water, alkali is added to adjust the pH value to 6-7, and after standing, the product is precipitated.

8. The method according to claim 1, characterized in that, The method includes: (1) 2,3-Dimethylpyridine, hydrogen peroxide and acetic acid undergo an oxidation reaction in the first microchannel reactor. Formaldehyde aqueous solution is introduced into the inlet of the last plate of the first microchannel reactor for quenching to obtain the oxidation reaction solution. Among them, 2,3-Dimethylpyridine, hydrogen peroxide and acetic acid are mixed and introduced into the inlet of the first microchannel reactor; or 2,3-Dimethylpyridine and acetic acid are mixed and introduced into one inlet of the first microchannel reactor, and hydrogen peroxide is introduced into the other inlet of the first microchannel reactor. The volume ratio of acetic acid to 2,3-dimethylpyridine is 1-4:1, the molar ratio of hydrogen peroxide to 2,3-dimethylpyridine is 1-2:1, and the molar ratio of formaldehyde to 2,3-dimethylpyridine is 0.1-1:1; the concentration of hydrogen peroxide is 30-40 wt%, the concentration of formaldehyde aqueous solution is 18-55 wt%, the reaction temperature is 120-150℃, the quenching temperature is 30-70℃, the reaction pressure is 1.0-4.0 MPa, and the residence time is 5-40 min. (2) The oxidation reaction solution is sent to a concentration device to separate water, formaldehyde and part of acetic acid, reducing the acetic acid content to below 15 wt%. (3) The concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid are reacted in a microchannel reactor to obtain a nitration reaction solution; wherein, the concentrated reaction solution and concentrated sulfuric acid are mixed and introduced into one inlet of the second microchannel reactor, and the fuming nitric acid is introduced into the other inlet of the second microchannel reactor; or the concentrated reaction solution, concentrated sulfuric acid and fuming nitric acid are mixed and introduced into one inlet of the second microchannel reactor. The volumetric flow rate ratio of the concentrated reaction solution, concentrated sulfuric acid, and fuming nitric acid is 1:0.8-1.5:0.6-1.0, the reaction temperature is 100-130℃, the reaction pressure is 0.5-3.0 MPa, and the residence time is 10-60 min. (4) The nitration reaction solution is quenched with ice water, and the pH value is adjusted to 6-7 by adding alkali. After standing, the product is precipitated.

9. A system for the continuous synthesis of 2,3-dimethyl-4-nitropyridine-N-oxide based on microchannels, characterized in that, include: The first microchannel reactor is used for the oxidation reaction of 2,3-dimethylpyridine, hydrogen peroxide and acetic acid, and is quenched by the formaldehyde aqueous solution introduced through the inlet of the last plate to obtain the oxidation reaction solution. The concentration device is used to concentrate the oxidation reaction solution, separate formaldehyde, some water and some acetic acid, and reduce the acetic acid content to below 15 wt%. The second microchannel reactor is used to react the concentrated reaction solution, concentrated sulfuric acid, and nitric acid to obtain a nitration reaction solution. The concentrated reaction solution is mixed with concentrated sulfuric acid and introduced through one inlet of the second microchannel reactor, while nitric acid is introduced through the other inlet. Alternatively, the concentrated reaction solution is introduced through one inlet of the second microchannel reactor, and the mixed acid of concentrated sulfuric acid and nitric acid is introduced through the other inlet. Or, the concentrated reaction solution, concentrated sulfuric acid, and nitric acid are mixed and then introduced through one inlet of the second microchannel reactor. The reaction vessel is used to quench the nitration reaction solution with ice water, add alkali to adjust the pH value to 6-7, and let it stand. A separation device used to separate the obtained products.

10. The system according to claim 9, characterized in that, Both the first and second microchannel reactors are silicon carbide microchannel reactors. The first microchannel reactor has two or three inlets, one of which is located on the last plate. The second microchannel reactor has one or two inlets.

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