Method for preparing 1-chloro-2-methyl-3, 4-dinitrobenzene through microchannel-nitration reaction

Abstract

The invention relates to a method for preparing 1-chloro-2-methyl-3, 4-dinitrobenzene through microchannel-nitration reaction, which comprises the following steps: mixing nitric acid with sulfuric acid to obtain mixed acid, and mixing 2-chloro-6-nitrotoluene with sulfuric acid to obtain 2-chloro-6-nitrotoluene amp; the method comprises the following steps: inputting a mixed acid into a reaction cavity of a microchannel continuous flow reactor through a polytetrafluoroethylene constant-flux pump I, and amp 2-chloro-6-nitrotoluene; a sulfuric acid mixture is input into a reaction cavity of the microchannel continuous flow reactor through a polytetrafluoroethylene constant-flux pump II, and amp of 2-chloro-6-nitrotoluene is controlled; the method comprises the following steps: reacting a sulfuric acid mixture with mixed acid in a reaction cavity, obtaining a reaction product after the reaction is finished, and carrying out post-treatment on the reaction product to obtain the 1-chloro-2-methyl-3, 4-dinitrobenzene. According to the method, 2-chloro-6-nitrotoluene is used as a raw material, the micro-channel continuous flow reactor is adopted to prepare 1-chloro-2-methyl-3, 4-dinitrobenzene, the yield is high, the purity is high, the reaction is short, the selectivity is high, and few impurities are generated.

Description

Technical Field

[0001] The invention relates to a method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene through microchannel-nitration reaction, belonging to the technical field of pharmaceutical intermediate preparation. Background Art

[0002] 1-Chloro-2-methyl-3,4-dinitrobenzene is an intermediate of many active compounds and important marketed drugs, and its synthesis method is of great significance for industrial synthesis. The new N-(2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazol-3-yl)amide derivatives can inhibit S100 of calcium-binding protein and have good therapeutic effects on diseases such as cancer and neurodegenerative diseases. Daliresan hydrochloride (overseas trade name QUVIVIQTM) is a potential best-in-class innovative drug for the treatment of insomnia by blocking the binding of orexin neuropeptides (orexin A and orexin B) to their receptors. 1-Chloro-2-methyl-3,4-dinitrobenzene is a key intermediate of the above compounds.

[0003] The current production process uses a kettle reactor to intermittently react 2-chloro-6-nitrotoluene under mixed acid (sulfuric acid and nitric acid) conditions for a certain period of time. After the reaction is completed, ice water is used to quench the reaction and solids are precipitated, and the product is obtained after separation and purification. The reaction selectivity is poor, the separation is difficult, and the reaction exotherm is serious. The reaction equation is as follows:

[0004]

[0005] The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene reported in the literature is as follows:

[0006] Reference document China Invention Patent Publication No. CN116783182A, which uses 2-chloro-6-nitrotoluene as raw material, adds sulfuric acid and nitric acid mixed acid, does not add catalyst, and reacts in a kettle for 16-20 hours, with a yield of 62%. Using a kettle batch reactor, the production efficiency is low and the yield is not high.

[0007] Based on this, the present invention is proposed. Summary of the invention

[0008] In view of the deficiencies in the prior art, the present invention provides a method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction. The specific technical scheme is as follows:

[0009] A method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction comprises the following steps:

[0010] Step 1: Mixed acid preparation

[0011] Mix nitric acid and sulfuric acid to make a mixed acid;

[0012] Step 2: Preparation of 2-chloro-6-nitrotoluene & sulfuric acid mixture

[0013] Mixing 2-chloro-6-nitrotoluene with sulfuric acid to obtain a 2-chloro-6-nitrotoluene & sulfuric acid mixture;

[0014] Step 3: Microchannel-nitrification reaction

[0015] The mixed acid is input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 1, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture is input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 2, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid are controlled to react in the reaction chamber, and a reaction product is obtained after the reaction is completed.

[0016] As a further improvement, in step 1, nitric acid is added dropwise to sulfuric acid under ice bath conditions to prepare a mixed acid.

[0017] As a further improvement, in step 1, the mass fraction of nitric acid is 65% to 68%, the mass fraction of sulfuric acid is 98%, and the molar ratio of nitric acid to sulfuric acid is 1:(10 to 20).

[0018] As a further improvement, in step 2, the mass fraction of sulfuric acid is 98%, and the mass ratio of 2-chloro-6-nitrotoluene to sulfuric acid is 1:(5-20).

[0019] The volume of sulfuric acid in the mixture of 2-chloro-6-nitrotoluene & sulfuric acid is the same as the volume of sulfuric acid in the mixed acid.

[0020] As a further improvement, the reaction temperature of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid in the reaction chamber is 40-80°C.

[0021] As a further improvement, the molar ratio of 2-chloro-6-nitrotoluene to nitric acid in the reaction chamber is 1:3.

[0022] As a further improvement, the flow rates of the polytetrafluoroethylene advection pump 1 and the polytetrafluoroethylene advection pump 2 are both 4 mL / min, and the concentration of 2-chloro-6-nitrotoluene in the reaction chamber is 0.3 mmol / mL.

[0023] As a further improvement, the residence time of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid in the reaction chamber is 5 min to 20 min.

[0024] A further improvement is to post-treat the reaction product, make the reaction product flow into an ice-water mixture, and filter the reaction product to obtain a first filter cake; refine the first filter cake using a refining solvent, filter after the refining, and obtain a second filter cake; the second filter cake is dried to obtain the 1-chloro-2-methyl-3,4-dinitrobenzene.

[0025] As a further improvement, the first filter cake is refined by stirring at a temperature of 45°C using a refining solvent, wherein the refining solvent consists of water and an organic solvent, wherein the volume ratio of water to the organic solvent in the refining solvent is 1:2, and the organic solvent is one or more of methanol, ethanol, ethyl acetate, n-heptane, n-hexane, and n-octane.

[0026] In the post-treatment process of the present invention, if the refining stirring temperature is lower than 40° C., the residual 2-chloro-6-nitrotoluene cannot be effectively removed, resulting in low final purity.

[0027] The 1-chloro-2-methyl-3,4-dinitrobenzene obtained by the present invention is used as a key intermediate and a starting material in the reaction. The maximum single impurity of the final product prepared by the present invention can be controlled within 0.5%, and the total impurity can be controlled within 1%, which is conducive to easier removal in subsequent reaction steps.

[0028] The reaction time of the existing kettle reactor is long, and the reaction exotherm is serious, which leads to the easy temperature rise of the reaction, and the temperature rise easily leads to the increase of side reactions, which not only has a low yield, but also generates a lot of impurities, and requires a lot of reagent liquid for post-processing. The present invention solves the problems of poor selectivity, large impurity ratio, serious reaction exotherm, and large amount of three wastes in the kettle batch reactor.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention uses 2-chloro-6-nitrotoluene as a raw material and adopts a microchannel continuous flow reactor to prepare 1-chloro-2-methyl-3,4-dinitrobenzene. By optimizing the molar ratio of 2-chloro-6-nitrotoluene and nitric acid, the reaction temperature, the injection flow rate, the concentration of 2-chloro-6-nitrotoluene, and the dosage of nitric acid and sulfuric acid and other parameters, the yield (yield is as high as 88%) and the purity (can reach 99.9%) of 1-chloro-2-methyl-3,4-dinitrobenzene are significantly improved; the reaction time is greatly shortened, the selectivity is high, the impurity generation is small, especially the side reaction of generating impurity 1 and impurity 2 is significantly suppressed, and the conversion rate of the raw material 2-chloro-6-nitrotoluene is high.

[0031] 2. Compared with the existing methods, the present invention has relatively low production cost, high safety, good stability and repeatability, can be scaled up, and has a simple post-processing process, and has a good application prospect. DETAILED DESCRIPTION

[0032] In order to make the present invention more clearly understood, preferred embodiments are described in detail as follows.

[0033] Example 1 (corresponding to group 13 in Table 1)

[0034] Mixed acid preparation: nitric acid with a mass fraction of 65% to 68% is added dropwise to sulfuric acid with a mass fraction of 98% in an ice bath to prepare a mixed acid, wherein the volume ratio of nitric acid to sulfuric acid is 3:25.

[0035] Preparation of 2-chloro-6-nitrotoluene & sulfuric acid mixture: slowly add 2-chloro-6-nitrotoluene to 98% sulfuric acid by mass, stir until clear and transparent, and obtain a 2-chloro-6-nitrotoluene & sulfuric acid mixture. The molar concentration of 2-chloro-6-nitrotoluene in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is 0.6 mol / L, the volume of sulfuric acid in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is the same as the volume of sulfuric acid in the mixed acid, and the molar ratio of 2-chloro-6-nitrotoluene to sulfuric acid in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is 1:30.

[0036] Ice-water mixture preparation: crushed ice is added to water to prepare an ice-water mixture, wherein the volume ratio of the total amount of 98% sulfuric acid in the mixed acid and the mixture of 2-chloro-6-nitrotoluene & sulfuric acid to the ice-water mixture is 1:10.

[0037] The microchannel continuous flow reactor was adjusted so that the temperature of the reaction chamber was stabilized at 70°C.

[0038] The mixed acid is input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 1, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture is input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 2. The flow rate of the 2-chloro-6-nitrotoluene & sulfuric acid mixture is adjusted to 5 mL / min, and the flow rate of the mixed acid is adjusted to 5 mL / min, so that the molar ratio of 2-chloro-6-nitrotoluene to nitric acid entering the reaction chamber is 1:3, and the residence time of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid is controlled to be 8.8 min, and the reaction product is allowed to flow into the ice-water mixture, and the reaction product is filtered to obtain a first filter cake.

[0039] The first filter cake was refined by stirring at 45°C for 3 hours using a refining solvent, wherein the refining solvent consisted of water and n-heptane, the mass ratio of water to 2-chloro-6-nitrotoluene in the refining solvent was 1:1, and the mass ratio of n-heptane to 2-chloro-6-nitrotoluene in the refining solvent was 2:1. After the refining was completed, the second filter cake was obtained by suction filtration. The second filter cake was baked in an oven at 60°C for 3 hours to obtain the final product. The yield of the final product was 88.0% and the purity was 99.1%.

[0040] Example 2 (corresponding to group 10 in Table 1)

[0041] Mixed acid preparation: nitric acid with a mass fraction of 65% to 68% is added dropwise to sulfuric acid with a mass fraction of 98% in an ice bath to prepare a mixed acid, wherein the volume ratio of nitric acid to sulfuric acid is 3:25.

[0042] Preparation of 2-chloro-6-nitrotoluene & sulfuric acid mixture: slowly add 2-chloro-6-nitrotoluene to 98% sulfuric acid by mass, stir until clear and transparent, and obtain a 2-chloro-6-nitrotoluene & sulfuric acid mixture. The molar concentration of 2-chloro-6-nitrotoluene in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is 0.6 mol / L, the volume of sulfuric acid in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is the same as the volume of sulfuric acid in the mixed acid, and the molar ratio of 2-chloro-6-nitrotoluene to sulfuric acid in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is 1:30.

[0043] Ice-water mixture preparation: crushed ice is added to water to prepare an ice-water mixture, wherein the volume ratio of the total amount of 98% sulfuric acid in the mixed acid and the mixture of 2-chloro-6-nitrotoluene & sulfuric acid to the ice-water mixture is 1:10.

[0044] The microchannel continuous flow reactor was adjusted so that the temperature of the reaction chamber was stabilized at 70°C.

[0045] The mixed acid was input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 1, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture was input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 2. The flow rate of the 2-chloro-6-nitrotoluene & sulfuric acid mixture was adjusted to 2 mL / min, and the flow rate of the mixed acid was adjusted to 2 mL / min, so that the molar ratio of 2-chloro-6-nitrotoluene to nitric acid entering the reaction chamber was 1:3, and the residence time of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid was controlled to be 22 min. The reaction product was allowed to flow into the ice-water mixture, and the reaction product was filtered to obtain a first filter cake.

[0046] The first filter cake was refined by stirring at 45°C for 3 hours using a refining solvent, wherein the refining solvent consisted of water and n-heptane, the mass ratio of water to 2-chloro-6-nitrotoluene in the refining solvent was 1:1, and the mass ratio of n-heptane to 2-chloro-6-nitrotoluene in the refining solvent was 2:1. After the refining was completed, the second filter cake was obtained by suction filtration. The second filter cake was baked in an oven at 60°C for 3 hours to obtain the final product. The yield of the final product was 84.5% and the purity was 98.4%.

[0047] Example 3 (corresponding to group 12 in Table 1)

[0048] Mixed acid preparation: nitric acid with a mass fraction of 65% to 68% is added dropwise to sulfuric acid with a mass fraction of 98% in an ice bath to prepare a mixed acid, wherein the volume ratio of nitric acid to sulfuric acid is 3:25.

[0049] Preparation of 2-chloro-6-nitrotoluene & sulfuric acid mixture: slowly add 2-chloro-6-nitrotoluene to 98% sulfuric acid by mass, stir until clear and transparent, and obtain a 2-chloro-6-nitrotoluene & sulfuric acid mixture. The molar concentration of 2-chloro-6-nitrotoluene in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is 0.6 mol / L, the volume of sulfuric acid in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is the same as the volume of sulfuric acid in the mixed acid, and the molar ratio of 2-chloro-6-nitrotoluene to sulfuric acid in the 2-chloro-6-nitrotoluene & sulfuric acid mixture is 1:30.

[0050] Ice-water mixture preparation: crushed ice is added to water to prepare an ice-water mixture, wherein the volume ratio of the total amount of 98% sulfuric acid in the mixed acid and the mixture of 2-chloro-6-nitrotoluene & sulfuric acid to the ice-water mixture is 1:10.

[0051] The microchannel continuous flow reactor was adjusted so that the temperature of the reaction chamber was stabilized at 70°C.

[0052] The mixed acid was input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 1, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture was input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 2. The flow rate of the 2-chloro-6-nitrotoluene & sulfuric acid mixture was adjusted to 4 mL / min, and the flow rate of the mixed acid was adjusted to 4 mL / min, so that the molar ratio of 2-chloro-6-nitrotoluene to nitric acid entering the reaction chamber was 1:3, the residence time of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid was controlled to be 11 min, the reaction product was allowed to flow into the ice-water mixture, and the reaction product was filtered to obtain a first filter cake.

[0053] The first filter cake was refined by stirring at 45°C for 3 hours using a refining solvent, wherein the refining solvent consisted of water and n-heptane, the mass ratio of water to 2-chloro-6-nitrotoluene in the refining solvent was 1:1, and the mass ratio of n-heptane to 2-chloro-6-nitrotoluene in the refining solvent was 2:1. After the refining was completed, the second filter cake was obtained by suction filtration. The second filter cake was baked in an oven at 60°C for 3 hours to obtain the final product. The yield of the final product was 87.0% and the purity was 99.2%.

[0054] Test example

[0055] The parameters of the microchannel continuous flow reactor were adjusted, and the relevant test results are as follows:

[0056] Table 1

[0057]

[0058]

[0059] Table 2

[0060]

[0061] In Table 1: Pump 1 refers to polytetrafluoroethylene advection pump 1, and Pump 2 refers to polytetrafluoroethylene advection pump 2; Taking the test of Group 1 as an example, the flow rates of Pump 1 and Pump 2 are both 2 mL / min. In Table 1, 2-chloro-6-nitrotoluene and HNO3 are the concentrations in the reaction chamber; the mass fraction of H2SO4 is 98%; T refers to the reaction temperature in the reaction chamber.

[0062] The structural formula of impurity 1 is shown in Formula 1, and the structural formula of impurity 2 is shown in Formula 2:

[0063]

[0065] The flow rates of pump 1 and pump 2 were set to 4 mL / min, the ratio of nitric acid to 2-chloro-6-nitrotoluene was adjusted to 3 / 1, and the concentration of 2-chloro-6-nitrotoluene in the reaction chamber was 0.3 mol / L. The effect of different temperatures on the conversion rate of the target product (1-chloro-2-methyl-3,4-dinitrobenzene) was investigated. The results are shown in Table 3:

[0066] Table 3

[0067]

[0068] From the above, it can be seen that although the remaining raw material 2-chloro-6-nitrotoluene becomes less and less with the continuous increase of the reaction temperature, if the temperature is too high, for example, after the temperature exceeds 70°C, as the temperature increases further, the generation of impurity 1 and impurity 2 will also increase to varying degrees, resulting in the final product having a total impurity content that is too high and the conversion rate of the target product will decrease; therefore, preferably, the reaction temperature is 70°C.

[0069] When the ratio of 2-chloro-6-nitrotoluene to nitric acid is 1 / 3, the conversion rate of the final product is up to 91%, the conversion rate of impurity 1 is 6%, the conversion rate of impurity 2 is 2%, and the raw material: 2-chloro-6-nitrotoluene remains 1%.

[0070] Among them, according to group 5, group 7, group 8, and group 9, the ratio of 2-chloro-6-nitrotoluene to nitric acid is 1 / 1.5, 1 / 2, 1 / 3, and 1 / 4 respectively; it can be seen from the table that when other conditions are constant, when the ratio of 2-chloro-6-nitrotoluene to nitric acid gradually increases, the remaining raw material 2-chloro-6-nitrotoluene approaches the limit (1%), but the total conversion rate and the target product conversion rate gradually increase; when the ratio of 2-chloro-6-nitrotoluene to nitric acid is 1 / 4, the target product conversion rate decreases, and the impurity conversion rate increases. Therefore, the optimal ratio of 2-chloro-6-nitrotoluene to nitric acid is 1 / 3.

[0071] When the concentration of 2-chloro-6-nitrotoluene is 0.3 mmol / mL, the conversion rate of the final product is up to 93%, the conversion rate of impurity 1 is 4%, the conversion rate of impurity 2 is 2%, and the raw material: 2-chloro-6-nitrotoluene remains 1%.

[0072] When the flow rates of the dual pumps (pump 1 and pump 2) are both 4 mL / min, the total flow rate is 8 mL / min; the conversion rate of the final product is up to 94%, the conversion rate of impurity 1 is 3%, the conversion rate of impurity 2 is 2%, and the raw material: 2-chloro-6-nitrotoluene remains 1%.

[0073] The first filter cake (10 g) obtained from group 12 was refined under different refining solvents. The results are shown in Table 4:

[0074] Table 4

[0075] Refined solvent (45℃) purity Yield Impurity content Impurity II content 2-Chloro-6-nitrotoluene content 20mL methanol and 10mL water 99.5％ 71％ 0.3％ 0.1％ 0.1％ 20mL of ethanol and 10mL of water 99.7％ 58％ 0.2％ 0 0.1％ 20 mL of ethyl acetate and 10 mL of water 99.7％ 71％ 0.1％ 0.1％ 0.1％ 20 mL of n-heptane and 10 mL of water 99.2％ 87％ 0.5％ 0.2％ 0.1％ 20mL of n-hexane and 10mL of water 96.5％ 81％ 2.1％ 0.9％ 0.5％ 20mL of n-octane and 10mL of water 97.2％ 79％ 1.5％ 0.8％ 0.5％

[0076] As shown in Table 4, if the impurity 2 needs to be completely removed from the product, the refining solvent is preferably composed of water and ethanol in a volume ratio of 1:2. If the content of impurity 1 in the product is the lowest, the refining solvent is preferably composed of water and ethyl acetate in a volume ratio of 1:2. If the product yield is taken into account, the refining solvent is preferably composed of water and n-heptane in a volume ratio of 1:2.

[0077] Therefore, if the types of organic solvents contained in the refined solvent are different, the removal effects on different impurities will be different, and the yield of the product will be significantly affected.

[0078] 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 and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction, characterized in that: The following steps are involved: Step 1: Mixed acid preparation Mix nitric acid and sulfuric acid to make a mixed acid; Step 2: Preparation of 2-chloro-6-nitrotoluene & sulfuric acid mixture Mixing 2-chloro-6-nitrotoluene with sulfuric acid to obtain a 2-chloro-6-nitrotoluene & sulfuric acid mixture; Step 3: Microchannel-nitrification reaction The mixed acid is input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 1, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture is input into the reaction chamber of the microchannel continuous flow reactor through a polytetrafluoroethylene advection pump 2, and the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid are controlled to react in the reaction chamber, and a reaction product is obtained after the reaction is completed.

2. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: In step 1, nitric acid is added dropwise to sulfuric acid in an ice bath to prepare a mixed acid.

3. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: In step 1, the mass fraction of nitric acid is 65% to 68%, the mass fraction of sulfuric acid is 98%, and the molar ratio of nitric acid to sulfuric acid is 1:(10 to 20).

4. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: In step 2, the mass fraction of sulfuric acid is 98%, and the mass ratio of 2-chloro-6-nitrotoluene to sulfuric acid is 1:(5-20).

5. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: The reaction temperature of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid in the reaction chamber is 40-80°C.

6. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: The molar ratio of 2-chloro-6-nitrotoluene to nitric acid in the reaction chamber is 1:

3.

7. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: The flow rates of the sample introduction of the polytetrafluoroethylene advection pump 1 and the polytetrafluoroethylene advection pump 2 were both 4 mL / min, and the concentration of 2-chloro-6-nitrotoluene in the reaction chamber was 0.3 mmol / mL.

8. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: The residence time of the 2-chloro-6-nitrotoluene & sulfuric acid mixture and the mixed acid in the reaction chamber is 5 min to 20 min.

9. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 1, characterized in that: The reaction product is post-treated, the reaction product flows into an ice-water mixture, and the reaction product is filtered to obtain a first filter cake; the first filter cake is refined using a refining solvent, and after the refining is completed, the second filter cake is filtered to obtain a second filter cake, and the second filter cake is dried to obtain the 1-chloro-2-methyl-3,4-dinitrobenzene.

10. The method for preparing 1-chloro-2-methyl-3,4-dinitrobenzene by microchannel-nitration reaction according to claim 9, characterized in that: The first filter cake is refined by stirring with a refining solvent at a temperature of 45° C., wherein the refining solvent consists of water and an organic solvent, the volume ratio of water to the organic solvent in the refining solvent is 1:2, and the organic solvent is one or more of methanol, ethanol, ethyl acetate, n-heptane, n-hexane, and n-octane.

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