Method for continuously synthesizing 2-methyl-5-nitroimidazole based on microchannel reactor

Abstract

The invention relates to the field of fine chemical engineering, and discloses a method for continuously synthesizing 2-methyl-5-nitroimidazole based on a microchannel reactor, which comprises the following steps: 1) mixing 2-methylimidazole with concentrated sulfuric acid to obtain a mixture A; 2) mixing fuming nitric acid with glacial acetic acid to obtain a mixture C; 3) taking acetic anhydride as a material B, simultaneously, respectively and continuously conveying the mixture A, the material B and the mixture C into a microchannel reactor for nitration reaction, and controlling the temperature to be 10-30 DEG C; 4, quenching reaction is conducted after the reaction, solids are neutralized and separated out, and filtering, washing and drying are conducted to obtain the 2-methyl-5-nitroimidazole. According to the method, a low-temperature nitration system (10-30 DEG C) is adopted, yellow smoke can be prevented from being generated, the oxidation reaction can still be effectively inhibited under the condition that ammonium sulfate is not added, and therefore the purity and yield of the product can be effectively improved.

Description

Technical Field

[0001] This invention relates to the field of fine chemicals, and in particular to a method for the continuous synthesis of 2-methyl-5-nitroimidazole based on a microchannel reactor. Background Technology

[0002] 2-Methyl-5-nitroimidazole is an important intermediate in the synthesis of drugs such as metronidazole and ornidazole. Currently, the commonly used processes for the continuous synthesis of 2-methyl-5-nitroimidazole mainly involve the following two nitration systems: The first process: Taking CN115400708A as an example, 2-methylimidazole is first dissolved in concentrated sulfuric acid, then the antioxidant ammonium sulfate is added, and then urea (to reduce yellow smoke) is added to prepare one batch. The other batch is fuming nitric acid. The two batches are pumped into a microchannel reactor. The microchannel reactor controls the reaction temperature at 130-160℃ through high-temperature heat transfer oil. After the reaction is completed, the temperature is immediately lowered and the pH is adjusted to 7 with ammonia water to precipitate solids, finally obtaining 2-methyl-5-nitroimidazole.

[0003] The second process involves dissolving 2-methylimidazole in concentrated sulfuric acid, then adding acetic anhydride and stirring until dissolved to prepare one batch. Another batch is prepared by dissolving ammonium sulfate in fuming nitric acid. Both batches are pumped into a microchannel reactor, where the reaction temperature is controlled at 40-70°C using high-temperature heat transfer oil. After the reaction is complete, the mixture is immediately quenched with water and the pH is adjusted to 7 with ammonia to precipitate the solid, ultimately yielding 2-methyl-5-nitroimidazole.

[0004] Both of the aforementioned nitration systems have their own drawbacks. The first nitration system has a very high reaction temperature threshold, requiring 130-160℃ for successful reaction. However, high-temperature nitration produces a large amount of yellow fumes (formed by the decomposition of nitric acid), and the absorption of these fumes requires large amounts of sodium hydroxide and urea, increasing production costs. Simultaneously, the high temperature also leads to severe oxidation, resulting in a low yield. Therefore, to improve the yield, ammonium sulfate must be added to the first nitration system for antioxidant purposes. The second nitration system lowers the reaction temperature threshold to 40-70℃ by adding acetic anhydride, but ammonium sulfate is still required. Furthermore, the reaction has a large liquid holdup and a long reaction time, typically requiring four microchannel reactors connected in series for complete reaction. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for the continuous synthesis of 2-methyl-5-nitroimidazole based on a microchannel reactor. This method employs a low-temperature nitration system (10-30℃), which avoids the formation of yellow fumes and effectively inhibits oxidation reactions without the addition of ammonium sulfate, thereby significantly improving product purity and yield.

[0006] The specific technical solution of the present invention includes: a method for continuous synthesis of 2-methyl-5-nitroimidazole based on a microchannel reactor, comprising the following steps: 1) Mix 2-methylimidazole with concentrated sulfuric acid to obtain mixture A; 2) Fuming nitric acid is mixed with glacial acetic acid to obtain mixture C; 3) Using acetic anhydride as material B, mixture A, material B, and mixture C are simultaneously and continuously fed into a microchannel reactor for nitration reaction, with the temperature controlled at 10-30℃. 4) After the reaction is complete, the reaction is quenched, the precipitated solid is neutralized, filtered, washed and dried to obtain 2-methyl-5-nitroimidazole.

[0007] As described in the background section, the first nitration system suffers from a high reaction temperature threshold. High-temperature nitration produces a large amount of yellow fumes (requiring significant absorption by sodium hydroxide and urea) and leads to severe oxidation (requiring the addition of ammonium sulfate for antioxidant purposes). The second nitration system lowers the reaction temperature threshold to some extent by adding acetic anhydride, but still requires the addition of ammonium sulfate. Furthermore, it has a large liquid holdup and a long reaction time, typically requiring four microchannel reactors connected in series for complete reaction. In the applicant's preliminary experiments, attempts were made to further lower the reaction temperature of the second nitration system to reduce oxidation. However, this resulted in a dramatic increase in the viscosity of the entire reaction system, leading to difficulties in material flow.

[0008] Therefore, in subsequent experiments, this invention found that introducing an appropriate amount of glacial acetic acid into the nitration system can effectively reduce the viscosity of the reaction solution, resulting in a lower overall reaction system pressure (less than 1 MPa) and a more stable reaction operation. On the other hand, the oxidizing properties of the reaction solution are reduced after dilution, and less raw materials or products are oxidized and degraded, so there is no need to add ammonium sulfate. In addition, the glacial acetic acid in the mother liquor after the reaction can be recycled without increasing the cost of raw materials.

[0009] In summary, this invention utilizes a low-temperature nitration system (10-30℃), with a reaction temperature significantly lower than the 130-160℃ of the first process in the prior art, and also lower than the 40-70℃ of the second process. No yellow fumes are generated, and the reaction is safer. Furthermore, this invention avoids the use of solid ammonium sulfate, resulting in a more stable reaction process. The pressure throughout the microchannel reactor pipeline is lower (below 1 MPa), the reaction time is shorter (less than 12 seconds), and the yield and purity of 2-methyl-5-nitroimidazole are both higher. Finally, the three-stream feeding method of this invention avoids the violent exothermic reaction when acetic anhydride and concentrated sulfuric acid are mixed, ensuring the safety of the feed preparation process.

[0010] The mass ratio of 2-methylimidazole, concentrated sulfuric acid, acetic anhydride, fuming nitric acid, and glacial acetic acid in the microchannel reactor is 1:(2-3):(1.5-3):(0.8-1.5):(0.5-1.5).

[0011] This invention has revealed that the mass ratio of the aforementioned key substances is crucial for the purity and yield of 2-methyl-5-nitroimidazole. Within the specific mass ratio range described above, the purity and yield of the product are even better.

[0012] Preferably, step 1) specifically includes: adding concentrated sulfuric acid into a container, cooling to below 10°C, adding 2-methylimidazole in batches at a temperature not exceeding 60°C, stirring until the solid is completely dissolved, and cooling to below 30°C for later use.

[0013] Further preferably, in step 1), the concentration of the concentrated sulfuric acid is 95-99.5 wt%.

[0014] Preferably, in step 3), the microchannel reactor is preheated to the target reaction temperature before the reaction.

[0015] Preferably, in step 3), during the nitration reaction, the reaction time of the mixture A, material B, and mixture C in the microchannel reactor is less than 12 s, and the pressure is less than 1 MPa.

[0016] Preferably, in step 4), the reaction is quenched by water.

[0017] Preferably, in step 4), the neutralization involves adjusting the pH to 6.5-7.5; more preferably, ammonia is used for neutralization.

[0018] Preferably, the 2-methyl-5-nitroimidazole has a purity of ≥99.7% and a molar yield of greater than 89%.

[0019] Compared with the prior art, the beneficial effects of the present invention are: (1) In this invention, an appropriate amount of glacial acetic acid is introduced into the nitration system. On the one hand, it can effectively reduce the viscosity of the reaction liquid, thereby reducing the pressure of the reaction system, making the reaction run more smoothly and the reaction time shorter. On the other hand, the oxidation performance of the reaction liquid is reduced after dilution, and the raw materials or products are oxidized and degraded less, which can improve the purity and yield of the products. In addition, the glacial acetic acid in the mother liquor after the reaction can be recycled and reused without increasing the cost of raw materials.

[0020] (2) The present invention uses a low-temperature nitration system (10-30℃), which makes the reaction safer.

[0021] (3) The present invention can avoid the use of solid ammonium sulfate, making the reaction process more stable.

[0022] (4) The method of feeding the material in three streams in this invention can avoid the violent exothermic reaction when acetic anhydride and concentrated sulfuric acid are mixed, thus ensuring the safety of the batching process. Attached Figure Description

[0023] Figure 1 The HPCL spectrum of 2-methyl-5-nitroimidazole obtained in Example 1 is shown.

[0024] Figure 2 The HPCL spectrum of 2-methyl-5-nitroimidazole obtained in Comparative Example 1 is shown.

[0025] Figure 3 The HPCL spectrum of 2-methyl-5-nitroimidazole obtained in Comparative Example 2 is shown. Detailed Implementation

[0026] The present invention will be further described below with reference to embodiments.

[0027] General Implementation Examples A method for the continuous synthesis of 2-methyl-5-nitroimidazole based on a microchannel reactor, comprising the following steps: 1) Mix 2-methylimidazole with concentrated sulfuric acid to obtain mixture A; 2) Fuming nitric acid is mixed with glacial acetic acid to obtain mixture C; 3) Using acetic anhydride as material B, mixture A, material B, and mixture C are simultaneously and continuously fed into a microchannel reactor for nitration reaction, with the temperature controlled at 10-30℃. 4) After the reaction is complete, the reaction is quenched, the precipitated solid is neutralized, filtered, washed and dried to obtain 2-methyl-5-nitroimidazole.

[0028] The mass ratio of 2-methylimidazole, concentrated sulfuric acid, acetic anhydride, fuming nitric acid, and glacial acetic acid in the microchannel reactor is 1:(2-3):(1.5-3):(0.8-1.5):(0.5-1.5).

[0029] Preferably, step 1) specifically includes: adding concentrated sulfuric acid into a container, cooling to below 10°C, adding 2-methylimidazole in batches at a temperature not exceeding 60°C, stirring until the solid is completely dissolved, and cooling to below 30°C for later use.

[0030] Further preferably, in step 1), the concentration of the concentrated sulfuric acid is 95-99.5 wt%.

[0031] Preferably, in step 3), the microchannel reactor is preheated to the target reaction temperature before the reaction.

[0032] Preferably, in step 3), during the nitration reaction, the reaction time of the mixture A, material B, and mixture C in the microchannel reactor is less than 12 s, and the pressure is less than 1 MPa.

[0033] Preferably, in step 4), the reaction is quenched by water.

[0034] Preferably, in step 4), the neutralization involves adjusting the pH to 6.5-7.5; more preferably, ammonia is used for neutralization.

[0035] Preferably, the 2-methyl-5-nitroimidazole has a purity of ≥99.7% and a molar yield of greater than 89%.

[0036] Specific embodiments and comparative examples Example 1: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:1:1 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 13.6 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 143.8g of qualified product. The purity was 99.9% and the yield was 92.8% as determined by HPLC.

[0037] Example 2: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:3:2:1:1 (1) Ingredients: Mixture A ingredients: Add 300g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 150g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 24.6 ml / min, 15 ml / min, and 13.6 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 141.3g of qualified product. The purity was 99.4% as determined by HPLC, and the yield was 91.2%.

[0038] In the above reaction of Example 2, the proportion of concentrated sulfuric acid was increased from 2 to 3, the pressure of the reaction system increased slightly, and the excess sulfuric acid resulted in a decrease in the product degradation yield.

[0039] Example 3: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:1.5:1:1 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 150g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 11.3 ml / min, and 13.6 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 139.6g of qualified product. The purity was 99.6% as determined by HPLC, and the yield was 90.1%.

[0040] In Example 3, the proportion of acetic anhydride used in the above reaction was reduced from 2 to 1.5, resulting in 2.3% of the raw material remaining in the reaction solution.

[0041] Example 4: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid was 1:2:3:1:1 (1) Ingredients: (2) Mixture A: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keep the temperature below 60℃, stir until the solid is completely dissolved, cool to below 30℃ and set aside; Material B: Add 300g of acetic anhydride to a 500ml single-necked flask and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 18.7 ml / min, and 13.6 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 143.5g of qualified product. The purity was 99.8% as determined by HPLC, and the yield was 92.4%.

[0042] In Example 4, the proportion of acetic anhydride used in the above reaction was increased from 2 to 3. It was found that the yield did not increase, and the raw material cost was increased.

[0043] Example 5: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:0.8:1 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 80g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 12.3 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 138.8g of qualified product. The purity was 99.4% as determined by HPLC, and the yield was 89.8%.

[0044] In Example 5, the proportion of fuming nitric acid used in the above reaction was reduced from 1 to 0.8, that is, the amount of fuming nitric acid used was 1.04 equivalents, resulting in a raw material surplus of 2.6%.

[0045] Example 6: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:1.5:1 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 150g of fuming nitric acid, stir well and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 17 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 143.9g of qualified product. The purity was 99.8% as determined by HPLC, and the yield was 92.9%.

[0046] In Example 6, the amount of fuming nitric acid used in the above reaction was increased from 1 to 1.5. The result showed that the yield only increased by 0.1%, but increasing the amount of fuming nitric acid increased the risk of yellow smoke production.

[0047] Example 7: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:1:1 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 10℃, and pre-circulate 10℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 13.6 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 140.1g of qualified product. The purity was 99.6% as determined by HPLC, and the yield was 90.5%.

[0048] In the above reaction of Example 7, the reaction temperature was reduced by 10°C, and it was found that 2.2% of the reaction raw materials remained.

[0049] Example 8: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:1:1 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 100g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 30℃, and pre-circulate 30℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 13.6 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 142.5g of qualified product. The purity was 99.4% as determined by HPLC, and the yield was 92%.

[0050] In the above reaction of Example 8, the reaction temperature was increased to 30°C, and it was found that the impurities became larger and the purity of the reaction solution was slightly lower.

[0051] Example 9: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:1:0.5 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 50g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well, and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 10.2 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried to finally obtain 142.2g of qualified product. The purity was 99.2% as determined by HPLC, and the yield was 91.8%.

[0052] In the above reaction of Example 9, the proportion of glacial acetic acid was reduced from 1 to 0.5. As a result, the pressure of the reaction system increased slightly, the purity of the reaction solution was slightly lower, and about 1% of the raw materials remained.

[0053] Example 10: The mass ratio of 2-methylimidazole: sulfuric acid: acetic anhydride: nitric acid: glacial acetic acid is 1:2:2:1:1.5 (1) Ingredients: Mixture A ingredients: Add 200g of concentrated sulfuric acid (98%) to a 1000ml four-necked flask, cool to below 10℃, slowly add 100g of 2-methylimidazole in batches, keeping the temperature below 60℃, stir until the solid is completely dissolved, and cool to below 30℃ for later use; Material B preparation: Add 200g of acetic anhydride to a 500ml single-necked bottle and set aside; Mixture C ingredients: Add 150g of glacial acetic acid to a 1000ml four-necked flask, then add 100g of fuming nitric acid, stir well and set aside; (2) Reaction: Turn on the high and low temperature integrated machine, set the temperature to 20℃, and pre-circulate 20℃ heat transfer oil into the microchannel reactor; Three plunger pumps are set to flow rates of 20 ml / min, 15 ml / min, and 18.2 ml / min, respectively. Mixture A, material B, and mixture C are pumped into the microchannel reactor at the above flow rates. After mixing and reaction, the mixture flows out of the microchannel reactor and is immediately quenched with water. The quenched reaction solution was neutralized with ammonia water and the pH was adjusted to about 7, resulting in the precipitation of a large amount of solid. The solid was filtered, washed, and dried, and finally 143g of qualified product was obtained. The purity was 99.7% as determined by HPLC, and the yield was 92.3%.

[0054] In the above reaction of Example 10, the proportion of glacial acetic acid was increased from 1 to 1.5. The results showed that the pressure of the reaction system decreased slightly, but the yield did not increase.

[0055] Comparative Example 1: The first nitration system in the background art Step S1: 2-Methylimidazole is fed into the continuous batching module through the raw material feeding device, and sulfuric acid (98%) is fed into the continuous batching module through the sulfuric acid continuous feeding module. They are pre-mixed according to the mass ratio, the batching temperature is 120℃, and the residence time of the raw material mixture is 50min to obtain the raw material mixture, which is then fed into the mixing-reaction module through the raw material feeding metering device; nitric acid in the nitric acid storage device is fed into the mixing-reaction module through the nitric acid feeding device. Step S2: Mix the raw material mixture with nitric acid in the mixing-reaction module and carry out the nitration reaction at 150°C for 100 min to obtain the nitration reaction completed liquid. The generated gas enters the alkali absorption module for absorption through the exhaust module. Step S3: In the continuous post-processing unit, the nitration reaction solution is sequentially passed through a continuous quenching pH adjustment module, a continuous solid-liquid separation module, and a drying module for water quenching. The pH is adjusted using alkali supplied by the alkali supply module, and the pH is controlled at 3-6 using the pH monitoring module. The temperature does not exceed 65℃, and the retention time is 15 min. The resulting mixed product is transferred to a centrifuge for solid-liquid separation to obtain crude 2-methyl-5-nitroimidazole, which is then dried. The purity of the 2-methyl-5-nitroimidazole is 99.1%, and the reaction yield is 84.9%.

[0056] In this case, the reaction temperature was abnormally high (140-170℃), and a large amount of yellow fumes were generated. The absorption of the yellow fumes was difficult and required a large amount of alkaline water for gradual absorption. Moreover, the reaction time was long, reaching 100 minutes, which is close to the time of nitration in a kettle. Such a long time requires a reactor with a very large liquid holdup, equivalent to a small reaction kettle.

[0057] Comparative Example 2: The second nitration system in the background technology Step 1: Preparation of Mixture A: Turn on the mixing vessel of mixture A, add 900 kg of fuming nitric acid, turn on the cooling water switch of the mixing vessel of mixture A, and slowly add 330 kg of ammonium sulfate. Control the temperature during the preparation process to not exceed 50°C. After preparation, cool the material to 30°C with room temperature water.

[0058] Step 2: Preparation of Mixture B: Turn on the mixing vessel of mixture B, add 2000 kg of concentrated sulfuric acid (98%), turn on the cooling water switch of the mixing vessel of mixture B, slowly add 1000 kg of 2-methylimidazole, and control the temperature to not exceed 100℃. After the addition of 2-methylimidazole is completed, add 2000 kg of acetic anhydride, stir evenly, and cool down to 30℃.

[0059] Step 3: Mixture A and mixture B are fed into the microtube reactor for reaction: The four microtube reactors (reactor 1, reactor 2, reactor 3, and reactor 4) were preheated to 50°C using warm water circulation. The termination reaction injection pump was started first, with a set flow rate of 12000 g / min, and after stabilization, the A mixture steady-flow metering pump was started, with a set flow rate of 2070 g / min. After pump A stabilized, the B mixture steady-flow metering pump was started, with a set flow rate of 8070 g / min. Mixtures A and B were injected into mixer 1 via the A mixture steady-flow metering pump and the B mixture steady-flow metering pump, respectively, and then sequentially entered the multi-stage microtube reactors for reaction.

[0060] Step 4: Termination of the reaction The reaction liquid flowing out of the four-stage reactor enters the second mixer. At the same time, the water pump continuously injects water to dilute the reaction liquid until the reaction is terminated. The mixture after the reaction is terminated flows into the neutralization tank for neutralization. After neutralization, it is placed in a centrifuge for solid-liquid separation. After separation, the solid phase is washed with water and dried to obtain the finished product with a yield of 87% and a purity of 99.6%.

[0061] This case is relatively similar to the technical solution of this invention, but it uses ammonium sulfate. Adding solid ammonium sulfate to the system inevitably increases the viscosity of the reaction system, leading to increased pressure. Furthermore, it uses four reactors, resulting in a large liquid holdup. During production, high pressure combined with a large liquid holdup will inevitably increase safety risks. In addition, the yield in this system is less than 90%. Therefore, this case uses more reactors, has a longer reaction time, and the addition of ammonium sulfate increases viscosity and system pressure, increasing the risk of blockage, ultimately resulting in a yield of less than 90%.

[0062] The reaction conditions and results of the above embodiments and comparative examples are shown in the table below: The data comparison in the table above shows that: The main difference between Example 1 and Example 2 lies in the change of the amount of concentrated sulfuric acid used. In this comparison, Example 2 increases the proportion of concentrated sulfuric acid to 3, which slightly increases the pressure of the reaction system. At the same time, the excess concentrated sulfuric acid leads to a decrease in the product degradation yield.

[0063] The main difference between Examples 1, 3 and 4 lies in the change of the amount of acetic anhydride used. In Example 3, the proportion of acetic anhydride used was reduced to 1.5, resulting in a 2.3% residue of raw material. In Example 4, it was increased to 3, but the results showed that the yield did not increase, and the cost of raw materials also increased.

[0064] The main difference between Examples 1, 5 and 6 is the change in the amount of fuming nitric acid used. In Example 5, the proportion of fuming nitric acid used was reduced to 0.8, with an equivalent of 1.04, resulting in a 2.6% residue of raw material. In Example 6, it was increased to 1.5, but the yield only increased by 0.1%, and increasing the amount of fuming nitric acid increased the risk of yellow smoke generation.

[0065] The main difference between Examples 1, 7 and 8 is the change in reaction temperature. In Example 7, the reaction temperature was lowered to 10°C, and it was found that 2.2% of the raw material remained, while the system pressure increased. In Example 8, when the reaction temperature was raised to 30°C, it was found that the impurities were larger, the purity of the reaction solution was slightly lower, and the yield was also slightly lower (0.8%).

[0066] Example 1. The main difference between Example 9 and Example 10 is the change in the amount of acetic acid used. In Example 9, the proportion of acetic acid was reduced to 0.5, which led to an increase in the viscosity and pressure of the system, while about 1% of the raw material remained. In Example 10, after the proportion of acetic acid was increased to 1.5, the pressure of the reaction system decreased slightly, but the yield did not increase, and the cost of raw materials increased.

[0067] In Comparative Example 1, the reaction temperature was abnormally high (140-170℃), and a large amount of yellow fumes were generated. The absorption of the yellow fumes was relatively difficult and required a large amount of alkaline water for stepwise absorption. Moreover, the reaction time was long, reaching 100 minutes, which is close to the time of nitration in a kettle. Such a long time requires a reactor with a very large liquid holdup, equivalent to a small reaction kettle.

[0068] Comparative Example 2 is similar to the scheme of the embodiment of the present invention, but it uses ammonium sulfate. The addition of solid ammonium sulfate to the system will inevitably increase the viscosity of the reaction system, resulting in increased pressure. At the same time, it uses four reactors, resulting in a large liquid holdup. If high pressure, large liquid holdup and high temperature occur during the production process, it will inevitably increase the safety risk. The reaction temperature is 40-70℃. In addition, the final yield of this comparative example is less than 90%, which is lower than that of the embodiment of the present invention.

Claims

1. A process for the continuous synthesis of 2-methyl-5-nitroimidazole based on a microchannel reactor, characterized in that include: 1) Mix 2-methylimidazole with concentrated sulfuric acid to obtain mixture A; 2) Fuming nitric acid is mixed with glacial acetic acid to obtain mixture C; 3) Using acetic anhydride as material B, mixture A, material B, and mixture C are simultaneously and continuously fed into a microchannel reactor for nitration reaction, with the temperature controlled at 10-30℃; 4) After the reaction is complete, the reaction is quenched, the precipitated solid is neutralized, filtered, washed and dried to obtain 2-methyl-5-nitroimidazole.

2. The method of claim 1, wherein: The mass ratio of 2-methylimidazole, concentrated sulfuric acid, acetic anhydride, fuming nitric acid, and glacial acetic acid in the microchannel reactor is 1:(2-3):(1.5-3):(0.8-1.5):(0.5-1.5).

3. The method according to claim 1 or 2, characterized in that: Step 1) Specifically includes: adding concentrated sulfuric acid into a container, cooling to below 10°C, adding 2-methylimidazole in batches at a temperature not exceeding 60°C, stirring until the solid is completely dissolved, and cooling to below 30°C for later use.

4. The method of claim 1, wherein: In step 1), the concentration of the concentrated sulfuric acid is 95-99.5 wt%.

5. The method of claim 1 or 2, wherein: In step 3), the microchannel reactor is preheated to the target reaction temperature before the reaction.

6. The method of claim 1 or 2, wherein: In step 3), the reaction time of mixture A, material B, and mixture C in the microchannel reactor is less than 12 seconds.

7. The method of claim 1 or 2, wherein: In step 3), the pressure inside the microchannel reactor during the nitration reaction is less than 1 MPa.

8. The method of claim 1 or 2, wherein: In step 4), the reaction is quenched by water.

9. The method according to claim 1 or 2, characterized in that: In step 4), the neutralization is to adjust the pH to 6.5-7.

5.

10. The 2-methyl-5-nitroimidazole prepared by the method according to any one of claims 1-9, characterized in that: Purity ≥ 99.7%, molar yield > 89%.

Images