Method for continuously synthesizing 2-methyl-5-nitroimidazole through nitration

Abstract

The invention discloses a method for continuously synthesizing 2-methyl-5-nitroimidazole through nitration, which comprises the following steps: S1, dissolving 2-methylimidazole in concentrated sulfuric acid, then adding acetic anhydride to prepare a solution A for later use, dissolving 2-methylimidazole in concentrated sulfuric acid at the temperature of not more than 40 DEG C; s2, ammonium sulfate is added into concentrated sulfuric acid and fuming nitric acid, a solution B is prepared for standby application, and the temperature of the ammonium sulfate dissolved in the fuming nitric acid does not exceed 30 DEG C; s3, pumping the solution A into the microchannel reactor, and pumping the solution B into the microchannel reactor; carrying out nitration reaction; and S4, adding the reaction liquid output from the microchannel reactor into water, adjusting the pH value, cooling, crystallizing, filtering, washing and drying to obtain the 2-methyl-5-nitroimidazole. By adopting the method disclosed by the invention, the requirements of high-temperature nitration reaction on equipment materials are reduced, the use amount of fuming nitric acid is reduced, the reaction process is safe and stable, and the 2-methyl-5-nitroimidazole prepared by the method is relatively high in purity.

Description

Technical Field

[0001] The invention relates to the technical field of synthesizing 2-methyl-5-nitroimidazole, in particular to a method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration. Background Art

[0002] 2-Methyl-5-nitroimidazole, molecular formula C4H5N3O2, is generally a white or light yellow crystalline powder with a melting point of 252-254°C. It is insoluble in water, slightly soluble in methanol and ethanol, and easily soluble in strong acids and bases. 2-Methyl-5-nitroimidazole is usually used as an intermediate in the organic synthesis of other morpholiniazole drugs. For example, 2-methyl-5-nitroimidazole is subjected to a hydroxyalkylation reaction with ethylene oxide in a formic acid and sulfuric acid environment. The resulting product can be post-treated and refined to obtain metronidazole.

[0003] 2-Methyl-5-nitroimidazole is widely used in organic synthesis. The existing technical processes are roughly divided into high-temperature sulfuric acid-nitric acid mixed acid process above 140°C, acetic anhydride process, solid acid catalysis process, etc. Most of the domestic processes use high-temperature intermittent reactor processes above 140°C.

[0004] The 140 ℃ high temperature autoclave process uses 2-methylimidazole and sulfuric acid as raw materials, and gradually adds nitric acid in a sulfuric acid medium and high temperature conditions to carry out nitration reaction, thereby obtaining 2-methyl-5-nitroimidazole. However, this process has high reaction temperature, high energy consumption, high risk factor in the production process, and poor environmental protection.

[0005] Application No. CN202411333531.2 discloses a technology related to the synthesis of 2-methyl-5-nitroimidazole by micro-reaction. The reaction temperature of this technology is above 130 °C. At this temperature, nitric acid is easily decomposed, the amount of nitric acid consumed is large, and the amount of tail gas is large. In addition, the reaction residence time is more than 30 minutes, resulting in large investment in continuous flow reaction equipment, which is not suitable for industrial production.

[0006] In addition, application number CN202310174619.3 discloses a process for continuously preparing 2-methyl-5-nitroimidazole using 2-methylimidazole, tert-butyl nitrite, an oxidant and a catalyst, but this process requires vacuum concentration, extraction, rotary evaporation and other post-treatments of the reaction solution, which is cumbersome in operation, and the reaction conditions and temperatures are high, the energy consumption required in the production process is high, and the cost of catalyst raw materials is high. Application number CN201910495647.9 uses a microchannel reactor to load a solid superacid for catalytic reaction. Although the reaction temperature is low, the solid superacid is expensive, and the post-treatment of the reaction solution is complicated, and the production cost is high. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration, and the reaction process is safe and stable.

[0008] The technical solution adopted by the present invention to solve the above technical problem is: a method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration, comprising the following steps: S1. Dissolve 2-methylimidazole in concentrated sulfuric acid, then add acetic anhydride to prepare solution A for later use. 2-methylimidazole must be dissolved in concentrated sulfuric acid at a temperature not exceeding 40 °C. S2. Add ammonium sulfate to concentrated sulfuric acid and fuming nitric acid to prepare solution B for standby use. The temperature at which ammonium sulfate is dissolved in fuming nitric acid shall not exceed 30°C. S3, pumping the solution A formed in step S1 into the microchannel reactor, and pumping the solution B formed in step S2 into the microchannel reactor to carry out nitration reaction; S4, adding the reaction solution output from the microchannel reactor into water, adjusting the pH value, cooling and crystallizing, filtering, washing, and drying to obtain 2-methyl-5-nitroimidazole; In the step S1, the molar ratio of the materials in the material solution is: 2-methylimidazole: concentrated sulfuric acid: acetic anhydride = 1: 1.2-1.6: 1.5-1.8; In step S2, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate is 1: 0.8-0.9: 1.3-1.7: 0.15-0.20.

[0009] Preferably, in step S3, solution A is pumped into a first preheating module by a first pump for preheating, and the first preheating module outputs solution A preheated at 40 to 50°C and enters the microchannel reactor, and solution B is pumped into a second preheating module by a second pump for preheating, and the second preheating module outputs solution B preheated at 40 to 50°C and enters the microchannel reactor, and the reaction temperature of the microchannel reactor is 40 to 50°C.

[0010] More preferably, the reaction temperature of the microchannel reactor is 42-47°C.

[0011] Preferably, in step S4, the reaction liquid output from the microchannel reactor stays in the delay reactor for 3 to 10 minutes before entering the receiver, the reaction liquid in the receiver is added dropwise to water, the pH value is adjusted to 3.5 to 4.0 with ammonia water, the temperature is reduced for crystallization, filtration, washing, and drying to obtain 2-methyl-5-nitroimidazole.

[0012] More preferably, the reaction temperature of the delayed reactor is 40-50°C.

[0013] More preferably, the reaction temperature of the delayed reactor is 42-47°C.

[0014] Preferably, the microchannel reactor adopts a jet fish structure.

[0015] The beneficial effects of the present invention are as follows: the method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration of the present invention is adopted to control the reaction temperature below 50°C, reduce the requirements of the high-temperature nitration reaction on the equipment material, reduce the amount of fuming nitric acid, and the reaction process does not generate brown-yellow smoke. The reaction process is safe and stable, and the safety and environmental protection problems are solved.

[0016] The method of the present invention adopts a microchannel reactor with a jet fish structure to carry out the reaction, which can greatly improve the mixing effect, significantly reduce the reaction pressure, increase the heat exchange efficiency of the reaction process, improve the mass transfer and heat transfer rates between the materials, and ensure the continuous, stable, safe and efficient reaction of the nitration reaction.

[0017] The method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration belongs to the technical field of continuous nitration, reduces impurity generation, and ensures safe and environmentally friendly reactions. The 2-methyl-5-nitroimidazole product produced by the method has stable quality, and the prepared 2-methyl-5-nitroimidazole has high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a connection principle diagram of a preparation device applicable to the method for continuous nitration synthesis of 2-methyl-5-nitroimidazole of the present invention; Figure 2 It is a schematic structural diagram of the microchannel reactor used in the present invention; Wherein: 1. A container; 2. B container; 3. first pump; 4. second pump; 5. first preheating module; 6. second preheating module; 7. microchannel reactor; 8. time-delay reactor; 9. receiver; 10. controller; 11. first medium inlet; 12. second medium inlet; 13. medium outlet; 14. temperature detection port. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0020] A method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration comprises the following steps: S1. Dissolve 2-methylimidazole in concentrated sulfuric acid, then add acetic anhydride to prepare solution A for use. Place solution A in container A 1. 2-methylimidazole must be dissolved in concentrated sulfuric acid first and the temperature must not exceed 40 °C.

[0021] Preferably, in step S1, the material molar ratio of the material in the material solution is: 2-methylimidazole: concentrated sulfuric acid: acetic anhydride = 1: 1.2-1.6: 1.5-1.8. Further preferably, in step S1, the material molar ratio of the material in the material solution is: 2-methylimidazole: concentrated sulfuric acid: acetic anhydride == 1: 1.34: 1.69.

[0022] S2. Add ammonium sulfate to concentrated sulfuric acid and fuming nitric acid to prepare solution B for use. Place solution B in container B 2. The temperature at which ammonium sulfate is dissolved in fuming nitric acid does not exceed 30°C.

[0023] Preferably, in step S2, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate is 1: 0.8-0.9: 1.3-1.7: 0.15-0.20. Further preferably, in step S2, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate is 1: 0.88: 1.47: 0.17.

[0024] S3. Pump the solution A formed in step S1 into the microchannel reactor, and pump the solution B formed in step S2 into the microchannel reactor to carry out nitration reaction.

[0025] like Figure 1 The preparation device for the method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration of the present invention includes A container 1, B container 2, first pump 3, second pump 4, first preheating module 5, second preheating module 6, microchannel reactor 7, delay reactor 8, receiver 9, and controller 10. Preferably, in the step S3, the solution A in the A container 1 is pumped into the first preheating module 5 by the first pump 3 for preheating, and the first preheating module 5 outputs the solution A preheated at 40 to 50 ° C and enters the microchannel reactor 7, and the solution B in the B container 2 is pumped into the second preheating module 6 by the second pump 4 for preheating, and the second preheating module 6 outputs the solution B preheated at 40 to 50 ° C and enters the microchannel reactor 7, and the reaction temperature of the microchannel reactor 7 is 40 to 50 ° C. Further preferably, the reaction temperature of the microchannel reactor is 42 to 47 ° C. The temperatures of the first preheating module 5, the second preheating module 6, and the microchannel reactor 7 are controlled by the controller 10.

[0026] like Figure 2 As shown, further preferably, the microchannel reactor 7 adopts a jet fish structure. The jet fish structure has a first flow channel and a second flow channel with alternating cross-flow, a first medium inlet 11 of the microchannel reactor 7 is connected to the first flow channel, a second medium inlet 12 of the microchannel reactor 7 is connected to the second flow channel, an outlet of the jet fish structure is connected to a medium outlet 13 of the microchannel reactor 7, and a temperature detection port 14 is arranged at the outlet of the jet fish structure.

[0027] The present invention adopts a two-stream feeding method, which essentially avoids the risk of direct reaction in the reactor, thereby ensuring safety. A low-temperature reaction is adopted during the reaction process, thereby further improving safety. The production process has lower energy consumption, a low nitric acid decomposition rate, a high nitric acid utilization rate, and low overall cost.

[0028] S4. The reaction solution output from the microchannel reactor is added into water, the pH value is adjusted, the temperature is reduced for crystallization, the solution is filtered, washed and dried to obtain 2-methyl-5-nitroimidazole.

[0029] Preferably, in step S4, the reaction liquid output from the microchannel reactor 7 is passed through the delay reactor 8 for 3 to 10 minutes before entering the receiver 9, and the reaction liquid in the receiver 9 is then added dropwise to water for quenching, mainly to quench the acetic anhydride, and the pH value is adjusted to 3.5 to 4.0 with aqueous ammonia, and the reaction liquid is cooled, crystallized, filtered, washed, and dried to obtain 2-methyl-5-nitroimidazole.

[0030] More preferably, the reaction temperature of the delayed reactor is 40-50°C. More preferably, the reaction temperature of the delayed reactor is 42-47°C.

[0031] In the method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration of the present invention, step S1 and step S2 can be performed in any order and can be performed simultaneously, or step S1 or step S2 can be performed first, and after both step S1 and step S2 are completed, step S3 can be performed.

[0032] In the method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration of the present invention, the reaction equation is as follows:

[0033] Example 1: Add 290 g of concentrated sulfuric acid to a three-necked flask, control the temperature to <40°C, slowly add 200 g of 2-methylimidazole to dissolve it under stirring, and finally add 400 g of acetic anhydride to obtain solution A; in the proportion of Example 1, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: acetic anhydride is 1:1.21:1.61.

[0034] 200 g of concentrated sulfuric acid was added to a three-necked flask, the temperature was controlled to be less than 30° C., 245 g of fuming nitric acid was slowly added under stirring to dissolve, and finally 50 g of ammonium sulfate was added to obtain solution B; in the proportion of this embodiment 1, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate was 1:0.84:1.60:0.155.

[0035] The microchannel reactor was heated to 48°C, solution A and solution B were preheated and then transported to the microchannel reactor for reaction, and the reaction solution was received by a receiver after the residence time in the reactor was extended for 3.5 min; the reaction solution in the receiver was added dropwise to water, and the pH value was adjusted to 3.5-4.0 with ammonia water. The 2-methyl-5-nitroimidazole was obtained by cooling, crystallization, filtration, washing and drying with a purity of 99.8% and a yield of 92.4%.

[0036] Example 2: 380 g of concentrated sulfuric acid was added to a three-necked flask, the temperature was controlled at <40°C, 200 g of 2-methylimidazole was slowly added under stirring to dissolve, and finally 448 g of acetic anhydride was added to obtain solution A; in the proportion of Example 2, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: acetic anhydride = 1:1.59:1.80.

[0037] 215 g of concentrated sulfuric acid was added to a three-necked flask, the temperature was controlled to be less than 30° C., 250 g of fuming nitric acid was slowly added under stirring to dissolve, and finally 65 g of ammonium sulfate was added to obtain solution B; in the proportion of this embodiment 2, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate was 1:0.90:1.63:0.20.

[0038] The microchannel reactor was heated to 45°C, solution A and solution B were transported to the microchannel reactor for reaction, and the reaction solution was received by a receiver after the residence time in the reactor was extended for 7 minutes; the reaction solution in the receiver was added dropwise to water, and the pH value was adjusted to 3.5-4.0 with ammonia water. The reaction solution was cooled for crystallization, filtered, washed, and dried to obtain 2-methyl-5-nitroimidazole with a purity of 99.9% and a yield of 92.1%.

[0039] Example 3: Add 320g of concentrated sulfuric acid to a three-necked flask, control the temperature to <40°C, slowly add 200g of 2-methylimidazole to dissolve it under stirring, and finally add 420g of acetic anhydride to obtain solution A; in the proportion of Example 3, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: acetic anhydride = 1:1.34:1.69.

[0040] 210 g of concentrated sulfuric acid was added to a three-necked flask, the temperature was controlled to be less than 30° C., 225 g of fuming nitric acid was slowly added under stirring to dissolve, and finally 55 g of ammonium sulfate was added to obtain solution B; in the proportion of this embodiment 3, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate was 1:0.88:1.47:0.17.

[0041] The microchannel reactor was heated to 42°C, solution A and solution B were transported to the microchannel reactor for reaction, and after the residence time in the reactor was extended for 10 min, the reaction solution was received by a receiver; the reaction solution in the receiver was added dropwise to water, and the pH value was adjusted to 3.5-4.0 with ammonia water. The 2-methyl-5-nitroimidazole was obtained by cooling, crystallization, filtration, washing and drying with a purity of 99.9% and a yield of 92.8%.

[0042] Example 4: 350 g of concentrated sulfuric acid was added to a three-necked flask, the temperature was controlled at <40°C, 200 g of 2-methylimidazole was slowly added under stirring to dissolve, and finally 405 g of acetic anhydride was added to obtain solution A; in the proportion of Example 4, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: acetic anhydride = 1:1.47:1.63.

[0043] 200 g of concentrated sulfuric acid was added to a three-necked flask, the temperature was controlled to be less than 30° C., 240 g of fuming nitric acid was slowly added under stirring to dissolve, and finally 50 g of ammonium sulfate was added to obtain solution B; in the proportion of this embodiment 4, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate = 1: 0.84: 1.56: 0.155.

[0044] The microchannel reactor was heated to 48°C, solution A and solution B were transported to the microchannel reactor for reaction, and after the residence time in the reactor was extended for 6 min, the reaction solution was received by a receiver, and the reaction solution in the receiver was added dropwise to water, and the pH value was adjusted to 3.5-4.0 with ammonia water. The 2-methyl-5-nitroimidazole was obtained by cooling, crystallization, filtration, washing and drying with a purity of 99.9% and a yield of 92.5%.

[0045] Comparative example, preparation of mixture A: add 450g of fuming nitric acid to the reaction bottle, turn on stirring and cool down, slowly add 165g of ammonium sulfate, the temperature rises to 48°C, and after the preparation is completed, use normal temperature water to cool the material to 30°C. Preparation of mixture B: add 1000g of 98% concentrated sulfuric acid to the reaction bottle, turn on stirring and cool down, slowly add 500g of 2-methylimidazole, the temperature rises to 88°C, after the addition of 2-methylimidazole is completed, add 1000g of acetic anhydride. Stir evenly and cool to 30°C.

[0046] The reaction process of the comparative example: the temperature of the four-stage micro-tube reactor is controlled at 50°C, the plunger pump is turned on and the water flow rate is set to 60g / min, after stabilization, the A mixture steady flow delivery metering pump is turned on again, and the flow rate is set to 10.35g / min. After the A mixture steady flow delivery metering pump runs stably, the B mixture steady flow delivery metering pump is finally turned on, and the flow rate is set to 40.35g / min. The A mixture and the B mixture are respectively input into the four-stage micro-tube reactor by the A mixture steady flow delivery metering pump and the B mixture steady flow delivery metering pump for reaction. The water injection pump continuously injects water to dilute the reaction completion liquid flowing out of the four-stage micro-tube reactor until the reaction is terminated. The mixed liquid after the reaction is terminated flows into the neutralization kettle for neutralization. After the neutralization is completed, it enters the centrifuge for solid-liquid separation. After separation, the solid phase is washed and dried to obtain a finished product, with a yield of 80% and a purity of 98.6%. The yield of the comparative example is lower than that of Example 1-4.

[0047] Table 1 shows the purity and conversion rate of 2-methyl-5-nitroimidazole in Examples 1-4: Table 1:

[0048] The method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration belongs to the technical field of continuous nitration, reduces impurity generation, and ensures safe and environmentally friendly reactions. The 2-methyl-5-nitroimidazole product produced by the method has stable quality, a product purity of ≥99.8% and a molar yield of ≥92%, and realizes industrial continuous preparation of 2-methyl-5-nitroimidazole with a high purity.

[0049] In the prior art, for example, the method of adding only ammonium sulfate to fuming nitric acid will continuously generate bubbles, causing the metering pump used to generate pulses, and it is impossible to ensure stable feeding for a long time, thus affecting the reaction stability. In the present invention, after adding concentrated sulfuric acid to the fuming nitric acid, the fuming nitric acid can be diluted, which does not affect the reaction effect and can avoid bubbles generated by the decomposition of ammonium sulfate, so that the flow rate of the second pump is stable and uniform, ensuring the stable reaction.

[0050] The above description only describes the specific implementation mode of the present invention. Various examples do not limit the essential content of the present invention. After reading the description, ordinary technicians in the relevant technical field can modify or deform the specific implementation modes described above without departing from the essence and scope of the invention.

Claims

1. A method for continuously synthesizing 2-methyl-5-nitroimidazole by nitration, characterized in that: The steps include: S1. Dissolve 2-methylimidazole in concentrated sulfuric acid, then add acetic anhydride to prepare solution A for later use. 2-methylimidazole must be dissolved in concentrated sulfuric acid at a temperature not exceeding 40 °C. S2. Add ammonium sulfate to concentrated sulfuric acid and fuming nitric acid to prepare solution B for standby use. The temperature at which ammonium sulfate is dissolved in fuming nitric acid shall not exceed 30°C. S3, pumping the solution A formed in step S1 into the microchannel reactor, and pumping the solution B formed in step S2 into the microchannel reactor to carry out nitration reaction; S4, adding the reaction solution output from the microchannel reactor into water, adjusting the pH value, cooling and crystallizing, filtering, washing, and drying to obtain 2-methyl-5-nitroimidazole; In step S1, the molar ratio of the materials in the material solution is: 2-methylimidazole: concentrated sulfuric acid: acetic anhydride = 1: 1.2-1.6: 1.5-1.8; In step S2, the molar ratio of 2-methylimidazole: concentrated sulfuric acid: fuming nitric acid: ammonium sulfate is 1: 0.8-0.9: 1.3-1.7: 0.15-0.

20.

2. The method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration according to claim 1, characterized in that: In step S3, solution A is pumped into the first preheating module by the first pump for preheating, and the first preheating module outputs solution A preheated at 40 to 50°C and enters the microchannel reactor. Solution B is pumped into the second preheating module by the second pump for preheating, and the second preheating module outputs solution B preheated at 40 to 50°C and enters the microchannel reactor. The reaction temperature of the microchannel reactor is 40 to 50°C.

3. A method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration according to claim 2, characterized in that: The reaction temperature of the microchannel reactor is 42-47°C.

4. The method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration according to claim 2, characterized in that: In the step S4, the reaction liquid output from the microchannel reactor stays in the delay reactor for 3 to 10 minutes and then enters the receiver, the reaction liquid in the receiver is added dropwise to water, the pH value is adjusted to 3.5 to 4.0 with ammonia water, the temperature is reduced for crystallization, filtration, washing, and drying to obtain 2-methyl-5-nitroimidazole.

5. The method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration according to claim 4, characterized in that: The reaction temperature of the delayed reactor is 40-50°C.

6. The method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration according to claim 5, characterized in that: The reaction temperature of the delayed reactor is 42-47°C.

7. The method for continuous synthesis of 2-methyl-5-nitroimidazole by nitration according to claim 1, characterized in that: The microchannel reactor adopts a jet fish structure.

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