A fully continuous chemical synthesis of metronidazole

Abstract

The application belongs to the technical field of medicine and chemical industry, and particularly relates to a full-continuous chemical synthesis device and method of metronidazole. The full-continuous device is composed of multiple improved micro-mixers, micro-reactors, online solvent switching and reagent recycling, low-boiling-point reagent feeding and other equipment which are sequentially connected. High-purity metronidazole products are obtained through three-step chemical reactions and continuous operation, and the recycling of sulfuric acid and formic acid is realized. The problems such as precise continuous feeding of ethylene oxide are solved, the discharge of three wastes is obviously reduced, the continuous synthesis is realized, the production efficiency is greatly improved, the accuracy of process control is greatly improved, and the product quality is stable. The crude metronidazole is subjected to decolorization, recrystallization, filtration and drying to obtain pure metronidazole products with a purity of greater than 99.9%. The amount of sulfuric acid can be reduced by more than 80%, the generation of waste acid and waste salt is effectively reduced, and the production cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and specifically designs a fully continuous chemical synthesis method for metronidazole. Background Technology

[0002] Metronidazole (molecular formula: C6H9N3O3, CAS number: 443-48-1), chemical name: 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, is a white or slightly yellow crystalline powder. Metronidazole is a nitroimidazole antiprotozoal and antianaerobic drug, mainly used clinically for the prevention and treatment of infections caused by anaerobic bacteria, with a large global clinical demand. In 1978, metronidazole was selected by the World Health Organization as an essential drug for treating anaerobic infections.

[0003] Currently, metronidazole production generally employs a batch reactor process, which is time-consuming, energy-intensive, and results in low conversion rates of the main raw material, 2-methyl-5-nitroimidazole. Severe side reactions involving ethylene oxide also occur, generating large amounts of waste acid and salts. Patent CN110669011A developed a novel microtube reaction process for synthesizing metronidazole raw material. Using 2-methyl-5-nitroimidazole as the raw material, the mixture is mixed in the mixing section of a commercially available pre-filled coil reactor before entering a coil reactor with an inner diameter of 4-20 mm to undergo a hydroxyethylation reaction. This avoids the volatilization of low-boiling-point ethylene oxide and improves its utilization efficiency. However, it requires pre-cooling the ethylene oxide to a cryogenic liquid, increasing energy consumption. Furthermore, the low boiling point of ethylene oxide leads to significant vapor pressure variations under different room temperature conditions, which can cause poor accuracy of the metering pump, thus affecting the conversion rate and selectivity of the reaction. Patent CN 111574459A developed a method for preparing metronidazole, which also uses 2-methyl-5-nitroimidazole as raw material. The method improves the utilization rate of ethylene oxide and reduces its volatilization by adding it in multiple gradients through a batch reactor. However, the process is carried out in a batch reactor, and the multi-gradient addition of ethylene oxide is time-consuming, complicated, and has low production efficiency. Summary of the Invention

[0004] To address the problems existing in the prior art, the purpose of this invention is to provide a fully continuous chemical synthesis method for metronidazole that is highly efficient, produces high-quality products, and generates minimal waste.

[0005] The fully continuous chemical synthesis method for metronidazole provided by this invention uses 2-methylimidazole as the starting material and utilizes a micro-mixer, microreactor, a self-designed solvent switching system, and a self-designed ethylene oxide delivery system to synthesize high-purity metronidazole through three-step chemical reactions and continuous operation. It also realizes the recovery and reuse of sulfuric acid and formic acid, solves the problems of precise and continuous feeding of ethylene oxide, significantly reduces the emission of waste gas, wastewater, and solid waste, and greatly improves production efficiency and process control precision through continuous synthesis, ensuring stable product quality.

[0006] The metronidazole fully continuous chemical synthesis method provided by this invention utilizes a fully continuous apparatus consisting of multiple sequentially connected micromixers, microreactors, online solvent switching and reagent recovery devices, and low-boiling-point reagent feeding equipment. The specific steps are as follows: (a) Using glyoxal aqueous solution and acetaldehyde aqueous solution as raw materials, they are mixed as feed solution A, and ammonia water is used as feed solution B. Feed solution A and feed solution B are first fully mixed in the first mixer and then enter the first microreactor to generate a reaction solution containing 2-methylimidazole. The unreacted aldehyde, ammonia and solvent water are quickly removed in the first solvent switching system. The product 2-methylimidazole is mixed with nitric acid solution as feed solution C. (b) The feed solution C is thoroughly mixed with concentrated sulfuric acid in the second mixer and then enters the second microreactor to generate 2-methyl-5-nitroimidazole. The unreacted nitric acid in the reaction solution is removed in the negative pressure tank to obtain a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This solution is split, and part of it is fed into the next reaction as feed solution D. The other part is used to replace the reaction solution of concentrated sulfuric acid and 2-methylimidazole (4) to react and generate a higher concentration of 2-methyl-5-nitroimidazole sulfuric acid solution. This increases the concentration of 2-methyl-5-nitroimidazole in feed solution D and can greatly reduce the amount of sulfuric acid consumed. (c) The feed solution D is mixed with formic acid, and then mixed with ethylene oxide quantitatively output from the self-made ethylene oxide delivery system. The ring-opening reaction occurs in the microreactor to obtain the final product metronidazole solution. The metronidazole reaction solution enters the self-designed solvent switching system to remove formic acid and recover and reuse formic acid. The remaining reaction solution enters the purification process. (d) Purification of the reaction solution: The pH of the above reaction solution for removing formic acid was adjusted to 2-6 in the multifunctional stirred tank of the solvent switching system. After filtration, 2-methyl-5-nitroimidazole was recovered and reused. The pH was further adjusted to 8-14, and crude metronidazole was obtained by filtration. After decolorization, recrystallization, filtration and drying, pure metronidazole with a purity greater than 99.9% was obtained.

[0007] Preferably, the mixer described in steps (a) and (b) is specially designed and manufactured according to the present invention, and its structure is as follows: Figure 4 Specifically, it is a plate-type U-shaped channel structure; the channel width is 100μm-20mm, the length is 1-2000m; and the applicable throughput is 1mL-3000mL / min.

[0008] Preferably, the microreactor described in steps (a), (b), and (c) is a plate-type X-shaped channel structure with fluid channel dimensions between 100 μm and 20 mm, or a tubular baffle-filled channel structure with fluid channel dimensions between 300 μm and 50 mm (see [link to relevant documentation]). Figure 5 (As shown).

[0009] Preferably, the solvent switching system described in steps (a) and (c) is specially designed and manufactured according to the present invention, and there are two schemes. Scheme one, its structure is as follows: Figure 2 As shown, this is a multi-functional stirred tank connected to a vacuum system, a cooling system, and a heating circulation system. The cooling system is a serpentine condenser, the vacuum system is a vacuum pump, and the heating circulation system is a common high-low temperature integrated machine or a circulating heating oil bath, connected by pipes with flanges at the connection points. The multi-functional stirred tank adopts a jacketed heat exchange structure, with the heat exchange fluid entering from the bottom and exiting from the top. A serpentine baffle is installed in the heat exchange channel to ensure uniform heat exchange and eliminate heat exchange dead zones. A material inlet is provided at the top of the multi-functional stirred tank (the reaction liquid containing 2-methylimidazole in step (a) and metronidazole in step (c) enters the multi-functional stirred tank through this material inlet), with the lower end of the inlet extending to the lower 1 / 4 height of the tank body. An outlet is provided at the top of the tank body, which is connected to the bottom of the serpentine condenser via a pipe. Another outlet is also provided at the bottom of the serpentine condenser. The outlet, connected to a storage tank via pipeline, is used to collect the condensed and recovered liquid. The serpentine condenser tube has a bottom-in, top-out cooling fluid inlet and an upper-outlet configuration. Additionally, the top of the serpentine condenser tube is connected to a vacuum regulating valve and a vacuum pump via pipeline. The vacuum pump provides the negative pressure source. The vacuum regulating valve adjusts the negative pressure within the multi-functional stirred tank and condenser tube, controlling the vaporization rate of low-boiling-point compounds and preventing incomplete condensation of the vaporized substances at the condenser tube. A high-low temperature integrated unit or a circulating heating oil bath is connected to the multi-functional stirred tank via pipeline, with flanges at the connection points. Hot fluid is pumped in via a circulating pump. After removing low-boiling-point substances, nitric acid is added; that is, after removing water and other low-boiling-point compounds from the reaction solution, the solvent is switched to nitric acid solution. To achieve continuous, uninterrupted operation, two sets of multi-functional stirred tanks are used in parallel and alternately to achieve continuous preparation of feed liquid C and continuous application of the subsequent nitration reaction.

[0010] Option two involves filling a vertical channel with zigzag spoilers that have nitrogen purging capabilities (see [link]). Figure 3The reaction liquid containing 2-methylimidazole flowing out of the microreactor is concentrated in this channel. This vertical channel has six sets of zigzag baffles, a heat exchange jacket outside the channel, a nitrogen inlet at the bottom, and a nitrogen outlet at the top, facilitating the removal of low-boiling-point compounds by nitrogen. The zigzag baffles increase the liquid dispersion area and accelerate the vaporization rate of low-boiling-point compounds. The heat exchange jacket on the outer wall of the vertical channel ensures the temperature of the liquid inside the channel and prevents condensation of low-boiling-point compounds after vaporization. To further improve the removal efficiency of low-boiling-point compounds, the liquid to be concentrated can be preheated before entering the vertical channel, and an inert gas such as nitrogen can be used to purge and quickly remove volatiles to accelerate evaporation efficiency. The material inlet is located at the top of the vertical channel, extending 1 / 10 of its length, while the nitrogen inlet is at the bottom. Nitrogen and liquid come into full contact on the baffle plate, significantly accelerating the vaporization of low-boiling-point compounds. These compounds are then rapidly carried out of the vertical channel by the nitrogen flow, preventing reliquefaction of low-boiling-point compounds and enabling rapid evaporation below their boiling point. This is suitable for solvent switching of temperature-sensitive unstable compounds in the reaction solution. The nitrogen outlet is located at the top of the vertical channel and connects to a serpentine condenser in a multi-functional stirred tank to recover low-boiling-point compounds.

[0011] Preferably, the diverter mentioned in step (b) is an adjustable liquid flow controller connected to a valve. Its operation is as follows: the 2-methyl-5-nitroimidazole sulfuric acid solution obtained from the first reaction in the microreactor is distilled to recover unreacted nitric acid, which is then used as a substitute for concentrated sulfuric acid in the nitration reaction. This solution is then mixed with a new feed solution C and enters the microreactor to undergo a nitration reaction, resulting in a second 2-methyl-5-nitroimidazole sulfuric acid solution. This sulfuric acid solution can be used as feed solution D and enter the next reaction by opening the diverter. Alternatively, the second 2-methyl-5-nitroimidazole sulfuric acid solution can be mixed with a new feed solution C and enter the microreactor to undergo a nitration reaction, resulting in a third 2-methyl-5-nitroimidazole sulfuric acid solution, until a saturated sulfuric acid solution of 2-methyl-5-nitroimidazole is reached. This solution is then entered into the next reaction via the diverter, saving the consumption of concentrated sulfuric acid in the nitration reaction and realizing the multiple reuse of one part of sulfuric acid for the nitration of multiple parts of 2-methylimidazole.

[0012] Preferably, the ethylene oxide delivery system described in step (c) is specially designed and manufactured according to this invention, and its specific structure includes: a self-made buffer tank; the inlet pipe for the ethylene oxide in the buffer tank is located at 1 / 2 of the tank body, and the outlet pipe extends from the bottom into 1 / 5-1 / 4 of the tank body. After filling the buffer tank, nitrogen gas is used to pressurize it to 5-10 bar to prevent the ethylene oxide from vaporizing at room temperature, which would lead to poor feed stability. Then, an injection pump is used to draw a quantitative amount of ethylene oxide and deliver it to a mixer (that is, the ethylene oxide coming out of the buffer tank is directly pumped into a mixer) to be mixed with a 2-methyl-5-nitroimidazole sulfuric acid / formic acid solution to prepare the target product metronidazole.

[0013] Preferably, the specific operation procedure for purifying the reaction solution in step (d) is as follows: after recovering formic acid, the reaction solution of metronidazole is monitored for pH value using an online pH meter, ammonia or liquid ammonia is added to adjust the pH value, the reaction solution is pumped to an online filter using a plunger pump, and the filtrate is returned to the pH adjustment vessel until the pH value stabilizes at 2-6.

[0014] The metronidazole solution with a pH of 2-6 described in step (d) is added to a second pH adjustment vessel with ammonia or liquid ammonia to adjust the pH. The reaction solution is then pumped to an online filter using a plunger pump. The filtrate is returned to the pH adjustment vessel until the pH stabilizes at 8-14. The filter cake from the online filter is continuously scraped off with a rotary scraper to remove the crude metronidazole. After decolorization and recrystallization, refined metronidazole with a purity greater than 99.9% is obtained.

[0015] This invention achieves efficient metronidazole synthesis using microreactor technology by rationally combining micromixers and microreactors according to the characteristics of metronidazole synthesis processes. Furthermore, a self-designed solvent switching system enables continuous synthesis of metronidazole, significantly improving production efficiency. It also allows for the recovery and reuse of excess nitric acid and formic acid, and the rational use of a distributor enables multiple reuses of sulfuric acid, reducing sulfuric acid consumption by over 80%, effectively minimizing waste acid and salt generation and lowering production costs. Finally, a self-designed ethylene oxide delivery system ensures stable and accurate delivery of ethylene oxide to the pressurized microchannel reactor. Attached Figure Description

[0016] Figure 1 This is a flowchart illustrating the fully continuous chemical synthesis method of metronidazole.

[0017] Figure 2 This is a structural diagram of a multi-functional stirred tank connected to a vacuum system, a cooling system, and a heating circulation system.

[0018] Figure 3 A vertical channel containing a zigzag baffle for purging low-boiling-point compounds with nitrogen.

[0019] Figure 4 This is a schematic diagram of a U-shaped micromixer.

[0020] Figure 5 The diagram shows the structure of a microreactor. In the diagram, a is a plate-type X-shaped microchannel reactor, and b is a tubular baffle-filled microchannel reactor. Detailed Implementation

[0021] To illustrate the technical content, structural features, objectives, and effects of the technical solution in detail, the following description, in conjunction with specific embodiments and accompanying drawings, provides further explanation. This embodiment is implemented based on the technical solution of this invention, providing detailed implementation methods and specific operating procedures; however, the scope of protection of this invention is not limited to the following embodiments.

[0022] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. Example 1

[0023] Glyoxal aqueous solution and acetaldehyde aqueous solution are mixed in a 1:1 molar ratio to form feed solution A, and ammonia water is used as feed solution B, with a dosage of 1.2 equivalents. Feed solutions A and B are pumped into a U-shaped mixer according to the above molar ratio using a plunger pump and thoroughly mixed before entering an X-shaped microreactor to generate a reaction solution containing 2-methylimidazole. The reaction solution is then subjected to reduced pressure in a multi-functional stirred tank connected to a vacuum system, a cooling system, and a heating circulation system to remove unreacted aldehydes, ammonia, and solvent water. The resulting 2-methylimidazole product is mixed with a 70% nitric acid solution to form feed solution C, with the nitric acid dosage being 1.2 equivalents. Feed solution C is thoroughly mixed with concentrated sulfuric acid in a U-shaped mixer and then enters an X-shaped microreactor to generate 2-methyl-5-nitroimidazole. Unreacted nitric acid is removed from the reaction solution in a negative pressure tank to obtain a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This solution is then reused in a second mixing with the reaction solution replacing concentrated sulfuric acid and 2-methylimidazole to generate a higher concentration of 2-methyl-5-nitroimidazole sulfuric acid solution. This process is repeated a third time, yielding feed solution D. This process involves one batch of sulfuric acid participating in three batches of 2-methylimidazole nitration reactions, reducing sulfuric acid consumption. Feed solution D is mixed with formic acid and then with 1.1 equivalents of ethylene oxide supplied quantitatively by an ethylene oxide delivery system. A ring-opening reaction occurs in the X-shaped microreactor to produce the final product, metronidazole. The metronidazole reaction solution enters a spiral channel equipped with zigzag baffles to remove formic acid, which is then condensed and recycled. The remaining reaction solution was adjusted to pH 2-4, filtered to obtain 2-methyl-5-nitroimidazole for recycling, and the pH was further adjusted to 9-12. After filtration, crude metronidazole was obtained, which was then decolorized, recrystallized, filtered, and dried to obtain pure metronidazole with a purity greater than 99.9%. The amount of sulfuric acid used was reduced by 65% ​​compared to the single-pass consumption, the formic acid recovery rate was 95%, the single-pass yield of metronidazole was 80%, and the yield of 2-methyl-5-nitroimidazole (5) reached 96% after recycling. Example 2

[0024] Glyoxal aqueous solution and acetaldehyde aqueous solution are mixed in a molar ratio of 1:1 to form feed solution A, and ammonia water is used as feed solution B, with a dosage of 1.2 equivalents. Feed solutions A and B are pumped into a U-shaped mixer according to the above molar ratio using a plunger pump and thoroughly mixed before entering an X-shaped microreactor to generate a reaction solution containing 2-methylimidazole. The reaction solution is concentrated under negative pressure in a vertical channel equipped with zigzag baffles, removing low-boiling-point compounds and solvent water from the reaction solution flowing out of the microreactor. The resulting 2-methylimidazole product is mixed with 70% nitric acid solution to form feed solution C, with a nitric acid dosage of 1.2 equivalents. Feed solution C is thoroughly mixed with concentrated sulfuric acid in a U-shaped mixer and then enters an X-shaped microreactor to generate 2-methyl-5-nitroimidazole. The reaction solution is then subjected to a negative pressure tank to remove unreacted nitric acid, yielding a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This solution is reused to replace the concentrated sulfuric acid in the 2-methylimidazole reaction solution for a second mixing, generating a higher concentration of 2-methyl-5-nitroimidazole sulfuric acid solution. This allows one batch of sulfuric acid to participate in two batches of 2-methylimidazole nitration reactions, reducing sulfuric acid consumption. Feed solution D is mixed with formic acid and then with 1.1 equivalents of ethylene oxide supplied quantitatively by an ethylene oxide delivery system. A ring-opening reaction occurs in the X-shaped microreactor to produce the final product, metronidazole. The metronidazole reaction solution enters a spiral channel equipped with zigzag baffles to remove formic acid, which is then condensed and recycled. The remaining reaction solution was adjusted to pH 2-4, filtered to obtain 2-methyl-5-nitroimidazole for recycling, and the pH was further adjusted to 9-12. Crude metronidazole was obtained through decolorization, recrystallization, filtration, and drying to obtain pure metronidazole with a purity greater than 99.9%. The amount of sulfuric acid used was reduced by 45% compared to a single-pass application, the formic acid recovery rate was 95%, the single-pass metronidazole yield was 75%, and the yield of 2-methyl-5-nitroimidazole reached 93% after recycling. Example 3

[0025] Glyoxal aqueous solution and acetaldehyde aqueous solution are mixed in a molar ratio of 1:1 to form feed solution A, and ammonia water is used as feed solution B, with a dosage of 1.2 equivalents. Feed solutions A and B are pumped into a U-shaped mixer according to the above molar ratio using a plunger pump and thoroughly mixed before entering an X-shaped microreactor to generate a reaction solution containing 2-methylimidazole. The reaction solution is then concentrated in a vertical channel equipped with zigzag baffles under nitrogen purging and heating conditions to remove low-boiling-point compounds and solvent water from the microreactor. The resulting 2-methylimidazole product is mixed with a 70% nitric acid solution to form feed solution C, with a nitric acid dosage of 1.2 equivalents. Feed solution C is thoroughly mixed with concentrated sulfuric acid in a U-shaped mixer and then enters an X-shaped microreactor to generate 2-methyl-5-nitroimidazole. The reaction solution is then subjected to a negative pressure tank to remove unreacted nitric acid, yielding a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This solution is reused to replace the concentrated sulfuric acid in the 2-methylimidazole reaction solution for a second mixing, generating a higher concentration of 2-methyl-5-nitroimidazole sulfuric acid solution. This allows one batch of sulfuric acid to participate in two batches of 2-methylimidazole nitration reactions, reducing sulfuric acid consumption. Feed solution D is mixed with formic acid and then with 1.1 equivalents of ethylene oxide supplied quantitatively by an ethylene oxide delivery system. A ring-opening reaction occurs in the X-shaped microreactor to produce the final product, metronidazole. The metronidazole reaction solution enters a spiral channel equipped with zigzag baffles, where nitrogen purging and preheating of the reaction solution remove formic acid, which is then condensed and recycled. The remaining reaction solution was adjusted to pH 2-4, filtered to obtain 2-methyl-5-nitroimidazole for recycling, and the pH was further adjusted to 9-12. Crude metronidazole was obtained through decolorization, recrystallization, filtration, and drying to obtain pure metronidazole with a purity greater than 99.9%. The amount of sulfuric acid used was reduced by 45% compared to a single-pass application, the formic acid recovery rate was 98%, the single-pass metronidazole yield was 82%, and the yield of 2-methyl-5-nitroimidazole reached 95% after recycling.

[0026] It should be noted that although the above embodiments have been described herein, this does not limit the scope of patent protection of the present invention. Therefore, any changes and modifications made to the embodiments described herein based on the innovative concept of the present invention, or equivalent structural or procedural transformations made using the content of the present invention's specification and drawings, directly or indirectly applying the above technical solutions to other related technical fields, are all included within the scope of protection of the claims of the present invention.

Claims

1. A fully continuous chemical synthesis method for metronidazole, characterized in that, The fully continuous system, consisting of multiple sequentially connected micromixers, microreactors, online solvent switching and reagent recovery systems, and low-boiling-point reagent feeding devices, comprises the following steps: (a) Using glyoxal aqueous solution and acetaldehyde aqueous solution as raw materials, they are mixed as feed solution A, and ammonia water is used as feed solution B. Feed solution A and feed solution B are first fully mixed in the first mixer and then enter the first microreactor to generate a reaction solution containing 2-methylimidazole. The unreacted aldehyde, ammonia and solvent water are quickly removed in the first solvent switching system. The product 2-methylimidazole is mixed with nitric acid solution as feed solution C. (b) The feed solution C is thoroughly mixed with concentrated sulfuric acid in the second mixer and then enters the second microreactor to generate 2-methyl-5-nitroimidazole. The reaction solution removes unreacted nitric acid in a negative pressure tank to obtain a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This sulfuric acid solution is split, with part of it being fed into the next reaction as feed solution D, and the other part being mixed with the reaction solution of 2-methylimidazole instead of concentrated sulfuric acid to generate a higher concentration of 2-methyl-5-nitroimidazole sulfuric acid solution, thereby increasing the concentration of 2-methyl-5-nitroimidazole in feed solution D and reducing the amount of sulfuric acid consumed. (c) The feed solution D is mixed with formic acid, and then mixed with ethylene oxide quantitatively output from the ethylene oxide delivery system. The ring-opening reaction occurs in the microreactor to obtain the final product metronidazole solution. The metronidazole reaction solution enters the solvent switching system to remove formic acid and recover the reused formic acid. The remaining reaction solution enters the purification process. (d) Purification of the reaction solution: The pH of the above reaction solution for removing formic acid was adjusted to 2-6 in the multifunctional stirred tank of the solvent switching system. After filtration, 2-methyl-5-nitroimidazole was recovered and reused. The pH was further adjusted to 8-14, and crude metronidazole was obtained by filtration. After decolorization, recrystallization, filtration and drying, pure metronidazole with a purity greater than 99.9% was obtained.

2. The fully continuous chemical synthesis method for metronidazole according to claim 1, characterized in that, The mixer described in steps (a) and (b) adopts a plate-type U-shaped channel structure; the channel width is 100μm-20mm, the length is 1m-2000m, and the applicable throughput is 1 mL / min-3000 mL / min.

3. The fully continuous chemical synthesis method for metronidazole according to claim 1, characterized in that, The microreactors described in steps (a), (b), and (c) are plate-type X-shaped channel structures with fluid channel dimensions of 100μm-20mm, or tubular baffle-filled channel structures with fluid channel dimensions of 300μm-50mm.

4. The fully continuous chemical synthesis method for metronidazole according to claim 1, characterized in that, The solvent switching system described in steps (a) and (c) has two schemes: Option 1 is a multi-functional stirred tank connected to a vacuum system, a cooling system, and a heating circulation system. The cooling system is a serpentine condenser, the vacuum system is a vacuum pump, and the heating circulation system is a high-low temperature integrated machine or a circulating heating oil bath, connected by pipes with flanges at the connection points. The multi-functional stirred tank adopts a jacketed heat exchange structure, with the heat exchange fluid entering from the bottom and exiting from the top. A serpentine baffle is installed in the heat exchange channel to ensure uniform heat exchange and eliminate heat exchange dead zones. A material inlet is provided at the top of the multi-functional stirred tank. The reaction solution containing 2-methylimidazole in step (a) and metronidazole in step (c) enter the multi-functional stirred tank through this material inlet, with the lower end of the inlet extending to the lower 1 / 4 height of the tank body. An outlet is provided at the top of the tank body, which is connected to the bottom of the serpentine condenser via a pipe. Another outlet is also provided at the bottom of the serpentine condenser, which is connected via a pipe. A storage tank is used to collect the condensed and recovered liquid. The serpentine condenser has a bottom-in, top-out cooling fluid inlet and an upper-outlet cooling fluid outlet. Additionally, the top of the serpentine condenser is connected to a vacuum regulating valve and a vacuum pump via pipelines. The vacuum pump provides the negative pressure source. The vacuum regulating valve adjusts the negative pressure in the multi-functional stirred tank and condenser, controlling the vaporization rate of low-boiling-point compounds and preventing incomplete condensation of the vaporized substances at the condenser. A high-low temperature integrated unit or a circulating heating oil bath is connected to the multi-functional stirred tank via pipelines, with flanges at the connection points. Hot fluid is pumped in through a circulating pump. After removing low-boiling-point substances, nitric acid is added, meaning the solvent is switched to nitric acid solution after removing low-boiling-point compounds from the reaction liquid. To achieve continuous, uninterrupted operation, two sets of multi-functional stirred tanks are used in parallel and alternately to achieve continuous preparation of feed liquid C and continuous application of the subsequent nitration reaction. Option 2 involves using a vertical channel filled with zigzag baffles equipped with nitrogen purging capabilities to concentrate the reaction liquid containing 2-methylimidazole flowing out of the microreactor within this channel. This vertical channel has six sets of zigzag baffles, a heat exchange jacket outside the channel, a nitrogen inlet at the bottom, and a nitrogen outlet at the top, facilitating the removal of low-boiling-point compounds by nitrogen. The zigzag baffles increase the liquid dispersion area and accelerate the vaporization rate of low-boiling-point compounds. A heat exchange jacket on the outer wall of the vertical channel ensures the temperature of the liquid within the channel and prevents condensation of the vaporized low-boiling-point compounds. To further improve the removal efficiency of low-boiling-point compounds, the liquid to be concentrated... The material is preheated before entering the vertical channel, and inert nitrogen gas is used to purge and quickly remove volatiles, accelerating evaporation efficiency. The material inlet is located at the top of the vertical channel, extending 1 / 10 of its length, while the nitrogen inlet is at the bottom. Nitrogen and liquid are in full contact on the baffle plate to accelerate the vaporization of low-boiling-point compounds, which are then quickly carried out of the vertical channel with the flow of nitrogen. This not only prevents the reliquefaction of low-boiling-point compounds but also achieves rapid evaporation below their boiling point temperature, making it suitable for solvent switching of temperature-sensitive unstable compounds in the reaction solution. The nitrogen outlet is located at the top of the vertical channel and is connected to the same serpentine condenser in the multi-functional stirred tank to recover low-boiling-point compounds.

5. The fully continuous chemical synthesis method for metronidazole according to claim 1, characterized in that, The diverter mentioned in step (b) is an adjustable liquid flow controller connected to the valve. Its operation is as follows: the 2-methyl-5-nitroimidazole sulfuric acid solution obtained from the first reaction in the microreactor is distilled to recover unreacted nitric acid, which is then used as a substitute for concentrated sulfuric acid in the nitration reaction. It is then mixed with a new feed solution C and enters the microreactor to undergo a nitration reaction, resulting in a second 2-methyl-5-nitroimidazole sulfuric acid solution. This sulfuric acid solution is used as feed solution D and enters the next reaction by opening the diverter. Alternatively, the second 2-methyl-5-nitroimidazole sulfuric acid solution can be mixed with a new feed solution C and enter the microreactor to undergo a nitration reaction, resulting in a third 2-methyl-5-nitroimidazole sulfuric acid solution, until a saturated sulfuric acid solution of 2-methyl-5-nitroimidazole is reached. Then, it enters the next reaction through the diverter, thereby saving the consumption of concentrated sulfuric acid in the nitration reaction and realizing the multiple reuse of one part of sulfuric acid for the nitration of multiple parts of 2-methylimidazole.

6. The fully continuous chemical synthesis method of metronidazole according to claim 1, characterized in that, The ethylene oxide delivery system described in step (c) is specifically a buffer tank. The inlet pipe for the ethylene oxide in the buffer tank is located at 1 / 2 of the tank body, and the outlet pipe extends from the bottom into 1 / 5-1 / 4 of the tank body. After the buffer tank is filled, nitrogen gas is used to pressurize it to 5-10 bar to prevent the ethylene oxide from vaporizing at room temperature, which would cause instability in the feed. Then, an injection pump is used to draw ethylene oxide in a metered manner and deliver it to a mixer to mix with a 2-methyl-5-nitroimidazole sulfuric acid / formic acid solution to prepare the target product metronidazole.

7. The fully continuous chemical synthesis method for metronidazole according to claim 1, characterized in that, The specific operation procedure for purifying the reaction solution in step (d) is as follows: After recovering formic acid, the reaction solution of metronidazole (6) is monitored by an online pH meter. Ammonia or liquid ammonia is added to adjust the pH value. The reaction solution is pumped to an online filter using a plunger pump. The filtrate is returned to the pH adjustment vessel until the pH is stable at 2-5. The metronidazole solution with a pH of 2-6 described in step (c) is added to a second pH adjustment vessel to adjust the pH value. The reaction solution is then pumped to an online filter using a plunger pump. The filtrate is returned to the pH adjustment vessel until the pH stabilizes at 8-12. The filter cake from the online filter is continuously scraped off using a rotary scraper. After decolorization and recrystallization, refined metronidazole with a purity greater than 99.9% is obtained.

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