Apparatus and method for the complete continuous chemical synthesis of metronidazole

Abstract

To provide a full continuous chemical synthesis apparatus and method for metronidazole, which have high production efficiency, excellent product quality and less emission of three wastes (waste water, waste gas and solid waste generated in industrial production).SOLUTION: Using a full continuous apparatus comprising multiple improved micromixers, microreactors, on-line solvent switching systems, reagent recovery equipment, low-boiling-point reagent supply equipment, and other equipment communicated in sequence, a high-purity metronidazole product is synthesized from a starting material 2-methylimidazole through a three-step chemical reaction and continuous operation, and recovery and reuse of a sulfuric acid and a formic acid are realized, and the problem of accurate and continuous feeding of ethylene oxide is solved. The crude metronidazole is subjected to decoloring, recrystallization, filtration and drying to obtain pure metronidazole with purity of greater than 99.9%. The sulfuric acid consumption can be reduced by 80% or more, thereby efficiently reducing the production of a waste acid and a waste salt and reducing the production cost.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically to a complete continuous chemical synthesis apparatus and method for metronidazole.

Background Art

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

[0003] Currently, metronidazole production typically uses a batch-type kettle reaction process, which has problems such as long reaction times, high energy consumption, low conversion rate of the main raw material 2-methyl-5-nitroimidazole, severe ethylene oxide side reactions, and the generation of large amounts of waste acid and waste salt. Patent CN110669011A discloses a novel microtube reactor for synthesizing metronidazole active pharmaceutical ingredient. In this method, 2-methyl-5-nitroimidazole is used as a raw material, mixed in a mixed segment of a commercially available coil reactor filled with fillers, and then introduced into a coil reactor with an inner diameter of 4-20 mm to carry out the hydroxyethylation reaction. This avoids the volatilization of low-boiling point ethylene oxide and improves the efficiency of ethylene oxide utilization. However, because ethylene oxide needs to be cooled to a low-temperature liquid beforehand, energy consumption increases, and due to the low boiling point of ethylene oxide, the vapor pressure of ethylene oxide changes significantly under different room temperature conditions, reducing the accuracy of the metering pump and affecting the conversion rate and selectivity of the reaction. Patent CN111574459A discloses a method for producing metronidazole. Similarly, it uses 2-methyl-5-nitroimidazole as a raw material and improves the utilization rate of ethylene oxide and reduces ethylene oxide volatilization by adding ethylene oxide in multiple stages in a multi-batch process. However, this is carried out in a kettle-type reactor, and the multi-stage ethylene oxide addition takes a long time, the operation is complex, and the production efficiency is low. [Overview of the Initiative]

[0004] In response to the problems of the prior art, the object of the present invention is to provide a fully continuous chemical synthesis apparatus and method for metronidazole that has high production efficiency, good product quality, and low emissions of the three types of waste (waste liquid, waste gas, and solid waste generated in industrial production).

[0005] In the fully continuous chemical synthesis method for metronidazole provided by the present invention, 2-methylimidazole is used as a starting material, and a micromixer, microreactor, a proprietary solvent exchange system, and a proprietary ethylene oxide transport system are used to synthesize metronidazole through a three-step chemical reaction and continuous operation to obtain a high-purity metronidazole product. At the same time, sulfuric acid and formic acid are recovered and reused, the problem of accurate and continuous supply of ethylene oxide is solved, the emission of three types of waste is significantly reduced, production efficiency and the accuracy of process control are greatly improved through continuous synthesis, and the stability of product quality is guaranteed.

[0006] The present invention provides a fully continuous chemical synthesis method for metronidazole, which utilizes a fully continuous apparatus comprising a plurality of sequentially interconnected micromixers, a microreactor, and equipment for online solvent exchange and reagent recovery, low-boiling point reagent supply, etc. The specific steps are as follows: (a) A mixture of an aqueous glyoxal solution and an aqueous acetaldehyde solution is prepared as raw material solution A, and aqueous ammonia is prepared as raw material solution B. Raw material solution A and raw material solution B are thoroughly mixed in the first mixer and then introduced into the first microreactor to produce a reaction solution containing 2-methylimidazole. The reaction solution enters the first solvent exchange system, where unreacted aldehyde, ammonia, and the solvent water are rapidly removed, and the product 2-methylimidazole is mixed with a nitric acid solution to produce raw material solution C. (b) The starting material C and concentrated sulfuric acid are thoroughly mixed in the second mixer, then introduced into the second microreactor to produce 2-methyl-5-nitroimidazole. The reaction solution enters a negative pressure tank, where unreacted nitric acid is removed to obtain a sulfuric acid solution of the product, 2-methyl-5-nitroimidazole. A portion of this solution is separated by a flow divider and added to the next reaction as starting material D. The remaining portion is reused and mixed in place of the reaction solution of concentrated sulfuric acid and 2-methylimidazole (4). The reaction produces a higher concentration 2-methyl-5-nitroimidazole sulfuric acid solution. This increases the concentration of 2-methyl-5-nitroimidazole in starting material D and significantly reduces the amount of sulfuric acid consumed. (c) The raw material liquid D and formic acid are mixed, then mixed with ethylene oxide quantitatively transported from our own ethylene oxide transport system, a ring-opening reaction occurs in the microreactor to produce the final product, metronidazole solution, the metronidazole reaction solution enters our own designed solvent exchange system, where formic acid is removed and recovered for reuse, and the remaining reaction solution enters the purification process, (d) Reaction solution purification: The reaction solution from which formic acid has been removed is adjusted to pH 2-6 in a multi-functional stirring vessel in a solvent exchange system, filtered to obtain 2-methyl-5-nitroimidazole, recovered and reused, and subsequently adjusted to pH 8-14, filtered to obtain crude metronidazole, and decolorized, recrystallized, filtered, and dried to obtain a metronidazole product with a purity of more than 99.9%. That is the case.

[0007] Preferably, the mixer in steps (a) and (b) is specially designed in the present invention, and its structure is, specifically, a plate-type circular channel structure as shown in Figure 4, with a channel width of 100 μm to 20 mm, a length of 1 to 2000 m, and an applicable flow rate of 1 mL to 3000 mL / min.

[0008] Preferably, the microreactor in steps (a), (b), and (c) is a plate-type X-shaped passage structure with a fluid passage size of 100 μm-20 mm, or a tubular curved plate-filled passage structure with a fluid passage size of 300 μm-50 mm (see Figure 5).

[0009] Preferably, the solvent exchange system in steps (a) and (c) is specially designed for the present invention and includes two embodiments. Embodiment 1: The structure, as shown in Figure 2, is specifically a multi-functional stirring kettle connected to a vacuum system, a cooling system, and a heating circulation system. The cooling system is a Diemroth condenser, the vacuum system is a vacuum pump, and the heating circulation system is a high / low temperature combination or a circulating heated oil bath, all connected via piping with flanges at the connection points. The multi-functional stirring kettle uses a jacketed heat exchange structure as its body, with the heat exchange fluid introduced from below and discharged from above, and a meandering spoilage within the heat exchange passage. A vent is provided, thereby ensuring uniform heat exchange and avoiding a heat exchange dead zone. A material inlet is provided at the top of the multi-functional stirring vessel. In step (a), the reaction solution containing 2-methylimidazole enters the multi-functional stirring vessel through this material inlet, and in step (c), the reaction solution containing metronidazole enters through this material inlet. The lower end of the inlet extends to a quarter of the height from the bottom of the vessel. An outlet is provided at the top of the vessel, and this outlet is connected to the bottom of the Diemroth condenser via a pipe. Another outlet is provided at the bottom of the Diemroth condenser. Another outlet is connected to a reservoir tank for collecting the condensed liquid via a pipeline. In the meandering pipeline within the Diemroth condenser, the cold fluid is introduced from below and discharged from above; that is, a cold fluid inlet is provided at the bottom and a cold fluid outlet at the top. The top of the Diemroth condenser is connected via a pipeline to a vacuum adjustment valve and a vacuum pump. The vacuum pump provides a negative pressure source, and the vacuum adjustment valve adjusts the negative pressure in the multi-function stirring vessel and condenser, controlling the vaporization rate of low-boiling point compounds and ensuring that vaporized material is completely contained within the condenser. To prevent condensation from failing, a high / low temperature combined machine or a circulating heated oil bath is used, connected to a multi-functional stirring kettle via a pipeline, with flanges used as connection points. The heat flow is introduced by a circulation pump, and after removing low-boiling-point substances, nitric acid is added. That is, after removing low-boiling-point compounds such as water from the reaction solution, the solvent is replaced with a nitric acid solution. To achieve uninterrupted continuous operation, two sets of multi-functional stirring kettle are connected in parallel and used alternately, thereby achieving continuous preparation of the starting material solution C and continuous application of the next nitration reaction. Embodiment 2: A vertical passage filled with U-shaped spoilers having a nitrogen purging function is used (see Figure 3) to concentrate the reaction solution containing 2-methylimidazole that has flowed out of the microreactor within this passage. This vertical passage has six sets of U-shaped spoilers, a heat exchange jacket is provided on the outside of the vertical passage, a nitrogen gas inlet is provided at the bottom, and a nitrogen gas outlet is provided at the top, which facilitates the nitrogen gas to carry the low-boiling point compounds and discharge them from the vertical passage. The U-shaped spoilers are used to increase the dispersion area of ​​the liquid and improve the vaporization rate of the low-boiling point compounds. A heat exchange jacket is provided on the outer wall of the vertical passage, which ensures the temperature of the liquid in the passage and prevents recondensation after the low-boiling point compounds have vaporized, thereby improving the removal efficiency of the low-boiling point compounds. To achieve this, the liquid to be concentrated is preheated before being introduced into the vertical passage, and at the same time, it is purged with an inert gas such as nitrogen to quickly remove volatiles and improve evaporation efficiency. The material inlet is located 1 / 10 of the way in from the top of the vertical passage, and the nitrogen gas inlet is at the bottom of the vertical passage. The nitrogen gas and liquid are in sufficient contact on the spoiler, which greatly accelerates the vaporization of low-boiling point compounds. As the nitrogen gas flows, the low-boiling point compounds are quickly discharged from the vertical passage, preventing reliquefaction of the low-boiling point compounds. Rapid evaporation below the boiling point temperature of the low-boiling point compounds is achieved, which is applicable to solvent exchange of temperature-sensitive and unstable compounds in the reaction solution. The nitrogen gas outlet is located at the top of the vertical passage and is further connected to a similar Liebig condenser in a multi-functional stirring vessel to recover the low-boiling point compounds.

[0010] Preferably, the splitter in step (b) is an adjustable liquid flow controller connected to a valve, which is operated as follows: the 2-methyl-5-nitroimidazole sulfuric acid solution obtained by the first reaction in the microreactor is distilled to recover unreacted nitric acid, which is then mixed with new starting material C instead of concentrated sulfuric acid for the nitration reaction, and introduced into the microreactor to carry out the nitration reaction to obtain a second 2-methyl-5-nitroimidazole sulfuric acid solution, and this sulfuric acid solution is used as starting material D, and the splitter is opened for the next reaction. Alternatively, the second 2-methyl-5-nitroimidazole sulfuric acid solution may be added immediately, or it may be mixed with fresh starting liquid C and then introduced into the microreactor for nitration to obtain a third 2-methyl-5-nitroimidazole sulfuric acid solution. Once this becomes a saturated sulfuric acid solution of 2-methyl-5-nitroimidazole, it can be added to the next reaction via a flow divider. This saves on the amount of concentrated sulfuric acid consumed in the nitration reaction, and enables the nitration of multiple batches of 2-methylimidazole using one batch of sulfuric acid multiple times.

[0011] Preferably, the ethylene oxide transport system in step (c) is specially designed in the present invention and its specific structure includes a proprietary buffer tank, in which the ethylene oxide pipeline inlet is located at the 1 / 2 position of the tank, and the outlet pipeline extends from the bottom to the 1 / 5-1 / 4 position of the tank, and after the buffer tank is filled, it is pressurized with nitrogen gas to 5-10 bar, thereby preventing the low stability of material supply due to the vaporization of ethylene oxide at room temperature, and further, the ethylene oxide is drawn up with a syringe pump and quantitatively transported into one mixer (i.e., the ethylene oxide from the buffer tank is directly transported to the next mixer by pump) and mixed with a 2-methyl-5-nitroimidazole sulfate / formic acid solution to prepare the target product, metronidazole.

[0012] Preferably, the specific operational process for purifying the reaction solution in step (d) is: After recovering the formic acid, the pH of the reaction with metronidazole (6) is monitored using an online pH meter, and the pH is adjusted by adding aqueous ammonia or liquid ammonia. The reaction mixture is then transported to an online filter using a plunger pump, and the filtrate is returned to the pH adjustment kettle until the pH stabilizes at 2-6. In step (d), the metronidazole solution has a pH of 2-6. Ammonia water or liquid ammonia is added to a second pH adjustment vessel to adjust the pH. The reaction mixture is then transported to an online filter using a plunger pump. The filtrate is returned to the pH adjustment vessel until the pH stabilizes at 8-14. Crude metronidazole is continuously scraped off the filter cake of the online filter using a rotary blade. Decolorization and recrystallization yield refined metronidazole with a purity higher than 99.9%. That is the case.

[0013] This invention enables efficient synthesis of metronidazole using microreactor technology by rationally combining a micromixer and a microreactor based on the characteristics of the metronidazole synthesis process. Furthermore, a proprietary solvent exchange system enables continuous synthesis of metronidazole, significantly improving production efficiency and allowing for the recovery and reuse of excess nitric acid and formic acid. In addition, the rational use of flow dividers enables multiple reuses of sulfuric acid, thereby reducing sulfuric acid usage by more than 80%, effectively reducing the production of waste acids and waste salts, and lowering production costs. A proprietary ethylene oxide transport system enables stable and accurate transport of ethylene oxide to the pressurized microchannel reactor. [Brief explanation of the drawing]

[0014] [Figure 1] This is a flowchart of the complete, continuous chemical synthesis method for metronidazole. [Figure 2] This is a schematic diagram of the structure of a multi-functional stirring vessel connected to a vacuum system, a cooling system, and a heating circulation system. [Figure 3]This is a vertical passage containing a U-shaped spoiler that removes low-boiling point compounds by nitrogen purging. [Figure 4] This is a schematic diagram of the structure of a round-shaped micromixer. [Figure 5] This is a schematic diagram of a microreactor structure. Explanation of symbols: a represents a plate-type X-shaped microchannel reactor, and b represents a tubular curved plate-filled microchannel reactor. [Modes for carrying out the invention]

[0015] To explain the technical content, structural features, purpose, and effects of the technical means, further details will be provided below with reference to the drawings and specific embodiments. The following embodiments are based on the technical means of the present invention, and detailed embodiments and specific operating procedures have been given, but the scope of protection of the present invention is not limited to the following embodiments.

[0016] To better illustrate the object, technical means, and advantages of the present invention, the present invention will be further described below with reference to specific examples.

[0017] Example 1 A mixture of a glyoxal aqueous solution and an acetaldehyde aqueous solution was prepared in a molar ratio of 1:1 to form starting material solution A, and aqueous ammonia was prepared as starting material solution B, with a total amount of 1.2 equivalents used. Starting material solutions A and B were transported in the above molar ratio into a rotary mixer using a plunger pump and thoroughly mixed. The mixture was then introduced into an X-shaped microreactor to produce a reaction solution containing 2-methylimidazole. The reaction solution was then placed in a multi-functional stirring vessel connected to a vacuum system, a cooling system, and a heating circulation system. Under reduced pressure, unreacted methylidehyde, ammonia, and the solvent water were removed. The resulting product, 2-methylimidazole, was mixed with a 70% nitric acid solution to form starting material solution C, with a total amount of 1.2 equivalents of nitric acid used. After thoroughly mixing starting material C and concentrated sulfuric acid in a rotary mixer, the mixture was introduced into an X-shaped microreactor to produce 2-methyl-5-nitroimidazole. Unreacted nitric acid was 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 was reused and subjected to a second mixing instead of the reaction solution of concentrated sulfuric acid and 2-methylimidazole to produce a higher concentration 2-methyl-5-nitroimidazole sulfuric acid solution. A third mixing was then performed instead of the reaction solution of concentrated sulfuric acid and 2-methylimidazole to produce a higher concentration 2-methyl-5-nitroimidazole sulfuric acid solution, thereby obtaining starting material D. As a result, one batch of sulfuric acid was involved in the nitration reaction of three batches of 2-methylimidazole, thus reducing the amount of sulfuric acid consumed. After mixing the starting material solution D with formic acid, the mixture was further combined with 1.1 equivalents of ethylene oxide quantitatively transported from an ethylene oxide transport system. A ring-opening reaction was then carried out in an X-shaped microreactor to obtain the final product, metronidazole. The metronidazole reaction solution entered a spiral passage equipped with a U-shaped spoiler, where the formic acid was removed, followed by condensation, recovery, and reuse. The remaining reaction solution was adjusted to pH 2-4, filtered to obtain 2-methyl-5-nitroimidazole, which was then recovered and reused. Subsequently, the pH was adjusted to 9-12, filtered to obtain crude metronidazole, and then decolorized, recrystallized, filtered, and dried to obtain purified metronidazole. The purity was higher than 99.9%.The amount of sulfuric acid used was reduced by 65% ​​compared to single-pass use, the formic acid recovery rate was 95%, the single-pass yield of metronidazole was 80%, and the yield after reusing 2-methyl-5-nitroimidazole (5) reached 96%.

[0018] Example 2 A mixture of a glyoxal aqueous solution and an acetaldehyde aqueous solution in a molar ratio of 1:1 was prepared as raw material solution A, and aqueous ammonia was prepared as raw material solution B, with a total amount of 1.2 equivalents used. Raw material solutions A and B were transported in the above molar ratio into a rotary mixer by a plunger pump and thoroughly mixed. The mixture was then introduced into an X-shaped microreactor to produce a reaction solution containing 2-methylimidazole. The reaction solution containing 2-methylimidazole that flowed out of the microreactor under negative pressure in a vertical passage equipped with a U-shaped spoiler was concentrated to remove low-boiling point compounds and the solvent, water. The resulting product, 2-methylimidazole, was mixed with a 70% nitric acid solution to prepare raw material solution C, with a total amount of 1.2 equivalents of nitric acid used. After thoroughly mixing starting material C and concentrated sulfuric acid in a rotary mixer, the mixture was introduced into an X-shaped microreactor to produce 2-methyl-5-nitroimidazole. Unreacted nitric acid was removed from the reaction mixture in a negative-pressure tank to obtain a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This solution was reused and subjected to a second mixing instead of the reaction mixture of concentrated sulfuric acid and 2-methylimidazole to produce a higher concentration sulfuric acid solution of 2-methyl-5-nitroimidazole. This reduced the consumption of sulfuric acid, as one batch of sulfuric acid was involved in the nitration reaction of two batches of 2-methylimidazole. After mixing starting material D and formic acid, the mixture was further mixed with 1.1 equivalents of ethylene oxide quantitatively transported from an ethylene oxide transport system, and a ring-opening reaction occurred in the X-shaped microreactor to obtain the final product, metronidazole. The metronidazole reaction mixture entered a spiral passage equipped with a U-shaped spoiler, where the formic acid was removed, condensed, recovered, and reused. The remaining reaction solution was adjusted to pH 2-4, filtered to obtain 2-methyl-5-nitroimidazole, which was then recovered and reused. The pH was then adjusted to 9-12, filtered to obtain crude metronidazole, which was then decolorized, recrystallized, filtered, and dried to obtain purified metronidazole. The purity was higher than 99.9%. The amount of sulfuric acid used was reduced by 45% compared to the single-pass use, the formic acid recovery rate was 95%, the single-pass yield of metronidazole was 75%, and the yield after reusing 2-methyl-5-nitroimidazole reached 93%.

[0019] Example 3 A mixture of a glyoxal aqueous solution and an acetaldehyde aqueous solution in a molar ratio of 1:1 was prepared as raw material solution A, and aqueous ammonia was prepared as raw material solution B, with a total amount of 1.2 equivalents used. Raw material solutions A and B were transported in the above molar ratio into a rotary mixer by a plunger pump and thoroughly mixed. After that, the mixture was introduced into an X-shaped microreactor to produce a reaction solution containing 2-methylimidazole. The reaction solution containing 2-methylimidazole that flowed out of the microreactor was concentrated in a vertical passage equipped with a U-shaped spoiler under nitrogen purging and heating conditions to remove low-boiling point compounds and the solvent, water. The resulting product, 2-methylimidazole, was mixed with a 70% nitric acid solution to prepare raw material solution C, with a total amount of 1.2 equivalents of nitric acid used. After thoroughly mixing starting material C and concentrated sulfuric acid in a rotary mixer, the mixture was introduced into an X-shaped microreactor to produce 2-methyl-5-nitroimidazole. Unreacted nitric acid was removed from the reaction mixture in a negative-pressure tank to obtain a sulfuric acid solution of the product 2-methyl-5-nitroimidazole. This solution was reused and subjected to a second mixing instead of the reaction mixture of concentrated sulfuric acid and 2-methylimidazole to produce a more concentrated sulfuric acid solution of 2-methyl-5-nitroimidazole. This reduced the consumption of sulfuric acid, as one batch of sulfuric acid was involved in the nitration reaction of two batches of 2-methylimidazole. After mixing starting material D and formic acid, the mixture was further mixed with 1.1 equivalents of ethylene oxide quantitatively transported from an ethylene oxide transport system, and a ring-opening reaction occurred in the X-shaped microreactor to obtain the final product, metronidazole. The metronidazole reaction solution entered a spiral passage equipped with a U-shaped spoiler. Formic acid was removed by nitrogen purging and preheating of the reaction solution, after which it was condensed, recovered, and reused. The remaining reaction solution was adjusted to pH 2-4, filtered to obtain 2-methyl-5-nitroimidazole, which was recovered and reused. Subsequently, the pH was adjusted to 9-12, filtered to obtain crude metronidazole, and then decolorized, recrystallized, filtered, and dried to obtain purified metronidazole. The purity was higher than 99.9%.The usage amount of sulfuric acid was reduced by 45% compared to the single-pass usage consumption amount, the recovery rate of formic acid was 98%, the single-pass yield of metronidazole was 82%, and the yield after reusing 2-methyl-5-nitroimidazole reached 95%.

[0020] In addition, although each of the above examples has been described in this specification, these examples do not limit the protection scope of the present invention. Therefore, changes and modifications made to the examples in this specification based on the idea of the present invention, or equivalent structural or equivalent process changes made according to the specification and drawings of the present invention, or the direct or indirect application of the above technical means to other related technologies are all included within the scope of the claims of the present invention.

Claims

1. A fully continuous chemical synthesis method for metronidazole using a fully continuous apparatus comprising a series of interconnected micromixers, a microreactor, a solvent exchange system, and equipment for reagent recovery and low-boiling point reagent supply, wherein the specific steps are: (a) A mixture of an aqueous glyoxal solution and an aqueous acetaldehyde solution is used as raw material solution A, and aqueous ammonia is used as raw material solution B. Raw material solution A and raw material solution B are thoroughly mixed in the first mixer and then introduced into the first microreactor to produce a reaction solution containing 2-methylimidazole. The reaction solution enters the first solvent exchange system, where unreacted aldehyde, ammonia, and the solvent water are rapidly removed, and the product 2-methylimidazole is mixed with a nitric acid solution to produce raw material solution C. (b) The raw material solution C and concentrated sulfuric acid are thoroughly mixed in the second mixer, then introduced into the second microreactor to produce 2-methyl-5-nitroimidazole. The reaction solution enters a negative pressure tank where unreacted nitric acid is removed to obtain a sulfuric acid solution of the product, 2-methyl-5-nitroimidazole. A portion of this solution is separated by a flow divider and added to the next reaction as raw material solution D. The remaining portion is reused and mixed in place of the reaction solution of concentrated sulfuric acid and 2-methylimidazole to produce a higher concentration 2-methyl-5-nitroimidazole sulfuric acid solution. This increases the concentration of 2-methyl-5-nitroimidazole in raw material solution D and reduces the amount of sulfuric acid consumed. (c) The starting material D and formic acid are mixed, and then mixed with ethylene oxide quantitatively transported from the ethylene oxide transport system. A ring-opening reaction occurs in the microreactor to produce the final product, a metronidazole solution. The metronidazole reaction solution enters the solvent exchange system, where the formic acid is removed, recovered, and reused. The remaining reaction solution then enters the purification process. (d) Reaction solution purification: The reaction solution from which formic acid has been removed is adjusted to pH 2-6 in a multi-functional stirring vessel in a solvent exchange system, filtered to obtain 2-methyl-5-nitroimidazole, which is recovered and reused, and subsequently adjusted to pH 8-14, filtered to obtain crude metronidazole, which is then decolorized, recrystallized, filtered, and dried to obtain a metronidazole product with a purity of more than 99.9%. A method for the complete continuous chemical synthesis of metronidazole, characterized by the following:

2. The method for the complete continuous chemical synthesis of metronidazole according to claim 1, characterized in that the mixer in steps (a) and (b) uses a plate-type circular passage structure, the passage width is 100 μm to 20 mm, the length is 1 to 2000 m, and the applicable flow rate is 1 mL to 3000 mL / min.

3. The method for the complete continuous chemical synthesis of metronidazole according to claim 1, characterized in that the microreactor in steps (a), (b), and (c) is a plate-type X-shaped passage structure with a fluid passage size of 100 μm to 20 mm, or a tubular curved plate-filled passage structure with a fluid passage size of 300 μm to 50 mm.

4. The solvent exchange system in steps (a) and (c) includes the following two embodiments: Embodiment 1: Specifically, a multi-functional stirring kettle connected to a vacuum system, a cooling system, and a heating circulation system, wherein the cooling system is a Diemroth condenser, the vacuum system is a vacuum pump, and the heating circulation system is a high / low temperature combination machine or a circulating heated oil bath, connected via piping, with flanges used at the connection points, the multi-functional stirring kettle using a jacketed heat exchange structure as its body, the heat exchange fluid being introduced from below and discharged from above, and a meandering spoiler provided in the heat exchange passage, This ensures uniform heat exchange and avoids a heat exchange dead zone. A material inlet is provided at the top of the multifunctional stirring vessel, and in step (a), the reaction solution containing 2-methylimidazole enters the multifunctional stirring vessel through this material inlet. The lower end of the inlet extends to a quarter of the height from the bottom of the vessel, and an outlet is provided at the top of the vessel, which is connected to the bottom of the Diemroth condenser via a pipe. Another outlet is provided at the bottom of the Diemroth condenser, and this other outlet is The condensed liquid is collected via a pipeline and connected to a liquid reservoir tank. In the meandering pipeline within the Diemroth condenser, the cold fluid is introduced from below and discharged from above; that is, a cold fluid inlet is provided at the bottom and a cold fluid outlet is provided at the top. The top of the Diemroth condenser is connected via a pipeline to a vacuum adjustment valve and a vacuum pump. The vacuum pump provides a negative pressure source, and the vacuum adjustment valve adjusts the negative pressure in the multi-functional stirring vessel and condenser, controlling the vaporization rate of low-boiling point compounds and ensuring that vaporized material is completely contained within the condenser. To prevent condensation from failing, a high / low temperature combined machine or a circulating heated oil bath is used, connected to a multi-functional stirring vessel via a pipeline, with flanges used as connection points. The heat flow is introduced by a circulation pump, and after removing low-boiling point substances, nitric acid is added. That is, after removing low-boiling point compounds from the reaction solution, the solvent is replaced with a nitric acid solution. To achieve uninterrupted continuous operation, two sets of multi-functional stirring vessels are connected in parallel and used alternately, thereby achieving continuous preparation of the starting material solution C and continuous application of the subsequent nitration reaction. Embodiment 2: A vertical passage filled with U-shaped spoilers having a nitrogen purging function is used to concentrate the reaction solution containing 2-methylimidazole that has flowed out of the microreactor within this passage. This vertical passage has six sets of U-shaped spoilers, a heat exchange jacket is provided on the outside of the vertical passage, a nitrogen gas inlet is provided at the bottom, and a nitrogen gas outlet is provided at the top, which facilitates the nitrogen gas to carry the low-boiling point compounds and discharge them from the vertical passage. The U-shaped spoilers are used to increase the dispersion area of ​​the liquid and improve the vaporization rate of the low-boiling point compounds. A heat exchange jacket is provided on the outer wall of the vertical passage, which ensures that the temperature of the liquid in the passage and the low-boiling point compounds do not recondense after vaporization, thereby improving the removal efficiency of the low-boiling point compounds. To achieve this, the liquid to be concentrated is preheated before being introduced into the vertical passage, and simultaneously purged with nitrogen gas, an inert gas, to quickly remove volatile substances and improve evaporation efficiency. The material inlet is located 1 / 10 of the way in from the top of the vertical passage, and the nitrogen gas inlet is at the bottom of the vertical passage. The nitrogen gas and liquid are in sufficient contact on the spoiler, which accelerates the vaporization of low-boiling point compounds. As the nitrogen gas flows, the liquid is quickly discharged from the vertical passage, preventing reliquefaction of low-boiling point compounds and achieving rapid evaporation below the boiling point of the low-boiling point compounds. This is applicable to solvent exchange of temperature-sensitive and unstable compounds in the reaction solution. The nitrogen gas outlet is located at the top of the vertical passage and is further connected to a similar Liebig condenser in a multi-functional stirring vessel to recover the low-boiling point compounds. A method for the complete continuous chemical synthesis of metronidazole according to claim 1, characterized in that it is a method for the complete continuous chemical synthesis of metronidazole as described in claim 1.

5. The flow divider in step (b) is an adjustable liquid flow controller connected to a valve, and is operated as follows: A method for the complete continuous chemical synthesis of metronidazole according to claim 1, characterized in that the 2-methyl-5-nitroimidazole sulfate solution obtained by the first reaction in a microreactor is distilled to recover unreacted nitric acid, and then, instead of concentrated sulfuric acid for the nitration reaction, is mixed with new starting material solution C and introduced into the microreactor to carry out the nitration reaction, thereby obtaining a second 2-methyl-5-nitroimidazole sulfate solution, which is then used as starting material solution D and introduced into the next reaction by opening the flow divider, or the second 2-methyl-5-nitroimidazole sulfate solution is subsequently mixed with new starting material solution C and introduced into the microreactor to carry out the nitration reaction, thereby obtaining a third 2-methyl-5-nitroimidazole sulfate solution, which, after becoming a saturated sulfuric acid solution of 2-methyl-5-nitroimidazole, is introduced into the next reaction via the flow divider, thereby saving the amount of concentrated sulfuric acid consumed in the nitration reaction and enabling the nitration of multiple batches of 2-methylimidazole using one batch of sulfuric acid multiple times.

6. The method for the complete continuous chemical synthesis of metronidazole according to claim 1, characterized in that the ethylene oxide transport system in step (c) is specifically a buffer tank, in which the ethylene oxide pipeline inlet is located at the 1 / 2 position of the tank, the outlet pipeline extends from the bottom to the 1 / 5-1 / 4 position of the tank, after the buffer tank is filled, it is pressurized with nitrogen gas to 5-10 bar, thereby preventing instability in material supply due to vaporization of ethylene oxide at room temperature, and furthermore, ethylene oxide is drawn up with a syringe pump and quantitatively transported into a mixer and mixed with a 2-methyl-5-nitroimidazole sulfate / formic acid solution to prepare the target product, metronidazole.

7. The specific operational process for purifying the reaction solution in step (d) is as follows: After recovering the formic acid, the pH of the reaction with metronidazole (6) is monitored using an online pH meter, and the pH is adjusted by adding aqueous ammonia or liquid ammonia. The reaction mixture is then transported to an online filter using a plunger pump, and the filtrate is returned to the pH adjustment kettle until the pH stabilizes at 2-5. In step (c), the metronidazole solution has a pH of 2-6. Ammonia water or liquid ammonia is added to a second pH adjustment vessel to adjust the pH. The reaction mixture is then transported to an online filter using a plunger pump. The filtrate is returned to the pH adjustment vessel until the pH stabilizes at 8-12. Crude metronidazole is continuously scraped off the filter cake of the online filter using a rotary blade. Decolorization and recrystallization yield refined metronidazole with a purity higher than 99.9%. A method for the complete continuous chemical synthesis of metronidazole according to claim 1, characterized in that...

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