Device and method for synthesizing metronidazole by simulating critical state atomized flow hydroxylation

Abstract

The invention discloses a device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation. It includes a hydroxylation kettle, a discharge valve, an EO feeding system, a sulfuric acid feeding system and a formic acid feeding system; the sulfuric acid feeding system and the formic acid feeding system are respectively connected to the feed end of the hydroxylation kettle; the discharge valve is located at the lower end of the discharge pipe, and one end of the discharge pipe is connected to the discharge end of the hydroxylation kettle; it also includes an external circulation loop system of the hydroxylation kettle; one end of the external circulation loop system of the hydroxylation kettle is connected to the feed end of the hydroxylation kettle through a process pipeline, and the other end is connected to the discharge end of the hydroxylation kettle through a process pipeline; the EO feeding system is connected to the external circulation loop system of the hydroxylation kettle through a process pipeline. The invention has the advantages of safe and reliable production, reduced EO loss, and improved EO utilization. The invention also discloses a method for synthesizing metronidazole by using the device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation.

Description

Technical Field

[0001] The invention relates to the technical field of preparing metronidazole by chemical synthesis, and more specifically, it is a device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation. The invention also relates to a method for synthesizing metronidazole by using the device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation. Background Art

[0002] Metronidazole has a wide range of uses and has good anti-anaerobic effects. It has been recommended by the World Health Organization (WHO) as the first choice drug against anaerobic bacteria and has been listed as one of my country's basic medicines. Its export growth rate is also relatively fast, resulting in an increasing demand.

[0003] The raw materials used in the preparation of metronidazole hydroxylation synthesis are as follows: formic acid as a catalyst, sulfuric acid as a regulating solvent, 2-methyl-5-nitroimidazole (referred to as nitration) as a precursor compound; ethylene oxide (English abbreviation EO) as a hydroxyethylation reagent (referred to as a hydroxylation agent).

[0004] The chemical reaction formula of metronidazole hydroxylation is as follows:

[0005] C4H5N3O2+C2H4O→C6H9N3O3

[0006] Where: C4H5N3O2 is a nitrate, a white or light yellow crystalline powder, with a slight odor, bitter and slightly salty taste, soluble in water, slightly soluble in ethanol, and is a precursor compound for the preparation of metronidazole;

[0007] C2H4O is ethylene oxide, which is a colorless gas at room temperature and a colorless, easy-flowing liquid at low temperature. It has the smell of ether and is toxic. Its density is 0.8694, its melting point is -111°C, its boiling point is 10.7°C, and it is soluble in water, ethanol, and ether. It has very active chemical properties and can react with many compounds. It is a hydroxylating agent for the preparation of metronidazole.

[0008] C6H9N3O3 is the product metronidazole, a white powder, soluble in hot water and slightly soluble in cold water. It is a widely used chemical synthetic drug, mainly used to kill anaerobic bacteria. It is also one of the basic drugs in my country.

[0009] The current process for the synthesis of metronidazole hydroxylation is as follows: first, a certain amount of sulfuric acid and formic acid are added to the hydroxylation reactor, and then a certain amount of nitrate is added to dissolve in the mixed solution of sulfuric acid and formic acid, the reaction temperature is adjusted, and then EO is slowly introduced to the bottom of the hydroxylation reactor, and EO and the nitrate in the mixed solution of nitrate in the reactor undergo a hydroxylation synthesis reaction, which is a heterogeneous reaction. The mixed solution of nitrate after the nitrate is dissolved in sulfuric acid and formic acid is a liquid phase, and the slowly introduced EO is a gas phase. In this heterogeneous reaction, only a small part of EO (about 1 / 4 of EO) is converted into metronidazole product; most of EO (about 2 / 4 of EO) is converted into by-products; and a small part (about 1 / 4) of EO that has not reacted in time escapes from the liquid surface of the mixed solution of nitrate in the reactor and is lost (in the absence of an EO recovery system).

[0010] The following is a table of main raw material consumption for the production of metronidazole:

[0011] Table 1 Raw material consumption table (unit: kg / ton)

[0012] Raw material name Actual consumption of traditional technology Theoretical consumption 2-Methyl-5-nitroimidazole 980 742.7 Ethylene oxide (EO) 1220～1350 257.3 Formic acid 1130 No product reaction sulfuric acid 1000 No product reaction Neutralization and alkali consumption Liquid caustic soda 5300 No product reaction

[0013] From the above, it can be seen that metronidazole is prepared by the hydroxylation reaction of 2-methyl-5-nitroimidazole (nitrate) with EO under the catalysis of formic acid. The theoretical consumption of EO257.3kg is consumed in the chemical synthesis of metronidazole. Obviously, in the process of metronidazole hydroxylation reaction, for every ton of metronidazole product produced, 962.7 to 1092.7 kg (1220 to 1350-257.3) of EO is wasted; the wasted EO actually becomes "three wastes" (waste gas, waste water and waste residue):

[0014] Among them, the exhaust gas is mainly caused by EO escape;

[0015] Wastewater: Pollutants in metronidazole synthetic wastewater are mainly caused by by-products produced during the hydroxylation synthesis reaction, with EO being the main contributor. The CODcr concentration of wastewater is as high as 130,000 to 200,000 mg / l, and it is biologically toxic (metronidazole directly kills anaerobic bacteria). It is a typical high-concentration organic wastewater that is difficult to treat and is very difficult to treat.

[0016] Waste residue is a high-salt (sulfate and formates alone reach a mass concentration of 13-15%), a high-CODcr high-boiling substance, and has biological toxicity. It is mainly caused by the current process of metronidazole hydroxylation synthesis. At present, incineration is usually used to treat waste residue.

[0017] The existing application number is CN201210443516.4, and the patent name is "Method for preparing metronidazole". It discloses a method for preparing a metronidazole raw material by using mixed acid to provide acidic conditions, suitable reaction raw material ratios, and appropriate control of reaction parameters; however, it adopts the traditional metronidazole production process, and the three wastes (waste gas, waste water, and waste residue) are relatively high; this is also a major problem commonly existing in the metronidazole production industry.

[0018] Therefore, it is urgent to develop a device and method for synthesizing metronidazole by hydroxylation with reduced EO consumption. Summary of the invention

[0019] The first purpose of the invention is to provide a device for simulating critical state atomized flow hydroxylation to synthesize metronidazole, which can produce safely and reliably, reduce EO loss, improve EO utilization, make the best use of materials, and reduce EO consumption.

[0020] The second purpose of the invention is to provide a method for synthesizing metronidazole using the device for synthesizing metronidazole by hydroxylation of simulated critical state atomized flow, which is safe and reliable in production, fundamentally improves the production technology level of metronidazole hydroxylation synthesis, greatly reduces the EO consumption of hydroxylation synthesis of metronidazole, is beneficial to resource conservation, is beneficial to the treatment of three wastes, and is beneficial to environmental protection, and has important practical significance for resource conservation and environmental protection.

[0021] In order to achieve the first purpose of the above invention, the technical scheme of the invention is: a device for simulating critical state atomized flow hydroxylation to synthesize metronidazole, comprising a hydroxylation kettle, a discharge valve, an EO feeding system, a sulfuric acid feeding system and a formic acid feeding system; the sulfuric acid feeding system and the formic acid feeding system are respectively connected to the feed end of the hydroxylation kettle; the discharge valve is located at the lower end of the discharge pipe, and one end of the discharge pipe is connected to the discharge end of the hydroxylation kettle; it is characterized in that: it also includes a hydroxylation kettle external circulation loop system;

[0022] One end of the external circulation loop system of the hydroxylation kettle is connected to the feed end of the hydroxylation kettle through a process pipeline, and the other end is connected to the discharge end of the hydroxylation kettle through a process pipeline;

[0023] The EO feeding system is connected to the external circulation loop system of the hydroxylation kettle through a process pipeline.

[0024] In the above technical solution, the external circulation loop system of the hydroxylation kettle includes a discharge valve at the bottom of the hydroxylation kettle, an external circulation one-way valve and an atomizing flow functional pump;

[0025] The atomizing flow functional pump has one or more;

[0026] The discharge valve at the bottom of the hydroxylation kettle is connected to the discharge end of the hydroxylation kettle;

[0027] The atomizing flow functional pump is connected to the feed end of the hydroxylation kettle through a process pipeline;

[0028] The bottom discharge valve of the hydroxylation kettle, the external circulation one-way valve, and the atomizing flow functional pump are sequentially connected in series through a process pipeline.

[0029] In the above technical solution, the external circulation loop system of the hydroxylation kettle further includes a tubular mixer; the tubular mixer is located between the atomizing flow functional pump and the external circulation one-way valve;

[0030] The bottom discharge valve of the hydroxylation kettle, the external circulation one-way valve, the tubular mixer and the atomizing flow functional pump are connected in series through a process pipeline in sequence;

[0031] The EO feeding system is connected to the tubular mixer through a process pipeline.

[0032] In the above technical solution, a PLC control system is also included; the PLC control system is installed on the top or side of the hydroxylation kettle.

[0033] In the above technical solution, the EO feeding system includes an EO metering tank, an EO flow meter and an EO one-way valve;

[0034] The EO metering tank, the EO flow meter and the EO one-way valve are sequentially connected in series and communicated with the tubular mixer through a process pipeline.

[0035] The sulfuric acid feeding system includes a sulfuric acid metering tank, a sulfuric acid flow meter and a sulfuric acid check valve;

[0036] The sulfuric acid metering tank, the sulfuric acid flow meter and the sulfuric acid one-way valve are sequentially connected in series and then communicated with the feed end of the hydroxylation kettle through a process pipeline;

[0037] The formic acid feeding system includes a formic acid metering tank, a formic acid flow meter, and a formic acid check valve;

[0038] The formic acid metering tank, the formic acid flowmeter, and the formic acid one-way valve are sequentially connected in series and then communicated with the feed end of the hydroxylation kettle through a process pipeline;

[0039] In the above technical solution, the atomizing flow functional pump is an atomizing flow high shear homogenizing pump and / or a high-efficiency gas-liquid mixed flow pump with high-strength functions.

[0040] In the above technical solution, the liquid phase material flow rate of the tubular reactor is greater than 85%.

[0041] In order to achieve the second purpose of the above invention, the technical scheme of the invention is: a method for synthesizing metronidazole using a device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation, characterized in that it comprises the following steps:

[0042] Step 1: Add formic acid into the formic acid metering tank, and add sulfuric acid into the sulfuric acid metering tank;

[0043] Add EO into the EO metering tank;

[0044] Step 2: The device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation is ready for start-up;

[0045] The formic acid feeding system and the sulfuric acid feeding system are controlled by the PLC control system to deliver a fixed amount of formic acid and sulfuric acid to the hydroxylation kettle respectively;

[0046] Step 3: formic acid and sulfuric acid are mixed in a hydroxylation kettle to form a mixed acid; the hydroxylation kettle is heated to raise the temperature of the mixed acid to 65-75° C.;

[0047] Adding the nitrate into the hydroxylation kettle from the nitrate feed port of the hydroxylation kettle;

[0048] The nitrate is dissolved in the mixed acid to form a nitrate mixed solution;

[0049] The external circulation loop system of the hydroxylation kettle is started, and the nitrate mixed solution circulates in the hydroxylation kettle and the external circulation loop system of the hydroxylation kettle;

[0050] Step 4: The EO feeding system is controlled by the PLC control system to continuously feed EO into the tubular mixer;

[0051] EO is mixed with the nitrate mixed solution circulating through the tubular mixer or the nitrate mixed solution after the hydroxylation reaction and then flows into the atomizing flow functional pump, and is converted into an atomizing flow simulating a critical state by the atomizing flow functional pump. The atomizing flow enters the hydroxylation kettle from the feed end for reaction;

[0052] Repeat step 4 until the metered feeding reaction is completed, control the EO feeding system through the PLC control system to stop feeding EO into the tubular mixer, and the hydroxylation kettle external circulation loop system continues to operate for 20 to 30 minutes, and then control the hydroxylation kettle external circulation loop system to stop through the PLC control system;

[0053] Step 5: Open the discharge valve to discharge the material until all the reaction materials in the hydroxylation reactor are discharged, and the device for simulating critical state atomized flow hydroxylation to synthesize metronidazole is stopped.

[0054] In the above technical solution, in step 1 to step 3, the mixed acid is a mixture of formic acid and sulfuric acid; wherein the ratio of formic acid to sulfuric acid is 4 to 2.5:1;

[0055] The formic acid is formic acid with a purity greater than or equal to 95%; and the sulfuric acid is sulfuric acid with a purity of 98%.

[0056] In the above technical solution, in step 4 to step 5, the operating temperature of the tubular mixer is lower than or equal to 90° C.; the pressure is normal pressure;

[0057] In steps 3 to 5, the operating temperature of the atomizing flow functional pump is lower than or equal to 90° C.;

[0058] In step 3 to step 5, the operating temperature of the hydroxylation reactor is lower than or equal to 90° C.; the pressure is normal pressure; and the hydroxylation reaction time is 3 to 4 hours.

[0059] The PLC control system mainly includes temperature control, pressure control, liquid level control, flow control, temperature alarm and pressure alarm; the tubular mixer is an existing product; the atomizing flow functional pump is a new technology and new product recently domestically produced purchased on the market.

[0060] The EO feeding system, sulfuric acid feeding system and formic acid feeding system are all existing systems in the prior art production line.

[0061] The present invention has the following advantages:

[0062] (1) The present invention proposes for the first time to directly simulate the critical state and use atomized flow reaction to synthesize metronidazole by hydroxylation, aiming to innovate the current process, produce safely and reliably, reduce EO loss, improve EO utilization, make the best use of materials, and reduce EO consumption;

[0063] (2) The present invention provides a PLC control system with functions of regulating the flow of EO material and mixed acid, controlling the flow, interlocking temperature control and alarming, and providing an external circulation loop of the hydroxylation kettle, so as to ensure that the introduced EO fully reacts with the nitrate dissolved in the mixed acid of sulfuric acid and formic acid; avoids the loss of the part of EO that escapes from the liquid surface before reacting, improves the utilization rate of EO, saves production costs, and overcomes the problem of waste gas pollution caused by EO escape;

[0064] (3) The present invention adopts a tubular mixer and a special function pump for atomizing flow to mix the reaction materials evenly, greatly increase the collision frequency and rate of EO and nitrate, greatly improve the reaction speed of hydroxylation synthesis, and extremely effectively avoid the occurrence of hydroxylation synthesis side reactions, thereby greatly reducing the consumption of EO, the raw material for metronidazole production, and greatly reducing the CODcr concentration of wastewater, fundamentally reducing the difficulty of treating metronidazole hydroxylation synthesis wastewater, and at the same time, greatly reducing the amount of waste residue generated in metronidazole production; improving the utilization rate of EO, and greatly reducing the problem of wastewater and waste residue pollution caused by the conversion of EO into by-products;

[0065] (4) The present invention fundamentally improves the production technology level of metronidazole hydroxylation synthesis by innovating the current process of metronidazole hydroxylation synthesis from chemical thermodynamic analysis to chemical kinetics research, greatly reduces the EO consumption of metronidazole, is beneficial to resource conservation, is beneficial to the treatment of three wastes, and is beneficial to environmental protection, and has important practical significance for resource conservation and environmental protection.

[0066] The invention simulates critical state atomized flow hydroxylation to synthesize metronidazole, which is an innovation that achieves multiple goals at one stroke. It can reduce the consumption of EO, a raw material for metronidazole production, and is beneficial to both resource conservation and three wastes treatment. Moreover, for the three wastes treatment in metronidazole production, it is both a symptomatic treatment and a fundamental solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 The schematic diagram of the structure of the device for simulating critical state atomized flow hydroxylation to synthesize metronidazole according to the present invention is shown in FIG. Figure 1 .

[0068] Figure 2 The schematic diagram of the structure of the device for simulating critical state atomized flow hydroxylation to synthesize metronidazole according to the present invention is shown in FIG. Figure 2 .

[0069] In the figure, 1-hydroxylation kettle, 2-discharging valve at the bottom of hydroxylation kettle, 3-discharging valve, 4-external circulation one-way valve, 5-sulfuric acid one-way valve, 6-sulfuric acid flowmeter, 7-sulfuric acid metering tank, 8-EO metering tank, 9-EO flowmeter, 10-PLC control system, 11-EO one-way valve, 12-tubular mixer, 13-atomizing flow functional pump, 14-EO feeding system, 15-sulfuric acid feeding system, 16-hydroxylation kettle external circulation loop, 17-formic acid feeding system, 18-formic acid metering tank, 19-formic acid flowmeter, 20-formic acid one-way valve, 21-device for simulating critical state atomizing flow hydroxylation synthesis of metronidazole, and 22-discharging pipe. DETAILED DESCRIPTION

[0070] The following is a detailed description of the implementation of the invention in conjunction with the accompanying drawings, but they do not constitute a limitation of the invention and are only examples. At the same time, the description makes the advantages of the invention clearer and easier to understand.

[0071] Referring to the attached drawings, it can be seen that the device for simulating critical state atomized flow hydroxylation to synthesize metronidazole comprises a hydroxylation kettle 1, a discharge valve 3, an EO feed system 14, a sulfuric acid feed system 15 and a formic acid feed system 17; the sulfuric acid feed system 15 and the formic acid feed system 17 are respectively connected to the feed end of the hydroxylation kettle 1;

[0072] The discharge valve 3 is located at the lower end of the discharge pipe 22; the discharge valve 3 is located below the discharge valve 2 at the bottom of the hydroxylation kettle and below the external circulation loop 16 of the hydroxylation kettle;

[0073] One end of the discharge pipe 22 is connected to the discharge end of the hydroxylation kettle 1, and the discharge valve 3 is used for discharging the metronidazole product of the present application; it is characterized in that: it also includes a hydroxylation kettle external circulation loop system 16;

[0074] One end of the hydroxylation kettle external circulation loop system 16 is connected to the feed end of the hydroxylation kettle 1 through a process pipeline, and the other end is connected to the discharge end of the hydroxylation kettle 1 through a process pipeline;

[0075] The EO feeding system 14 is connected to the hydroxylation kettle external circulation loop system 16 through a process pipeline; wherein the hydroxylation kettle 1 (i.e. the main equipment of the metronidazole hydroxylation synthesis reaction) is used as the central device for the hydroxylation synthesis of metronidazole.

[0076] Furthermore, the hydroxylation kettle external circulation loop system 16 includes a hydroxylation kettle bottom discharge valve 2, an external circulation one-way valve 4 and an atomizing flow functional pump 13;

[0077] There are one or more atomizing flow function pumps 13; the atomizing flow special function pump can greatly increase the collision frequency and rate of EO and nitrate, improve the reaction speed of hydroxylation synthesis, and effectively avoid the occurrence of hydroxylation synthesis side reactions, so that the heterogeneous reaction between the nitrate mixed solution (liquid phase, continuous phase) after the nitrate is dissolved in sulfuric acid and formic acid and the slowly introduced EO (gas phase, dispersed phase) is transformed into a homogeneous reaction of the atomizing flow type simulating the critical state, reducing EO loss, improving the utilization rate of EO, and striving to make the best use of it, thereby greatly reducing the consumption of EO, the raw material for metronidazole production;

[0078] Compared with one atomizing flow functional pump 13, multiple atomizing flow functional pumps 13 connected in series can speed up the reaction speed, further shorten the hydroxylation reaction time, and reduce the consumption of EO.

[0079] The discharge valve 2 at the bottom of the hydroxylation kettle is connected to the discharge end of the hydroxylation kettle 1;

[0080] The external circulation one-way valve 4 is connected to the discharge valve 2 at the bottom of the hydroxylation reactor through a process pipeline;

[0081] The atomizing flow functional pump 13 is connected to the feed end of the hydroxylation kettle 1 through a process pipeline;

[0082] The discharge valve 2 at the bottom of the hydroxylation reactor, the external circulation one-way valve 4 and the atomizing flow functional pump 13 are sequentially connected in series through a process pipeline.

[0083] Furthermore, the hydroxylation kettle external circulation loop system 16 also includes a tubular mixer 12; the tubular mixer 12 is located between the atomizing flow functional pump 13 and the external circulation one-way valve 4;

[0084] The discharge valve 2 at the bottom of the hydroxylation reactor, the external circulation one-way valve 4, the tubular mixer 12 and the atomizing flow functional pump 13 are connected in series through a process pipeline in sequence;

[0085] The EO feeding system 14 is connected to the tubular mixer 12 through a process pipeline to ensure the normal progress of the process of the present invention.

[0086] Furthermore, a PLC control system 10 is included; used to adjust and control the process ratio flow rate of the mixed material and EO in the hydroxylation reactor 1;

[0087] The PLC control system 10 is installed on the top or side of the hydroxylation kettle 1 (i.e., installed in front of the hydroxylation kettle 1), or installed in other suitable locations, such as: installed in the central control room of the metronidazole hydroxylation synthesis center for centralized control; the PLC control system has the functions of regulating the flow of EO, sulfuric acid and formic acid materials and their control, interlocking temperature and pressure control and alarm.

[0088] The EO feeding system 14 includes an EO metering tank 8, an EO flow meter 9 and an EO one-way valve 11;

[0089] The EO metering tank 8, EO flowmeter 9 and EO one-way valve 11 are connected in series in sequence and then communicated with the tubular mixer 12 through a process pipeline; the existing EO feeding system of the original process is utilized and modified and connected to the tubular mixer 12, so as to reasonably utilize resources;

[0090] The sulfuric acid feeding system 15 includes a sulfuric acid metering tank 7, a sulfuric acid flow meter 6 and a sulfuric acid check valve 5;

[0091] The sulfuric acid metering tank 7, the sulfuric acid flowmeter 6 and the sulfuric acid one-way valve 5 are sequentially connected in series and then communicated with the feed end of the hydroxylation kettle 1 through a process pipeline;

[0092] The formic acid feeding system 17 includes a formic acid metering tank 18, a formic acid flow meter 19, and a formic acid one-way valve 20;

[0093] The formic acid metering tank 18, the formic acid flowmeter 19, and the formic acid one-way valve 20 are sequentially connected in series and communicated with the feed end of the hydroxylation kettle 1 through a process pipeline, so as to reasonably utilize resources.

[0094] Furthermore, the atomizing flow functional pump 13 is a high-strength atomizing flow high-shear homogenizing pump and / or a high-efficiency gas-liquid mixed flow pump; the flow rate of the atomizing flow functional pump 13 is less than 1m 3 / h, and the head is about 10mH2O, which is an atomizing flow functional pump with small flow and low pressure level; according to production needs, one or more atomizing flow functional pumps 13 can be set.

[0095] Furthermore, the liquid phase material flow rate of the tubular reactor is greater than 85%, ensuring the smooth flow of the liquid phase material in the tubular reactor and ensuring the smooth repeated flow of the material in the external circulation loop 16 of the hydroxylation reactor.

[0096] Furthermore, the process pipeline, the bottom discharge valve 2 of the hydroxylation kettle, the external circulation one-way valve 4, the tubular mixer 12 and the atomizing flow functional pump 13 in the external circulation loop 16 of the hydroxylation kettle are all made of anti-corrosion materials including stainless steel 316L, titanium, polytetrafluoroethylene, etc.; the anti-corrosion effect of each component of the external circulation loop 16 of the hydroxylation kettle is ensured, and the normal operation of the external circulation loop 16 of the hydroxylation kettle is ensured;

[0097] The process pipeline, EO metering tank 8, EO flowmeter 9 and EO one-way valve 11 in the EO feeding system 14 are all made of anti-corrosion materials including stainless steel 316L, titanium, etc.; ensuring the normal operation of the EO feeding system 14;

[0098] The process pipeline, sulfuric acid metering tank 7, sulfuric acid flowmeter 6 and sulfuric acid check valve 5 in the sulfuric acid feeding system 15 are all made of anti-corrosion materials including stainless steel 316L, titanium, etc.; the anti-corrosion effect of each component of the sulfuric acid feeding system 15 is ensured, and the normal operation of the sulfuric acid feeding system 15 is ensured;

[0099] The process pipeline, formic acid metering tank 18, formic acid flowmeter 19, and formic acid one-way valve 20 in the formic acid feeding system 17 are all made of anti-corrosion materials including stainless steel 316L, titanium, etc., to ensure the anti-corrosion effect of each component of the formic acid feeding system 17 and ensure the normal operation of the formic acid feeding system 17.

[0100] The elbows in the connecting pipelines of the hydroxylation kettle external circulation loop 16, the EO feeding system 14, the sulfuric acid feeding system 15 and the formic acid feeding system 17 are all arc elbows, and the bending radius (R) of the arc elbow matches the pipe diameter of the pipe used; ensuring that the fluid in the pipeline has no dead angle and can flow smoothly.

[0101] Referring to the attached drawings, it can be seen that the method for synthesizing metronidazole using a device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation comprises the following steps:

[0102] Step 1: Add formic acid into the formic acid metering tank 18, and add sulfuric acid into the sulfuric acid metering tank 7;

[0103] Add EO into EO metering tank 8;

[0104] Step 2: The device 21 for synthesizing metronidazole by hydroxylation of atomized flow simulating a critical state is ready to start;

[0105] The formic acid feeding system 17 and the sulfuric acid feeding system 15 are controlled by the PLC control system 10 to deliver a fixed amount of formic acid and sulfuric acid to the hydroxylation reactor 1, respectively;

[0106] Step 3: formic acid and sulfuric acid are mixed in a hydroxylation kettle 1 to form a mixed acid; the hydroxylation kettle 1 is heated to raise the temperature of the mixed acid to 65-75° C., which is conducive to dissolving the nitrate mixed solution;

[0107] Adding the nitrate into the hydroxylation reactor 1 from the nitrate feed port of the hydroxylation reactor 1;

[0108] The nitrate is dissolved in the mixed acid to form a nitrate mixed solution;

[0109] The hydroxylation kettle external circulation loop system 16 is started, and the nitrate mixed solution circulates in the hydroxylation kettle 1 and the hydroxylation kettle external circulation loop system 16;

[0110] Step 4: The EO feeding system 14 is controlled by the PLC control system 10 to continuously feed EO into the tubular mixer 12;

[0111] EO is introduced into the external circulation loop system 16 of the hydroxylation kettle, that is, EO is continuously mixed with the nitrate mixed solution circulating through the tubular mixer 12 or the nitrate mixed solution after the hydroxylation reaction, and then flows into the atomizing flow function pump 13, and is converted into an atomizing flow simulating a critical state by the atomizing flow function pump 13, and the atomizing flow enters the hydroxylation kettle 1 from the feed end to carry out a (hydroxylation) reaction;

[0112] Repeat the operation of introducing EO into the external circulation loop system 16 of the hydroxylation kettle (repeat step 4) until the metering addition of EO by the EO flowmeter 9 is completed, and the EO feeding system is controlled by the PLC control system 10 to stop introducing EO into the tubular mixer 12; the external circulation loop system 16 of the hydroxylation kettle continues to operate for 20 to 30 minutes, and then the external circulation loop system 16 of the hydroxylation kettle is controlled by the PLC control system 10 to stop;

[0113] Step 5: Open the discharge valve 3 to discharge the material until all the reaction materials in the hydroxylation reactor 1 are completely discharged, and the device 21 for simulating critical state atomized flow hydroxylation to synthesize metronidazole is stopped.

[0114] Furthermore, in step 1 to step 3, the mixed acid is a mixture of formic acid and sulfuric acid; wherein the ratio of formic acid to sulfuric acid is 4 to 2.5:1;

[0115] The formic acid is formic acid with a purity greater than or equal to 95%; and the sulfuric acid is sulfuric acid with a purity of 98%.

[0116] Furthermore, in step 4 to step 5, the operating temperature of the tubular mixer 12 is lower than or equal to 90° C.; the pressure is normal pressure;

[0117] In step 3 to step 5, the operating temperature of the atomizing flow functional pump 13 is lower than or equal to 90° C. The atomizing flow functional pump 13 has the functions of high-efficiency shearing, crushing, dispersing, mixing, and homogenizing until atomization is achieved, ensuring that the heterogeneous materials entering the atomizing flow functional pump 13 are converted into homogeneous materials of the atomizing flow type simulating the critical state; providing atomizing reaction conditions for simulating the critical state by using the atomizing flow reaction to carry out hydroxylation synthesis of metronidazole;

[0118] In step 3 to step 5, the working temperature of the hydroxylation reactor 1 is lower than or equal to 90° C.; the pressure is normal pressure; and the reaction time is 3 to 4 hours to ensure the safe production of hydroxylation synthesis and the quality of metronidazole products.

[0119] Example 1

[0120] The device for simulating the critical state atomized flow hydroxylation synthesis of metronidazole is characterized in that a hydroxylation kettle 1 (the main equipment for the metronidazole hydroxylation synthesis reaction) is used as the central device for the hydroxylation synthesis of metronidazole; a 316L material, DN25 stainless steel pipeline is used to connect the bottom valve 2 of the hydroxylation kettle, a one-way valve 4, a tubular mixer 12, and an atomizing flow functional pump 13; the atomizing flow functional pump 13 has one (atomizing flow high shear homogenizing pump or a high-efficiency gas-liquid mixed flow pump); the feed pipe of the atomizing flow functional pump 13 is connected to the bottom valve of the kettle; the liquid outlet delivery pipe of the atomizing flow functional pump 13 is made of 316L material and DN32 A stainless steel pipeline is fed into the hydroxylation kettle 1; a stainless steel pipeline of 316L material and DN20 is used to connect the EO metering tank 8, the EO flowmeter 9, and the one-way valve 11, and then connected to the tubular mixer 12; a stainless steel pipeline of 316L material and DN20 is used to connect the sulfuric acid metering tank 7, the sulfuric acid flowmeter 6, the one-way valve 5, and then connected to the tubular mixer 12; the elbows in each pipeline are arc elbows, and the R of the arc elbow matches the pipe diameter used; a PLC regulating control system 10 is used to regulate the flow of the nitrate mixed solution after the EO matching nitrate is dissolved.

[0121] The method for synthesizing metronidazole by using the device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation comprises the following steps:

[0122] Step 1: Add formic acid into the formic acid metering tank 18, and add sulfuric acid into the sulfuric acid metering tank 7;

[0123] Add EO into EO metering tank 8;

[0124] Step 2: The device 21 for synthesizing metronidazole by hydroxylation of atomized flow simulating a critical state is ready to start;

[0125] The formic acid feeding system 17 and the sulfuric acid feeding system 15 are controlled by the PLC control system 10 to deliver a fixed amount of formic acid and sulfuric acid to the hydroxylation reactor 1, respectively;

[0126] Step 3: formic acid and sulfuric acid are mixed in the hydroxylation reactor 1 to form a mixed acid; the mixed acid is a mixture of formic acid and sulfuric acid; wherein the ratio of formic acid to sulfuric acid is 4 to 2.5:1;

[0127] Heat the hydroxylation reactor 1 to raise the temperature of the mixed acid to 65-75°C;

[0128] Adding the nitrate into the hydroxylation reactor 1 from the nitrate feed port of the hydroxylation reactor 1;

[0129] The nitrate is dissolved in the mixed acid to form a nitrate mixed solution;

[0130] The hydroxylation kettle external circulation loop system 16 is started, and the nitrate mixed solution circulates in the hydroxylation kettle 1 and the hydroxylation kettle external circulation loop system 16;

[0131] Step 4: The EO feeding system 14 is controlled by the PLC control system 10 to continuously feed EO into the tubular mixer 12; the operating temperature of the tubular mixer 12 is lower than or equal to 90° C.; the pressure is normal pressure;

[0132] EO is mixed with the nitrate mixed solution circulating through the tubular mixer 12 or the nitrate mixed solution after the hydroxylation reaction and then flows into the atomizing flow functional pump 13, and is converted into an atomizing flow simulating a critical state by the atomizing flow functional pump 13; the operating temperature of the atomizing flow functional pump 13 is lower than or equal to 90° C.; it ensures that the heterogeneous materials entering the atomizing flow functional pump 13 are converted into homogeneous materials of the atomizing flow type simulating a critical state; and provides basic conditions for simulating a critical state by using an atomizing flow reaction to perform hydroxylation synthesis of metronidazole;

[0133] The atomized flow enters the hydroxylation reactor 1 from the feed end to carry out (hydroxylation) reaction; the operating temperature of the hydroxylation reactor 1 is lower than or equal to 90° C.; the pressure is normal pressure; the reaction time is 3 to 4 hours;

[0134] Until the metering addition of EO flowmeter 9 is completed, the EO feeding system is controlled by PLC control system 10 to stop feeding EO into tubular mixer 12, and the hydroxylation kettle external circulation loop system 16 continues to operate for 30 minutes, and then the hydroxylation kettle external circulation loop system 16 is controlled by PLC control system 10 to stop;

[0135] Step 5: Open the discharge valve 3 to discharge the material until all the reaction materials in the hydroxylation reactor 1 are completely discharged, and the device 21 for simulating the critical state atomization flow hydroxylation synthesis of metronidazole is stopped (such as Figure 1 shown).

[0136] Conclusion: Compared with the prior art, the EO consumption of this embodiment is less; in this embodiment, the EO consumption is reduced by about 3 / 10 relative to the prior art; the market price of EO is about 10 yuan / kg; using the device and method of this embodiment to produce 1 ton of metronidazole, the total EO consumption is reduced by nearly 4,000 yuan; then, if the annual production of metronidazole is 1,000 tons, the total EO consumption is reduced by nearly 4 million; the annual production of metronidazole in China is more than 7,000 tons, and the total EO consumption is reduced by nearly 30 million yuan by using the device and method of this embodiment. More importantly, this embodiment also has significant social benefits in protecting the environment.

[0137] Example 2

[0138] The device and method for simulating critical state atomization flow hydroxylation to synthesize metronidazole are the same as those in Example 1; the difference is that: there are two atomization flow functional pumps 13, and the two atomization flow functional pumps 13 (one of which is an atomization flow high shear homogenizing pump and the other is an efficient gas-liquid mixed flow pump) are connected in series (such as Figure 2 shown).

[0139] The two atomizing flow function pumps 13 connected in series can further accelerate the reaction speed, shorten the hydroxylation reaction time, and reduce the consumption of EO.

[0140] Conclusion: Compared with the prior art, the EO consumption of this embodiment is less; in this embodiment, the EO consumption is reduced by about 2 / 5 relative to the prior art; the market price of EO is about 10 yuan / kg; using the device and method of this embodiment to produce 1 ton of metronidazole, the total EO consumption is reduced by nearly 5,000 yuan; then, if the annual production of metronidazole is 1,000 tons, the total EO consumption is reduced by nearly 5 million yuan; the annual production of metronidazole in China is more than 7,000 tons, and the total EO consumption is reduced by about 35 million yuan using the device and method of this embodiment. More importantly, this embodiment also has significant social benefits in protecting the environment.

[0141] In order to more clearly illustrate the advantages of the device and method for synthesizing metronidazole by simulating critical state atomized flow hydroxylation of the present invention compared with the existing metronidazole hydroxylation synthesis technology, the staff compared the two technical solutions, and the comparison results are shown in Table 2 below:

[0142] Table 2 Comparison results (unit: kg / ton)

[0143]

[0144] As can be seen from Table 2 above, compared with the existing metronidazole hydroxylation synthesis technology, the device and method for simulating critical state atomized flow hydroxylation to synthesize metronidazole according to the present invention actually consumes less than or equal to 800 kg of EO and less than or equal to 900 kg of 2-methyl-5-nitroimidazole in producing metronidazole according to Example 1 of the present invention; much less than the amount of EO consumed in the production of metronidazole by the existing traditional process (1220-1350 kg) and the amount of 2-methyl-5-nitroimidazole consumed (980 kg).

[0145] Example 3

[0146] The device uses two high shear homogenizing pumps connected in series.

[0147] Example 4

[0148] The device uses two high-efficiency gas-liquid mixed flow pumps connected in series.

[0149] Other parts not described belong to the prior art.

Claims

1. A method for synthesizing metronidazole by simulating critical state atomized flow hydroxylation, characterized in that: The invention comprises a device for synthesizing metronidazole by simulating critical state atomized flow hydroxylation, and the device comprises a hydroxylation kettle (1), a discharge valve, an EO feed system (14), a sulfuric acid feed system (15) and a formic acid feed system (17); the sulfuric acid feed system (15) and the formic acid feed system (17) are respectively connected to the feed end of the hydroxylation kettle (1); the discharge valve is located at the lower end of a discharge pipe (22), and one end of the discharge pipe (22) is connected to the discharge end of the hydroxylation kettle (1); and the device also comprises an external circulation loop system (16) of the hydroxylation kettle; One end of the hydroxylation kettle external circulation loop system (16) is connected to the feed end of the hydroxylation kettle (1) through a process pipeline, and the other end is connected to the discharge end of the hydroxylation kettle (1) through a process pipeline; The EO feed system (14) is connected to the hydroxylation kettle external circulation loop system (16) through a process pipeline; The hydroxylation kettle external circulation loop system (16) comprises a discharge valve at the bottom of the hydroxylation kettle, an external circulation one-way valve (4) and an atomizing flow function pump (13); The atomizing flow function pump (13) has one or more; The discharge valve at the bottom of the hydroxylation kettle is connected to the discharge end of the hydroxylation kettle (1); The atomizing flow functional pump (13) is connected to the feed end of the hydroxylation kettle (1) through a process pipeline; The bottom discharge valve of the hydroxylation reactor, the external circulation one-way valve (4) and the atomizing flow functional pump (13) are connected in series in sequence through a process pipeline; The hydroxylation kettle external circulation loop system (16) further comprises a tubular mixer (12); the tubular mixer (12) is located between the atomizing flow functional pump (13) and the external circulation one-way valve (4); The bottom discharge valve of the hydroxylation reactor, the external circulation one-way valve (4), the tubular mixer (12) and the atomizing flow functional pump (13) are sequentially connected in series through a process pipeline; The EO feeding system (14) is connected to the tubular mixer (12) through a process pipeline; It also includes a PLC control system (10); the PLC control system (10) is installed on the top or side of the hydroxylation kettle (1); The method comprises the following steps: Step 1: adding formic acid into a formic acid metering tank (18), and adding sulfuric acid into a sulfuric acid metering tank (7); Add EO to the EO metering tank (8); Step 2: The device (21) for synthesizing metronidazole by simulating critical state atomized flow hydroxylation is ready to start up; The formic acid feeding system (17) and the sulfuric acid feeding system (15) are controlled by the PLC control system (10) to respectively deliver a fixed amount of formic acid and sulfuric acid to the hydroxylation reactor (1); Step 3: formic acid and sulfuric acid are mixed in a hydroxylation kettle (1) to form a mixed acid; the hydroxylation kettle (1) is heated to raise the temperature of the mixed acid to 65-75° C.; Adding the nitrate into the hydroxylation kettle (1) from the nitrate feed port of the hydroxylation kettle (1); The nitrate is dissolved in the mixed acid to form a nitrate mixed solution; The hydroxylation kettle external circulation loop system (16) is started, and the nitrate mixed solution circulates in the hydroxylation kettle (1) and the hydroxylation kettle external circulation loop system (16); Step 4: The EO feeding system (14) is controlled by the PLC control system (10) to continuously feed EO into the tubular mixer (12); EO is mixed with the nitrate mixed solution circulating through the tubular mixer (12) or the nitrate mixed solution after the hydroxylation reaction and then flows into the atomizing flow function pump (13), and is converted into an atomizing flow simulating a critical state by the atomizing flow function pump (13). The atomizing flow enters the hydroxylation kettle (1) from the feed end to react; Repeat step 4 until the metered addition is completed, and the EO feeding system is controlled by the PLC control system (10) to stop feeding EO into the tubular mixer (12), and the hydroxylation kettle external circulation loop system (16) continues to operate for 20 to 30 minutes, and then the hydroxylation kettle external circulation loop system (16) is controlled by the PLC control system (10) to stop; Step 5: Open the discharge valve to discharge the material until all the reaction materials in the hydroxylation reactor (1) are completely discharged, and the device (21) for simulating the critical state atomized flow hydroxylation to synthesize metronidazole is stopped; The PLC control system (10) has the functions of regulating the flow of the EO material route and the mixed acid route and its control, interlocking temperature control and alarm; The tubular mixer (12) and the atomizing flow functional pump (13) make the reaction materials mix evenly, greatly increase the collision frequency and rate of EO and nitrate, greatly improve the reaction speed of hydroxylation synthesis, and extremely effectively avoid the occurrence of hydroxylation synthesis side reactions.

2. The method for synthesizing metronidazole by hydroxylation of simulated critical state atomized flow according to claim 1, characterized in that: The EO feeding system (14) comprises an EO metering tank (8), an EO flow meter (9) and an EO one-way valve (11); The EO metering tank (8), the EO flowmeter (9) and the EO one-way valve (11) are sequentially connected in series and communicated with the tubular mixer (12) through a process pipeline; The sulfuric acid feeding system (15) comprises a sulfuric acid metering tank (7), a sulfuric acid flow meter (6) and a sulfuric acid one-way valve (5); The sulfuric acid metering tank (7), the sulfuric acid flow meter (6) and the sulfuric acid one-way valve (5) are sequentially connected in series and then communicated with the feed end of the hydroxylation kettle (1) through a process pipeline; The formic acid feeding system (17) comprises a formic acid metering tank (18), a formic acid flow meter (19), and a formic acid one-way valve (20); The formic acid metering tank (18), the formic acid flowmeter (19), and the formic acid one-way valve (20) are sequentially connected in series and communicated with the feed end of the hydroxylation kettle (1) through a process pipeline.

3. The method for synthesizing metronidazole by hydroxylation of simulated critical state atomized flow according to claim 2, characterized in that: The atomizing flow functional pump (13) is an atomizing flow homogenizing pump and / or a high-efficiency gas-liquid mixed flow pump with high-strength functions.

4. The method for synthesizing metronidazole by hydroxylation of simulated critical state atomized flow according to claim 3, characterized in that: The liquid phase material flow rate of the tubular mixer (12) is greater than 85%.

5. The method for synthesizing metronidazole by hydroxylation of simulated critical state atomized flow according to claim 1, characterized in that: In step 1 to step 3, the mixed acid is a mixture of formic acid and sulfuric acid; wherein the ratio of formic acid to sulfuric acid is 4 to 2.5:1; The formic acid is formic acid with a purity greater than or equal to 95%; and the sulfuric acid is sulfuric acid with a purity of 98%.

6. The method for synthesizing metronidazole by hydroxylation of simulated critical state atomized flow according to claim 5, characterized in that: In step 4 to step 5, the operating temperature of the tubular mixer (12) is lower than or equal to 90° C. and the pressure is normal pressure; In steps 3 to 5, the operating temperature of the atomizing flow functional pump (13) is lower than or equal to 90° C.; In step 3 to step 5, the operating temperature of the hydroxylation reactor (1) is lower than or equal to 90° C.; the pressure is normal pressure; and the hydroxylation reaction time is 3 to 4 hours.

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