CN114573511A - Continuous synthesis method of metronidazole - Google Patents
Continuous synthesis method of metronidazole Download PDFInfo
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- CN114573511A CN114573511A CN202210261313.7A CN202210261313A CN114573511A CN 114573511 A CN114573511 A CN 114573511A CN 202210261313 A CN202210261313 A CN 202210261313A CN 114573511 A CN114573511 A CN 114573511A
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Abstract
The invention discloses a continuous synthesis method of metronidazole, relating to the technical field of chemical synthesis. The continuous metronidazole synthesis method comprises the following steps: heating an acidic dissolving solution containing 2-methyl-5-nitroimidazole and 2-chloroethanol to generate a hydroxyethylation reaction, cooling a reaction solution flowing out of a hydroxyethylation microchannel reactor after the reaction is completed, adjusting the pH value of the reaction solution to 3-4, performing solid-liquid separation to obtain a filtrate, adjusting the pH value of the filtrate to 9-11, performing crystallization to obtain a metronidazole crude product, and recrystallizing to obtain the metronidazole. In the application, the 2-methyl-5-nitroimidazole and the 2-chloroethanol are in a dissolved and clarified state under an acidic condition, and can be fed together, so that feeding and accurate metering are facilitated. In addition, the hydroxyethylation microchannel reactor has large reaction specific surface area and high heat exchange efficiency, can increase the pressure and improve the reaction temperature, and after the reaction is finished, the residual 2-chloroethanol is evaporated out under reduced pressure, thereby avoiding generating a large amount of salt and wastewater.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a continuous synthetic method of metronidazole.
Background
Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol) is an antibiotic and antiprotozoal agent. It is mainly used for treating or preventing systemic or topical infection caused by anaerobic bacteria, such as anaerobic bacteria infection of abdominal cavity, digestive tract, female reproductive system, lower respiratory tract, skin and soft tissue, bone and joint, etc., and also has therapeutic effect on septicemia, endocarditis, meningeal infection and colitis caused by antibiotic. Tetanus is often treated in combination with Tetanus Antitoxin (TAT). Can also be used for oral cavity anaerobe infection.
The conventional production method of metronidazole is obtained by adding 2-methyl-5-nitroimidazole and ethylene oxide. 2-methyl-5-nitroimidazole is dissolved in formic acid, ethylene oxide is added successively at 30-40 ℃ and sulfuric acid is added in the middle of the addition. After the addition, the reaction was carried out for 1 hour. Recovering formic acid under reduced pressure, dissolving in water, cooling to 10 deg.C, and filtering. Adjusting the pH of the filtrate to 10 with sodium hydroxide solution, standing, cooling, filtering, and washing with water. Recrystallizing with water. Decolorizing with active carbon to obtain metronidazole.
However, since ethylene oxide is a colorless transparent liquid at low temperature, it is a colorless pungent odor gas at normal temperature and is not easy to store. When ethylene oxide is used for the hydroxyethylation reaction, the ethylene oxide must be liquefied, and a distributed feeding method is adopted, so that the ethylene oxide is easy to vaporize in the process, and the feeding difficulty and the feeding amount are inaccurate.
And also easily produces impurities upon addition reaction of 2-methyl-5-nitroimidazole with ethylene oxide:
according to experimental phenomena and literature reports, impurity 1 is very easy to generate in an alkaline environment (such as under the catalysis of tetrabutylammonium bromide); the impurity 2 and the temperature are too high, the ethylene oxide equivalent is too large, the reaction time is too long, the hydroxyethylation reaction of the 2-methyl-5-nitroimidazole belongs to an exothermic reaction, and the temperature in the system is excessively and violently increased under the condition of too fast ethylene oxide introduction speed or cooling failure until the raw materials are completely consumed, so that the impurity 2 is easily generated.
Therefore, the metronidazole prepared by reacting 2-methyl-5-nitroimidazole with ethylene oxide has the problems of difficult feeding, inaccurate feeding amount and high impurity content.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a continuous synthesis method of metronidazole.
The invention is realized by the following steps:
in a first aspect, the present invention provides a continuous metronidazole synthesis method, which includes: introducing an acidic dissolving solution containing 2-methyl-5-nitroimidazole and 2-chloroethanol into a hydroxyethylation microchannel reactor, heating to generate hydroxyethylation reaction, cooling a reaction solution flowing out of the hydroxyethylation microchannel reactor after the reaction is completed, adjusting the pH value of the reaction solution to 3-4, performing solid-liquid separation to obtain a filtrate, adjusting the pH value of the filtrate to 9-11, crystallizing to obtain a metronidazole crude product, and recrystallizing to obtain metronidazole.
The invention has the following beneficial effects:
according to the continuous metronidazole synthesis method, 2-methyl-5-nitroimidazole and 2-chloroethanol are subjected to hydroxyethylation reaction in a hydroxyethylation microchannel reactor to prepare metronidazole, and the 2-methyl-5-nitroimidazole and 2-chloroethanol are in a dissolved and clarified state under an acidic condition, so that feeding and accurate metering are facilitated. Meanwhile, the acidic dissolving solution containing the 2-methyl-5 nitroimidazole and the 2-chloroethanol can be introduced into the hydroxyethylation microchannel reactor together, the 2-methyl-5 nitroimidazole and the 2-chloroethanol do not need to be introduced independently or in multiple strands, the feeding is more convenient, in addition, the hydroxyethylation microchannel reactor has large reaction specific surface area and high heat exchange efficiency, the pressure can be increased to improve the reaction temperature, after the reaction is finished, the residual 2-chloroethanol is evaporated out under reduced pressure for the next batch feeding, and the generation of a large amount of salt and wastewater caused by the large amount of acid in the system during the later pH adjustment is avoided.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a flow chart of an apparatus for synthesizing 2-methylimidazole in the metronidazole continuous synthesis method provided by the present application;
FIG. 2 is a flow chart of an apparatus for synthesizing 2-methyl-5-nitroimidazole by nitration reaction in a metronidazole continuous synthesis method provided by the present application;
fig. 3 is a schematic structural diagram of a nitration microreactor for synthesizing 2-methyl-5-nitroimidazole through nitration reaction in the metronidazole continuous synthesis method provided by the application;
FIG. 4 is a flow chart of the apparatus for hydroxyethylation reaction in the continuous metronidazole synthesis process provided by the present application;
fig. 5 is a schematic structural diagram of a hydroxyethylation microreactor for hydroxyethylation reaction in the continuous metronidazole synthesis method provided by the present application.
Icon: 101-ammonia water tank; a 102-aldehyde water bucket; 103-a weighing module; 104-a feed pump; 105-a mixer; 106-heating constant temperature groove; 107-a first tubular reactor; 108-a cooling tube; 109-a cryostat; 110-a first back pressure valve; 111-a gas-liquid separator; 112-sulfuric acid absorption barrel;
201-a first plunger pump; 202-a second plunger pump; 203-a nitration microreactor; 204-a feed distributor; 205-a second tubular reactor; 206-a nitrification receiving kettle; 207-nitrification neutralization kettle; 208-a second backpressure valve; 209-tail gas absorption tank; 2031-a second reaction preheating channel; 2032-a second reaction channel;
301-dissolution kettle; 302-plunger pump; 303-hydroxyethylation microchannel reactor; 304-a concentration kettle; 305-a hydroxyethylation receiving kettle; 306-a first hydroxyethylation neutralization kettle; 307-a first pressure filter; 308-a second hydroxyethylation neutralization kettle; 309-a second pressure filter; 3031-first reaction preheating channel; 3032-first reaction channel.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The invention provides a continuous synthesis method of metronidazole, which comprises the following reactions:
s1, synthesizing 2-methylimidazole.
FIG. 1 shows a flow chart of a synthesis apparatus:
mixing aldehyde mixed solution of glyoxal and acetaldehyde with ammonia water, precooling to 10-20 ℃, entering an SK type tubular reactor to react under 1.8-2.0Mpa, and controlling the temperature of the reaction liquid to be 55-60 ℃; the reaction time is 18-22 min; after the reaction is finished, cooling to 10-15 ℃, then concentrating at 58-62 ℃ for 1-3h, and then crystallizing; filtering and washing to obtain the 2-methylimidazole.
Specifically, in the application, acetaldehyde and glyoxal are mixed uniformly in advance at a temperature of below 20 ℃ and then placed in an aldehyde water bucket 102, the acetaldehyde and an ammonia water solution in an ammonia water bucket 101 are accurately metered by a weighing module 103 and then are respectively fed into a jacket mixer 105 by a feed pump 104, precooled to 10-20 ℃, then enter a fan-tooth mixer, are mixed again and then enter a phi 850 m first tubular reactor 107 with an SK built therein, and the temperature of the tubular reactor is controlled to be 50-60 ℃ by a heating constant temperature bath 106. The temperature of the reaction liquid is controlled at 55-60 ℃, the reaction liquid after the reaction is introduced into a cooling pipe 108 of a low-temperature constant temperature bath 109 for cooling, the reaction liquid after the reaction is introduced into a gas-liquid separator 111 for gas-liquid separation after the cooling, the overflowed gas can be discharged into a sulfuric acid absorption barrel 112 through a first back pressure valve 110 for absorption, and then the reaction liquid in the gas-liquid separator 111 is concentrated, crystallized, washed and filtered.
When the acetaldehyde equivalent is in slight excess, the reaction is facilitated. The ammonia water is required to be excessive because free ammonia in the ammonia water is easy to volatilize when being heated. Glyoxal equivalent weight 1: at 1, the yield of the 2-methylimidazole is 75 percent; the equivalent of acetaldehyde is continuously increased, and when the equivalent reaches 1.2eq, the yield of the 2-methylimidazole reaches over 86 percent. When the acetaldehyde equivalent is further increased, the yield increase is insignificant.
The research of the application finds that the reaction temperature is increased to shorten the reaction retention time at a lower temperature, but the reaction temperature has a larger influence on the formation of impurities, and in order to improve the yield, increase the reaction temperature and change the reaction retention time, when the temperature reaches 60 ℃ and the retention time is 20min, the theoretical yield is up to 93 percent, and when the temperature exceeds 60 ℃, the higher the temperature is, the more tar-like impurities are, and the lower the yield is; the theoretical yield is 73% at the maximum when the retention time is 10min and the temperature is 70-80 ℃, and 79% at the maximum when the retention time is 15min and the temperature is 70-80 ℃. Therefore, the reaction temperature of the reaction liquid in the SK type tubular reactor is limited to 55-60 ℃; the reaction time is 18-22 min.
Since the reaction system is not quenched before concentration, the reaction is still in progress during concentration, and concentration at a high temperature for a long time results in increase of reaction impurities, and the darker the color of the reaction solution, the lower the yield. The experiment shows that: the concentration temperature is 58-62 ℃, the concentration time is 1-3h, the yield and the purity are better, preferably, the concentration temperature is 60 ℃, the concentration time is 3h, the yield and the purity are optimal, and the color of the feed liquid is lightest.
The crystallization comprises adding sodium hydroxide into the concentrated solution, cooling to 35-45 ℃, adding sodium chloride batch by batch until solid is separated out, slowly cooling to 0-2 ℃, stirring for 25-35min, filtering, washing the filter cake with NaCl or NaOH solution at 0-2 ℃, and drying the filter cake to obtain 2-methylimidazole with yield of 85%, HPLC purity of 99% and light yellow color.
S2, nitration reaction to synthesize 2-methyl-5-nitroimidazole
Synthesis apparatus flow diagrams see fig. 2 and 3:
an imidazole sulfuric acid solution mixed with 2-methylimidazole and sulfuric acid and nitric acid are respectively pumped into a nitration microreactor 203 by a first plunger pump 201 and a second plunger pump 202 to carry out nitration reaction for 10-18min, a reaction solution flowing out of the nitration microreactor 203 enters a second tubular reactor 205 to continue to react for 30-50min, after the reaction is finished, a reaction system is pumped into a nitration receiving kettle 206 to be cooled to room temperature, the cooled reaction solution is pumped into a nitration neutralization kettle 207 to be quenched, alkali liquor is added to adjust the pH value to 3.5-4.5, stirring is carried out at the room temperature for 15-25min, then a filter cake is filtered, rinsed and dried to obtain 2-methyl-5-nitroimidazole, and gas overflowing from the nitration receiving kettle 206 is pumped into a tail gas absorption tank 209 to be absorbed through a second ice water valve 208.
In this application, the nitration microreactor 203 includes a second reaction preheating channel 2031 and a plurality of second reaction channels 2032 sequentially communicated with each other, the second reaction preheating channel 2031 is communicated with the second reaction channel 2032, and the second reaction preheating channel 2031 and the second reaction channel 2032 are both provided with a feed inlet; the imidazole sulfuric acid solution is sent into the second reaction preheating channel 2031, the nitric acid is divided into a plurality of strands, the plurality of strands enter the plurality of second reaction channels 2032 through the feeding distributor 204, the imidazole sulfuric acid solution in the second reaction preheating channel 2031 enters the first second reaction channel 2032 to react with the first strand of nitric acid in a mixing manner after the temperature of the imidazole sulfuric acid solution reaches 110 ℃, the reaction mixture flows out of the first second reaction channel 2032 and then enters the second reaction channel 2032 to react with the second strand of nitric acid in a mixing manner, and so on until the reaction mixture flows out of the last second reaction channel 2032.
Preferably, the nitration microreactor 203 is heated by adopting an oil bath, the external temperature is 110-120 ℃, and the internal temperature is 120-140 ℃; since the nitration reaction itself is an exothermic reaction, the internal temperature of the nitration microreactor 203 may be higher than the external temperature. The reaction channel is 5-15 pieces, and the nitric acid is correspondingly divided into 5-15 strands of feeding materials.
In the prior art, nitration reaction is generally carried out in a tank reactor, and the main reaction formula is as follows:
during the main reaction, impurities and their interconversion are also present:
according to experimental phenomena and literature reports, the impurity IP-2a is very easy to generate. When the nitric acid is nitrified at a lower temperature (less than 80 ℃), or a nitric acid, dilute nitric acid and nitric acid-acetic anhydride-acetic acid system with a dilute concentration is used for nitrifying, or the dropping speed is too high, and IP-2a in the reaction system is a main product. IP-2a can be converted into a target product MNZ-2 under high-temperature conditions. Or further converted into the impurity IP-2b in a nitration system. The impurity IP-2b can be partially converted into product MNZ-2 and impurity IP-2c under high temperature conditions. When the nitric acid in the reaction system is excessive, MNZ-2 can be further nitrified into the dinitrated products IP-2b and IP-2 c. And all nitration products can be decomposed into small molecules which can not be detected under HPLC-UV conditions at high temperature in a nitration system of nitric acid and sulfuric acid. According to this principle, the chromatographic purity of the reaction system can be improved by maintaining stirring at a high temperature for a suitable period of time after the completion of the nitration reaction, but the MNZ-2 is reduced. The stability sequences of the various impurities under high temperature conditions are IP-2c > IP-2b > IP-2 a. Impurities generated in the nitration reaction can also be removed by a recrystallization method, and under the acidic pH condition, the water solubility of 2a, 2b and 2c is far greater than that of MNZ-2. Crystallization at pH 4 can therefore remove most of the reaction impurities.
As the nitration reaction of the 2-methylimidazole belongs to a strong exothermic reaction, under the condition of excessively high dropping speed or cooling failure, the temperature in the system can be increased sharply until the temperature exceeds the decomposition temperature of the 2-methyl-5-nitroimidazole (the initial decomposition temperature is 260 ℃ measured by DSC), and further explosion is caused. The difficulty in the tank reaction is that if the temperature is excessively lowered for safety, for example, the reaction temperature is lower than 120 ℃ C, side reactions, particularly IP-2a and IP-2b, in the reaction system will be the main products. Therefore, in the industrial production process, nitric acid can be dripped only when the internal temperature in the kettle-type reactor reaches more than 130 ℃, but the reaction heat is difficult to effectively release at the moment, so that the risk of runaway temperature runaway is high, nitric acid is decomposed into nitrogen oxides at high temperature, and the operation condition of a workshop is poor. In order to inhibit the temperature from rising too fast, a large amount of sulfate is added into a reaction system in most of the generation processes, so that the specific heat capacity of the reaction system is improved; in some reported processes, urea is also added into a reaction system to eliminate nitrogen oxides, improve reaction conditions and inhibit a possible nitrosation reaction. However, the current environmental protection pressure of the method is large, and a large amount of solid waste generated at the tail end of the process cannot be treated, so that the application of the method is severely limited.
The reaction that the adoption of this application novelty nitrify micro-reactor 203 and second tubular reactor 205 and combine together carries out nitration, compare in traditional kettle-type reactor, this application has higher than heat transfer area, adopt in this application and nitrify micro-reactor 203 in the strong heat release and concentrated acid stage, 2-methylimidazole dissolves in concentrated sulfuric acid in advance, send into second reaction by first plunger pump 201 and preheat passageway 2031, the nitric acid must divide the feed point that the stranded got into the different positions of second reaction channel 2032 respectively, the nitric acid feed point is more, impurity is less, the system temperature is steady more. Wherein nitric acid is used as 1 strand or 2 strands of feed, and byproducts IP-2a and IP-2b are mainly generated in the reaction; when the nitric acid is divided into 5 to 15 strands (preferably 10 strands) and enters the mixer, the purity of the liquid chromatogram before the post-treatment of the reaction system can reach over 84 percent. In the dilute acid heating stage, the second tubular reactor 205 is adopted to continue the reaction, so that the reaction time can be prolonged, and the yield can be improved.
Preferably, after the reaction mixture is discharged from second tubular reactor 205, it is cooled to room temperature, then it is quenched by adding ice water, and then it is quenched by adding saturated sodium hydroxide solution to adjust the pH of the system to 4-4.5, and the addition of base is stopped. It is worth noting that at this point, solid still precipitates upon further addition of the liquid caustic, but mostly impurities and inorganic salts. The sodium hydroxide in this application cannot be replaced by potassium hydroxide because the potassium salt has poor solubility, most of the sodium hydroxide will precipitate and mix with nitroimidazole, and the sodium salt will precipitate less.
S3, and carrying out a hydroxyethylation reaction.
The synthesis reaction formula is as follows:
the flow chart of the synthesis equipment is shown in fig. 4 and 5:
heating an acidic dissolving solution containing 2-methyl-5-nitroimidazole and 2-chloroethanol to perform a hydroxyethylation reaction, after the reaction is completed, evaporating unreacted 2-chloroethanol in a reaction system and recycling, then cooling the reaction system, adjusting the pH value of the reaction system to 3-4, cooling the reaction system to 0-5 ℃, stirring for 1-2h, filtering, taking a filter cake of unreacted 2-methyl-5-nitroimidazole, taking a filtrate, adjusting the pH value of the filtrate to 9-11, stirring for crystallization, filtering to obtain a metronidazole crude product, and recrystallizing to obtain metronidazole.
The preparation method of the acidic dissolving solution comprises the following steps: firstly, respectively introducing 2-methyl-5-nitroimidazole and 2-chloroethanol into a dissolving kettle 301 for mixing, stirring to form a suspension, and then adding dry hydrogen chloride gas, a hydrogen chloride solution or a sulfuric acid solution into the suspension in the dissolving kettle 301; preferably, dry hydrogen chloride gas is added into the suspension, and researches show that the addition of the dry hydrogen chloride gas into the suspension is quicker in reaction and is beneficial to saving reaction time, wherein the amount of the dry hydrogen chloride gas, the hydrogen chloride solution or the sulfuric acid solution is controlled by limiting the pH value of the acidic dissolving solution to be 2-3, or the amount of the dry hydrogen chloride gas, the hydrogen chloride solution or the sulfuric acid solution is judged by judging whether the suspension is completely dissolved.
In the application, the mass ratio of 2-methyl-5-nitroimidazole to 2-chloroethanol is 1-2: 5-8, and the mode that the 2-chloroethanol is added in excess can be seen to ensure that the 2-methyl-5-nitroimidazole reacts as much as possible, and the unreacted 2-methyl-5-nitroimidazole and the 2-chloroethanol can be recycled.
It is noted that the acidic dissolving solution in the present application is precisely fed by the plunger pump 302 and introduced into the hydroxyethylation microchannel reactor 303 to perform the hydroxyethylation reaction; the hydroxyethylation microchannel reactor 303 comprises a first reaction preheating channel 3031 and a plurality of first reaction channels 3032 which are sequentially communicated, wherein the first reaction preheating channel 3031 is communicated with the first reaction channels 3032; and (3) sending the acidic solution into the first reaction preheating channel 3031, entering the first reaction channel 3032 to continue reacting after the temperature reaches 110 ℃, entering the second reaction channel 3032 to continue reacting after the reaction mixture flows out of the first reaction channel 3032, and repeating the steps until the reaction mixture flows out of the last first reaction channel 3032. The reaction time of the hydroxyethylation reaction is 1-2h, the reaction temperature is 130-150 ℃, and the hydroxyethylation reaction is carried out under the pressure condition of 2-3 Mpa.
The conventional use of 2-chloroethanol for the hydroxyethylation reaction has the disadvantages of long reaction time and low conversion rate, the application innovatively provides that the hydroxyethylation reaction is carried out in the hydroxyethylation microchannel reactor 303, the problem can be solved, because the reaction specific surface area of the microchannel is large, the heat exchange efficiency is high, the reaction temperature can be increased by pressurization, and the 2-methyl-5-nitroimidazole and 2-chloroethanol are in a dissolved and clarified state under an acidic condition, so that the feeding and accurate metering are facilitated.
After the reaction, the reaction liquid flows out to the concentration kettle 304 so as to evaporate the residual 2-chloroethanol under reduced pressure, and the evaporated 2-chloroethanol is received by the hydroxyethylation receiving kettle 305 for the next batch of feeding, and simultaneously, a large amount of salt and wastewater generated in the later period of pH adjustment due to a large amount of acid in the system can be avoided.
Next, the reaction system was cooled by passing it through a first hydroxyethylation neutralization kettle 306, wherein the first hydroxyethylation neutralization kettle 306 was filled with ice water and jacketed using a high and low temperature integrated machine. After the reaction liquid is completely quenched by ice water, adding liquid caustic soda (40 wt%), adjusting the pH value to 3-4, generating a large amount of solid at this time, cooling the reaction system to 0-5 ℃ after neutralization, stirring for 1-2h, carrying out all operations in the first hydroxyethylation neutralization kettle 306 by strong stirring, allowing the solid generated in the first hydroxyethylation neutralization kettle 306 to enter a first pressure filter 307 for pressure filtration, and rinsing the filter cake twice by normal-temperature water. Drying the mixture in an oven at 80 ℃ under reduced pressure overnight after drying, thus obtaining the unreacted 2-methyl-5 nitroimidazole.
The cooled reaction solution enters a second hydroxyethylation neutralization kettle 308, wherein ice water is filled in the second hydroxyethylation neutralization kettle 308, and jacket cooling is carried out by using a high-temperature and low-temperature integrated machine. After the reaction solution was completely quenched with ice water, liquid caustic soda (40 wt%) was added to adjust the pH to 10, in which case a large amount of solid was generated, and the reaction solution was stirred at room temperature for 20min after the neutralization was completed. All operations in the second hydroxyethylation neutralization tank 308 are equipped with strong agitation, the solids produced in the second hydroxyethylation neutralization tank 308 are passed into a second pressure filter 309 for pressure filtration, and the filter cake is rinsed twice with normal temperature water. After drying, the mixture is put into an oven to be dried overnight at 80 ℃ under reduced pressure.
The recrystallization of the crude metronidazole product comprises the following steps: adding water and active carbon into the metronidazole crude product for recrystallization; the mass ratio of the metronidazole crude product to the water to the active carbon is 1:4-6: 0.4-0.6.
It should be further noted that steps S1 and S2 can be omitted, that is, commercially available 2-methyl-5-nitroimidazole can be directly reacted with 2-chloroethanol without pre-synthesizing 2-methyl-5-nitroimidazole.
The structures of the hydroxyethylation microchannel reactor 303 and the nitrification microreactor 203 mentioned in the present application are substantially the same as those of the microchannel reactor in the prior art, and the present application is not particularly limited. In this application, only the microchannel reactor is utilized to carry out specific reaction, and the reaction specific surface area is large through the hydroxyethylation microchannel reactor 303 and the nitration microreactor 203, the heat exchange efficiency is high, the reaction speed can be improved through the characteristics of pressurization, reaction temperature improvement and the like, and the yield and the purity are improved.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1: synthesizing 2-methylimidazole.
10kg of 40% glyoxal and 9.1kg of 40% acetaldehyde are premixed at the temperature below 20 ℃, then are respectively sent into a jacket mixer with an ammonia water solution through a feed pump, precooled to 15 ℃, then enter a fan-tooth mixer, and are mixed again, and then enter a phi 850 m first tubular reactor 107 with an SK built-in type, so as to carry out reaction under the pressure of 2.0MPa, the oil temperature of the first tubular reactor 107 is controlled to be 55 ℃, the temperature of a reaction liquid is controlled to be 55 ℃, and the reaction time is 18-22 min. When the reaction solution flows out of the first tubular reactor 107, the reaction solution enters a cooling pipe 108 after temperature sensing (reaction temperature is monitored at any time), the temperature is reduced to 15 ℃, the reaction solution is concentrated under reduced pressure, the concentration temperature is 60 ℃, the concentration time is 2 hours, 4.8kg of light yellow solid is obtained by cooling, crystallization, filter pressing, recrystallization and drying, the purity is 98%, and the yield is 28.4%.
Example 2: synthesis of 2-methyl-5-nitroimidazole by nitration reaction
Sending imidazole sulfuric acid solution mixed with 2-methylimidazole and sulfuric acid into a second reaction preheating channel 2031 at a flow rate of 20g/min, dividing the nitric acid into 10 strands, respectively entering 10 second reaction channels 2032 at a flow rate of 15g/min (the internal temperature is 120-, after the reaction is finished, cooling the reaction system to room temperature, quenching the cooled reaction liquid with ice water, adding a saturated sodium hydroxide solution to adjust the pH value to 4, stirring at the room temperature for 20min, filtering to obtain a filter cake, rinsing and drying to obtain the 2-methyl-5-nitroimidazole, wherein the purity is higher than 98%, and the yield is 52%.
Example 3: hydroxyethylation reaction
Putting 20g of 2-methyl-5 nitroimidazole and 50g of 2-chloroethanol into a dissolving kettle 301, stirring to obtain suspension, introducing dry hydrogen chloride gas to fully dissolve solids to form acidic solution, sending the acidic solution into a first reaction preheating channel 3031 of a hydroxyethylation microchannel reactor 303, entering a first reaction channel 3032 to continue reaction after the temperature reaches 110 ℃, allowing the reaction mixture to flow out of the first reaction channel 3032, entering a second reaction channel 3032 to continue reaction, and repeating the steps until the reaction mixture flows out of the last first reaction channel 3032, wherein the retention time of the reaction solution in the hydroxyethylation microchannel reactor 303 is 2 hours; evaporating unreacted 2-chloroethanol, cooling, adjusting pH to 3 with sodium hydroxide solution, cooling to 0 deg.C, stirring for 1h, and vacuum filtering to obtain filter cake of unreacted 2-methyl-5-nitroimidazole. Adding sodium hydroxide solution into the filtrate to adjust the pH value to be about 10.0, stirring and crystallizing for 2h, and performing suction filtration to obtain a crude metronidazole product of 10.0g, wherein the purity is 98% and the yield is 37%. Adding purified water and active carbon into the crude metronidazole product for recrystallization to obtain 8.5g of metronidazole, wherein the purity is more than 99 percent, and the yield is 85 percent.
Comparative example 1
The comparative example provides a method for preparing metronidazole by using a kettle reactor, which comprises the following steps:
dissolving 2-methyl-5-nitroimidazole in a system of formic acid (3.33 times of the weight of 2-methyl-5-nitroimidazole) and 98 percent sulfuric acid (0.5 time of the weight of 2-methyl-5-nitroimidazole) under the cooling condition of an ice water bath. Keeping the internal temperature below 35 ℃, controlling the internal temperature at 60 ℃, and dripping ethylene oxide for about 2 hours. After the completion of the dropwise addition, the purity in HPLC was controlled to 50% or more at this point. The reaction solution was concentrated (solvent was recovered), 1 equivalent of ice water was added, the internal temperature was maintained at 25 ℃ and 40% aqueous sodium hydroxide solution was added until the pH was 4, and a solid precipitated. And (3) continuously stirring for 40min, filtering, rinsing the filter cake for 2 times by using deionized water, and drying to obtain a white-like solid, namely the raw material which is not completely reacted: 2-methyl-5-nitroimidazole, HPLC > 90%. Mixing the filtrate and the washing solution, adding 40% sodium hydroxide aqueous solution until pH is 10, separating out solids, stirring for 40min, filtering, rinsing the filter cake with deionized water for 2 times, and drying to obtain white or off-white solid, i.e. metronidazole, with HPLC purity of more than 99% and yield of 30%.
Comparative example 2
The comparative example provides a method for preparing metronidazole by using a microreactor, which comprises the following steps:
1.5kg of concentrated sulfuric acid and 3.0kg of 2-methyl-4 (5) -nitroimidazole are added into a 1.10L glass lining kettle in batches into 10kg of formic acid, a large amount of heat is released in the dissolving process, ice water is needed for cooling, and the internal temperature is controlled not to exceed 40 ℃.
2. The nitroimidazole formic acid solution is fed into a reaction preheating section (a first microreactor) by a plunger pump at the flow rate of 35g/min, and when the temperature reaches 55 ℃, the reaction section (a second microreactor) is fed into a reaction section (a first microreactor) to be mixed with a first stream of ethylene oxide EA (ethylene oxide: EA is 1: 1) for reaction. And the reaction mixed liquid flows out of the second microreactor, is mixed with a second strand of ethylene oxide EA, enters a third microreactor for reaction, and the like. All 11 microreactor modules were integrated and placed in a 60 ℃ oil bath.
3. And feeding the ethylene oxide EA into a distributor by using a plunger pump, and then respectively feeding the ethylene oxide EA into the second to eleventh microreactors in ten strands to be mixed and reacted with the nitroimidazole sulfuric acid formic acid solution.
4. And after the reaction mixed liquid flows out of the eleventh microreactor, the reaction mixed liquid enters a 50-meter tubular reactor with the inner diameter of 8mm for continuous reaction. The oil bath temperature of the tubular reactor was controlled at 65 ℃.
5. After the reaction liquid flows out of the tubular reactor, the reaction liquid enters a receiving concentration kettle to be subjected to reduced pressure concentration to recover formic acid, and the system is heated to 65 ℃. Wherein the volatilized formic acid and the remaining ethylene oxide are subjected to an acid absorption treatment.
6. After the concentration is finished, the cooled reaction solution enters a quenching neutralization kettle, wherein 3.0kg of ice water is filled in the kettle, and the kettle is jacketed and cooled by a high-temperature and low-temperature integrated machine. After the reaction solution was completely quenched with ice water, 1.0kg of liquid alkali (40%) was added to adjust the pH to 4, in which case a large amount of solid was generated, and the reaction solution was stirred at room temperature for 20min after the neutralization was completed. All operations in the neutralization kettle were equipped with vigorous stirring.
7. The solid generated in the neutralization kettle enters a filter press for filter pressing, and the filter cake is rinsed twice by 0.6kg of normal temperature water. Drying the mixture in an oven at 80 ℃ for overnight under reduced pressure after blow-drying to obtain white or off-white solid, wherein HPLC is more than 90%, and the recovery rate is 30%, namely the 2-methyl-5-nitroimidazole.
8. And (3) feeding the filtrate and the rinsing liquid into a neutralization kettle of the next step, feeding the reaction liquid after continuous cooling into a quenching neutralization kettle, wherein 3.0kg of ice water is filled in the kettle, and performing jacket cooling by using a high-temperature and low-temperature integrated machine. After the reaction solution was completely quenched with ice water, 1.0kg of liquid alkali (40%) was added thereto, and the pH was adjusted to 10, in which case a large amount of solid was generated, and the reaction solution was stirred at room temperature for 20min after the completion of neutralization. All operations in the neutralization kettle were equipped with vigorous stirring.
9. The solid generated in the neutralization kettle enters a filter press for filter pressing, and the filter cake is rinsed twice by 0.6kg of normal temperature water. Drying the mixture in an oven at 80 ℃ for one night under reduced pressure after drying to obtain white or off-white solid, namely metronidazole, HPLC is more than 99 percent, and the yield is 45 percent.
Comparative example 3
This comparative example is essentially the same as example 3 except that example 3 was reacted in a reaction kettle without passage into a hydroxyethylation microchannel reactor. The metronidazole prepared by the method has HPLC more than 99 percent and the yield is 31 percent.
Comparative example 4
This comparative example is essentially the same as example 3 except that the 2-chloroethanol of example 3 was replaced with ethylene oxide. The metronidazole prepared by the method has HPLC more than 99 percent and the yield is 44 percent.
Comparative example 5
The comparative example is basically the same as comparative example 2, except that in the comparative example, the ethylene oxide EA is not fed into the microchannel reactor through the distributor by 10 strands, but is directly mixed with the nitroimidazole sulfuric acid solution in step 1 before being fed into the microchannel reactor, and then is fed into the microchannel reactor. The obtained 2-methyl-5-nitroimidazole has HPLC (high performance liquid chromatography) of more than 90 percent and the yield of 30 percent.
Comparative example 6
This comparative example is essentially the same as example 2, except that: the "reaction liquid flowing out of the nitration microreactor enters the tubular reactor to continue the reaction for 30-50 min" in example 2 is omitted, that is, in this comparative example, the nitration reaction is carried out only in the nitration microreactor. The obtained 2-methyl-5-nitroimidazole has HPLC (high performance liquid chromatography) of more than 99 percent and the yield of 35 percent.
Comparative example 7
This comparative example is essentially the same as example 2, except that: the "adjustment of pH to 4 by addition of saturated sodium hydroxide solution" in example 2 was replaced by "adjustment of pH to 4 by addition of aqueous ammonia". The obtained 2-methyl-5-nitroimidazole has HPLC (high performance liquid chromatography) of more than 99 percent and the yield of 52 percent.
In summary, the continuous synthesis method of metronidazole provided by the application adopts 2-methyl-5-nitroimidazole and 2-chloroethanol to carry out hydroxyethylation reaction in a hydroxyethylation microchannel reactor to prepare metronidazole, and the 2-methyl-5-nitroimidazole and 2-chloroethanol are in a dissolved and clarified state under an acidic condition, so that feeding and accurate metering are facilitated. Meanwhile, the acidic dissolving solution containing the 2-methyl-5 nitroimidazole and the 2-chloroethanol can be introduced into the hydroxyethylation microchannel reactor together, the 2-methyl-5 nitroimidazole and the 2-chloroethanol do not need to be introduced independently or in multiple strands, the feeding is more convenient, in addition, the hydroxyethylation microchannel reactor has large reaction specific surface area and high heat exchange efficiency, the pressure can be increased to improve the reaction temperature, after the reaction is finished, the residual 2-chloroethanol is evaporated out under reduced pressure for the next batch feeding, and the generation of a large amount of salt and wastewater caused by the large amount of acid in the system during the later pH adjustment is avoided.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A metronidazole continuous synthesis method is characterized by comprising the following steps: introducing an acidic dissolving solution containing 2-methyl-5-nitroimidazole and 2-chloroethanol into a hydroxyethylation microchannel reactor, heating to generate hydroxyethylation reaction, cooling a reaction solution flowing out of the hydroxyethylation microchannel reactor after the reaction is completed, adjusting the pH value of the reaction solution to 3-4, performing solid-liquid separation to obtain a filtrate, adjusting the pH value of the filtrate to 9-11, crystallizing to obtain a metronidazole crude product, and recrystallizing to obtain metronidazole.
2. The continuous metronidazole synthesis method according to claim 1, wherein the preparation method of the acidic dissolving solution comprises: mixing the 2-methyl-5-nitroimidazole and the 2-chloroethanol, stirring to form a suspension, and then adding dry hydrogen chloride gas, a hydrogen chloride solution or a sulfuric acid solution into the suspension;
preferably, dry hydrogen chloride gas is added to the suspension;
preferably, the pH of the acidic dissolving solution is 2-3;
preferably, the mass ratio of the 2-methyl-5-nitroimidazole to the 2-chloroethanol is 1-2: 5-8.
3. The continuous metronidazole synthesis method according to claim 1, wherein the hydroxyethylation microchannel reactor comprises a first reaction preheating channel and a plurality of first reaction channels which are communicated in sequence, and the first reaction preheating channel is communicated with the first reaction channels; and sending the acidic solution into the first reaction preheating channel, entering a first reaction channel to continue reacting after the temperature reaches 110 ℃, and entering a second reaction channel to continue reacting after the reaction mixture flows out of the first reaction channel, and repeating the steps until the reaction mixture flows out of the last first reaction channel.
4. The continuous metronidazole synthesis method as claimed in claim 3, wherein the reaction time of the hydroxyethylation reaction is 1-2h, the reaction temperature is 130-150 ℃, and the hydroxyethylation reaction is carried out under the pressure condition of 2-3 Mpa.
5. The continuous metronidazole synthesis method of claim 1, wherein the recrystallization of the crude metronidazole product comprises: adding water and active carbon into the metronidazole crude product for recrystallization;
preferably, the mass ratio of the metronidazole crude product to the water to the active carbon is 1:4-6: 0.4-0.6.
6. The continuous metronidazole synthesis method according to claim 1, wherein after the hydroxyethylation reaction is completed and before the reaction solution is cooled, the method further comprises distilling out unreacted 2-chloroethanol in the reaction solution and recycling the 2-chloroethanol.
7. The continuous metronidazole synthesis method according to claim 1, wherein after the reaction solution is brought to pH 3-4, the reaction solution is cooled to 0-5 ℃ and stirred for 1-2h before being filtered.
8. The continuous metronidazole synthesis method according to claim 1, further comprising synthesizing the 2-methyl-5-nitroimidazole by nitration;
preferably, the nitration reaction comprises the steps of respectively introducing imidazole sulfuric acid solution mixed with 2-methylimidazole and sulfuric acid and nitric acid into a nitration microreactor for nitration reaction, allowing reaction liquid flowing out of the nitration microreactor to enter a second tubular reactor for continuous reaction, cooling reaction mixed liquid flowing out of the second tubular reactor to room temperature after the reaction is finished, quenching the cooled reaction mixed liquid with ice water, adding alkali liquor to adjust the pH value to 3.5-4.5, stirring at the room temperature for 15-25min, filtering, taking a filter cake, rinsing and drying to obtain the 2-methyl-5-nitroimidazole.
9. The metronidazole continuous synthesis method according to claim 8, wherein the nitration microreactor comprises a second reaction preheating channel and a plurality of second reaction channels which are sequentially communicated, the second reaction preheating channel is communicated with the second reaction channels, and the second reaction preheating channel and the second reaction channels are provided with feed inlets; sending the imidazole sulfuric acid solution into the second reaction preheating channel, wherein the nitric acid is divided into a plurality of strands which respectively enter a plurality of second reaction channels, the imidazole sulfuric acid solution in the second reaction preheating channel enters a first second reaction channel and is mixed and reacted with a first strand of nitric acid after the temperature of the imidazole sulfuric acid solution reaches 110 ℃, a reaction mixture flows out of the first second reaction channel, enters a second reaction channel and is mixed and reacted with a second strand of nitric acid, and the like, until a reaction mixed solution flows out of the last second reaction channel;
preferably, the nitration microreactor is heated by adopting an oil bath, the external temperature is 110-120 ℃, and the internal temperature is 120-140 ℃;
preferably, the reaction channel is 5-15 sheets, and the nitric acid is correspondingly divided into 5-15 feeding materials;
preferably, the reaction mixed liquid flows out after reacting for 10-18min from the nitration microreactor and enters the tubular reactor to continue reacting for 30-50 min;
preferably, after the reaction mixed solution is discharged from the tubular reactor, the reaction mixed solution is cooled to room temperature, then ice water is added for quenching, and then saturated sodium hydroxide solution is added to adjust the pH value of the system to 4-4.5, and the addition of the alkali is stopped.
10. The continuous metronidazole synthesis method according to claim 1, further comprising the synthesis of 2-methylimidazole: mixing aldehyde mixed solution of glyoxal and acetaldehyde with ammonia water, precooling to 10-20 ℃, and reacting in a first tubular reactor, wherein the temperature of the reaction liquid is 55-60 ℃; the reaction time is 18-22 min; after the reaction is finished, cooling to 10-15 ℃, and then concentrating and crystallizing the reaction solution; filtering and washing to obtain the 2-methylimidazole;
preferably, the 2-methylimidazole synthesis reaction is carried out at 1.8-2.0 MPa;
preferably, the concentration is carried out at a temperature of 55-65 ℃ for 2-4 h;
preferably, the crystallization comprises the steps of adding sodium hydroxide into the concentrated solution, cooling to 35-45 ℃, adding sodium chloride batch by batch until solid is separated out, slowly cooling to 0-2 ℃, stirring for 25-35min, filtering, washing a filter cake with NaCl or NaOH solution at 0-2 ℃, and drying the filter cake to obtain the 2-methylimidazole.
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