Patent Application
20240270696
This application claims the benefit of priority from Chinese Patent Application No. 202311442699.2, filed on Nov. 1, 2023. The content of the aforementioned application, including any intervening amendments thereto, is incorporated herein by reference in its entirety.
This application relates to pharmaceutical chemicals, and more particularly to a full continuous synthesis device and method for metronidazole.
Metronidazole (C6H9N3O3 with CAS number of 443-48-1), also called 1-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole, is a white or yellowish crystal or crystalline powder. Metronidazole is a nitroimidazole antiprotozoal and anti-anaerobic drug mainly used in clinical prevention and treatment of anaerobic infections, and has a large global clinical demand. Metronidazole has been approved by the World Health Organization as an essential drug against anaerobic infections in 1978.
At present, the production of metronidazole generally adopts a batch reactor, which has long reaction time, high energy consumption, low conversion of 2-methyl-5-nitroimidazole (main raw material), serious by-reaction of ethylene oxide and large production of waste acid and salt. Chinese Patent Publication No. 110669011A developed a microtubular reaction process for synthesizing metronidazole from 2-methyl-5-nitroimidazole. The raw materials are mixed in the mixing zone of a commercially-available pre-packed coiled reactor, and then enter the rection zone with an inner diameter of 4-20 mm for hydroxyethylation, which avoids volatilization of ethylene oxide with a low boiling point and improves utilization efficiency of ethylene oxide. However, it is required to cool ethylene oxide into a low-temperature liquid in advance, which increases the energy consumption. Moreover, due to the low boiling point, the vapor pressure of ethylene oxide varies significantly under different room temperature conditions, which renders the measuring pump less accurate, thereby affecting the conversion rate and selectivity of the reaction. Chinese Patent Publication No. 111574459A developed a preparation method of metronidazole from 2-methyl-5-nitroimidazole, in which the ethylene oxide is added batchwise to a kettle reactor, such that the volatilization of ethylene oxide is alleviated, and the utilization efficiency of ethylene oxide is increased. However, the batchwise addition of ethylene oxide is time-consuming, and has complex operation and low production efficiency.
In view of the problems of the prior art, this application provides a full continuous synthesis device and method for metronidazole, which has high production efficiency, excellent product quality and less emission of three wastes (waste water, waste gas and industrial residue).
The present disclosure provides a full continuous synthesis method for metronidazole using 2-methylimidazole as a starting material, in which a micromixer, a microreactor, a self-designed solvent switching system and a self-designed ethylene oxide conveying system are integrated to synthesize high-purity metronidazole product through three-step reactions and continuous operation, and realize the recovery of sulfuric acid and formic acid, which enables the accurate and continuous feeding of ethylene oxide, and significantly mitigates the emission of the three wastes. Based on the fully-continuous synthesis, the production efficiency and control accuracy are greatly improved, thereby ensuring the stability of product quality.
The present disclosure provides a full continuous synthesis method for metronidazole using a full continuous synthesis device, the full continuous synthesis device comprising a first mixer, a first microreactor, a first solvent switching system, a second mixer, a second microreactor, an ethylene oxide conveying system, a third microreactor and a second solvent switching system communicated in sequence; and the full continuous synthesis method comprising:
In an embodiment, the first mixer and the second mixer are specially designed and manufactured and each have a plate-type homocentric-square channel structure with a width of 100 μm-20 mm, a length of 1 m-2000 m and an applicable flux of 1 mL/min-3000 mL/min.
In an embodiment, the first microreactor, the second microreactor and the third microreactor are each independently have a plate-type X-shaped channel structure with a fluid channel size of 100μm-20 mm or a tubular baffle filled channel structure with a fluid channel size of 300μm-50 mm (referring to
In an embodiment, the first solvent switching system and the second solvent switching system are specially designed and manufactured, and is provided in two schemes. Referring to
In an embodiment, referring to
In an embodiment, the splitter is an adjustable liquid flowmeter connected with a valve. The splitter is configured such that a part of the 2-methyl-5-nitroimidazole sulfuric acid solution obtained after a first nitrification reaction in the second microreactor is used to replace the concentrated sulfuric acid to participate in a second nitrification reaction in the second microreactor to obtain a primarily-concentrated 2-methyl-5-nitroimidazole sulfuric acid solution. The splitter is opened to deliver the primarily-concentrated 2-methyl-5-nitroimidazole sulfuric acid solution to participate a next step reaction, or the primarily-concentrated 2-methyl-5-nitroimidazole sulfuric acid solution is used to participate in a third nitrification reaction in the second microreactor to obtain a secondarily-concentrated 2-methyl-5-nitroimidazole sulfuric acid solution, and so forth until a saturated 2-methyl-5-nitroimidazole sulfuric acid solution is obtained which is used in a next step through the splitter, so as to save a consumption of concentrated sulfuric acid in the nitration reaction and realize that one sulfuric acid is used multiple times to nitrate multiple 2-methylimidazole.
In an embodiment, the ethylene oxide conveying system is specially designed and manufactured. The ethylene oxide conveying system includes a buffer tank provided with an ethylene oxide inlet pipe and an ethylene oxide outlet pipe. The ethylene oxide inlet pipe is arranged in the buffer tank at ½ height of the buffer tank, and the ethylene oxide outlet pipe is configured to extend from a bottom of the buffer tank to a position inside the buffer tank which is away from the bottom of the buffer tank at a distance of ⅕-¼ height of the buffer tank. The buffer tank is pressurized to 5 bar-10 bar with nitrogen after filled with ethylene oxide. The ethylene oxide conveying system further includes an injection pump; and the injection pump is configured to quantitatively feed the ethylene oxide to be mixed with a 2-methyl-5-nitroimidazole sulfuric acid-formic acid mixture to prepare metronidazole.
In an embodiment, in step (d), a pH value of the residual metronidazole solution is monitored by an on-line pH meter, and is adjusted with aqueous ammonia or liquid ammonia; the residual metronidazole solution is pumped to an on-line filter through a plunger pump to obtain a first filtrate; and the first filtrate is returned to a first pH-adjusting tank until a pH value of the first filtrate is kept within 2-6.
The first filtrate with the pH value of 2-6 is adjusted with aqueous ammonia or liquid ammonia in a second pH-adjusting tank pumped to the on-line filter through the plunger pump to obtain a second filtrate, and the second filtrate is returned to the second pH-adjusting tank until a pH value of the second filtrate is kept within 8-14. A filter cake of the on-line filter is continuously scraped by using a rotatory scraper to obtain the crude metronidazole. The crude metronidazole is decolorized and crystallized to obtain pure metronidazole with the purity greater than 99.9%.
Compared to the prior art, this application has the following beneficial effects.
In the present disclosure, the efficient continuous synthesis of metronidazole is realized through reasonable combination of a series of micromixers and microreactor according to synthesis process of metronidazole. Moreover, the continuous synthesis of metronidazole is realized through the solvent switching system designed herein, which greatly improves the production efficiency and realizes the recovery and utilization of excess nitric acid and formic acid. By means of the splitter, the sulfuric acid can be repeatedly recycled, such that the sulfuric acid consumption can be reduced by more than 80%, thereby efficiently reducing the production of waste acid and waste salt and reducing the production cost. In addition, the ethylene oxide conveying system designed herein can effectively ensure the stable and accurate feeding of ethylene oxide to the pressurized microchannel reactor.
In order to illustrate the technical solutions, structure characteristics, objectives and effects of the present disclosure in detail, the present disclosure will be described below with reference to the accompanying drawings and embodiments. The embodiments described below are illustrative, and are not intended to limit the scope of this application.
In order to make purposes, technical solutions and beneficial effects of the present disclosure clearer, the present disclosure will be clearly and completely described below with reference to the accompanying drawings and embodiments.
An aqueous glyoxal solution was mixed with an aqueous acetaldehyde water solution in a molar ratio of 1:1 to obtain a reagent A. The reagent A and aqueous ammonia (1.2 equiv., reagent B) were pumped to a homocentric-square mixer through a plunger pump, fully mixed and reacted in an X-shaped microreactor to produce a 2-methylimidazole-containing reaction mixture. The 2-methylimidazole-containing reaction mixture is treated under reduced pressure in a multi-function stirred tank connected with a vacuum system, a cooling system and a heating circulation system to remove unreacted aldehyde, ammonia and water. The resultant 2-methylimidazole was mixed with a 70% nitric acid solution (1.2 equiv.) to obtain a reagent C, which was mixed with concentrated sulfuric acid in another homocentric-square mixer and then reacted in another X-shaped microreactor to produce a 2-methyl-5-nitroimidazole-containing reaction mixture. The 2-methyl-5-nitroimidazole-containing reaction mixture was conveyed to a negative-pressure tank to remove the unreacted nitric acid, so as to obtain a 2-methyl-5-nitroimidazole sulfuric acid solution. The 2-methyl-5-nitroimidazole sulfuric acid solution was used to replace the concentrated sulfuric acid to participate in the nitration of the 2-methylimidazole to produce a primarily-concentrated 2-methyl-5-nitroimidazole sulfuric acid solution, and such operation was repeated again to obtain a secondarily-concentrated 2-methyl-5-nitroimidazole sulfuric acid solution as reagent D. In this way, one batch of sulfuric acid was used to participate in three batches of 2-methylimidazole nitration, reducing the consumption of sulfuric acid. The reagent D was mixed with formic acid and then mixed with ethylene oxide (1.1 equiv.) quantitatively output from an ethylene oxide conveying system, and subjected to a ring-opening reaction in another X-shaped microreactor to obtain a final product metronidazole. The metronidazole-containing reaction liquid entered a spiral channel with a zigzag baffle to remove formic acid by condensation and recovery. The residual reaction liquid was adjusted to pH 2-4, and filtered to recover 2-methyl-5-nitroimidazole. The filtrate was further adjusted to pH 9-12, and filtered to obtain crude metronidazole. The crude metronidazole is decolored, crystallized, filtered and dried to obtain pure metronidazole with a purity greater than 99.9%. Compared to the conventional one-through synthesis, the consumption of sulfuric acid of this embodiment was reduced by 65%; the recovery rate of formic acid was 95%; a one-through yield of metronidazole was 80%; and the yield of 2-methyl-5-nitroimidazole reached 96% after repeated recycling.
An aqueous glyoxal solution was mixed with an aqueous acetaldehyde water solution in a molar ratio of 1:1 to obtain a reagent A. The reagent A and aqueous ammonia (1.2 equiv., reagent B) were pumped to a homocentric-square mixer through a plunger pump, fully mixed and reacted in an X-shaped microreactor to produce a 2-methylimidazole-containing reaction mixture. The 2-methylimidazole-containing reaction mixture is treated under reduced pressure in a zigzag baffle-filled vertical channel to be concentrated and remove low-boiling-point compounds and water. The resultant 2-methylimidazole was mixed with a 70% nitric acid solution (1.2 equiv.) to obtain a reagent C, which was mixed with concentrated sulfuric acid in another homocentric-square mixer and then reacted in another X-shaped microreactor to produce a 2-methyl-5-nitroimidazole-containing reaction mixture. The 2-methyl-5-nitroimidazole-containing reaction mixture was conveyed to a negative-pressure tank to remove the unreacted nitric acid, so as to obtain a 2-methyl-5-nitroimidazole sulfuric acid solution. The 2-methyl-5-nitroimidazole sulfuric acid solution was used to replace the concentrated sulfuric acid to participate in the nitration of the 2-methylimidazole to produce a concentrated 2-methyl-5-nitroimidazole sulfuric acid solution as reagent D. In this way, one batch of sulfuric acid was used to participate in two batches of 2-methylimidazole nitration, reducing the consumption of sulfuric acid. The reagent D was mixed with formic acid and then mixed with ethylene oxide (1.1 equiv.) quantitatively output from an ethylene oxide conveying system, and subjected to a ring-opening reaction in another X-shaped microreactor to obtain a final product metronidazole. The metronidazole-containing reaction liquid entered a spiral channel with a zigzag baffle to remove formic acid by condensation and recovery. The residual reaction liquid was adjusted to pH 2-4, and filtered to recover 2-methyl-5-nitroimidazole. The filtrate was further adjusted to pH 9-12, and filtered to obtain crude metronidazole. The crude metronidazole is decolored, crystallized, filtered and dried to obtain pure metronidazole with a purity greater than 99.9%. Compared to the conventional one-through synthesis, the consumption of sulfuric acid of this embodiment was reduced by 45%; the recovery rate of formic acid was 95%; a one-through yield of metronidazole was 75%; and the yield of 2-methyl-5-nitroimidazole reached 93% after repeated recycling.
An aqueous glyoxal solution was mixed with an aqueous acetaldehyde water solution in a molar ratio of 1:1 to obtain a reagent A. The reagent A and aqueous ammonia (1.2 equiv., reagent B) were pumped to a homocentric-square mixer through a plunger pump, fully mixed and reacted in an X-shaped microreactor to produce a 2-methylimidazole-containing reaction mixture. The 2-methylimidazole-containing reaction mixture is treated under nitrogen purging and heating condition in a zigzag baffle-filled vertical channel to be concentrated and remove low-boiling-point compounds and water. The resultant 2-methylimidazole was mixed with a 70% nitric acid solution (1.2 equiv.) to obtain a reagent C, which was mixed with concentrated sulfuric acid in another homocentric-square mixer and then reacted in another X-shaped microreactor to produce a 2-methyl-5-nitroimidazole-containing reaction mixture. The 2-methyl-5-nitroimidazole-containing reaction mixture was conveyed to a negative-pressure tank to remove the unreacted nitric acid, so as to obtain a 2-methyl-5-nitroimidazole sulfuric acid solution. The 2-methyl-5-nitroimidazole sulfuric acid solution was used to replace the concentrated sulfuric acid to participate in the nitration of the 2-methylimidazole to produce a concentrated 2-methyl-5-nitroimidazole sulfuric acid solution as reagent D. In this way, one batch of sulfuric acid was used to participate in two batches of 2-methylimidazole nitration, reducing the consumption of sulfuric acid. The reagent D was mixed with formic acid and then mixed with ethylene oxide (1.1 equiv.) quantitatively output from an ethylene oxide conveying system, and subjected to a ring-opening reaction in another X-shaped microreactor to obtain a final product metronidazole. The metronidazole-containing reaction liquid entered a spiral channel with a zigzag baffle to remove formic acid using nitrogen purging and preheating by condensation and recovery. The residual reaction liquid was adjusted to pH 2-4, and filtered to recover 2-methyl-5-nitroimidazole. The filtrate was further adjusted to pH 9-12, and filtered to obtain crude metronidazole. The crude metronidazole is decolored, crystallized, filtered and dried to obtain pure metronidazole with a purity greater than 99.9%. Compared to the conventional one-through synthesis, the consumption of sulfuric acid of this embodiment was reduced by 45%; the recovery rate of formic acid was 98%; a one-through yield of metronidazole was 82%; and the yield of 2-methyl-5-nitroimidazole reached 95% after repeated recycling.
It should be noted that the embodiments described above are only to illustrate this application rather than limiting the scope of this application. Therefore, any other changes and modifications made by those skilled in the art without departing from the spirit of the application shall fall within the scope of this application defined by the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202311442699.2 | Nov 2023 | CN | national |
