CN108129393A - A kind of method of by-product and solvent recycled in metronidazole production - Google Patents
A kind of method of by-product and solvent recycled in metronidazole production Download PDFInfo
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- CN108129393A CN108129393A CN201711396636.2A CN201711396636A CN108129393A CN 108129393 A CN108129393 A CN 108129393A CN 201711396636 A CN201711396636 A CN 201711396636A CN 108129393 A CN108129393 A CN 108129393A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
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Abstract
The present invention provides a kind of method of by-product and solvent recycled in metronidazole production, the corresponding formic acid esters of low-carbon alcohols separated will be distilled in the method for the present invention to mix with steaming raffinate, stirring, the corresponding formic acid esters of low-carbon alcohols carries out ester exchange reaction with the ethylene glycol steamed in raffinate and obtains formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, strengthen the boiling point that heat is brought rapidly up the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols, and isolate the corresponding formic acid esters of the low-carbon alcohols, it obtains steaming raffinate simultaneously；And by above step repetitive operation, until reaching 95% to ethylene glycol ester rate in raffinate is steamed with gas chromatographic detection, the steaming raffinate of formic acid glycol ester and unconverted ethylene glycol is finally obtained.The formic acid glycol ester of generation puts into next reaction step, serves as solvent, reduces formic acid solvent dosage while improves the utilization rate of ethylene oxide, has saved production cost.
Description
Technical field
The invention belongs to by-product and solvent recycleds in organic synthesis field more particularly to a kind of production of metronidazole
Method.
Background technology
Metronidazole is white or yellowish crystallization or crystalline powder, for treating enteron aisle and parenteral amcbiasis (such as
Amebic abscess, pleura amcbiasis etc.).It can also be used to treat trichomoniasis, balantidiasis and cutaneous Leishmaniasis, wheat
That imperial nematode infections of ground etc..It is also widely used in the treatment of anaerobic infection at present, anti-anaerobism is used as by the World Health Organization (WHO)
The choice drug of bacterium.
The current technology for synthesizing metronidazole is that 2- 5-nitro imidazoles are dissolved in formic acid, is gradually added at 30-40 DEG C
Enter ethylene oxide, and sulfuric acid is added among charging.It finishes, reaction 1h must be hydroxylated liquid.With sodium hydroxide solution, liquid tune will be hydroxylated
To pH=10, cooling is placed, is crystallized, filtering obtains metronidazole.
A kind of method that formic acid solvent is recycled in metronidazole production process of patent of invention of my application
(201610203339.7), methanol first is added in into hydroxylation liquid, esterification occurs, distills to obtain formic acid esters；Again into steaming raffinate
It adds in sodium hydroxide solution and is adjusted to pH=10, place cooling, crystallize, filtering obtains metronidazole；Then moisture content in filtrate is evaporated, is put
Cooling is put, is crystallized, filtering obtains sodium sulphate；It is finally evaporated under reduced pressure, obtains the by-products such as ethylene glycol and its ether.But current ethylene glycol and
The by-products such as its ether can only make fuel, and value is little, some enterprise's direct emissions.The methyl formate of recycling can only also go out at a low price
It sells.
Existing metronidazole synthesis technology, the utilization rate of raw material ethylene oxide only have 20%.Utility model patent metronidazole hydroxyl
Change reaction kettle (201020227836.2), by the increase of the ratio between autoclave body height and internal diameter；Utility model patent metronidazole hydroxylation reaction
Kettle ethylene oxide access equipment (201020247143.X) improves the distribution situation for being passed through gas；A kind of raising first of patent of invention
The Processes and apparatus (201310215220.1) of nitre azoles raw materials for production utilization rate of ethylene oxide, using three kettles series winding and multi-stage condensing
Measure.Although above three patent all increases ethylene oxide and the catalytic chance of material, epoxy to some extent
The utilization rate of ethane is still no more than 25%.This is because ethylene oxide reacts generation formic acid glycol ester with formic acid, it is hydroxylated in liquid
There are following chemical reaction equilibriums：
Balance must be promoted otherwise to be reduced to the movement of generation metronidazole direction with the presence of enough formic acid glycol esters
The hydroxylation rate of -5 nitroimidazole of 2- methyl.Patent of invention one kind of my application by-product cyclic in metronidazole production process recycles
The method (201710581168.X) applied mechanically, by the by-products circulating sleeve such as the ethylene glycol generated in metronidazole building-up process and its ether
With ethylene glycol is reacted with solvent formic acid under acid catalysis, generates formic acid glycol ester and water.Ethylene glycol can replace epoxy second
Ring reacts the generation required formic acid glycol ester of equilibrium system with formic acid, it appears that can reduce the usage amount of ethylene oxide, carry
Its high utilization rate, but it generates water simultaneously, and water meets ethylene oxide and generates ethylene glycol again, counteracts above-mentioned ethylene oxide usage amount
It reduces.So while by-product ethylene glycol is added, it is necessary to try to reduce the content of moisture content.
Invention content
For above-mentioned technical problem, the side of by-product and solvent recycled in being produced the present invention provides a kind of metronidazole
Method.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：
A kind of method of by-product and solvent recycled in metronidazole production, which is characterized in that include the following steps：
Step 1)：2- 5-nitro imidazoles are added in reaction kettle, the formic acid solvent of more than 85% concentration, which is added dropwise, makes 2-
5-nitro imidazole dissolves, and ethylene oxide is gradually added at 30-40 DEG C, while add the sulfuric acid or hair of more than 98% concentration
Cigarette sulfuric acid is warming up to 85-95 DEG C, and reaction 1h must be hydroxylated liquid；
Step 2)：Low-carbon alcohols are added in, control temperature model below 10 DEG C of the boiling point of formic acid esters corresponding higher than the low-carbon alcohols
In enclosing, esterification is carried out, distillation condenses the steam steamed, obtains the corresponding formic acid esters of the low-carbon alcohols；
Step 3)：Temperature is risen above below 10 DEG C of the low-carbon alcohols boiling point in range, and distillation obtains low-carbon alcohols；
Step 4)：Liquid to be hydroxylated is cooled to 10 DEG C, and pH=10 is adjusted to alkali hydroxide soln, places cooling, knot
Metronidazole is obtained by filtration in crystalline substance；
Step 5)：The filtrate that step 4) is obtained is concentrated by evaporation, cooling, crystallization, filters, and obtains the production of alkali metal sulfates solid
Product；
Step 6)：The filtrate that vacuum distillation step 5) obtains, obtains ethylene glycol by-product；
Step 7)：The ethylene glycol mixing that the corresponding formic acid esters of low-carbon alcohols and step 6) that step 2) is obtained obtain, is stirred
It mixes, carries out ester exchange reaction and obtain formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, it is fast to strengthen heat
Speed is warming up to the boiling point of the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols,
And the corresponding formic acid esters of the low-carbon alcohols is isolated, while obtain steaming raffinate；
Step 8)：The corresponding formic acid esters of low-carbon alcohols that distillation is separated is led back and is steamed in raffinate, is mixed, is stirred, is carried out
Ester exchange reaction obtains formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, strengthens heat and is brought rapidly up
To the boiling point of the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols, and detach
Go out the corresponding formic acid esters of the low-carbon alcohols, while obtain steaming raffinate；This step is repeated 8) until residual to steaming with gas chromatographic detection
Ethylene glycol ester rate reaches 95% in liquid, finally obtains the steaming raffinate of formic acid glycol ester and unconverted ethylene glycol；
Step 9)：It takes 2- 5-nitro imidazoles and steaming raffinate that step 8) finally obtains is added in reaction kettle, be added dropwise dense
The formic acid solvent of more than 85% degree dissolves 2- 5-nitro imidazoles, and ethylene oxide is gradually added at 30-40 DEG C, is added simultaneously
Add the sulfuric acid or oleum of more than 98% concentration, be warming up to 85-95 DEG C, reaction 1h must be hydroxylated liquid；
Step 10)：By step 2) to step 9) circulate operation.
Further, the low-carbon alcohols are methanol, and the corresponding formic acid esters of the low-carbon alcohols is methyl formate.
Further, the low-carbon alcohols are ethyl alcohol, and the corresponding formic acid esters of the low-carbon alcohols is Ethyl formate.
Further, the low-carbon alcohols are propyl alcohol, and the corresponding formic acid esters of the low-carbon alcohols is propyl formate.
Further, alkali hydroxide soln described in step 4) is sodium hydroxide solution, alkali metal sulphur in step 5)
Hydrochlorate is sodium sulphate.
Step 8) of the present invention, which leads back the corresponding formic acid esters of low-carbon alcohols that distillation is separated, steams in raffinate, mixes, stirring,
The corresponding formic acid esters of low-carbon alcohols carries out ester exchange reaction with the ethylene glycol steamed in raffinate and obtains formic acid glycol ester and the low-carbon
Alcohol after ester exchange reaction reaches balance, strengthens the boiling point that heat is brought rapidly up the low-carbon alcohols, and flash distillation is unconverted low
The corresponding formic acid esters of carbon alcohol and converted product low-carbon alcohols, and the corresponding formic acid esters of the low-carbon alcohols is isolated, while obtain steaming residual
Liquid；This step is repeated 8) until reaching 95% to ethylene glycol ester rate in raffinate is steamed with gas chromatographic detection, finally obtains first
The steaming raffinate of sour glycol ester and unconverted ethylene glycol.By said mixture in metronidazole production process recycled, obtain
To formic acid glycol ester serve as solvent in step 9), reduce formic acid solvent dosage while improve the utilization of ethylene oxide
Rate has saved production cost.
Specific embodiment
Embodiment 1
Step 1)：2- 5-nitro imidazoles are added in reaction kettle, the formic acid solvent of concentration 85%, which is added dropwise, makes 2- first
Base -5- nitroimidazoles dissolve, and ethylene oxide are gradually added at 30-40 DEG C, while add the sulfuric acid of concentration 98%, are warming up to 95
DEG C, reaction 1h must be hydroxylated liquid；
Step 2)：Methanol is added in, control temperature in range, be esterified anti-below 10 DEG C of the boiling point higher than methyl formate
Should, distillation condenses the steam steamed, obtains methyl formate；
Step 3)：Temperature is risen above below 10 DEG C of methanol boiling point in range, and distillation obtains methanol；
Step 4)：Liquid to be hydroxylated is cooled to 10 DEG C, is adjusted to pH=10 with sodium hydroxide solution, places cooling, crystallizes, filtering
Obtain metronidazole；
Step 5)：The filtrate that step 4) is obtained is concentrated by evaporation, cooling, crystallization, filters, and obtains solid sodium sulfate product；
Step 6)：The filtrate that vacuum distillation step 5) obtains, obtains ethylene glycol by-product；
Step 7)：The ethylene glycol mixing that the methyl formate and step 6) that step 2) is obtained obtain, stirring carry out ester friendship
It changes and formic acid glycol ester and methanol is obtained by the reaction, after ester exchange reaction reaches balance, strengthen the boiling that heat is brought rapidly up methanol
Point, the unconverted methyl formate of flash distillation and converted product methanol, and the methyl formate is isolated, while obtain steaming residual
Liquid；
Step 8)：The corresponding formic acid esters of low-carbon alcohols that distillation is separated is led back and is steamed in raffinate, is mixed, is stirred, is carried out
Ester exchange reaction obtains formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, strengthens heat and is brought rapidly up
To the boiling point of the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols, and detach
Go out the corresponding formic acid esters of the low-carbon alcohols, while obtain steaming raffinate；This step is repeated 8) until residual to steaming with gas chromatographic detection
Ethylene glycol ester rate reaches 95% in liquid, finally obtains the steaming raffinate of formic acid glycol ester and unconverted ethylene glycol；
Step 9)：It takes 2- 5-nitro imidazoles and steaming raffinate that step 8) finally obtains is added in reaction kettle, be added dropwise dense
The formic acid solvent of degree 85% dissolves 2- 5-nitro imidazoles, ethylene oxide is gradually added at 30-40 DEG C, while add dense
The sulfuric acid of degree 98% is warming up to 85-95 DEG C, and reaction 1h must be hydroxylated liquid；
Step 10)：By step 2) to step 9) circulate operation.
Embodiment 2
Step 1)：2- 5-nitro imidazoles are added in reaction kettle, the formic acid solvent of concentration 95%, which is added dropwise, makes 2- first
Base -5- nitroimidazoles dissolve, and ethylene oxide are gradually added at 30-40 DEG C, while add the sulfuric acid of concentration 98%, are warming up to 95
DEG C, reaction 1h must be hydroxylated liquid；
Step 2)：Methanol is added in, control temperature in range, be esterified anti-below 10 DEG C of the boiling point higher than methyl formate
Should, distillation condenses the steam steamed, obtains methyl formate；
Step 3)：Temperature is risen above below 10 DEG C of methanol boiling point in range, and distillation obtains methanol；
Step 4)：Liquid to be hydroxylated is cooled to 10 DEG C, is adjusted to pH=10 with sodium hydroxide solution, places cooling, crystallizes, filtering
Obtain metronidazole；
Step 5)：The filtrate that step 4) is obtained is concentrated by evaporation, cooling, crystallization, filters, and obtains solid sodium sulfate product；
Step 6)：The filtrate that vacuum distillation step 5) obtains, obtains ethylene glycol by-product；
Step 7)：The ethylene glycol mixing that the methyl formate and step 6) that step 2) is obtained obtain, stirring carry out ester friendship
It changes and formic acid glycol ester and methanol is obtained by the reaction, after ester exchange reaction reaches balance, strengthen the boiling that heat is brought rapidly up methanol
Point, the unconverted methyl formate of flash distillation and converted product methanol, and the methyl formate is isolated, while obtain steaming residual
Liquid；
Step 8)：The corresponding formic acid esters of low-carbon alcohols that distillation is separated is led back and is steamed in raffinate, is mixed, is stirred, is carried out
Ester exchange reaction obtains formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, strengthens heat and is brought rapidly up
To the boiling point of the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols, and detach
Go out the corresponding formic acid esters of the low-carbon alcohols, while obtain steaming raffinate；This step is repeated 8) until residual to steaming with gas chromatographic detection
Ethylene glycol ester rate reaches 95% in liquid, finally obtains the steaming raffinate of formic acid glycol ester and unconverted ethylene glycol；
Step 9)：It takes 2- 5-nitro imidazoles and steaming raffinate that step 8) finally obtains is added in reaction kettle, be added dropwise dense
The formic acid solvent of degree 85% dissolves 2- 5-nitro imidazoles, ethylene oxide is gradually added at 30-40 DEG C, while add dense
The sulfuric acid of degree 98% is warming up to 85-95 DEG C, and reaction 1h must be hydroxylated liquid；
Step 10)：By step 2) to step 9) circulate operation.
Embodiment 3
Step 1)：2- 5-nitro imidazoles are added in reaction kettle, the formic acid solvent of concentration 85%, which is added dropwise, makes 2- first
Base -5- nitroimidazoles dissolve, and ethylene oxide are gradually added at 30-40 DEG C, while add the oleum of concentration 105%, heat up
To 95 DEG C, reaction 1h must be hydroxylated liquid；
Step 2)：Methanol is added in, control temperature in range, be esterified anti-below 10 DEG C of the boiling point higher than methyl formate
Should, distillation condenses the steam steamed, obtains methyl formate；
Step 3)：Temperature is risen above below 10 DEG C of methanol boiling point in range, and distillation obtains methanol；
Step 4)：Liquid to be hydroxylated is cooled to 10 DEG C, is adjusted to pH=10 with sodium hydroxide solution, places cooling, crystallizes, filtering
Obtain metronidazole；
Step 5)：The filtrate that step 4) is obtained is concentrated by evaporation, cooling, crystallization, filters, and obtains solid sodium sulfate product；
Step 6)：The filtrate that vacuum distillation step 5) obtains, obtains ethylene glycol by-product；
Step 7)：The ethylene glycol mixing that the methyl formate and step 6) that step 2) is obtained obtain, stirring carry out ester friendship
It changes and formic acid glycol ester and methanol is obtained by the reaction, after ester exchange reaction reaches balance, strengthen the boiling that heat is brought rapidly up methanol
Point, the unconverted methyl formate of flash distillation and converted product methanol, and the methyl formate is isolated, while obtain steaming residual
Liquid；
Step 8)：The corresponding formic acid esters of low-carbon alcohols that distillation is separated is led back and is steamed in raffinate, is mixed, is stirred, is carried out
Ester exchange reaction obtains formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, strengthens heat and is brought rapidly up
To the boiling point of the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols, and detach
Go out the corresponding formic acid esters of the low-carbon alcohols, while obtain steaming raffinate；This step is repeated 8) until residual to steaming with gas chromatographic detection
Ethylene glycol ester rate reaches 95% in liquid, finally obtains the steaming raffinate of formic acid glycol ester and unconverted ethylene glycol；
Step 9)：It takes 2- 5-nitro imidazoles and steaming raffinate that step 8) finally obtains is added in reaction kettle, be added dropwise dense
The formic acid solvent of degree 85% dissolves 2- 5-nitro imidazoles, ethylene oxide is gradually added at 30-40 DEG C, while add dense
The oleum of degree 105% is warming up to 85-95 DEG C, and reaction 1h must be hydroxylated liquid；
Step 10)：By step 2) to step 9) circulate operation.
Claims (5)
1. a kind of method of by-product and solvent recycled in metronidazole production, which is characterized in that include the following steps：
Step 1)：2- 5-nitro imidazoles are added in reaction kettle, the formic acid solvent of more than 85% concentration, which is added dropwise, makes 2- first
Base -5- nitroimidazoles dissolve, and ethylene oxide are gradually added at 30-40 DEG C, while add sulfuric acid or the smoke of more than 98% concentration
Sulfuric acid is warming up to 85-95 DEG C, and reaction 1h must be hydroxylated liquid；
Step 2)：Low-carbon alcohols are added in, control temperature below 10 DEG C of the boiling point of formic acid esters corresponding higher than the low-carbon alcohols in range,
Esterification is carried out, distillation condenses the steam steamed, obtains the corresponding formic acid esters of the low-carbon alcohols；
Step 3)：Temperature is risen above below 10 DEG C of the low-carbon alcohols boiling point in range, and distillation obtains low-carbon alcohols；
Step 4)：Liquid to be hydroxylated is cooled to 10 DEG C, and pH=10 is adjusted to alkali hydroxide soln, places cooling, crystallization, mistake
Filter obtains metronidazole；
Step 5)：The filtrate that step 4) is obtained is concentrated by evaporation, cooling, crystallization, filters, and obtains alkali metal sulfates solid product；
Step 6)：The filtrate that vacuum distillation step 5) obtains, obtains ethylene glycol by-product；
Step 7)：The ethylene glycol mixing that the corresponding formic acid esters of low-carbon alcohols and step 6) that step 2) is obtained obtain, stirring, into
Row ester exchange reaction obtains formic acid glycol ester and the low-carbon alcohols, after ester exchange reaction reaches balance, strengthens the rapid liter of heat
Temperature arrives the boiling point of the low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols, and divides
The corresponding formic acid esters of the low-carbon alcohols is separated out, while obtains steaming raffinate；
Step 8)：The corresponding formic acid esters of low-carbon alcohols that distillation is separated is led back and is steamed in raffinate, is mixed, stirring carries out ester friendship
It changes and formic acid glycol ester and the low-carbon alcohols is obtained by the reaction, after ester exchange reaction reaches balance, strengthen heat and be brought rapidly up institute
The boiling point of low-carbon alcohols, the corresponding formic acid esters of the unconverted low-carbon alcohols of flash distillation and converted product low-carbon alcohols are stated, and isolate institute
The corresponding formic acid esters of low-carbon alcohols is stated, while obtains steaming raffinate；This step is repeated 8) until in gas chromatographic detection to steaming raffinate
Ethylene glycol ester rate reaches 95%, finally obtains the steaming raffinate of formic acid glycol ester and unconverted ethylene glycol；
Step 9)：It takes 2- 5-nitro imidazoles and steaming raffinate that step 8) finally obtains is added in reaction kettle, concentration is added dropwise
More than 85% formic acid solvent dissolves 2- 5-nitro imidazoles, and ethylene oxide is gradually added at 30-40 DEG C, is added simultaneously
The sulfuric acid or oleum of more than 98% concentration are warming up to 85-95 DEG C, and reaction 1h must be hydroxylated liquid；
Step 10)：By step 2) to step 9) circulate operation.
2. the method for by-product and solvent recycled in metronidazole production according to claim 1, which is characterized in that institute
Low-carbon alcohols are stated as methanol, the corresponding formic acid esters of the low-carbon alcohols is methyl formate.
3. the method for by-product and solvent recycled in metronidazole production according to claim 1, which is characterized in that institute
Low-carbon alcohols are stated as ethyl alcohol, the corresponding formic acid esters of the low-carbon alcohols is Ethyl formate.
4. the method for by-product and solvent recycled in metronidazole production according to claim 1, which is characterized in that institute
Low-carbon alcohols are stated as propyl alcohol, the corresponding formic acid esters of the low-carbon alcohols is propyl formate.
5. metronidazole synthetic method as claimed in any of claims 1 to 4, which is characterized in that described in step 4)
Alkali hydroxide soln is sodium hydroxide solution, and alkali metal sulfates are sodium sulphate in step 5).
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| CN109293573A (en) * | 2018-11-29 | 2019-02-01 | 黄冈师范学院 | The method, apparatus and application of ethylene glycol by-product recycled in metronidazole production |
| CN109336822A (en) * | 2018-11-27 | 2019-02-15 | 湖北省宏源药业科技股份有限公司 | A kind of metronidazole production method |
| CN109438361A (en) * | 2018-11-29 | 2019-03-08 | 黄冈师范学院 | A kind of method that by-product ethylene glycol is applied in metronidazole production process |
| CN111303037A (en) * | 2019-05-29 | 2020-06-19 | 南京师范大学 | Zwitterionic oil-displacing agent and preparation method and application thereof |
| CN111574459A (en) * | 2020-05-15 | 2020-08-25 | 石家庄四药有限公司 | Preparation method of metronidazole |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336822A (en) * | 2018-11-27 | 2019-02-15 | 湖北省宏源药业科技股份有限公司 | A kind of metronidazole production method |
| CN109293573A (en) * | 2018-11-29 | 2019-02-01 | 黄冈师范学院 | The method, apparatus and application of ethylene glycol by-product recycled in metronidazole production |
| CN109438361A (en) * | 2018-11-29 | 2019-03-08 | 黄冈师范学院 | A kind of method that by-product ethylene glycol is applied in metronidazole production process |
| CN109293573B (en) * | 2018-11-29 | 2023-10-27 | 黄冈师范学院 | Method, device and application for recycling ethylene glycol byproducts in metronidazole production |
| CN111303037A (en) * | 2019-05-29 | 2020-06-19 | 南京师范大学 | Zwitterionic oil-displacing agent and preparation method and application thereof |
| CN111574459A (en) * | 2020-05-15 | 2020-08-25 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN111574459B (en) * | 2020-05-15 | 2021-05-04 | 石家庄四药有限公司 | Preparation method of metronidazole |
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