CN102321028B - Method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol - Google Patents
Method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol Download PDFInfo
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- CN102321028B CN102321028B CN 201110185009 CN201110185009A CN102321028B CN 102321028 B CN102321028 B CN 102321028B CN 201110185009 CN201110185009 CN 201110185009 CN 201110185009 A CN201110185009 A CN 201110185009A CN 102321028 B CN102321028 B CN 102321028B
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Abstract
The invention provides a method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol, which comprises the following steps: the mixed solution of 2-methyl-5-nitroimidazole, formic acid and sulfuric acid is prepared according to the mole ratio of 1:0.5-0.7:1.2-1.7; ethylene oxide and concentrated sulfuric acid with the mole ratio of 1:0.08-0.3 are alternately added into the mixed solution for 3-4 times; the reaction temperature is 72-108 DEG C, the reaction time is 2.5-5 hours, and after reaction, sodium hydroxide is added to regulate the PH value of the solution to 9.5-10.5, and a finished product is precipitated through crystallization; and a 2-methyl-5-nitroimidazole-1-ethanol finished product is obtained through purification. In the method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol provided by the invention, the mixed solution of formic acid and sulfuric acid is used as a solvent, the conversion rate and the yield are obviously improved, formic acid and sodium hydroxide consumption is less, and the production cost is low.
Description
Technical field
The present invention relates to a kind of method of synthetic Metronidazole, belong to technical field of organic chemistry.
Background technology
Metronidazole (having another name called metronidazole) is widely used a kind of microbiotic bulk drug in the medication chemistry industry, most of anerobes are had to powerful anti-microbial effect, and antimicrobial spectrum comprises that bacteroides fragilis belongs to and other Bacteroidess, fusiform bacilarmature, aerogenesis clostridium, Eubacterium, Wei Rong coccus, dyspepsiacoccus and peptostreptococcus etc.Simultaneously, Metronidazole can also be as the raw material of producing the medicines such as benzoic methyl nitroazole, tinidazole, and purposes is very extensive.
Metronidazole is usually prepared and is obtained by 2-5-nitro imidazole and ethylene oxide synthesis, and step comprises: the 2-5-nitro imidazole is dissolved in to the formic acid solution that concentration is 98%; Successively add oxyethane at 30-40 ℃ of temperature, and add sulfuric acid in the middle of reinforced; Finish, react 1 hour; Then reclaim under reduced pressure formic acid, be cooled to 10 ℃ after being dissolved in water, and filters; Then filtrate is adjusted to pH=10 with sodium hydroxide solution, places coolingly, refilter, be washed near in reconstruction; The water recrystallization; Finally use activated carbon decolorizing, obtain the metronidazole finished product.
But, there is open defect in the method for the synthetic Metronidazole of prior art: at first, the solubleness of 2-5-nitro imidazole in formic acid is not high, reduced the transformation efficiency of 2-5-nitro imidazole, and the yield rate of final product Metronidazole; Secondly, need the formic acid solution that working concentration is 98%, cost is higher; Again, the pH that reaction generates is lower, needs to use more sodium hydroxide to regulate the pH value, has increased production cost; Finally, reactor is used tank reactor, and material flow pattern is complete mixing flow, and the material back-mixing is large, has reduced reaction efficiency and finished product transformation efficiency.
Summary of the invention
The transformation efficiency of the 2-5-nitro imidazole existed for the method for the synthetic Metronidazole of prior art and the yield rate of final product Metronidazole are low, consume formic acid and amount of sodium hydroxide large, production cost is high, and the shortcomings and deficiencies that the reaction efficiency of tank reactor is low, a kind of method of synthetic Metronidazole is provided, use the mixing solutions of formic acid and sulfuric acid as solvent, significantly improved the yield rate of transformation efficiency and the final product Metronidazole of 2-5-nitro imidazole, and consume formic acid and sodium hydroxide less, production cost is low, and conversion unit adopts the tubular type recirculation reactor, reaction efficiency is high.
The present invention realizes that the technical scheme that technical purpose adopts is:
A kind of method of synthetic Metronidazole is characterized in that comprising the following steps:
(1) configure the mixing solutions of formic acid, sulfuric acid and 2-5-nitro imidazole and add in the tubular type recirculation reactor, wherein, the mass concentration of formic acid is 70%～98%, mole proportioning that the mass concentration of sulfuric acid is 90%～98%, 2-5-nitro imidazole, formic acid, sulfuric acid is 1:0.5～0.7:1.2～1.7;
(2) mixing solutions of configuration is added in the tubular type recirculation reactor, and be warming up to gradually 72～108 ℃;
(3) to alternately adding the vitriol oil 3～4 times that oxyethane and mass concentration are 90%～98% in the tubular type recirculation reactor, mole proportioning of described oxyethane and the vitriol oil is 1:0.08～0.3;
(4) keep 72～108 ℃ of the temperature of tubular type recirculation reactor, oxyethane and the 2-5-nitro imidazole generation Metronidazole that reacts, the reaction times is 2.5～5 hours;
(5) after completion of the reaction, solution is cooled to room temperature, adds water and stir, and the pH value that adds sodium hydroxide to adjust solution is 3.0～3.5, part Metronidazole crystallization;
(6) solution is cooled to room temperature again, after filtration, washing, decolouring, drying, obtains part Metronidazole finished product;
(7) continue to add sodium hydroxide to the solution after filtering, adjust pH to 9.5～10.5, residue Metronidazole crystallization, more after filtration, washing, decolouring, drying, obtain the Metronidazole finished product.
A kind of method of synthetic Metronidazole, in described step (3), mole proportioning of oxyethane and the vitriol oil is 1:0.1.
Compared with prior art, characteristics of the present invention are:
1. the mixing solutions that uses formic acid and sulfuric acid, as solvent, has good solvability to the 2-5-nitro imidazole, can effectively improve the yield rate of transformation efficiency and the final product Metronidazole of 2-5-nitro imidazole.
2. the formic acid solution concentration that solvent is used is 88%, and concentration, far below 98% formic acid solution of prior art, is used the formic acid solution of lower concentration effectively to reduce production costs.
3. the pH value of the mixing solutions that reaction generates is higher, and the sodium hydroxide of consumption is less, can effectively reduce production costs.
4. use the tubular type recirculation reactor, material flow pattern is plug flow, and the material back-mixing is little, and reaction efficiency and finished product transformation efficiency are high.
Embodiment
Embodiment 1
In the tubular type recirculation reactor stirred at the 500ML band, add the formic acid that 52 parts of mass concentrations are 70%, drip the sulfuric acid that 35 parts of mass concentrations are 95%, control temperature below 20 ℃, add again 80 parts of 2-5-nitro imidazoles, be configured to mixing solutions, and mixing solutions slowly is warmed up to 72 ℃.Then alternately add to the tubular type recirculation reactor sulfuric acid that oxyethane and mass concentration are 95%, the oxyethane add-on is respectively: 18,10,14 and 12 parts, sulphuric acid is respectively 6,3 and 2.5 parts.After alternately adding, keep 72 ℃ of tubular type recirculation reactor temperature, 2-5-nitro imidazole and reacting ethylene oxide, generate Metronidazole, 5 hours reaction times.Then will after reacted solution, be cooled to room temperature, stir after adding suitable quantity of water, it is 5 that hydro-oxidation sodium is regulated the pH value.Again solution is cooled to room temperature, after filtration, washing, decolouring, drying, obtains 2-5-nitro imidazole finished product 42 grams.Mother liquor after filtration continues to add sodium hydroxid, regulates pH value to 9.5, more after filtration, washing, decolouring, drying, obtain 2-5-nitro imidazole finished product 37.5 grams.The 2-5-nitro imidazole purity made is 99.8%, fusing point 160-161.5 ℃, the yield rate 73.3% of product.
Embodiment 2
In the tubular type recirculation reactor stirred at the 500ML band, add the formic acid that 43 parts of mass concentrations are 98%, drip the sulfuric acid that 38 parts of mass concentrations are 90%, control temperature below 20 ℃, add again 80 parts of 2-5-nitro imidazoles, be configured to mixing solutions, and mixing solutions slowly is warmed up to 85 ℃.Then alternately add to the tubular type recirculation reactor sulfuric acid that oxyethane and mass concentration are 90%, the oxyethane add-on is respectively: 20,12,14 and 9 parts, sulphuric acid is respectively 4,4 and 2 parts.After alternately adding, keep 85 ℃ of tubular type recirculation reactor temperature, 2-5-nitro imidazole and reacting ethylene oxide, generate Metronidazole, 2.5 hours reaction times.Then will after reacted solution, be cooled to room temperature, stir after adding suitable quantity of water, regulating the pH value with sodium hydroxide is 3.5.Again solution is cooled to room temperature, after filtration, washing, decolouring, drying, obtains 2-5-nitro imidazole 40 grams.Mother liquor after filtration continues to add sodium hydroxid, regulates pH value to 10, more after filtration, washing, decolouring, drying, obtain 2-5-nitro imidazole finished product 40.5 grams.The 2-5-nitro imidazole purity made is 99.8%, 160 ℃-161.5 ℃ of fusing points, the yield rate 75.2% of product.
Embodiment 3
In the tubular type recirculation reactor stirred at the 500ML band, add the formic acid that 46 parts of mass concentrations are 88%, drip the sulfuric acid that 30 parts of mass concentrations are 98%, control temperature below 20 ℃, add again 80 parts of 2-5-nitro imidazoles, be configured to mixing solutions, and mixing solutions slowly is warmed up to 108 ℃.Then alternately add to the tubular type recirculation reactor sulfuric acid that oxyethane and mass concentration are 98%, the oxyethane add-on is respectively: 20,12,14 and 9 parts, sulphuric acid is respectively 4,4 and 2 parts.After alternately adding, keep 108 ℃ of tubular type recirculation reactor temperature, 2-5-nitro imidazole and reacting ethylene oxide, generate Metronidazole, 3.5 hours reaction times.Then will after reacted solution, be cooled to room temperature, stir after adding suitable quantity of water, it is 4 that hydro-oxidation sodium is regulated the pH value.Again solution is cooled to room temperature, after filtration, washing, decolouring, drying, obtains 2-5-nitro imidazole finished product 43 grams.Mother liquor after filtration continues to add sodium hydroxid, regulates pH value to 10.5, more after filtration, washing, decolouring, drying, obtain 2-5-nitro imidazole finished product 36 grams.The 2-5-nitro imidazole purity made is 99.8%, 160 ℃-161.5 ℃ of fusing points, the yield rate 72.1% of product.
Claims (2)
1. the method for a synthetic Metronidazole is characterized in that comprising the following steps:
(1) configure the mixing solutions of formic acid, sulfuric acid and 2-5-nitro imidazole and add in the tubular type recirculation reactor, wherein, the mass concentration of formic acid is 70%～98%, mole proportioning that the mass concentration of sulfuric acid is 90%～98%, 2-5-nitro imidazole, formic acid, sulfuric acid is 1:0.5～0.7:1.2～1.7;
(2) mixing solutions of configuration is added in the tubular type recirculation reactor, and be warming up to gradually 72～108 ℃;
(3) to alternately adding the vitriol oil 3～4 times that oxyethane and mass concentration are 90%～98% in the tubular type recirculation reactor, mole proportioning of described oxyethane and the vitriol oil is 1:0.08～0.3;
(4) keep 72～108 ℃ of the temperature of tubular type recirculation reactor, oxyethane and the 2-5-nitro imidazole generation Metronidazole that reacts, the reaction times is 2.5～5 hours;
(5) after completion of the reaction, solution is cooled to room temperature, adds water and stir, and the pH value that adds sodium hydroxide to adjust solution is 3.0～3.5, part Metronidazole crystallization;
(6) solution is cooled to room temperature again, after filtration, washing, decolouring, drying, obtains part Metronidazole finished product;
(7) continue to add sodium hydroxide to the solution after filtering, adjust pH to 9.5～10.5, residue Metronidazole crystallization, more after filtration, washing, decolouring, drying, obtain the Metronidazole finished product.
2. the method for a kind of synthetic Metronidazole according to claim 1 is characterized in that: in described step (3), mole proportioning of oxyethane and the vitriol oil is 1:0.1.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102911122B (en) * | 2012-11-08 | 2015-01-21 | 兰亚朝 | Metronidazole preparation method |
| CN104072424A (en) * | 2013-03-29 | 2014-10-01 | 黄冈师范学院 | Environmental novel co-production technology of metronidazole and composite fertilizer |
| CN104177297B (en) * | 2013-05-20 | 2016-09-28 | 东港市宏达制药有限公司 | A kind of metronidazole API synthesis clean production method |
| CN103483265B (en) * | 2013-09-05 | 2015-07-15 | 湖北省宏源药业科技股份有限公司 | Metronidazole production method |
| CN110172039A (en) * | 2018-05-11 | 2019-08-27 | 武汉武药制药有限公司 | A kind of method of solid acid catalysis synthesis metronidazole |
| CN109289744B (en) * | 2018-11-30 | 2023-10-03 | 黄冈师范学院 | Metronidazole production method, device and application for improving nitric acid utilization rate |
| CN109776425A (en) * | 2019-03-25 | 2019-05-21 | 河池市金兴生物科技有限公司 | The conversion recyclable device of formic acid solvent in metronidazole production process |
| CN110669011A (en) * | 2019-10-31 | 2020-01-10 | 湖北大学 | Novel microtubule reaction process for synthesizing metronidazole raw material medicine and application thereof |
| CN111848524B (en) * | 2020-07-27 | 2022-02-18 | 南京甘倍加生物科技有限责任公司 | Method for synthesizing metronidazole at low temperature |
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| US3275649A (en) * | 1966-09-27 | Process for the preparation of | ||
| CN1035288A (en) * | 1988-01-15 | 1989-09-06 | 罗纳-布朗克制药公司 | The preparation method of 1-hydroxyalkyl-5-nitroimidazole |
| CN1035289A (en) * | 1988-01-15 | 1989-09-06 | 罗纳-普兰克制药公司 | The preparation method of 1-hydroxyalkyl-2-methyl-5-nitro imidazoles |
| CN1055536A (en) * | 1990-03-12 | 1991-10-23 | 罗纳-布朗克·罗莱尔股份有限公司 | The preparation method of 1-hydroxyalkyl-5-nitroimidazole |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3275649A (en) * | 1966-09-27 | Process for the preparation of | ||
| CN1035288A (en) * | 1988-01-15 | 1989-09-06 | 罗纳-布朗克制药公司 | The preparation method of 1-hydroxyalkyl-5-nitroimidazole |
| CN1035289A (en) * | 1988-01-15 | 1989-09-06 | 罗纳-普兰克制药公司 | The preparation method of 1-hydroxyalkyl-2-methyl-5-nitro imidazoles |
| CN1055536A (en) * | 1990-03-12 | 1991-10-23 | 罗纳-布朗克·罗莱尔股份有限公司 | The preparation method of 1-hydroxyalkyl-5-nitroimidazole |
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Address after: 438600 Fengshan City, Huanggang province Luotian County, north of the town of water Yi Road, No. 428 Patentee after: HUBEI HONGYUAN PHARMACEUTICAL TECHNOLOGY CO., LTD. Address before: 438600 Fengshan City, Huanggang province Luotian County, north of the town of water Yi Road, No. 428 Patentee before: Hubei Hongyuan Pharmaceutical Co., Ltd. |
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Denomination of invention: A method for synthesizing 2-methyl-5-nitroimidazole-1-ethanol Effective date of registration: 20220512 Granted publication date: 20131225 Pledgee: Industrial and Commercial Bank of China Limited Luotian sub branch Pledgor: HUBEI HONGYUAN PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: Y2022420000116 |