CN101747281A - Method for preparing 2-nitroimidazole - Google Patents
Method for preparing 2-nitroimidazole Download PDFInfo
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- CN101747281A CN101747281A CN200910273374A CN200910273374A CN101747281A CN 101747281 A CN101747281 A CN 101747281A CN 200910273374 A CN200910273374 A CN 200910273374A CN 200910273374 A CN200910273374 A CN 200910273374A CN 101747281 A CN101747281 A CN 101747281A
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Abstract
The invention discloses a method for preparing 2-nitroimidazole, which comprises the following steps of: adding 40% of fluoboric acid and water in 2-amino-imidazole sulfate; dropwise adding a sodium nitrite aqueous solution at -30-3 DEG C while stirring to obtain a diazonium salt; pouring the diazonium salt into a copper salt aqueous solution or a mixed catalyst aqueous solution of the copper salt which is -5-10 DEG C while stirring; adding sodium nitrite and stirring for 2-9 hours at room temperature and then adjusting the pH value to be 2; extracting continuously by using an extractor, concentrating an extract and standing to separate out a rough product; and recentralizing the rough product, wherein mother liquid can be added in an extraction kettle for recycling. The invention has the advantages of reducing the volume of reaction liquid, lowering the consumption of the extract during recycling the extract, improving the yield and facilitating the industrialized production.
Description
Technical field
The invention belongs to technical field of organic chemistry, be specifically related to a kind of synthetic method of 2-nitroimidazole.
Background technology
The 2-nitroimidazole is the intermediate of tumor radiotherapy sensitive-increasing agent Misonidazole (Misonidazole).The synthetic method of 2-nitroimidazole mainly contains following several at present:
1.J.Am.Chem.Soc., 1965,87 (2), 387-9. it use copper sulfate to make catalyzer, placed 16 hours, and nitric acid carries out acidifying, and purification process is the recrystallize that distils earlier, and its productive rate has 40%.
2. Chinese Journal of Pharmaceuticals, 1994,25 (4), 181 and Chinese Journal of Pharmaceuticals, 2001,32 (12), the described method of 557-8 is to carry out diazotization with fluoroboric acid, has reacted the back with extracting crystallization, productive rate 55～66% behind the hcl acidifying.
3. after the described method of patent CN1461749 is diazotization, used catalyzer 4-lutidine in mantoquita, reaction finishes the back with re-using efficient extraction kettle extraction 20 hours after the hydrochloric acid acid adjustment, revolves the steaming post crystallization.
There is following shortcoming in aforesaid method: method one, and used long reaction time, yield are low excessively; Method two, reaction solution is more during extraction, causes extraction efficiency not high, and the extraction liquid of use is too much; Method three, reaction solution is more during extraction causes the extraction time also longer, catalyzer 4-lutidine large usage quantity, cost is high.
Summary of the invention
Problem to be solved by this invention is the preparation method who proposes a kind of 2-nitroimidazole, and this method can reduce cost, and improves productive rate, improves product purity.
Technical scheme provided by the invention is:
A kind of preparation method of 2-nitroimidazole comprises the steps:
1) preparation of diazonium salt: add fluoroboric acid and water in 2-aminooimidazole vitriol ,-30 ℃～3 ℃ stirrings drip the aqueous solution of Sodium Nitrite down, obtain diazonium salt;
2) preparation of 2-nitroimidazole: in the aqueous solution that the following mixed catalyst of the above-mentioned diazonium salt that makes being poured into-5～10 ℃ mantoquita of stirring is formed, add Sodium Nitrite again, transferring pH after stirring at room 2-9 hour is 2, extract with extraction plant then, extraction liquid concentrates, leave standstill and separate out thick product, thick product can obtain the 2-nitroimidazole with ethyl alcohol recrystallization; The mixed catalyst of used mantoquita is made up of mantoquita and dipyridyl, quaternary ammonium salt or pyridinium salt.
In above-mentioned steps 2) with before the extraction plant extraction, exchange 1/4～3/4 the water that reaction solution decompression behind the pH steams the reaction solution cumulative volume.
The mass ratio of above-mentioned mantoquita and dipyridyl, quaternary ammonium salt or pyridinium salt is 100: 1～10: 1.
In above-mentioned steps 1) in, 2-aminooimidazole vitriol: fluoroboric acid: the mol ratio of Sodium Nitrite is 1: 1～100: 1～100; Preferred 1: 4～8: 4～8.
In above-mentioned steps 1) in the concentration of aqueous solution of used Sodium Nitrite be 0.001～0.8g/mL.
Described mantoquita is cupric nitrate or copper sulfate.
Above-mentioned steps 1) temperature of preparation diazonium salt is-10～-3 ℃.
Above-mentioned steps 1) regulating the used acid of pH is hydrochloric acid or nitric acid.
The above-mentioned recrystallization solvent for use of the present invention is methyl alcohol, ethanol, propyl alcohol or propyl carbinol.
The present invention uses mantoquita and pyridinium salt, and the mixed catalyst that dipyridyl or quaternary ammonium salt are formed has improved reaction yield greatly, uses comparatively cheap catalyzer simultaneously, and consumption is less, has effectively controlled cost, helps suitability for industrialized production.
The present invention adopts first extraction, and after having extracted, the non-direct evaporate to dryness of extraction liquid is directly separated out crystal can improve product purity but concentrate, and is good inadequately if direct evaporate to dryness recrystallize obtains product color.Simultaneously Recycling Mother Solution makes and is used as next step extraction liquid and can further improve productive rate.
In addition, the present invention can steam the portion water in the reaction solution before the extraction of preparation 2-nitroimidazole, to reduce the reaction solution volume, save extraction solvent, improves extraction efficiency, shortens the extraction time.Reduce device volume simultaneously, saved cost.
Embodiment
The present invention further is illustrated by following unrestriced embodiment, but needs to understand described embodiment only in order to explanation the present invention, but not in order to limit the scope of the invention.
Embodiment 1. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40wt% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 0 ℃, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, uses ethyl acetate extraction 12 hours in liquid liquid extraction plant, and the extraction liquid reconcentration is to 1/4 of cumulative volume, separate out light yellow crystal 10.3g yield 80% after leaving standstill cooling, mother liquor gives over to extraction next time and uses.
Embodiment 2. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 0 ℃, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, in liquid liquid extraction plant, use ethyl acetate extraction 12 hours, the part extraction liquid is with the mother liquor that reclaimed among the last embodiment, extracted back extraction liquid reconcentration to 1/4 of cumulative volume, left standstill cooling and separate out light yellow crystal 11.0g, yield 86%.
Comparative example 1
In Erlenmeyer flask, add 2-aminooimidazole vitriol 1.57g, 40% fluoroboric acid 9mL and water 10mL bathe cooling with cryosel, under constantly stirring, drip and be dissolved in the solution that 10mL water is made by Sodium Nitrite 4.1g, continue again after adding to stir 30 minutes, get brown-green liquid, pouring cupric sulfate pentahydrate 29.7g then into is dissolved in the solution that 200mL water makes, the limit edged stirs, add Sodium Nitrite 4.1g again in stirring at room 2 hours, transferring reaction solution pH with concentrated hydrochloric acid is 2, extracts 20 hours with liquid liquid extraction plant again, extracting solution is spin-dried for after with dried over sodium sulfate, residue dehydrated alcohol crystallization gets 0.74g, yield 55%.
Comparative example 2
In flask, add 8.2g 2-aminooimidazole vitriol, 40% fluoroboric acid 60mL and water 80mL, in-10 to 0 ℃, constantly stir and drip the solution that the 21.4g Sodium Nitrite is dissolved in 52mL water down, dripping Bi Jixu stirred 2 hours at low temperatures, pour 120 gram cupric sulfate pentahydrates then into and be dissolved in the catalyzer that 800mL water and 10g 4-diamino-pyridine form, the limit edged stirs, and adds Sodium Nitrite 25g again, be to stir 5 hours under the room temperature, it is reacted completely, and transferring reaction solution pH with concentrated hydrochloric acid again is 2, extracts 20 hours with liquid liquid extraction plant, extracting solution is spin-dried for after with dried over sodium sulfate, obtain yellow solid, get yellow product 4.9g, productive rate 70% with alcohol crystal again.
Embodiment 3. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 5 ℃, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, decompression steams the water of half, use ethyl acetate extraction 12 hours again in liquid liquid extraction plant, the part extraction liquid has extracted back extraction liquid reconcentration to 1/4 of cumulative volume with what reclaimed among the last embodiment, leave standstill cooling and separate out light yellow crystal 10.9g, yield 85%.
Embodiment 4. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, stirred at low temperatures after adding 1 hour, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g quaternary ammonium salt, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, and decompression steams the water of half, in liquid liquid extraction plant, use ethyl acetate extraction 12 hours again, the extraction liquid reconcentration leaves standstill cooling and separates out light yellow crystal 10.4g, yield 81% to 1/4 of cumulative volume.
Embodiment 5. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 0 ℃, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 4g tosic acid pyridinium salt, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, and decompression steams the water of half, uses ethyl acetate extraction 12 hours again in liquid liquid extraction plant, the extraction liquid reconcentration is separated out light yellow crystal 10.3g to 1/4 postcooling of cumulative volume, yield 80%.
Embodiment 6. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 0 ℃, pour into then in the 1.5L water that contains the 200g cupric sulfate pentahydrate, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, and decompression steams the water of half, in liquid liquid extraction plant, use ethyl acetate extraction 12 hours again, the extraction liquid reconcentration is to 1/4 of cumulative volume, separates out light yellow crystal 9.1g, yield 71% after leaving standstill cooling.
Embodiment 7. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, stirred at low temperatures after adding 1 hour, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, and decompression steams 3/4 water, uses ethyl acetate extraction 12 hours again in liquid liquid extraction plant, the extraction liquid reconcentration is to 1/4 of cumulative volume, separates out light yellow crystal 10.1g yield 79% after leaving standstill cooling.
Embodiment 8. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 0 ℃, pour into then in the 1.5L water that contains 200g nitrate trihydrate copper and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, and decompression steams the water of half, in liquid liquid extraction plant, use ethyl acetate extraction 12 hours again, the extraction liquid reconcentration is to 1/4 of cumulative volume, separates out light yellow crystal 10.5g, yield 82% after leaving standstill cooling.
Embodiment 9. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, stirred at low temperatures after adding 1 hour, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated nitric acid (68%) accent pH again is 2, and decompression steams the water of half, uses ethyl acetate extraction 12 hours again in liquid liquid extraction plant, the extraction liquid reconcentration is to 1/4 of cumulative volume, separates out light yellow crystal 9.8g yield 76% after leaving standstill cooling.
Embodiment 10. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-3 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at 0 ℃, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2, decompression steams the water of half, uses ethyl acetate extraction 12 hours again in liquid liquid extraction plant, adds the dehydrated alcohol crystallization after extraction liquid concentrates and does and gets canescence powder-like product 10.1g yield 79%.
Embodiment 11. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL, drip the 100mL aqueous solution that contains the 40g Sodium Nitrite after being cooled to about-25 ℃, dripped off in about 45 minutes, adding the back stirred 1 hour down at-5 ℃, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl, add the 40g Sodium Nitrite when stirring again, added the back stirring at room 3 hours, adding concentrated hydrochloric acid (37%) accent pH again is 2, and decompression steams the water of half, uses ethyl acetate extraction 12 hours again in liquid liquid extraction plant, the extraction liquid reconcentration is to 1/4 of cumulative volume, separates out light yellow crystal 10.8g yield 84% after leaving standstill cooling.
Claims (10)
1. the preparation method of a 2-nitroimidazole comprises the steps:
1) preparation of diazonium salt: add fluoroboric acid and water in 2-aminooimidazole vitriol ,-30 ℃～3 ℃ stirrings drip the aqueous solution of Sodium Nitrite down, obtain diazonium salt;
2) preparation of 2-nitroimidazole: in the aqueous solution that the following mixed catalyst of the above-mentioned diazonium salt that makes being poured into-5～10 ℃ mantoquita of stirring is formed, add Sodium Nitrite again, transferring pH after stirring at room 2-9 hour is 2, extract with extraction plant then, extraction liquid concentrates, leave standstill and separate out thick product, thick product obtains the 2-nitroimidazole with ethyl alcohol recrystallization; The mixed catalyst of used mantoquita is made up of mantoquita and dipyridyl, quaternary ammonium salt or pyridinium salt.
2. preparation method according to claim 1 is characterized in that: in above-mentioned steps 2) with before the extraction plant extraction, exchange 1/4～3/4 the water that reaction solution decompression behind the pH steams the reaction solution cumulative volume.
3. preparation method according to claim 1 and 2 is characterized in that: the mass ratio of mantoquita and dipyridyl, quaternary ammonium salt or pyridinium salt is 100: 1～10: 1.
4. preparation method according to claim 1 and 2 is characterized in that: in above-mentioned steps 1) in, 2-aminooimidazole vitriol: fluoroboric acid: the mol ratio of Sodium Nitrite is 1: 1～100: 1～100.
5. preparation method according to claim 4 is characterized in that: in above-mentioned steps 1) in, 2-aminooimidazole vitriol: fluoroboric acid: the mol ratio of Sodium Nitrite is 1: 4～8: 4～8.
6. preparation method according to claim 1 and 2 is characterized in that: in above-mentioned steps 1) in the concentration of aqueous solution of used Sodium Nitrite be 0.001～0.8g/mL.
7. preparation method according to claim 1 and 2 is characterized in that: described mantoquita is cupric nitrate or copper sulfate.
8. preparation method according to claim 1 and 2 is characterized in that: above-mentioned steps 1) temperature of preparation diazonium salt is-10～-3 ℃.
9. preparation method according to claim 1 and 2 is characterized in that: above-mentioned steps 1) regulating the used acid of pH is hydrochloric acid or nitric acid.
10. preparation method according to claim 1 and 2 is characterized in that: the recrystallization solvent for use is methyl alcohol, ethanol, propyl alcohol or propyl carbinol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241634A (en) * | 2011-05-18 | 2011-11-16 | 西安近代化学研究所 | Preparation method of 2-nitro-4,5-dicyan-1H-imidazole |
| CN111018788A (en) * | 2019-11-14 | 2020-04-17 | 黄冈师范学院 | Preparation method of 2-nitroimidazole |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241634A (en) * | 2011-05-18 | 2011-11-16 | 西安近代化学研究所 | Preparation method of 2-nitro-4,5-dicyan-1H-imidazole |
| CN102241634B (en) * | 2011-05-18 | 2013-09-25 | 西安近代化学研究所 | Preparation method of 2-nitro-4,5-dicyan-1H-imidazole |
| CN111018788A (en) * | 2019-11-14 | 2020-04-17 | 黄冈师范学院 | Preparation method of 2-nitroimidazole |
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