CN101747281B - Method for preparing 2-nitroimidazole - Google Patents
Method for preparing 2-nitroimidazole Download PDFInfo
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- CN101747281B CN101747281B CN200910273374XA CN200910273374A CN101747281B CN 101747281 B CN101747281 B CN 101747281B CN 200910273374X A CN200910273374X A CN 200910273374XA CN 200910273374 A CN200910273374 A CN 200910273374A CN 101747281 B CN101747281 B CN 101747281B
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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 compound method of 2-nitroimidazole.
Background technology
The 2-nitroimidazole is the midbody of tumor radiotherapy sensitive-increasing agent SRI 1354 (Misonidazole).The compound method of 2-nitroimidazole mainly contains following several kinds 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 said method of patent CN1461749 is diazotization, in mantoquita, used catalyzer 4-lutidine, 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: in 2-aminooimidazole vitriol, add fluoroboric acid and water ,-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, and with the extraction plant extraction, extraction liquid concentrates then; 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 TV.
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.
Said 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, practice thrift extraction solvent, improves extraction efficiency, shortens the extraction time.Reduce device volume simultaneously, practiced thrift cost.
Embodiment
The present invention further explains through following unrestriced embodiment, but needs are understood said embodiment only in order to explanation the present invention, but not in order to limit scope of the present invention.
Embodiment 1. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40wt% fluoroboric acid 100mL are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl at 0 ℃; Add the 40g Sodium Nitrite again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; In liquid liquid extraction plant with ethyl acetate extraction 12 hours; 1/4 of extraction liquid reconcentration to TV is separated out light yellow crystal 10.3g yield 80% after leaving standstill cooling, and 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 are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl at 0 ℃; Add the 40g Sodium Nitrite when stirring again; Add back stirring at room 3 hours, adding concentrated hydrochloric acid again, to transfer pH be 2, in liquid liquid extraction plant with 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 TV, 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 to be dissolved in the solution that 10mL water is processed by Sodium Nitrite 4.1g; Continue to stir again 30 minutes after adding, brown-green liquid, pour cupric sulfate pentahydrate 29.7g then into and be dissolved in the solution that 200mL water processes; The limit edged stirs, and adds Sodium Nitrite 4.1g again in stirring at room 2 hours, and using concentrated hydrochloric acid to transfer reaction solution pH is 2; Extracted 20 hours with liquid liquid extraction plant, extracting solution revolves after with dried over sodium sulfate dried again, and residue is used the absolute ethyl alcohol crystallization; Get 0.74g, yield 55%.
Comparative example 2
In flask, add 8.2g 2-aminooimidazole vitriol, 40% fluoroboric acid 60mL and water 80mL, constantly stir and drip the solution that the 21.4g Sodium Nitrite is dissolved in 52mL water down by in-10 to 0 ℃; Drip Bi Jixu and stirred at low temperatures 2 hours, pour 120 gram cupric sulfate pentahydrates then into and be dissolved in the catalyzer that 800mL water and 10g 4-diamino-pyridine form the stirring of limit edged; Add Sodium Nitrite 25g again, be to stir 5 hours under the room temperature, it is reacted completely; Using concentrated hydrochloric acid to transfer reaction solution pH again is 2, extracts 20 hours with liquid liquid extraction plant, and extracting solution revolves after with dried over sodium sulfate dried; 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 are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl at 5 ℃; Add the 40g Sodium Nitrite again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; Decompression steams half the water; Again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, the part extraction liquid has extracted back extraction liquid reconcentration to 1/4 of TV 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 are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips 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 again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; Decompression steams half the water, again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 of extraction liquid reconcentration to TV; Leave standstill cooling and separate out light yellow crystal 10.4g, yield 81%.
Embodiment 5. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 4g tosic acid pyridinium salt at 0 ℃; Add the 40g Sodium Nitrite again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; Decompression steams half the water; Again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 postcooling of extraction liquid reconcentration to TV is separated out light yellow crystal 10.3g, yield 80%.
Embodiment 6. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains the 200g cupric sulfate pentahydrate at 0 ℃; Add the 40g Sodium Nitrite again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; Decompression steams half the water, again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 of extraction liquid reconcentration to TV; Separate out light yellow crystal 9.1g after leaving standstill cooling, yield 71%.
Embodiment 7. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips 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 again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; Decompression steams 3/4 water; Again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 of extraction liquid reconcentration to TV is separated 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 are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g nitrate trihydrate copper and 2g dipyridyl at 0 ℃; Add the 40g Sodium Nitrite again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid accent pH again is 2; Decompression steams half the water, again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 of extraction liquid reconcentration to TV; Separate out light yellow crystal 10.5g after leaving standstill cooling, yield 82%.
Embodiment 9. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips 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 again when stirring, added the back stirring at room 3 hours, adding concentrated nitric acid (68%) accent pH again is 2; Decompression steams half the water; Again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 of extraction liquid reconcentration to TV is separated 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 are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-3 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl at 0 ℃; 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 half the water; Again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, extraction liquid concentrates to be done the back and adds the absolute ethyl alcohol crystallization and get pearl powder-like product 10.1g yield 79%.
Embodiment 11. adds 15g 2-aminooimidazole vitriol in flask, water 100mL and 40% fluoroboric acid 100mL are cooled to the back 100mL aqueous solution that contains the 40g Sodium Nitrite that drips about-25 ℃; Dripped off in about 45 minutes, and added the back and stirred 1 hour down, pour into then in the 1.5L water that contains 200g cupric sulfate pentahydrate and 2g dipyridyl at-5 ℃; Add the 40g Sodium Nitrite again when stirring, added the back stirring at room 3 hours, adding concentrated hydrochloric acid (37%) accent pH again is 2; Decompression steams half the water; Again in liquid liquid extraction plant with ethyl acetate extraction 12 hours, 1/4 of extraction liquid reconcentration to TV is separated out light yellow crystal 10.8g yield 84% after leaving standstill cooling.
Claims (9)
1. the preparation method of a 2-nitroimidazole comprises the steps:
1) preparation of diazonium salt: in 2-aminooimidazole vitriol, add fluoroboric acid and water ,-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, and with the extraction plant extraction, extraction liquid concentrates then; 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 or pyridinium salt; The mass ratio of mantoquita and dipyridyl or pyridinium salt is 100: 1.
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 TV.
3. 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.
4. preparation method according to claim 3 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.
5. 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.
6. preparation method according to claim 1 and 2 is characterized in that: said mantoquita is cupric nitrate or copper sulfate.
7. preparation method according to claim 1 and 2 is characterized in that: above-mentioned steps 1) temperature of preparation diazonium salt is-10～-3 ℃.
8. 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.
9. 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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