CN105254569B - Ornidazole injection impurity 1（3 Chloroallyls）The preparation method of the nitroimidazole of 2 methyl 5 - Google Patents
Ornidazole injection impurity 1（3 Chloroallyls）The preparation method of the nitroimidazole of 2 methyl 5 Download PDFInfo
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- CN105254569B CN105254569B CN201510732404.4A CN201510732404A CN105254569B CN 105254569 B CN105254569 B CN 105254569B CN 201510732404 A CN201510732404 A CN 201510732404A CN 105254569 B CN105254569 B CN 105254569B
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- 0 Cc1ncc(*)[n]1CCCCl Chemical compound Cc1ncc(*)[n]1CCCCl 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- 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
- C07D233/93—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by halogen atoms, attached to other ring members
Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation method of the nitroimidazole of 2 methyl of ornidazole injection impurity 1 (3 Chloroallyl) 5.Described preparation method comprises the following steps：By 2 methylimidazoles, 1,3 dichloropropylenes, alkali soluble are heated to backflow and reacted in solvent, and reaction finishes, post-treated to obtain product 1 (3 Chloroallyl) 2 methylimidazoles；Above-mentioned product is added in the reactor for fill fuming nitric aicd and carries out nitration reaction, is finished, adds dehydrating agent into system in batches, it is post-treated to obtain the nitroimidazole of 1 (3 Chloroallyl) 2 methyl 5.The present invention has simple to operate, and reaction is gentle, and yield is higher, and product purity is high, suitable for advantages such as quality researches, has good commercial value, and the quality for raising Ornidazole provides guarantee.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of ornidazole injection impurity 1- (chloro- propylene of 3-
Base) -2- 5-nitro imidazoles preparation method.
Background technology
Ornidazole (Ornidazole) is third generation nitro imidazole derivatives, is a kind of strength anaerobe resistant and antiprotozoan
The medicine of infection, and after be newly developed into after metronidazole the effect of it is higher, the course for the treatment of is shorter, tolerance is more preferable, distribution is wider in vivo
Nitro imidazole derivatives.The anti-microbial effect of Ornidazole is to be reduced into by the nitro in its molecule in oxygen-free environment
Amino, or interacted by the form of free radical with cell component, so as to cause the death of microorganism.The blood plasma of Ornidazole disappears
Except half-life period is 14 hours, plasma protein binding rate is distributed widely in tissue and body fluid less than 15%, including cerebrospinal fluid.It is difficult to understand
Nitre azoles is metabolized in liver, is mainly drained in the form of urine metabolite, is drained on a small quantity in excrement.
In the quality research to ornidazole injection, inventor, which amounts to, have studied 5 impurity, Ornidazole and its impurity name
Title is respectively：Ornidazole：1- (the chloro- 2- hydroxypropyls of 3-) -2- 5-nitro imidazoles；Impurity I：2- 5-nitro imidazoles；
Impurity II：1- (2,3- glycidyl) -2- 5-nitro imidazoles；Impurity III：1- (2,3- dihydroxypropyls) -2- methyl -5-
Nitroimidazole；Impurity IV：1- (2- oxopropyls) -2- 5-nitro imidazoles；Impurity V：1- (the chloro- acrylic of 3-) -2- first
Base -5- nitroimidazoles.
Wherein impurity I, impurity II, impurity III, impurity IV in the literature more has been reported that, impurity V is in patent
Its producing cause and detection method are reported in CN102539564A.The following institute of the structural formula of Ornidazole and its impurity
Show：
In the impurity of Ornidazole, impurity I is the intermediate of reaction, and is commercially available prod, here to its preparation method not
It is described.Impurity II, impurity III, the preparation method of impurity IV also have been reported that inventor is also to be prepared for this according to literature method
Three impurity.The producing cause and detection method of impurity V are refer in patent CN102539564A, but its preparation method is also
There is no document and patent report, in order to preferably carry out quality research to Ornidazole bulk drug, it is ensured that product quality, the present inventor
The impurity V that document report is there are no to preparation method has carried out chemical synthesis research.First, inventor is considered directly with difficult to understand
Nitre azoles carries out elimination dehydration and obtains impurity V, has consulted lot of documents, has taken a variety of removing methods, and equal yield is extremely low,
Some generates even without target product, it is difficult to obtains the product that enough quality researches use.And the impurity is not easily-synthesized, such as
Fruit takes conventional method directly to be synthesized with 2- 5-nitro imidazoles with the docking of corresponding 1,3- dichloropropylenes, can give birth to
Into its isomer 1- (the chloro- acrylic of 3-) -2- methyl-4-nitro iminazoles.
The content of the invention
It is an object of the invention to provide a kind of ornidazole injection impurity 1- (the chloro- acrylic of 3-) -2- methyl-5-nitro miaows
The preparation method of azoles, it is difficult to solve the problems, such as prepared by impurity, there is the characteristics of yield is higher, environment-friendly, easily operated.
The preparation side of ornidazole injection impurity 1- (the chloro- acrylic of 3-) -2- 5-nitro imidazoles of the present invention
Method, comprise the following steps：
(1) substitution reaction：By 2-methylimidazole, 1,3- dichloropropylenes, alkali soluble in solvent, it is heated to backflow and carries out instead
Should, reaction finishes, post-treated to obtain 1- (the chloro- acrylic of 3-) -2-methylimidazole V -2；
(2) nitration reaction：Step (1) product is added in the reactor for fill fuming nitric aicd and carries out nitration reaction, is added
Finish, add dehydrating agent into system in batches, it is post-treated to obtain 1- (the chloro- acrylic of 3-) -2- 5-nitro imidazoles V.
Wherein：
Alkali in step (1) is one kind in potassium carbonate, sodium carbonate, sodium hydroxide or hydrofining, preferably potassium carbonate or hydrogen
Change potassium.
Solvent in step (1) is one kind in tetrahydrofuran, acetone, acetonitrile or carbon tetrachloride, preferably tetrahydrofuran.
The mol ratio of 2-methylimidazole, 1,3 dichloropropylenes, alkali in step (1) is 1:1~1.5:1~1.5.
Reaction time in step (1) is 12~20 hours.
Post processing in step (1) is：Filter and remove insoluble impurities, solvent is then evaporated off, obtained crude product is through post layer
Analysis is further purified, and obtains 1- (the chloro- acrylic of 3-) -2-methylimidazole.
Dehydrating agent in step (2) is one kind in phosphorus pentoxide, glacial acetic acid, the concentrated sulfuric acid or acetic anhydride, preferably five oxygen
Change two phosphorus.
0~5 DEG C of the temperature of nitration reaction in step (2), add during dehydrating agent in step (2), temperature control 0~
5 DEG C, after dehydrating agent adds, insulation reaction 3~6 hours, then post-treated obtain 1- (the chloro- acrylic of 3-) -2- methyl-5-nitros
Imidazoles.
Post-processed in step (2) and be：Reaction solution is poured into water, adjusting pH value to alkalescence, organic solvent with weak base extracts,
Organic phase is taken, organic solvent is removed, obtains crude material, purified through column chromatography, obtain 1- (the chloro- acrylic of 3-) -2- methyl -5-
Nitroimidazole.Wherein, weak base is one kind in ammoniacal liquor, sodium carbonate, potassium carbonate or sodium acid carbonate, preferably ammoniacal liquor.
Reaction equation of the present invention is as follows：
Beneficial effects of the present invention are as follows：
The present invention has simple to operate, and reaction is gentle, and yield is higher, and product purity is high, suitable for advantages such as quality researches,
With good commercial value, guarantee is provided to improve the quality of Ornidazole.
Embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
By 2-methylimidazole (20.0g, 0.24mol), 1,3- dichloropropylenes (26.4g, 0.24mol), hydrofining (12.0g,
0.30mol), tetrahydrofuran 500ml is added in 1L there-necked flask, heating, is warming up to backflow, insulation reaction 12h, and reaction finishes,
Filtering, is spin-dried for, into grease, column chromatography (dichloromethane：Methanol=50:1, filling gel is 200~300 mesh) obtain intermediate products
V -235.5g, yield：87.0%.
50ml fuming nitric aicds are measured in 250ml there-necked flasks, are cooled to 0 DEG C, the centre of upper step is slowly added into system
Product (20g, 0.12mol), control 0~5 DEG C of temperature.After adding, phosphorus pentoxide 25g is added portionwise into system, added
0~5 DEG C of temperature control in journey.Then insulation reaction 4h at 0~5 DEG C.After completion of the reaction, reaction solution is poured into and is cooled to 0 DEG C of purifying
In water, stirring, it is about 8~9 to adjust pH with ammoniacal liquor, then adds NaCl by system saturation, is extracted with the ethyl acetate of 100ml × 3
Three times.Organic phase anhydrous sodium sulfate drying.Drier is filtered, filtrate is spin-dried for, into grease, column chromatography (eluant, eluent DCM：
MeOH=50:1, filling gel is 200~300 mesh) separate to obtain off-white powder, the 22.5g of impurity V.HPLC detects purity
99.4%, yield：87.2%.
Embodiment 2
By 2-methylimidazole (20.0g, 0.24mol), 1,3- dichloropropylenes (33.0g, 0.30mol), potassium carbonate (48.3g,
0.35mol), acetonitrile 500ml is added in 1L there-necked flask, heating, is warming up to backflow, insulation reaction 16h, and reaction finishes, filtering,
It is spin-dried for, into grease, column chromatography (dichloromethane：Methanol=50:1, filling gel is 200~300 mesh) intermediate products V-
233.0g, yield：80.8%.
50ml fuming nitric aicds are measured in 250ml there-necked flasks, are cooled to 0 DEG C, the centre of upper step is slowly added into system
Product (20g, 0.12mol), control 0~5 DEG C of temperature.After adding, acetic anhydride 30g is slowly added dropwise into system, in adition process
0~5 DEG C of temperature control.Then insulation reaction 5h at 0~5 DEG C.After completion of the reaction, reaction solution is poured into and is cooled to 0 DEG C of purified water
In, stirring, it is about 8~9 to adjust pH with saturated sodium carbonate solution, then adds NaCl by system saturation, with the acetic acid of 100ml × 3
Ethyl ester extracts three times.Organic phase anhydrous sodium sulfate drying.Drier is filtered, filtrate is spin-dried for, into grease, column chromatography (elution
Agent is DCM：MeOH=50:1, filling gel is 200~300 mesh) separate to obtain off-white powder, the 21.2g of impurity V.HPLC is examined
It is 99.5% to survey purity, yield：82.2%.
The gained ornidazole injection impurity V of Example 2 carries out structural identification, and data are shown in Table 1, table 2, table 3：
Proton nmr spectra (1H-NMR) and carbon spectrum (13C-NMR)
INSTRUMENT MODEL：Varian INOVA-600 nuclear magnetic resonance chemical analysers
Test condition：Solvent DMSO-d6
The Ornidazole impurity V of table 1 hydrogen nuclear magnetic resonance modal data
The Ornidazole impurity V of table 2 carbon-13 nmr spectra data
Mass spectrum (ESI-MS)
INSTRUMENT MODEL：Agilent Technonlgies 6520Accuratr-Mass Q-TOF
Test condition：Ion gun：Dual ESI capillary voltage 4000V ESI (+)
The molecular ion peak and ownership of the Ornidazole impurity V of table 3
Claims (8)
1. a kind of preparation method of ornidazole injection impurity 1- (the chloro- acrylic of 3-) -2- 5-nitro imidazoles, its feature
It is to comprise the following steps：
(1) substitution reaction：By 2-methylimidazole, 1,3- dichloropropylenes, alkali soluble in solvent, it is heated to backflow and is reacted, instead
It should finish, it is post-treated to obtain 1- (the chloro- acrylic of 3-) -2-methylimidazole；
(2) nitration reaction：Step (1) product is added in the reactor for fill fuming nitric aicd and carries out nitration reaction, is finished, point
Criticize and dehydrating agent is added into system, it is post-treated to obtain 1- (the chloro- acrylic of 3-) -2- 5-nitro imidazoles；
Post processing in step (1) is：Filter and remove insoluble impurities, solvent is then evaporated off, obtained crude product enters through column chromatography
One step purifies, and obtains 1- (the chloro- acrylic of 3-) -2-methylimidazole；
Post-processed in step (2) and be：Reaction solution is poured into water, pH value is adjusted to alkalescence with weak base, organic solvent extraction, has taken
Machine phase, organic solvent is removed, crude material is obtained, is purified through column chromatography, obtain 1- (the chloro- acrylic of 3-) -2- methyl-5-nitros
Imidazoles.
2. preparation method according to claim 1, it is characterised in that：Alkali in step (1) is potassium carbonate, sodium carbonate, hydrogen
One kind in sodium oxide molybdena or hydrofining.
3. preparation method according to claim 1, it is characterised in that：Solvent in step (1) is tetrahydrofuran, acetone,
One kind in acetonitrile or carbon tetrachloride.
4. according to the preparation method described in claim 1,2 or 3, it is characterised in that：2-methylimidazole in step (1), 1,3 2
Chloropropene, the mol ratio of alkali are 1:1~1.5:1~1.5.
5. preparation method according to claim 4, it is characterised in that：Reaction time in step (1) is 12~20 hours.
6. preparation method according to claim 1, it is characterised in that：Dehydrating agent in step (2) is phosphorus pentoxide, ice
One kind in acetic acid, the concentrated sulfuric acid or acetic anhydride.
7. preparation method according to claim 1, it is characterised in that：0~5 DEG C of the temperature of nitration reaction in step (2), step
Suddenly being added in (2) during dehydrating agent, temperature control is at 0~5 DEG C, after dehydrating agent adds, insulation reaction 3~6 hours, then after
Processing obtains 1- (the chloro- acrylic of 3-) -2- 5-nitro imidazoles.
8. preparation method according to claim 7, it is characterised in that：Weak base is ammoniacal liquor, sodium carbonate, potassium carbonate or bicarbonate
One kind in sodium.
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| CN110903442B (en) * | 2019-09-26 | 2022-04-12 | 西北民族大学 | Flame-retardant modified corn straw and preparation method thereof |
| CN111559980A (en) * | 2020-06-16 | 2020-08-21 | 湖南方盛制药股份有限公司 | Ornidazole isomer and preparation method thereof |
| CN113968820A (en) * | 2021-11-30 | 2022-01-25 | 湖北省宏源药业科技股份有限公司 | 1, 1-bis (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole chloride compound and preparation method thereof |
| CN115141103B (en) * | 2022-06-29 | 2023-06-16 | 理道新材(北京)科技有限公司 | Perdeuterated 1, 1-diamino-2, 2-dinitroethylene and preparation method and application thereof |
Citations (2)
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| CN102539564A (en) * | 2011-12-28 | 2012-07-04 | 成都金典药物科技开发有限公司 | Detection method for ornidazole injection impurities and content measuring method |
| CN104016922A (en) * | 2014-06-19 | 2014-09-03 | 西安工程大学 | Preparation method of 2-ethylimidazole ionic liquid and application thereof |
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Patent Citations (2)
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|---|---|---|---|---|
| CN102539564A (en) * | 2011-12-28 | 2012-07-04 | 成都金典药物科技开发有限公司 | Detection method for ornidazole injection impurities and content measuring method |
| CN104016922A (en) * | 2014-06-19 | 2014-09-03 | 西安工程大学 | Preparation method of 2-ethylimidazole ionic liquid and application thereof |
Non-Patent Citations (1)
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Denomination of invention: Preparation of 1 - (3-chloro-propenyl) - 2-methyl-5-nitroimidazole impurity in ornidazole injection Effective date of registration: 20211208 Granted publication date: 20180130 Pledgee: Qi commercial bank Limited by Share Ltd. Linzi branch Pledgor: SHANDONG QIDU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980014351 |