CN105254569A - Preparation method of ornidazole injection impurity 1-(3-chloro-propenyl)-2-methyl-5-nitroimidazole - Google Patents
Preparation method of ornidazole injection impurity 1-(3-chloro-propenyl)-2-methyl-5-nitroimidazole Download PDFInfo
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- CN105254569A CN105254569A CN201510732404.4A CN201510732404A CN105254569A CN 105254569 A CN105254569 A CN 105254569A CN 201510732404 A CN201510732404 A CN 201510732404A CN 105254569 A CN105254569 A CN 105254569A
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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 the technical field of drug synthesis, and particularly relates to a preparation method of ornidazole injection impurity 1-(3-chloro-propenyl)-2-methyl-5-nitroimidazole. The preparation method comprises the following steps: dissolving 2-methylimidazole, 1,3-dichloropropene and alkali into a solvent, heating to backflow for performing a reaction, and after the reaction, a product, namely the 1-(3-chloro-propenyl)-2-methylimidazole is obtained through post-treatment; adding the product into a reactor containing nitrosonitric acid for performing a nitration reaction, after adding, adding a dehydrating agent in batches into a system, and obtaining 1-(3-chloro-propenyl)-2-methyl-5-nitroimidazole through post-treatment. The preparation method provided by the invention has the advantages of being simple to operate, mild in reaction, relatively high in yield, high in product purity, suitable for quality research and the like, has excellent commercial value, and provides a guarantee for the quality of ornidazole.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the preparation method of a kind of ornidazole injection impurity 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole.
Background technology
Ornidazole (Ornidazole) is third generation nitro imidazole derivatives, being the medicine that a kind of powerful anaerobe resistant and protozoacide infect, is also the nitro imidazole derivatives that curative effect is higher, the course for the treatment of is shorter, tolerance is better, distribution in vivo is wider be newly developed into after metronidazole.The anti-microbial effect of ornidazole in oxygen-free environment, is reduced into amino by the nitro in its molecule, or interacted by the form of free radical and cellular constituent, thus cause the death of microorganism.The plasma elimination half life of ornidazole is 14 hours, and plasma protein binding ratio, less than 15%, is distributed widely in tissue and body fluid, comprises cerebrospinal fluid.Ornidazole is metabolism in liver, mainly with the excretion of urine metabolite form, drains on a small quantity in ight soil.
To in the quality approach of ornidazole injection, contriver have studied 5 impurity altogether, and ornidazole and impurity title thereof are respectively: ornidazole: 1-(the chloro-2-hydroxypropyl of 3-)-2-5-nitro imidazole; Impurity I: 2-5-nitro imidazole; Impurity II: 1-(2,3-epoxypropyl)-2-5-nitro imidazole; Impurity III: 1-(2,3-dihydroxypropyl)-2-5-nitro imidazole; Impurity IV: 1-(2-oxopropyl)-2-5-nitro imidazole; Impurity V: 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole.
Wherein impurity I, impurity II, impurity III, impurity IV in the literature more report, and impurity V is reported its producing cause and detection method in patent CN102539564A.The structural formula of ornidazole and impurity thereof is as follows:
In the impurity of ornidazole, impurity I is the intermediate of reaction, and is commercially available prod, is not described here to its preparation method.The preparation method of impurity II, impurity III, impurity IV also has report, and contriver has prepared this three impurity according to literature method.Producing cause and the detection method of impurity V is refer at patent CN102539564A, but its preparation method does not also have document and patent report, in order to carry out quality approach to ornidazole bulk drug better, guarantee quality product, the present inventor has carried out chemosynthesis research to preparation method there are no the impurity V of bibliographical information.First, contriver considers that direct ornidazole carries out elimination dehydration reaction and obtains impurity V, and consulted lot of documents, taken multiple removing method, equal yield is extremely low, and the target product that even do not have had generates, and is difficult to the product obtaining enough quality approaches use.And this impurity not easily synthesizes, synthesize if take conventional method directly to use 2-5-nitro imidazole and 1,3-corresponding dichloropropylene to dock, its isomers 1-(the chloro-propenyl of 3-)-2-methyl-4-nitro iminazole can be generated.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of ornidazole injection impurity 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole, solve the problem of impurity preparation difficulty, have that yield is higher, the feature of environmental friendliness, easy handling.
The preparation method of ornidazole injection impurity 1-of the present invention (the chloro-propenyl of 3-)-2-5-nitro imidazole, comprises the steps:
(1) substitution reaction: be dissolved in solvent by glyoxal ethyline, 1,3-dichloropropylene, alkali, be heated to backflow and react, react complete, obtains 1-(the chloro-propenyl of 3-)-glyoxal ethyline V-2 through aftertreatment;
(2) nitration reaction: step (1) product is joined in the reactor filling nitrosonitric acid and carries out nitration reaction, finish, in system, add dewatering agent in batches, obtain 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole V through aftertreatment.
Wherein:
Alkali in step (1) is the one in salt of wormwood, sodium carbonate, sodium hydroxide or potassium hydride KH, preferred salt of wormwood or potassium hydride KH.
Solvent in step (1) is the one in tetrahydrofuran (THF), acetone, acetonitrile or tetracol phenixin, preferred tetrahydrofuran (THF).
Glyoxal ethyline, 1 in step (1), the mol ratio of 3 dichloropropylenes, alkali is 1:1 ~ 1.5:1 ~ 1.5.
Reaction times in step (1) is 12 ~ 20 hours.
Aftertreatment in step (1) is: suction filtration removes insoluble impurities, and then steam and desolventize, the crude product obtained is further purified through column chromatography, obtains 1-(the chloro-propenyl of 3-)-glyoxal ethyline.
Dewatering agent in step (2) is the one in Vanadium Pentoxide in FLAKES, Glacial acetic acid, the vitriol oil or diacetyl oxide, preferred Vanadium Pentoxide in FLAKES.
The temperature 0 ~ 5 DEG C of nitration reaction in step (2), add in step (2) in dewatering agent process, temperature controls at 0 ~ 5 DEG C, after dewatering agent adds, insulation reaction 3 ~ 6 hours, then obtain 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole through aftertreatment.
In step (2), aftertreatment is: by reaction solution impouring water, by weak base adjust ph to alkalescence, and organic solvent extraction, get organic phase, removing organic solvent, obtains crude material, purify through column chromatography, obtain 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole.Wherein, weak base is the one in ammoniacal liquor, sodium carbonate, salt of wormwood or sodium bicarbonate, preferred ammoniacal liquor.
Reaction equation of the present invention is as follows:
Beneficial effect of the present invention is as follows:
The present invention has simple to operate, reaction temperature and, yield is higher, and product purity is high, is applicable to the advantages such as quality approach, has good commercial value, provides guarantee for improving the quality of ornidazole.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
By glyoxal ethyline (20.0g, 0.24mol), 1,3-dichloropropylene (26.4g, 0.24mol), potassium hydride KH (12.0g, 0.30mol), tetrahydrofuran (THF) 500ml add in the there-necked flask of 1L, heating, be warming up to backflow, insulation reaction 12h, react complete, filter, be spin-dried for, become oily matter, column chromatography (methylene dichloride: methyl alcohol=50:1, filling gel is 200 ~ 300 orders) obtain intermediates V-235.5g, productive rate: 87.0%.
Measure 50ml nitrosonitric acid in 250ml there-necked flask, be cooled to 0 DEG C, in system, slowly add the intermediates (20g, 0.12mol) of upper step, control temperature 0 ~ 5 DEG C.After adding, in system, add Vanadium Pentoxide in FLAKES 25g, temperature control 0 ~ 5 DEG C in adition process in batches.Then insulation reaction 4h at 0 ~ 5 DEG C.After completion of the reaction, reaction solution impouring be cooled in the purified water of 0 DEG C, stir, regulate pH to be about 8 ~ 9 with ammoniacal liquor, it is saturated by system then to add NaCl, with 100ml × 3 extraction into ethyl acetate three times.Organic phase anhydrous sodium sulfate drying.Filter siccative, filtrate is spin-dried for, and become oily matter, column chromatography (eluent is DCM:MeOH=50:1, and filling gel is 200 ~ 300 orders) is separated to obtain off-white color solid, impurity V 22.5g.It is 99.4% that HPLC detects purity, productive rate: 87.2%.
Embodiment 2
By glyoxal ethyline (20.0g, 0.24mol), 1,3-dichloropropylene (33.0g, 0.30mol), salt of wormwood (48.3g, 0.35mol), acetonitrile 500ml add in the there-necked flask of 1L, heating, be warming up to backflow, insulation reaction 16h, react complete, filter, be spin-dried for, become oily matter, column chromatography (methylene dichloride: methyl alcohol=50:1, filling gel is 200 ~ 300 orders) obtain intermediates V-233.0g, productive rate: 80.8%.
Measure 50ml nitrosonitric acid in 250ml there-necked flask, be cooled to 0 DEG C, in system, slowly add the intermediates (20g, 0.12mol) of upper step, control temperature 0 ~ 5 DEG C.After adding, in system, slowly drip diacetyl oxide 30g, temperature control 0 ~ 5 DEG C in adition process.Then insulation reaction 5h at 0 ~ 5 DEG C.After completion of the reaction, reaction solution impouring be cooled in the purified water of 0 DEG C, stir, regulate pH to be about 8 ~ 9 with saturated sodium carbonate solution, it is saturated by system then to add NaCl, with 100ml × 3 extraction into ethyl acetate three times.Organic phase anhydrous sodium sulfate drying.Filter siccative, filtrate is spin-dried for, and become oily matter, column chromatography (eluent is DCM:MeOH=50:1, and filling gel is 200 ~ 300 orders) is separated to obtain off-white color solid, impurity V 21.2g.It is 99.5% that HPLC detects purity, productive rate: 82.2%.
Example 2 gained ornidazole injection impurity V carries out structural identification, and data are in table 1, table 2, table 3:
Proton nmr spectra (
1h-NMR) and carbon spectrum (
13c-NMR)
INSTRUMENT MODEL: VarianINOVA-600 nuclear magnetic resonance spectrometer
Test condition: solvent DMSO-d6
The hydrogen nuclear magnetic resonance modal data of table 1 ornidazole impurity V
The carbon-13 nmr spectra data of table 2 ornidazole impurity V
Mass spectrum (ESI-MS)
INSTRUMENT MODEL: AgilentTechnonlgies6520Accuratr-MassQ-TOF
Test condition: ion source: DualESI capillary voltage 4000VESI (+)
The molecular ion peak of table 3 ornidazole impurity V and ownership
Claims (10)
1. a preparation method for ornidazole injection impurity 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole, is characterized in that comprising the steps:
(1) substitution reaction: be dissolved in solvent by glyoxal ethyline, 1,3-dichloropropylene, alkali, be heated to backflow and react, react complete, obtains 1-(the chloro-propenyl of 3-)-glyoxal ethyline through aftertreatment;
(2) nitration reaction: step (1) product is joined in the reactor filling nitrosonitric acid and carries out nitration reaction, finish, in system, add dewatering agent in batches, obtain 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole through aftertreatment.
2. preparation method according to claim 1, is characterized in that: the alkali in step (1) is the one in salt of wormwood, sodium carbonate, sodium hydroxide or potassium hydride KH.
3. preparation method according to claim 1, is characterized in that: the solvent in step (1) is the one in tetrahydrofuran (THF), acetone, acetonitrile or tetracol phenixin.
4. the preparation method according to claim 1,2 or 3, is characterized in that: the glyoxal ethyline, 1 in step (1), and the mol ratio of 3 dichloropropylenes, alkali is 1:1 ~ 1.5:1 ~ 1.5.
5. preparation method according to claim 4, is characterized in that: the reaction times in step (1) is 12 ~ 20 hours.
6. preparation method according to claim 5, it is characterized in that: the aftertreatment in step (1) is: suction filtration removes insoluble impurities, then steam and desolventize, the crude product obtained is further purified through column chromatography, obtains 1-(the chloro-propenyl of 3-)-glyoxal ethyline.
7. preparation method according to claim 1, is characterized in that: the dewatering agent in step (2) is the one in Vanadium Pentoxide in FLAKES, Glacial acetic acid, the vitriol oil or diacetyl oxide.
8. preparation method according to claim 1, it is characterized in that: the temperature 0 ~ 5 DEG C of nitration reaction in step (2), add in step (2) in dewatering agent process, temperature controls at 0 ~ 5 DEG C, after dewatering agent adds, insulation reaction 3 ~ 6 hours, then obtain 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole through aftertreatment.
9. the preparation method according to claim 1 or 8, it is characterized in that: in step (2), aftertreatment is: by reaction solution impouring water, by weak base adjust ph to alkalescence, organic solvent extraction, get organic phase, removing organic solvent, obtains crude material, purify through column chromatography, obtain 1-(the chloro-propenyl of 3-)-2-5-nitro imidazole.
10. preparation method according to claim 9, is characterized in that: weak base is the one in ammoniacal liquor, sodium carbonate, salt of wormwood or sodium bicarbonate.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110684311A (en) * | 2019-09-26 | 2020-01-14 | 西北民族大学 | Modified corn straw flame-retardant degradable foam material 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 |
| CN115141103A (en) * | 2022-06-29 | 2022-10-04 | 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 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110684311A (en) * | 2019-09-26 | 2020-01-14 | 西北民族大学 | Modified corn straw flame-retardant degradable foam material and preparation method thereof |
| CN110684311B (en) * | 2019-09-26 | 2022-02-11 | 西北民族大学 | Modified corn straw flame-retardant degradable foam material 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 |
| CN115141103A (en) * | 2022-06-29 | 2022-10-04 | 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 |
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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 |