CN109134374A - Edaravone derivative and preparation method thereof, detection method and purposes - Google Patents
Edaravone derivative and preparation method thereof, detection method and purposes Download PDFInfo
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- CN109134374A CN109134374A CN201810888177.8A CN201810888177A CN109134374A CN 109134374 A CN109134374 A CN 109134374A CN 201810888177 A CN201810888177 A CN 201810888177A CN 109134374 A CN109134374 A CN 109134374A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The present invention relates to the compound of such as flowering structure, and preparation method thereof, detection method and purposes.Preparation method is characterized in that Edaravone being dissolved in organic solvent, then it is reacted with aqueous hydrogen peroxide solution, reversed-phased high performace liquid chromatographic is recycled to separate above-mentioned Edaravone reaction solution, (Z) -2- (3- methyl -5- oxygen -1- phenyl -4,5- dihydro-1 h-pyrazole -4- base) -3- [(E)-phenylazo] -2- butenoic acid is made.Furthermore the present invention also provides the detection methods of the compound.The compound can be used for impurity phenylhydrazine reference substance, convenient for the amount of control edaravone raw material medicine and the compound of related preparations.
Description
It is " on April 3rd, 2013 " that the application, which is the applying date, and application No. is " 201310116354.8 " entitled " Yi Dala
Give derivative and preparation method thereof, detection method and purposes " application for a patent for invention divisional application.
Invention field
The present invention relates to a kind of edaravone derivatives, i.e. (Z) -2- (3- methyl -5- oxygen -1- phenyl -4,5- dihydro -1H-
Pyrazoles -4- base) -3- [(E)-phenylazo] -2- butenoic acid, and preparation method thereof, detection method and purposes.
Background technique
Edaravone (compound of formula I) is a kind of cerebral protective agent.Acute period of cerebral infarction patient give Edaravone, can inhibit
The reduction of periinfarct local cerebral blood flow, NAA content is significantly raised compared with glycerol control group in the 28th day brain after the onset of making.According to reaching
Drawing, which is given, can remove free radical, anti-lipid peroxidation, to inhibit the oxidation damage of brain cell, vascular endothelial cell, nerve cell
Wound.
As clinical commonly used drug, Edaravone is in its production, storage, use process due to pyroprocesses such as sterilizings
Drug quality is caused to decline in the presence of, it is possible to produce impurity.
More, such as the reaction raw materials of related substances research of the country for Edaravone durings production, storage etc.
Acetoacetate second vinegar and phenylhydrazine, 3, the 3'- dimethyl -1,1'- generated in the preparation and long-term storage of Edaravone Injection
Diphenyl -1H, 1'H- [bis- pyrazoles of 4,4'-] -5,5'(4H, 4'H)-diketone etc..For edaravone raw material medicine in storage process
The related substance report of middle generation is less.
Therefore, the impurity and impurity preparation method, detection side edaravone raw material generated during preparation and storage
Method carry out research be very it is necessary to.
Summary of the invention
We it has been investigated that, due to oxidation reaction etc., edaravone raw material can generate impurity during storage, we
Separation detection is carried out using high performance liquid chromatography to the edaravone raw material for placing certain time, discovery truly has impurity peaks, wherein
Including a kind of new impurity compound.Specific method is by above-mentioned edaravone raw material methanol: water: glacial acetic acid=45:55:
0.1 mixed solution dissolves and constant volume, is configured to the sample that Edaravone content is 0.2mg/ml, then uses high-efficient liquid phase color
Spectrometry, chromatographic column are Agilent Eclipse XDB-C18,4.6*150mm (3.5 μm), and mobile phase a is methanol: water: glacial acetic acid
=45:55:0.1, mobile phase b are methanol, and flow rate of mobile phase 0.8ml/min, column temperature is 20 DEG C, Detection wavelength 244nm, into
Sample amount is 20ml.Gradient elution is as follows:
| Time (min) | Mobile phase a ratio (%) | Mobile phase b ratio (%) |
| 0 | 100 | 0 |
| 22 | 100 | 0 |
| 52 | 36 | 64 |
| 72 | 36 | 64 |
| 80 | 100 | 0 |
The compound that testing result discovery appearance time is 17.3min is a kind of new compound.
An object of the present invention is to be to provide such noval chemical compound such as II structure of following formula:
(Z) -2- (3- methyl -5- oxygen -1- phenyl -4,5- dihydro-1 h-pyrazole -4- base) -3- [(E)-phenylazo] -2-
Butenoic acid, hereinafter referred to as compound A.
Under certain condition, the enol form and keto-acid of compound A can mutually convert.
The second object of the present invention is to provide a kind of method for preparing above compound A, to achieve the above object, use with
Lower preparative separation technique:
Edaravone addition solvent is configured to solution or turbid solution, then after being reacted with aqueous hydrogen peroxide solution, rotation
It removes partial solvent, is separated with reversed-phase high performance liquid chromatography, is protected from light at 0-40 DEG C after being spin-dried for obtain the final product.
Further, the mass ratio of Edaravone and hydrogen peroxide is 1:1~1:3, preferably 1:2~1:2.5.
Further, the solvent is organic solvent, and the organic solvent is selected from alcohols, acetonitrile, the preferred methanol of alcohols, institute
The reaction temperature for stating Edaravone and aqueous hydrogen peroxide solution is 15~20 DEG C, and the reaction time is 48~72 hours.
Further, the reversed-phase high performance liquid chromatography uses octadecylsilane chemically bonded silica for the chromatography of filler
Column, mobile phase are the mixed solvents of organic phase and water phase, and Detection wavelength is 240~254nm, preferably 244nm.
Further, the volume ratio of organic phase and water phase is 45:55~80:20 in mobile phase, and the organic phase is selected from first
Alcohol or acetonitrile, the water phase pH are 3.0~5.5, and water phase is selected from effumability weakly acidic aqueous solution, preferably acetic acid aqueous solution or formic acid
Aqueous solution.
Compound A is finally analyzed into its purity with HPLC, and its structure is confirmed using MS, NMR.
The third object of the present invention is to provide a kind of method for detecting above compound A.This method is using efficient liquid phase
Chromatography, using octadecylsilane chemically bonded silica as filler, mobile phase is the mixed solvent of organic phase and water phase, flow rate of mobile phase
For 0.7~0.9ml/min, Detection wavelength is 240~254nm, wherein the volume ratio of organic phase and water phase is in the mobile phase
45:55~80:20.
Further, the mobile phase is selected from methanol aqueous systems, methanol buffer salt system, acetonitrile buffer salt system, preferably first
Alcohol-acetic acid aqueous solution, flow rate of mobile phase 0.8ml/min, Detection wavelength 244nm.
Edaravone be fully synthetic cerebral apoplexy neuroprotective agent, preparation and storage during since there are high-temperature sterilizations, oxygen
The factors such as change, causes quality to decline there may be compound A in bulk pharmaceutical chemicals or preparation.The compound A's that the present invention uses
Preparation method is simple, and product purity is high, and detection method is easy, can be used as impurity phenylhydrazine reference substance, convenient for control Yi Dala
Give the amount of compound A in bulk pharmaceutical chemicals and its related preparations.
Detailed description of the invention
Fig. 1 is Edaravone, raw material and impurity positioning figure.(wherein chromatographic peak: 1: phenylhydrazine；2: Edaravone；3:(Z) -2-
(3- methyl -5- oxygen -1- phenyl -4,5- dihydro-1 h-pyrazole -4- base) -3- [(E)-phenylazo] -2- butenoic acid.)
Fig. 2 is Edaravone and impurity positioning figure.(wherein chromatographic peak A be (Z) -2- (phenyl -4 3- methyl -5- oxygen -1-,
5- dihydro-1 h-pyrazole -4- base) -3- [(E)-phenylazo] -2- butenoic acid.)
Specific embodiment
The present invention is further elaborated combined with specific embodiments below, but does not limit the present invention.
Edaravone raw material medicine is provided by the vast Pharmaceutical Co in Jilin, other agents useful for same be it is commercially available can
?.
Embodiment 1: the preparation of compound A
It takes edaravone raw material medicine 10g that methanol 200ml dissolution is added, is slowly added to the hydrogen peroxide that mass fraction is 30%
50ml, 20 DEG C of room temperature are stirred 48 hours, and 10 DEG C of temperature backspins go partial solvent, solution for standby.
Then above-mentioned solution is separated using rp-hplc, chromatographic condition are as follows: chromatographic column is
Waters Nova-Pak C18,6 μm, 190*300mm, mobile phase a are methanol: water: glacial acetic acid=45:55:0.1, mobile phase b
For methanol, flow velocity: 20ml/min, column temperature: 20 DEG C, Detection wavelength: 244nm, sample volume: 0.5ml.Gradient elution is as follows:
| Time (min) | Mobile phase a ratio (%) | Mobile phase b ratio (%) |
| 0 | 100 | 0 |
| 22 | 100 | 0 |
| 52 | 36 | 64 |
| 72 | 36 | 64 |
| 80 | 100 | 0 |
The preparation solution that relative retention time is 3.0-3.6 is acquired, solvent is spin-dried at a temperature of 10 DEG C, obtains compound A-45 mg,
Yield 0.048%.
Final products nuclear-magnetism, mass spectrum carry out Structural Identification, and attached data are described as follows.
Compound A:
1, LC-MS (ESI (+)) molecular ion peak (M+1), m/z=363.1；
LC-MS (ESI (-)) molecular ion peak (M-1), m/z=361.2；
MS-MS fragment peak (ESI (+)), m/z=345.2；M/z=317.1；M/z=77.1；
(ESI (-)), m/z=317.1；M/z=276.2.
2、NMR(CD3OD)
Compound A largely exists in the form of enol form in deuterated methanol:
Embodiment 2: the preparation of compound A
It takes edaravone raw material medicine 10g that acetonitrile 200ml dissolution is added, is slowly added to the hydrogen peroxide that mass fraction is 30%
50ml, 20 DEG C of room temperature are stirred 48 hours, and 10 DEG C of temperature backspins go partial solvent, solution for standby.
Then above-mentioned solution is separated using rp-hplc, chromatographic condition are as follows: chromatographic column is
Waters Nova-Pak C18,6 μm, 190*300mm, mobile phase a are water: glacial acetic acid=99.9:0.1, and mobile phase b is acetonitrile,
Flow velocity: 20ml/min, column temperature: 20 DEG C, Detection wavelength: 244nm, sample volume: 0.5ml.Gradient elution is as follows:
| Time (min) | Mobile phase a ratio (%) | Mobile phase b ratio (%) |
| 0 | 75 | 25 |
| 10 | 75 | 25 |
| 30 | 45 | 55 |
| 40 | 45 | 55 |
The preparation solution that relative retention time is 2.3-2.9 is acquired, solvent is spin-dried at a temperature of 10 DEG C, obtains compound A-45 mg,
Yield 0.07%.
Embodiment 3: the detection of compound A
The preparation of sample: precision weighs edaravone raw material medicine 10mg, is placed in 50ml volumetric flask, with methanol: water: ice vinegar
Acid=45:55:0.1 mixed solution dissolution and constant volume, be configured to Edaravone content be 0.2mg/ml sample, 4 DEG C of temperature controls,
Now match in half an hour and now does.
Chromatographic condition and detection:
Instrument: 1200 HPLC of Agilent
Chromatographic column: Agilent Eclipse XDB-C18,4.6*150mm (3.5 μm)；
Mobile phase a be methanol: water: glacial acetic acid=45:55:0.1, mobile phase b be methanol, flow velocity: 0.8ml/min, column temperature:
20 DEG C, Detection wavelength: 244nm, sample volume: 20ml.Gradient elution is as follows:
| Time (min) | Mobile phase a ratio (%) | Mobile phase b ratio (%) |
| 0 | 100 | 0 |
| 22 | 100 | 0 |
| 52 | 36 | 64 |
| 72 | 36 | 64 |
| 80 | 100 | 0 |
Testing result: compound A appearance time is 17.3min, and raw material phenylhydrazine appearance time is 1.8min.(attached drawing 1)
Embodiment 4: the detection of compound A
The preparation of sample: precision weighs edaravone raw material medicine 10mg, is placed in 50ml volumetric flask, is dissolved and determined with acetonitrile
Hold, be configured to the sample that Edaravone content is 0.2mg/ml, 4 DEG C of temperature controls are now matched in half an hour and now done.
Chromatographic condition and detection:
Instrument: 1200 HPLC of Agilent
Chromatographic column: Agilent Eclipse XDB-C18,4.6*150mm (3.5 μm)；
Mobile phase a be water: glacial acetic acid=99.9:0.1, mobile phase b be acetonitrile, flow velocity: 0.8ml/min, column temperature: 20 DEG C,
Detection wavelength: 244nm, sample volume: 20ml.Gradient elution is as follows:
| Time (min) | Mobile phase a ratio (%) | Mobile phase b ratio (%) |
| 0 | 75 | 25 |
| 20 | 75 | 25 |
| 60 | 55 | 45 |
| 70 | 55 | 45 |
| 71 | 75 | 25 |
Testing result: compound A appearance time is 27.7min.(attached drawing 2).
Claims (10)
1. a kind of compound, has the following structure:
2. a kind of method for preparing compound described in claim 1, this method includes by Edaravone and aqueous hydrogen peroxide solution
It after being reacted, is separated, is protected from light at 0~40 DEG C after being spin-dried for reversed-phase high performance liquid chromatography to obtain the final product.
3. preparation method according to claim 2, which is characterized in that, first will be according to before Edaravone and hydroperoxidation
Da Lafeng is added organic solvent and is configured to solution or turbid solution, and the organic solvent is selected from alcohols, acetonitrile, the preferred first of alcohols
Alcohol.
4. preparation method according to claim 2, it is characterised in that the mass ratio of Edaravone and hydrogen peroxide be 1:1~
1:3, preferably 1:2~1:2.5.
5. preparation method according to claim 2, which is characterized in that Edaravone reacts temperature with aqueous hydrogen peroxide solution
Degree is 15~20 DEG C, and the reaction time is 48~72 hours.
6. preparation method according to claim 2, which is characterized in that the reversed-phase high performance liquid chromatography uses octadecyl silicon
Alkane bonded silica gel is the chromatographic column of filler, and mobile phase is the mixed solvent of organic phase and water phase, Detection wavelength is 240~
254nm, preferably 244nm.
7. preparation method according to claim 6, which is characterized in that the volume ratio of organic phase and water phase is 45 in mobile phase:
55~80:20, the organic phase are selected from methanol or acetonitrile, and the water phase pH is 3.0~5.5, and water phase is selected from effumability weak acid
Aqueous solution, preferably acetic acid aqueous solution or aqueous formic acid.
8. a kind of method of compound described in detection claim 1, it is characterised in that: high performance liquid chromatography is used, with octadecane
Base silane bonded silica gel is filler, and mobile phase is the mixed solvent of organic phase and water phase, and flow rate of mobile phase is 0.7~0.9ml/
Min, Detection wavelength are 240~254nm.
9. detection method according to claim 8, which is characterized in that the volume ratio of organic phase and water phase in the mobile phase
For 45:55~80:20, flow rate of mobile phase 0.8ml/min, Detection wavelength 244nm, the mobile phase is selected from methanol water body
System, methanol buffer salt system, acetonitrile buffer salt system, preferably methanol-acetic acid aqueous solution.
10. application of the compound described in claim 1 in preparation impurity phenylhydrazine reference substance.
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| CN201810888177.8A CN109134374A (en) | 2013-04-03 | 2013-04-03 | Edaravone derivative and preparation method thereof, detection method and purposes |
| CN201310116354.8A CN104098512A (en) | 2013-04-03 | 2013-04-03 | Edaravone derivative, and preparation method, detection method and application thereof |
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Families Citing this family (6)
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| CN105646530B (en) * | 2014-12-03 | 2020-05-12 | 南京先声东元制药有限公司 | Phenylpyrazole compound and preparation method and application thereof |
| CN106167465B (en) * | 2016-07-06 | 2018-06-22 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of Edaravone dimer impurity compound and preparation method thereof |
| CN108072710B (en) * | 2016-11-14 | 2020-10-02 | 江苏正大丰海制药有限公司 | Detection method for related substances of edaravone sodium chloride injection |
| KR102261931B1 (en) * | 2018-09-17 | 2021-06-07 | 제이투에이치바이오텍 (주) | Prodrug compounds of edaravone and their medical use for treating or alleviating neurodegenerative or motor neuron diseases |
| KR20210067005A (en) * | 2019-11-28 | 2021-06-08 | 제이투에이치바이오텍 (주) | Prodrug compounds of edaravone and their medical use for treating or alleviating neurodegenerative or motor neuron diseases |
| CN113125608B (en) * | 2021-04-21 | 2023-08-29 | 扬子江药业集团上海海尼药业有限公司 | Impurity detection method for edaravone sodium chloride injection |
Citations (1)
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| CN102180833A (en) * | 2010-07-29 | 2011-09-14 | 南京长澳医药科技有限公司 | Preparation method and detection method for edaravone dimer and tautomer thereof |
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| CN101968467A (en) * | 2010-09-14 | 2011-02-09 | 扬子江药业集团南京海陵药业有限公司 | Quality control method for edaravone and edaravone-containing preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102180833A (en) * | 2010-07-29 | 2011-09-14 | 南京长澳医药科技有限公司 | Preparation method and detection method for edaravone dimer and tautomer thereof |
Non-Patent Citations (1)
| Title |
|---|
| 姚枝玉，等: "LC-MS法分析研究依达拉奉中有关物质", 《药学进展》 * |
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Address after: 210042 -18, Xuanwu Avenue, Nanjing, Jiangsu, 699 Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant after: SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 -18, Xuanwu Avenue, Nanjing, Jiangsu, 699 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Applicant before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. |
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