CN106167465B - A kind of Edaravone dimer impurity compound and preparation method thereof - Google Patents
A kind of Edaravone dimer impurity compound and preparation method thereof Download PDFInfo
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- CN106167465B CN106167465B CN201610530038.9A CN201610530038A CN106167465B CN 106167465 B CN106167465 B CN 106167465B CN 201610530038 A CN201610530038 A CN 201610530038A CN 106167465 B CN106167465 B CN 106167465B
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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
Abstract
The present invention provides a kind of Edaravone dimer impurity compound, the structural formula of compound such as formula (I) is shown.The present invention also provides a kind of preparation methods of Edaravone dimer impurity compound, it is characterized in that, the preparation method is using II compound phenylhydrazine of formula, III compound acetyl ethyl acetate of formula and IV compound acetaldehyde of formula as raw material, and compound shown in formula (I) is made after carrying out synthetic reaction.The present invention has the following technical effect that：1）A kind of Edaravone dimer impurity compound is provided as impurity reference substance；To use external standard method（That is impurity Standard reference）Quality of stringent control Edaravone etc. contributes.2）The preparation method of the present invention can quickly, simply, efficiently obtain impurity reference substance, simple for process, purity is high, and the reference substance of qualification can be provided for the quality control of Edaravone.
Description
Technical field
The present invention relates to belong to medicinal chemistry art, and in particular to a kind of Edaravone dimer impurity compound and its system
Preparation Method.
Background technology
Edaravone (Formula V compound) 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 makes after morbidity in the 28th day brain NAA contents compared with the apparent increase of glycerol control group.According to up to
Drawing, which is given, can remove free radical, anti-lipid peroxidation, so as to inhibit the oxidation damage of brain cell, vascular endothelial cell, nerve cell
Wound.
The content of the active ingredient of drug is to reflect the important symbol of pharmaceutical purity, and the direct shadow of impurity present in drug
It rings to the generation that may simultaneously lead to toxic side effect the effect of drug.Impurity of the drug is the introduction or generation during production, storage
Drug other than other chemical substances, the presence of impurity not only influences the purity of drug, can also bring the poison of non-treatment activity
Side effect, it is necessary to be controlled.Safely and effectively to use drug, the quality standard of drug to the purity of effective ingredient and
The limit of impurity has more stringent regulation, it is however generally that, the impurity of the drug more than 0.1% should be reflected by process for selective
Determine and quantify.
Edaravone is described for the first time in patent US4857542.US4857542 discloses Edaravone structure, display
Going out has circulatory system disorder effective prevention and treatment, is treated particularly as lipid peroxidation inhibitor and brain disorder
With good effect.US4857542 discloses phenylhydrazine and the ethyl acetoacetate back flow reaction in alcoholic solvent, and Yi Dala is made
It gives, yield 65%.
The synthetic route of Edaravone is as follows：
During being synthesized according to above-mentioned technique, divide in the edaravone raw material test map of wherein a collection of enlarged experiment
A new unknown impuritie is separated out, by this new miscellaneous Quality Research, it is found that it participates in reacting formed two for residual acetaldehyde in alcohol
Aggressiveness impurity compound (compound of formula I).In order to which this impurity is better controlled in Edaravone, applicants have invented
The preparation method of this dimer impurity compound is significant for the correlative study of impurity phenylhydrazine.It can be used for according to
Impurity quantification and quantitative analysis in Da Lafeng productions are people's masses'safety so as to improve the quality of Edaravone
Medication provides important directive significance.
Invention content
In order to improve the quality of Edaravone, reduce the risk of clinical application, the object of the present invention is to provide one kind according to up to
Dimer impurity compound and preparation method thereof is given in drawing.
The present invention provides a kind of Edaravone dimer impurity compounds, and the structural formula of compound is as shown in formula I：
The present invention provides a kind of method for preparing above-mentioned Edaravone dimer impurity compound, the preparation methods
It is using II compound phenylhydrazine of formula, III compound acetyl ethyl acetate of formula and IV compound acetaldehyde of formula as raw material, carries out synthetic reaction
Compound shown in formula I is made afterwards, reaction equation is as follows：
The preparation method, comprises the following steps：
1) II compound phenylhydrazine of formula and III compound acetyl ethyl acetate of formula are dissolved in agitating and heating in appropriate alcoholic solvent, instead
After answering, continue to stir after adding in IV compound acetaldehyde of formula in above-mentioned reaction solution, be concentrated to dryness to obtain Formulas I after reaction
Crude compound；
2) compound of formula I crude product purifies to obtain Edaravone dimer impurity compound fine work by column chromatography.
In the step 1), the molar ratio of phenylhydrazine and ethyl acetoacetate is 1:(0.5~3), phenylhydrazine and acetaldehyde rub
You are than being 1:(0.2~2).
In the step 1), reaction dissolvent is the alcoholic solvent of C1~C5.The reaction dissolvent is preferably methanol, second
Alcohol, isopropanol or n-butanol.
In the step 1), the heating temperature is 40 DEG C~system reflux temperature, the heating reaction time for 1~
24h。
In the step 1), the acetaldehyde add in after reaction temperature for 0 DEG C~system reflux temperature, the reaction time
For 1~for 24 hours.
The present invention has the following technical effect that：
1) a kind of Edaravone dimer impurity compound is provided as impurity reference substance；It is (i.e. miscellaneous using external standard method
Matter Standard reference) quality of Edaravone etc. is strictly controlled to contribute.
2) method of the invention is reacted, side on the basis of Edaravone is synthesized by adding in acetaldehyde in the reaction system
Just Edaravone dimer impurity compound is made, and the impurity reference substance of high-purity is made by column chromatography.The present invention's
Preparation method can quickly, simply, efficiently obtain impurity reference substance, simple for process, purity is high, can be the matter of Edaravone
Amount control provides qualified reference substance.
Description of the drawings
Fig. 1 is the LC-MS figures of formula (I) compound.
Fig. 2 is the H of formula (I) compound1- NMR schemes.
Fig. 3 is the C of formula (I) compound13- NMR schemes.
Specific embodiment
Embodiment 1
The Edaravone dimer impurity compound producing step of the present embodiment：
1) phenylhydrazine (10.8g, 0.1mol) and ethyl acetoacetate (13.0g, 0.1mol) compound are dissolved in 100mL ethyl alcohol
In, reflux is heated with stirring to, after reacting 10h, addition acetaldehyde (2.2g, 0.05mol) continues afterwards in room temperature in above-mentioned reaction solution
Lower stirring is concentrated to dryness to obtain compound of formula I crude product after reaction.
2) compound of formula I crude product is purified by column chromatography, and eluant, eluent is petroleum ether and ethyl acetate mixed solvent (V:
V=1:1) it, collects product point and is concentrated to give 16.8g white solids, i.e. Edaravone dimer impurity compound, purity 95%,
Yield 90%.
Embodiment 2
The Edaravone dimer impurity compound producing step of the present embodiment：
1) phenylhydrazine (10.8g, 0.1mol) and ethyl acetoacetate (6.5g, 0.05mol) compound are dissolved in 100mL methanol
In, 40 DEG C are heated with stirring to, after reacting 1h, addition acetaldehyde (0.88g, 0.02mol) continues afterwards at 0 DEG C in above-mentioned reaction solution
Stirring, is concentrated to dryness to obtain compound of formula I crude product after reaction.
2) compound of formula I crude product is purified by column chromatography, and eluant, eluent is petroleum ether and ethyl acetate mixed solvent (V:
V=1:1) it, collects product point and is concentrated to give 6.4g white solids, i.e. Edaravone dimer impurity compound, purity 98%, production
Rate 85%.
Embodiment 3
The Edaravone dimer impurity compound producing step of the present embodiment：
1) phenylhydrazine (10.8g, 0.1mol) and ethyl acetoacetate (39.0g, 0.3mol) compound are dissolved in the positive fourths of 100mL
In alcohol, reflux is heated with stirring to, after reaction for 24 hours, addition acetaldehyde (8.8g, 0.2mol) continues afterwards in room temperature in above-mentioned reaction solution
Lower stirring is concentrated to dryness to obtain compound of formula I crude product after reaction.
2) compound of formula I crude product is purified by column chromatography, and eluant, eluent is petroleum ether and ethyl acetate mixed solvent (V:
V=1:1) it, collects product point and is concentrated to give 33.7g white solids, i.e. Edaravone dimer impurity compound, purity 95%,
Yield 90%.
Embodiment 4
The structural identification of Edaravone dimer impurity compound：
Mass spectrum (AGILENT 6330LC/MS mass spectrographs, ESI (+), 70V)
MS(ESI)：375.2[M+H]+, see attached drawing 1.
Nucleus magnetic hydrogen spectrum (1H-NMR) data (see attached drawing 2)：
| Proton serial number | Chemical shift (ppm) | Multiplicity | Proton number |
| 28 | 1.53-1.55 | d | 3 |
| 13,26 | 2.04 | s | 6 |
| 27 | 3.51-3.55 | m | 1 |
| 2,15 | 7.09-7.12 | m | 2 |
| 1,3,14,16 | 7.25-7.31 | m | 4 |
| 4,6,17,19 | 7.59-7.61 | m | 4 |
Nuclear-magnetism carbon spectrum (13C-NMR) data (see attached drawing 3)：
Claims (8)
1. a kind of Edaravone dimer impurity compound, which is characterized in that the structural formula of compound is as shown in formula I：
2. a kind of preparation method of Edaravone dimer impurity compound as described in claim 1, which is characterized in that described
Preparation method be using II compound phenylhydrazine of formula, III compound acetyl ethyl acetate of formula and IV compound acetaldehyde of formula as raw material, into
Compound shown in formula I is made after row synthetic reaction, reaction equation is as follows：
3. preparation method according to claim 2, which is characterized in that comprise the following steps：
1) II compound phenylhydrazine of formula and III compound acetyl ethyl acetate of formula are dissolved in agitating and heating in appropriate alcoholic solvent, reaction knot
Shu Hou continues to stir, is concentrated to dryness to obtain Formulas I chemical combination after reaction after adding in IV compound acetaldehyde of formula in above-mentioned reaction solution
Object crude product；
2) compound of formula I crude product purifies to obtain Edaravone dimer impurity compound fine work by column chromatography.
4. preparation method according to claim 3, which is characterized in that in the step 1), phenylhydrazine and acetoacetate second
The molar ratio of ester is 1:The molar ratio of (0.5~3), phenylhydrazine and acetaldehyde is 1:(0.2~2).
5. preparation method according to claim 3, which is characterized in that in the step 1), reaction dissolvent is C1~C5
Alcoholic solvent.
6. preparation method according to claim 5, which is characterized in that in the step 1), the reaction dissolvent is
Methanol, ethyl alcohol, isopropanol or n-butanol.
7. preparation method according to claim 3, which is characterized in that in the step 1), the heating temperature is
40 DEG C~system reflux temperature, the heating reaction time for 1~for 24 hours.
8. preparation method according to claim 3, which is characterized in that in the step 1), after the acetaldehyde adds in
Reaction temperature for 0 DEG C~system reflux temperature, the reaction time for 1~for 24 hours.
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| CN107098860B (en) * | 2017-05-23 | 2019-08-16 | 安徽天洋药业有限公司 | A kind of preparation method of the Edaravone in relation to substance |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805292A (en) * | 2010-04-27 | 2010-08-18 | 江苏先声药物研究有限公司 | Pyrazolines compound as well as application and preparation method thereof |
| 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 |
| CN102241631A (en) * | 2010-05-13 | 2011-11-16 | 吉林省博大制药有限责任公司 | Method for preparing edaravone raw material |
| CN102432540A (en) * | 2011-10-11 | 2012-05-02 | 沈阳药科大学 | Novel preparation method and use of bisedaravone and medicinal salts of bisedaravone |
| CN102887857A (en) * | 2011-07-21 | 2013-01-23 | 南京争锋信息科技有限公司 | Pyrazolone derivative, amd application and preparation method of pyrazolone derivative |
| CN104098512A (en) * | 2013-04-03 | 2014-10-15 | 江苏先声药物研究有限公司 | Edaravone derivative, and preparation method, detection method and application thereof |
| CN105418507A (en) * | 2014-09-19 | 2016-03-23 | 上海秩研医药科技有限公司 | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5255313B2 (en) * | 2008-04-01 | 2013-08-07 | キョーリンリメディオ株式会社 | Stable edaravone injection |
-
2016
- 2016-07-06 CN CN201610530038.9A patent/CN106167465B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805292A (en) * | 2010-04-27 | 2010-08-18 | 江苏先声药物研究有限公司 | Pyrazolines compound as well as application and preparation method thereof |
| CN102241631A (en) * | 2010-05-13 | 2011-11-16 | 吉林省博大制药有限责任公司 | Method for preparing edaravone raw material |
| 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 |
| CN102887857A (en) * | 2011-07-21 | 2013-01-23 | 南京争锋信息科技有限公司 | Pyrazolone derivative, amd application and preparation method of pyrazolone derivative |
| CN102432540A (en) * | 2011-10-11 | 2012-05-02 | 沈阳药科大学 | Novel preparation method and use of bisedaravone and medicinal salts of bisedaravone |
| CN104098512A (en) * | 2013-04-03 | 2014-10-15 | 江苏先声药物研究有限公司 | Edaravone derivative, and preparation method, detection method and application thereof |
| CN105418507A (en) * | 2014-09-19 | 2016-03-23 | 上海秩研医药科技有限公司 | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine |
Non-Patent Citations (4)
| Title |
|---|
| RP-HPLC法测定依达拉奉有关物质方法建立分析;郭强，等;《医药论坛杂志》;20140831;第35卷(第8期);第156-157页 * |
| 依达拉奉注射液杂质谱分析;许真玉;《中国执业药师》;20140831;第11卷(第8期);第27-30页 * |
| 高效液相色谱法测定依达拉奉注射液中依达拉奉及有关物质的含量;谷铁波，等;《药品鉴定》;20130731;第20卷(第21期);第61-63页 * |
| 高效液相色谱法测定依达拉奉注射液的含量及其有关物质;汤海燕，等;《海峡药学》;20101231;第22卷(第5期);第77-78页 * |
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Address after: 225321 No. 8, Tai Zhen Road, Taizhou medical hi tech Zone, Jiangsu Patentee after: Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group Address before: 225321 No. 8 Tai Zhen Road, Binjiang Industrial Park, Taizhou Economic Development Zone, Taizhou, Jiangsu. Patentee before: Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group |