CN102887857A - Pyrazolone derivative, amd application and preparation method of pyrazolone derivative - Google Patents
Pyrazolone derivative, amd application and preparation method of pyrazolone derivative Download PDFInfo
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- CN102887857A CN102887857A CN 201110204799 CN201110204799A CN102887857A CN 102887857 A CN102887857 A CN 102887857A CN 201110204799 CN201110204799 CN 201110204799 CN 201110204799 A CN201110204799 A CN 201110204799A CN 102887857 A CN102887857 A CN 102887857A
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Abstract
The invention relates to a new pyrazolone derivative of 4-(1-nitro-1-sulfonic group)ethyl-3-methyl-1-phenyl-2-pyrazol-5-ketone. The invention further relates to a method for preparing the new pyrazolone derivative and application of the pyrazolone derivative in an edaravone and related preparation quality control method as an impurity reference substance.
Description
Technical field:
The present invention relates to a kind of new pyrazolone derivative, its preparation method, and the application in the quality controlling means that relates to a kind of neuroprotection agent Edaravone and related preparations.
Background technology:
Edaravone (Edaravone) is a kind of in the pyrazolone derivative, its chemistry 3-methyl isophthalic acid-phenyl by name-2-pyrazoles woods-5-ketone, and chemical structural formula is as follows:
Because Edaravone might produce impurity in preparation production, storage and use procedure, thereby cause the pharmaceutical preparation Quality Down, therefore the determination of foreign matter method of a kind of effective Edaravone and related preparations is to the quality of control Edaravone preparation and guarantee that its clinical efficacy has great importance.
Prior art does not provide the new relevant information of pyrazolone derivative any and provided by the invention, has not both had the open report of compound and structural identification thereof, does not prepare the method report of this compound yet.
Summary of the invention:
The object of the present invention is to provide a kind of new pyrazolone derivative: 4-(1-nitro-1-sulfonic group) ethyl-3-methyl isophthalic acid-phenyl-2-pyrazoles woods-5-ketone.Chemical structural formula is as follows:
Another object of the present invention is to provide a kind of method for preparing above compound.
Further purpose of the present invention is this compound as the impurity reference substance, for the amount of control Edaravone and this compound of related preparations.
The invention provides a kind of method for preparing above new pyrazolone derivative.The method is reacted take Edaravone, cysteine hydrochloride, sodium bisulfite as starting raw material.The starting raw material preferred proportion is: the mass ratio of Edaravone, cysteine hydrochloride, sodium bisulfite is 2～20: 1～50: 1～10.
Above-mentioned starting raw material is added solvent be mixed with solution or suspension, solvent can be water or organic solvent.
This solution or suspension are placed normal temperature 5-30 days, or placed 65 ℃～125 ℃ of temperature environment 12-240 hour.
With mentioned solution or suspension process reverse-phase chromatography chromatographic separation, collect the parting liquid that contains the compounds of this invention, concentrating and separating liquid obtains the compounds of this invention.
The invention provides a kind of with the compounds of this invention as the impurity reference substance, be used for the method for control Edaravone and related preparations quality.Adopt photoelectric technology that the compounds of this invention in Edaravone and the related preparations thereof: 4-(1-nitro-1-sulfonic group) ethyl-3-methyl isophthalic acid-phenyl-2-pyrazoles woods-5-ketone has been carried out quantitative assay in the method.
Wherein the related preparations of Edaravone comprises the suitable pharmaceutical dosage form of acceptable on the physiology that contains Edaravone.
The preferred high performance liquid chromatography of method for quantitatively determining wherein, adopting silane group silica gel is the chromatographic column of weighting agent, with the mixed solvent of organic phase and water as moving phase.Wherein the ratio of organic phase and water is 10～50: 90～50, and preferred proportion is 20～40: 80～60.
Organic phase wherein can be methyl alcohol or acetonitrile.Water wherein can be acetate buffer or phosphate buffered saline buffer, and the pH scope is 3～8, and preferred pH scope is 3.5～5.5 phosphate buffered saline buffer.
Embodiment:
The present invention is further elaborated below in conjunction with embodiment, but the present invention is not had any restriction.
Embodiment 1: the preparation of the compounds of this invention 4-(1-nitro-1-sulfonic group) ethyl-3-methyl isophthalic acid-phenyl-2-pyrazoles woods-5-ketone
Take by weighing respectively in Edaravone 10g, cysteine hydrochloride 20g, the sodium bisulfite 10g adding 4L water, put in the 98-100 ℃ of water-bath and heated 24 hours.React complete, concentrated, to filter, filtrate is separated the compounds of this invention through preparative liquid chromatograph, collects the parting liquid that contains the compounds of this invention, and concentrating and separating liquid gets the compounds of this invention 0.3g, yield 3%.
Product carries out Structural Identification with nucleus magnetic resonance, single crystal X diffraction, and the nuclear magnetic resonance result data are as follows:
NMR(DMSO-d
6)
Embodiment 2: the content of 4-in the high effective liquid chromatography for measuring Edaravone preparation (1-nitro-1-sulfonic group) ethyl-3-methyl isophthalic acid-phenyl-2-pyrazoles woods-5-ketone
Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent, (contain 0.05mol/LNaH with water
2PO
4, H
3PO
4Transfer pH to 4.0)-methyl alcohol (60: 40) is moving phase, the detection wavelength is 243nm.
It is an amount of that the Edaravone formulation samples is got in the preparation of need testing solution, adds moving phase and make the solution that contains the 0.5mg Edaravone among every 1ml, as need testing solution.
4-(1-nitro-1-sulfonic group) is got in the preparation of reference substance solution, and ethyl-3-methyl isophthalic acid-phenyl-2-pyrazoles woods-5-ketone reference substance is an amount of, accurately weighed, adds moving phase and makes the solution that every 1ml contains 5.0 μ g, in contrast product solution.
Assay method respectively precision is measured need testing solution, each 20 μ L injection liquid chromatography of reference substance solution, presses external standard method with calculated by peak area, and get final product.
Claims (10)
1. following structural formula compound:
2. the preparation method of claim 1 compound, the method may further comprise the steps:
1) Edaravone, cysteine hydrochloride, sodium bisulfite are added solvent and be mixed with solution or suspension, solvent can be water or organic solvent;
2) this solution or suspension are placed normal temperature 5-30 days, or placed 65 ℃～125 ℃ of temperature environment 12-240 hour;
3) with mentioned solution or suspension process reverse-phase chromatography chromatographic separation, collect the parting liquid that contains the compounds of this invention, concentrating and separating liquid obtains product.
3. preparation method according to claim 2, the mass ratio that it is characterized in that Edaravone, cysteine hydrochloride, sodium bisulfite is 2～20: 1～50: 1～10.
4. claim 1 compound is as the impurity reference substance, the application in the quality controlling means of Edaravone and related preparations.
5. according to claim 4 described application is characterized in that adopting photoelectric technology that claim 1 compound in Edaravone and the related preparations thereof has been carried out quantitative assay.
6. described application method according to claim 5 is characterized in that the preferred high performance liquid chromatography of method for quantitatively determining.
7. described high performance liquid chromatography according to claim 6, it is characterized in that adopting silane group silica gel is the chromatographic column of weighting agent, as moving phase, wherein the ratio of organic phase and water is 10～50: 90～50 with the mixed solvent of organic phase and water.
8. high performance liquid chromatography according to claim 7 is characterized in that wherein the preferred proportion of organic phase and water is 20～40: 80～60.
9. described high performance liquid chromatography according to claim 7 is characterized in that organic phase wherein can be methyl alcohol or acetonitrile, and water wherein can be acetate buffer or phosphate buffered saline buffer, and the pH scope is 3～8.
10. high performance liquid chromatography according to claim 9 is characterized in that wherein the preferred pH scope of water is 3.5～5.5 phosphate buffered saline buffer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 201110204799 CN102887857A (en) | 2011-07-21 | 2011-07-21 | Pyrazolone derivative, amd application and preparation method of pyrazolone derivative |
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| CN 201110204799 CN102887857A (en) | 2011-07-21 | 2011-07-21 | Pyrazolone derivative, amd application and preparation method of pyrazolone derivative |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646530A (en) * | 2014-12-03 | 2016-06-08 | 江苏先声药业有限公司 | Phenyl pyrazole compound, preparation method and application thereof |
| CN106167465A (en) * | 2016-07-06 | 2016-11-30 | 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 |
| CN113125608A (en) * | 2021-04-21 | 2021-07-16 | 扬子江药业集团上海海尼药业有限公司 | Impurity detection method of edaravone sodium chloride injection |
| CN118026938A (en) * | 2024-04-08 | 2024-05-14 | 江西本草天工科技有限责任公司 | Pyrazolone ester compound and electrochemical synthesis method thereof |
| CN118026938B (en) * | 2024-04-08 | 2024-06-28 | 江西本草天工科技有限责任公司 | Pyrazolone ester compound and electrochemical synthesis method thereof |
-
2011
- 2011-07-21 CN CN 201110204799 patent/CN102887857A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646530A (en) * | 2014-12-03 | 2016-06-08 | 江苏先声药业有限公司 | Phenyl pyrazole compound, preparation method and application thereof |
| 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 |
| CN106167465A (en) * | 2016-07-06 | 2016-11-30 | 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 |
| 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 |
| CN113125608A (en) * | 2021-04-21 | 2021-07-16 | 扬子江药业集团上海海尼药业有限公司 | Impurity detection method of edaravone sodium chloride injection |
| 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 |
| CN118026938A (en) * | 2024-04-08 | 2024-05-14 | 江西本草天工科技有限责任公司 | Pyrazolone ester compound and electrochemical synthesis method thereof |
| CN118026938B (en) * | 2024-04-08 | 2024-06-28 | 江西本草天工科技有限责任公司 | Pyrazolone ester compound and electrochemical synthesis method thereof |
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Application publication date: 20130123 |