CN108203410B - Synthesis and application of edaravone impurity - Google Patents
Synthesis and application of edaravone impurity Download PDFInfo
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- CN108203410B CN108203410B CN201611181350.8A CN201611181350A CN108203410B CN 108203410 B CN108203410 B CN 108203410B CN 201611181350 A CN201611181350 A CN 201611181350A CN 108203410 B CN108203410 B CN 108203410B
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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
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
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- 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 invention relates to synthesis and application of edaravone impurities, and particularly relates to 2-amino-3- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-thio) propionic acid and a preparation method and application thereof. Comprises the steps of reacting edaravone, cysteine or hydrochloride thereof. The compound also relates to application of the compound as an impurity reference substance in quality control of edaravone bulk drugs and preparations thereof.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, relates to synthesis and application of phenyl pyrazole amino acid derivatives, and particularly relates to 2-amino-3- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-thio) propionic acid as well as a preparation method and application thereof.
Background
The edaravone has a structural formula shown in formula I: molecular formula C10H10N2O, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-ketone, colorless clear solution, is the first approved free radical scavenger in the world, has certain treatment effect on a plurality of nervous system diseases through a plurality of ways such as scavenging free radicals and protecting endoplasmic reticulum function, and can be used for treating acute cerebral infarction by combining with other medicines, and the curative effect is in an additive trend. In addition, the edaravone has a certain protection effect on the liver by scavenging free radicals, has potential application value on various diseases, and is a free radical scavenging medicament with a promising clinical application prospect.
As a clinical common medicine, the edaravone injection can cause the increase of impurity content and the reduction of medicine quality due to the existence of high temperature processes such as sterilization and the like in the production, storage and use processes, and the stability of the medicine can be improved by adding cysteine hydrochloride and sodium bisulfite as auxiliary materials. Most of domestic reports on relevant substances in the edaravone injection are reaction raw materials of acetoacetic acid and phenylhydrazine, but few research reports on relevant substances generated by the edaravone injection due to the action of the edaravone and auxiliary materials are reflected.
The edaravone and the cysteine react under the action of alkali, and the compound shown in the formula II is separated by silica gel column chromatography, so that the method is simple, the yield is high, the product purity is over 95 percent (HPLC), the edaravone can be used as an edaravone impurity reference substance, and the edaravone and related preparation related substance content can be conveniently controlled.
Disclosure of Invention
One of the purposes of the invention is to provide a phenylpyrazole amino acid derivative shown as a formula II: 2-amino-3- (5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-thio) propionic acid:
the compound may be a solvate compound or a pharmaceutically acceptable salt thereof.
The invention also provides a preparation method of the compound of the formula II, which comprises the following steps: reacting edaravone, cysteine or hydrochloride thereof to prepare the compound shown in the formula II.
Further, the solvent of the above reaction is selected from water or an organic solvent, preferably one or more of water, tetrahydrofuran, dioxane, acetonitrile, acetone, toluene, N-hexane, 1, 2-dichloroethane, dichloromethane, chloroform, methanol, ethanol, ethyl acetate, dimethylsulfoxide, N-dimethylformamide or N-methylpyrrolidone.
Further, adding alkali into the reaction. The base is an inorganic or organic base, preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine, 1, 8-diazabicycloundecen-7-ene or N-methylmorpholine.
Furthermore, the molar ratio of the edaravone to the cysteine hydrochloride to the alkali is 1-5: 1-5, preferably 1-2: 1-2.
Further, the reaction temperature of the preparation method is 50-100 ℃, and preferably 70-80 ℃.
Further, the reaction time is 72 to 100 hours, preferably 80 to 90 hours.
More specifically, to achieve the above object, the following synthesis and separation processes are adopted:
step (1): respectively weighing edaravone, cysteine hydrochloride and alkali, placing the edaravone, the cysteine hydrochloride and the alkali in a closed container, and adding a solvent to form a suspension;
step (2): placing the solution or the suspension at a reaction environment temperature in a closed manner, stirring, cooling to room temperature after the reaction is finished, and filtering to obtain a filtrate;
and (3): separating the solution by silica gel column chromatography to obtain the compound of formula II.
The final compound of formula II was prepared and analyzed for purity by HPLC and structure by MS, NMR.
The final product is subjected to structure identification by nuclear magnetic resonance and mass spectrometry, and data are attached.
1. LC-MS (ESI (+)) molecular ion peak (M +1), M/z is 294;
LC-MS (ESI (-)) molecular ion peak (M-1), M/z 292;
2、NMR(D2O)
| serial number | 13C-NMR | 1H-NMR |
| 3 | 163.75 | - |
| 4 | 90.50 | - |
| 5 | 152.59 | - |
| 6 | 135.41 | - |
| 7 | 123.41 | 7.4 |
| 8 | 129.52 | 7.4 |
| 9 | 127.94 | 7.3 |
| 10 | 129.52 | 7.4 |
| 11 | 123.41 | 7.4 |
| 12 | 36.65 | 2.9 |
| 13 | 53.72 | 3.6 |
| 14 | 172.82 | - |
| 15 | 10.80 | 2.24 |
The invention also relates to application of the compound shown in the formula II as an impurity reference substance in quality control of edaravone bulk drugs and preparations thereof.
The specific implementation mode is as follows:
the invention will now be further illustrated, but is not limited, by the following specific examples.
Example 1
8.7g of edaravone, 26g of cysteine hydrochloride, 16g of sodium carbonate and 50mL of water are weighed and placed in a closed container. And (3) heating and stirring the suspension in an oil bath at the temperature of 80 ℃ while opening, taking out after 72 hours, cooling to room temperature, and separating the compound solution of the formula II by adopting silica gel column chromatography, wherein the mobile phase ratio is methanol: dichloromethane ═ 3:1, and the color developed under an ultraviolet lamp was collected to give 5.86g of the compound of formula II in 40% yield.1H NMR(400MHz,DMSO,TMS):δ2.24(s,3H),2.87-3.04(m,2H),3.67(d,J＝4.4Hz,1H),7.34-7.45(m,5H)；13C NMR(100MHz,DMSO,TMS):δ10.8,36.7,53.7,90.5,123.4,127.9,129.5,135.4,152.6,163.8,172.8；MS(ESI)m/z:294(M+H+,100)；MS(ESI)m/z:292(M-H+100) HPLC purity 97%, specific chromatographic conditions were: the chromatographic column is a carbon-eighteen bonded silica gel column; the mobile phase is A: 50mM ammonium acetate (pH 6.0 adjusted with glacial acetic acid); b: methanol; gradient elution.
Example 2
Weighing 174mg of edaravone, 263mg of cysteine hydrochloride, 159mg of potassium carbonate and 10mL of tetrahydrofuran respectively, placing the edaravone, heating and stirring the edaravone, the cysteine hydrochloride, the potassium carbonate and the tetrahydrofuran in an oil bath at 70 ℃, taking out the edaravone after 100 hours, cooling the edaravone to room temperature, separating the compound solution of the formula II by silica gel column chromatography, wherein the mobile phase ratio is methanol: dichloromethane ═ 4:1, and the color developed under an ultraviolet lamp was collected to give 108mg of the compound of formula II in 37% yield.
Example 3
Respectively weighing 175mg of edaravone, 300mg of cysteine hydrochloride, 200mg of cesium carbonate and 10mL of dioxane, placing the edaravone, the cysteine hydrochloride, the cesium carbonate and the dioxane into a closed container, placing the container into an oil bath at 78 ℃, heating and stirring the mixture for 90 hours, taking the mixture out, cooling the mixture to room temperature, and separating the compound solution of the formula II by silica gel column chromatography, wherein the mobile phase ratio is methanol: dichloromethane 2:1, the developed fraction under uv lamp was collected to give 98mg of the compound of formula II in 33% yield.
Example 4
Weighing 185mg of edaravone, 900mg of cysteine hydrochloride, 900mg of sodium carbonate and 10mL of acetonitrile respectively, placing the edaravone, the cysteine hydrochloride, the sodium carbonate and the acetonitrile in a closed container, placing the edaravone in an oil bath at 50 ℃ for heating and stirring, taking out the edaravone after 80 hours, cooling the edaravone to room temperature, separating the compound solution of the formula II by silica gel column chromatography, wherein the mobile phase ratio is methanol: ethyl acetate 4:1, and the developed part under uv lamp was collected to give 102mg of the compound of formula II in 35% yield.
Example 5
Respectively weighing 170mg of edaravone, 300mg of cysteine hydrochloride, 200mg of potassium carbonate and 10mL of acetone, placing the edaravone, the cysteine hydrochloride, the potassium carbonate and the acetone into a closed container, placing the edaravone into an oil bath at 100 ℃, heating and stirring the edaravone, taking out the edaravone after 78 hours, cooling the edaravone to room temperature, separating the compound solution of the formula II by silica gel column chromatography, wherein the mobile phase ratio is methanol: ethyl acetate 5:1, and the developed portion under uv lamp was collected to give 80mg of the compound of formula II in 27% yield.
Example 6
Weighing 190mg of edaravone, 190mg of cysteine hydrochloride, 190mg of sodium carbonate and 10mL of toluene respectively, placing the edaravone, the cysteine hydrochloride, the sodium carbonate and the toluene in a closed container, placing the edaravone in an oil bath at 60 ℃, heating and stirring the edaravone, taking out the edaravone after 96 hours, cooling the edaravone to room temperature, separating the compound solution of the formula II by silica gel column chromatography, wherein the mobile phase ratio is methanol: ethyl acetate 3:1, and the color developed under uv lamp was collected to give 76mg of the compound of formula II in 26% yield.
Claims (9)
1. A process for preparing a compound of formula II, comprising: the compound shown in the formula II is prepared by the reaction of edaravone, cysteine or hydrochloride thereof, and the method also comprises the step of adding alkali into the reaction
2. The method according to claim 1, wherein the solvent for the reaction is one or more of water, tetrahydrofuran, dioxane, acetonitrile, acetone, toluene, N-hexane, 1, 2-dichloroethane, dichloromethane, chloroform, methanol, ethanol, ethyl acetate, dimethyl sulfoxide, N-dimethylformamide, and N-methylpyrrolidone.
3. The process according to claim 1, wherein the base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine, 1, 8-diazabicycloundecen-7-ene or N-methylmorpholine.
4. The preparation method according to claim 1, wherein the molar ratio of edaravone to cysteine hydrochloride to base is 1-5: 1-5.
5. The preparation method according to claim 4, wherein the molar ratio of edaravone to cysteine hydrochloride to base is 1-2: 1-2.
6. The method according to claim 1, wherein the reaction temperature is 50 to 100 ℃.
7. The method according to claim 6, wherein the reaction temperature is 70 to 80 ℃.
8. The method according to claim 1, wherein the reaction time is 72 to 100 hours.
9. The method according to claim 8, wherein the reaction time is 80 to 90 hours.
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| CN201611181350.8A CN108203410B (en) | 2016-12-20 | 2016-12-20 | Synthesis and application of edaravone impurity |
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| CN201611181350.8A CN108203410B (en) | 2016-12-20 | 2016-12-20 | Synthesis and application of edaravone impurity |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830852A (en) * | 2010-03-22 | 2010-09-15 | 海南美兰史克制药有限公司 | Edaravone compound synthesized by new method |
| 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 |
| CN102841170A (en) * | 2012-08-31 | 2012-12-26 | 成都百裕科技制药有限公司 | Method for detecting impurity phenylhydrazine in edaravone |
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- 2016-12-20 CN CN201611181350.8A patent/CN108203410B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830852A (en) * | 2010-03-22 | 2010-09-15 | 海南美兰史克制药有限公司 | Edaravone compound synthesized by new method |
| 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 |
| CN102841170A (en) * | 2012-08-31 | 2012-12-26 | 成都百裕科技制药有限公司 | Method for detecting impurity phenylhydrazine in edaravone |
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