CN102336710A - Method for synthesizing edaravone derivative - Google Patents
Method for synthesizing edaravone derivative Download PDFInfo
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- CN102336710A CN102336710A CN2011101940684A CN201110194068A CN102336710A CN 102336710 A CN102336710 A CN 102336710A CN 2011101940684 A CN2011101940684 A CN 2011101940684A CN 201110194068 A CN201110194068 A CN 201110194068A CN 102336710 A CN102336710 A CN 102336710A
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Abstract
The invention discloses a method for synthesizing an edaravone derivative. The method comprises the following steps of: making edaravone react with ethyl pyruvate under the catalytic action of pyridine to obtain Ed-SPA1; making Ed-SPA1 react with sodium bisulfite to obtain Ed-SPA2; and making the Ed-SPA2 generate the edaravone derivative under the action of sulfuric acid. The synthetic method has a simple and convenient process and high production efficiency; and counted by the edaravone serving as a raw material, the yield is over 70 percent. The chemical name of the novel edaravone derivative is 2-(1-phenyl-3-methyl-5-oxo-4-pyrazolyl)-2-sulfo propionic acid. The edaravone derivative is a colorless crystal, has the melting point of 158 DEG C and medicament activity similar to edaravone or other application properties, and can be taken as a precursor for synthesizing other medicaments or medicament intermediates.
Description
Technical field
The present invention relates to Edaravone, be specifically related to a kind of compound method of Edaravone verivate.
Background technology
The Edaravone chemistry is by name: 1-phenyl-3-antazoline-5-ketone (PMP) is a kind of free-radical scavengers.Medically be usually used in brain free-radical scavengers treatment acute cerebral infarction; It has the minimizing of RCBF on every side that the inhibition infraction causes, and can stop the progress of cerebral edema and cerebral infarction, and alleviates the nervous symptoms of being followed, and suppresses functions such as delayed neuronal death.Edaravone also can be used for preparing the relative disease that treatment wound, burn and endotoxemia cause.But the mixture of medically mainly forming with Edaravone and alkaline matter (like Tutofusin tris, l-arginine, sodium hydroxide and salt of wormwood etc.) is at present used.Though the research of PMP verivate is also arranged; Like publication number is the preparation technology that the application for a patent for invention of CN101747390 just discloses Edaravone glucuronidation product IV; Earlier glucuronic acid methyl ester is processed that resynthesis is the midbody II after the intermediate I; Midbody II and Edaravone react the midbody III, the reaction of midbody III and sodium hydroxide obtains Edaravone glucuronidation product IV.And for example chemistry is called the Edaravone verivate of 1-phenyl-3-methyl-4-carboxaldehyde radicals-2-pyrazolin-5-one; Can be synthetic at metal extraction, dyestuff, the application aspect oxidation inhibitor and the biological chemistry; The Edaravone verivate of chemistry 1-phenyl by name-3-methyl-4-carboxaldehyde radicals-5-chlorine pyrazoles can be in the application in the building-up reactions of biochemicals such as esterase inhibitor.
Summary of the invention
Technical problem to be solved by this invention provides a kind of compound method of novel Edaravone verivate; Its chemistry 2-(1-phenyl-3-methyl-5-oxo-4-pyrazolyl) by name-2-sulfo group propionic acid; This Edaravone verivate has the pharmaceutical activity similar with Edaravone; Other application performances are also arranged, can be as the precursor of synthetic other drug or pharmaceutical intermediate.
The present invention solves the problems of the technologies described above the technical scheme that is adopted: a kind of compound method of Edaravone verivate comprises the steps:
A, in four neck flasks of reflux condensing tube, TM and water trap are housed; Add the Edaravone of 0.1mol, Pyruvic Acid Ethyl ester, 100～200ml toluene and the 5～8ml pyridine of 0.1～0.15mol successively, heat temperature raising to reflux temperature is under 120～140 ℃ the condition, to react 3.5～4.5 hours; Stop reacting by heating; Toluene is removed in underpressure distillation, and nitrogen protection cooling down is cooled to room temperature, obtains Ed-SPA1;
B, in the three-necked flask that reflux condensing tube and TM are housed; Sodium sulfite anhy 96, the volumetric concentration that add the Ed-SPA1 of above-mentioned gained, adds 0.1～0.15mol again is methanol solution 250～350ml of 70～80%, and heat temperature raising to reflux temperature is under 80～100 ℃ the condition, reaction 7～9h; Stop reacting by heating; Methyl alcohol is removed in underpressure distillation, uses the ethanolic soln recrystallization of mass concentration 95% again, and recrystallization finishes and obtains Ed-SPA2;
C, in the three-necked flask that reflux condensing tube and TM are housed, add the Ed-SPA2 of above-mentioned gained, add volumetric concentration again and be sulphuric acid soln 250～350ml of 10～20%; Heat temperature raising to reflux temperature is under 110～130 ℃ the condition, reaction 5～7h, reaction finish be chilled to room temperature after; Place frozen water to cool off again; To be crystallized separating out fully filtered elimination filtrating, and crystallisate is with the ethanolic soln recrystallization of mass concentration 95%; Recrystallization finishes and obtains the Edaravone verivate, and the chemistry of this Edaravone verivate is called 2-(1-phenyl-3-methyl-5-oxo-4-pyrazolyl)-2-sulfo group propionic acid; Be clear crystal, fusing point is 158 ℃.
In step a: Pyruvic Acid Ethyl ester is 0.15mol, and toluene is 200ml, and pyridine is 6ml, and reflux temperature is 140 ℃, and the reaction times is 3.5 hours; Among the step b: sodium sulfite anhy 96 is 0.15 mol, and concentration of methanol solution is 80%, and volume is 250ml, and reflux temperature is 100 ℃, and the reaction times is 7h; Among the step c: the concentration of sulphuric acid soln is 10%, and volume is 350 ml, and reflux temperature is 130 ℃, and the reaction times is 5h.Industry synthetic economical efficiency is higher.
Compared with prior art, the invention has the advantages that a kind of compound method of Edaravone verivate, at first Edaravone and Pyruvic Acid Ethyl ester are reacted under the katalysis of pyridine and obtain Ed-SPA1; Ed-SPA1 obtains Ed-SPA2 with the sodium sulfite anhy 96 reaction again; Ed-SPA2 generates the Edaravone verivate under effect of sulfuric acid, synthetic method craft of the present invention is simple and direct, and production efficiency is higher; In the Edaravone raw material, productive rate is more than 70%.The chemistry of the Edaravone verivate that this is new is called 2-(1-phenyl-3-methyl-5-oxo-4-pyrazolyl)-2-sulfo group propionic acid; Be clear crystal; Fusing point is 158 ℃; This Edaravone verivate has the pharmaceutical activity similar with Edaravone, and other application performances are perhaps also arranged, can be as the precursor of synthetic other drug or pharmaceutical intermediate.
Description of drawings
Fig. 1 obtains the reaction formula of Ed-SPA1 for steps A of the present invention;
Fig. 2 obtains the reaction formula of Ed-SPA2 for step B of the present invention;
Fig. 3 obtains the reaction formula of Edaravone verivate for step C of the present invention.
Embodiment
Embodiment describes in further detail the present invention below in conjunction with accompanying drawing.
Embodiment 1
A kind of compound method of Edaravone verivate, step 1: in the 250ml that reflux condensing tube, TM and water trap are housed four neck flasks, add 17.4g (being equivalent to 0.1 mol) Edaravone, 11.6g (being equivalent to 0.1 mol) Pyruvic Acid Ethyl ester, 100ml toluene and 5ml pyridine successively; Heat temperature raising to reflux temperature is under 130 ℃ the condition; Follow the tracks of reaction with TLC, behind back flow reaction (reaction formula the is as shown in Figure 1) 4h, the water that tell in the water trap this moment reaches theoretical growing amount; Stop reacting by heating; Toluene is removed in underpressure distillation, and nitrogen protection cooling down is cooled to room temperature, obtains 23.5gEd-SPA1; Step 2: in the 500ml three-necked flask of reflux condensing tube and TM is housed; Add Ed-SPA1,10.4g (the being equivalent to 0.1 mol) sodium sulfite anhy 96 of above-mentioned gained, the methanol solution 300ml of volumetric concentration 75% successively; Heat temperature raising to reflux temperature is reaction (reaction formula is as shown in Figure 2) 8h under 90 ℃ the condition; Stop reacting by heating, methyl alcohol is removed in underpressure distillation, with the ethanolic soln 300ml recrystallization of mass concentration 95%; Just can basically the Ed-SPA2 crystallization be gone out, obtain 29.0 gEd-SPA2; Step 3: in the 500ml three-necked flask of reflux condensing tube and TM is housed, add the Ed-SPA2 of above-mentioned gained, add volumetric concentration again and be 15% sulphuric acid soln 300ml; Heat temperature raising to reflux temperature is reaction (reaction formula is as shown in Figure 3) 6h under 120 ℃ the condition, stops reacting by heating, places frozen water to cool off again after being chilled to room temperature; To be crystallized separating out fully filtered elimination filtrating, and crystallisate is with the ethanolic soln 200ml recrystallization of mass concentration 95%; Just can accomplish crystallization basically; Obtain 23.2g Edaravone verivate, in Edaravone weight, the productive rate of synthetic Edaravone verivate is 71.2%.
Embodiment 2
Basic identical with embodiment 1, in the different just step 1: the Pyruvic Acid Ethyl ester quality is 17.4g (0.15 mol), and toluene is 200ml, and pyridine is 6ml, and reflux temperature is 140 ℃, and reflux time is 3.5h; In the step 2: the quality of sodium sulfite anhy 96 is 15.2g (0.15 mol), and concentration of methanol solution is 80%, and volume is 250ml, and reflux temperature is 100 ℃, and reflux time is 7h; In the step 3: the concentration of sulphuric acid soln is 10%, and volume is 350 ml, and reflux temperature is 130 ℃, and reflux time is 5h, and the productive rate of synthetic Edaravone verivate is 72.5%.
Embodiment 3
Basic identical with embodiment 1, in the different just step 1: the Pyruvic Acid Ethyl ester quality is 14.6g, and toluene is 150ml, and pyridine is 8ml, and reflux temperature is 120 ℃, and reflux time is 4.5h; In the step 2: the sodium sulfite anhy 96 quality is 12.8g, and concentration of methanol solution is 70%, and volume is 350ml, and reflux temperature is 80 ℃, and reflux time is 9h; In the step 3: the concentration of sulphuric acid soln is 20%, and volume is 250 ml, and reflux temperature is 110 ℃, and reflux time is 7h; The productive rate of synthetic Edaravone verivate is 71.8%.
The chemistry of the Edaravone verivate that the foregoing description obtains after measuring 2-(1-phenyl-3-methyl-5-oxo-4-pyrazolyl) by name-2-sulfo group propionic acid is clear crystal, and fusing point is 158 ℃.
Claims (3)
1. the compound method of an Edaravone verivate is characterized in that comprising the steps:
A, in four neck flasks of reflux condensing tube, TM and water trap are housed; Add the Edaravone of 0.1mol, Pyruvic Acid Ethyl ester, 100～200ml toluene and the 5～8ml pyridine of 0.1～0.15mol successively, heat temperature raising to reflux temperature is under 120～140 ℃ the condition, to react 3.5～4.5 hours; Stop reacting by heating; Toluene is removed in underpressure distillation, and nitrogen protection cooling down is cooled to room temperature, obtains Ed-SPA1;
B, in the three-necked flask that reflux condensing tube and TM are housed; Sodium sulfite anhy 96, the volumetric concentration that add the Ed-SPA1 of above-mentioned gained, adds 0.1～0.15mol again is methanol solution 250～350ml of 70～80%, and heat temperature raising to reflux temperature is under 80～100 ℃ the condition, reaction 7～9h; Stop reacting by heating; Methyl alcohol is removed in underpressure distillation, uses the ethanolic soln recrystallization of mass concentration 95% again, and recrystallization obtains Ed-SPA2 fully;
C, in the three-necked flask that reflux condensing tube and TM are housed, add the Ed-SPA2 of above-mentioned gained, add volumetric concentration again and be sulphuric acid soln 250～350ml of 10～20%; Heat temperature raising to reflux temperature is under 110～130 ℃ the condition, reaction 5～7h, reaction finish be chilled to room temperature after; Place frozen water to cool off again, to be crystallized separating out fully filtered elimination filtrating; Crystallisate is with the ethanolic soln recrystallization of mass concentration 95%, and recrystallization obtains the Edaravone verivate fully.
2. the compound method of a kind of Edaravone verivate as claimed in claim 1 is characterized in that among the step a: Pyruvic Acid Ethyl ester is 0.15mol, and toluene is 200ml, and pyridine is 6ml, and reflux temperature is 140 ℃, and the reaction times is 3.5 hours; Among the step b: sodium sulfite anhy 96 is 0.15 mol, and the methanol solution volumetric concentration is 80%, and volume is 250ml, and reflux temperature is 100 ℃, and the reaction times is 7h; Among the step c: the volumetric concentration of sulphuric acid soln is 10%, and volume is 350 ml, and reflux temperature is 130 ℃, and the reaction times is 5h.
3. the compound method of a kind of Edaravone verivate as claimed in claim 1 is characterized in that the chemistry of this Edaravone verivate is called 2-(1-phenyl-3-methyl-5-oxo-4-pyrazolyl)-2-sulfo group propionic acid; Be clear crystal, fusing point is 158 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316957A (en) * | 2015-06-15 | 2017-01-11 | 江苏正大丰海制药有限公司 | Edaravone impurity intermediate, preparation method and application thereof |
| CN107382866A (en) * | 2017-03-27 | 2017-11-24 | 陕西科技大学 | A kind of gossypol Edaravone condensation product and its synthetic method with antitumor activity |
| CN108314652A (en) * | 2017-01-18 | 2018-07-24 | 周意 | Edaravone derivative and application thereof |
| WO2023006565A1 (en) | 2021-07-26 | 2023-02-02 | Medichem, S.A. | Process for preparing formulations of edaravone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004115508A (en) * | 2002-09-06 | 2004-04-15 | Mitsubishi Pharma Corp | Medicine for improving function of thermally injured skin tissue |
| CN101721408A (en) * | 2009-12-15 | 2010-06-09 | 江苏先声药物研究有限公司 | New application of 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone |
| 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 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004115508A (en) * | 2002-09-06 | 2004-04-15 | Mitsubishi Pharma Corp | Medicine for improving function of thermally injured skin tissue |
| CN101721408A (en) * | 2009-12-15 | 2010-06-09 | 江苏先声药物研究有限公司 | New application of 3-methyl-4-(2-oxo-propyl)-1-phenyl-1H-pyrazol-5(4H)-ketone |
| 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 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316957A (en) * | 2015-06-15 | 2017-01-11 | 江苏正大丰海制药有限公司 | Edaravone impurity intermediate, preparation method and application thereof |
| CN106316957B (en) * | 2015-06-15 | 2018-12-28 | 江苏正大丰海制药有限公司 | A kind of intermediate of impurity phenylhydrazine and its preparation method and application |
| CN108314652A (en) * | 2017-01-18 | 2018-07-24 | 周意 | Edaravone derivative and application thereof |
| CN107382866A (en) * | 2017-03-27 | 2017-11-24 | 陕西科技大学 | A kind of gossypol Edaravone condensation product and its synthetic method with antitumor activity |
| WO2023006565A1 (en) | 2021-07-26 | 2023-02-02 | Medichem, S.A. | Process for preparing formulations of edaravone |
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