CN102180834A - Preparation method for edaravone - Google Patents
Preparation method for edaravone Download PDFInfo
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- CN102180834A CN102180834A CN 201110072032 CN201110072032A CN102180834A CN 102180834 A CN102180834 A CN 102180834A CN 201110072032 CN201110072032 CN 201110072032 CN 201110072032 A CN201110072032 A CN 201110072032A CN 102180834 A CN102180834 A CN 102180834A
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Abstract
The invention discloses a preparation method for edaravone. The preparation method comprises the following steps of: reacting phenylhydrazine with ethyl acetoacetate in an alcohol solvent under the action of a catalyst to prepare the edaravone; and after the reaction, adding a non-alcohol solvent to cool and crystallize to obtain the edaravone crude product. The high-yield and high-purity edaravone is prepared from the phenylhydrazine and the ethyl acetoacetate which serve as the raw materials in the presence of acid serving as the catalyst. The quality of the edaravone product is high; the process is simple; the reaction condition is mild and easy to control; the aftertreatment is simple; the problem of three wastes is avoided; cost is low; and the preparation method is suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of Edaravone.
Background technology
Edaravone (Edaravone, 3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one) is a kind of potent free-radical scavengers and antioxidant, and this product belongs to the lipophilic compounds, easily sees through hemato encephalic barrier and is absorbed.Edaravone is the cerebral protective agent that Mitsubishi chemical company develops, and goes on the market in Japan June 1 calendar year 2001.Its mechanism of action is to remove the free radical that increases behind the ischemic, suppresses peroxidatic reaction of lipid, and tissue is played a protective role.Clinically, this product can be used for improving symptoms such as acute period of cerebral infarction patient's nerve, daily life behavior, and its side effect is slight, and is evident in efficacy, and good prognosis effect is arranged.Its molecular structural formula is as follows:
Edaravone is to describe first in patent US4857542.US4857542 discloses the Edaravone structure, demonstrates that disorder has effective prevention and treatment to the recycle system, has good effect as lipid peroxidation inhibitor and disordered brain function treatment especially.US4857542 discloses phenylhydrazine and methyl aceto acetate back flow reaction in dehydrated alcohol, makes Edaravone, and yield is 65%.
WO2006//71730 disclose phenylhydrazine and methyl aceto acetate in acetic acid, 50 ℃ of reactions, and concentrated acetic acid is used ethyl acetate extraction again, prepares Edaravone, and yield is 86%.Because such technology that the acetic acid boiling point, adopts than higher and acid more intense can cause huge energy consumption waste and equipment corrosion, is not suitable for suitability for industrialized production.
Summary of the invention
The objective of the invention is on the basis of existing technology, provide that a kind of technology is simple, cost is low, yield is high, quality is good, environmental friendliness and be fit to the preparation method of industrial Edaravone.
Purpose of the present invention can reach by following measure:
A kind of preparation method of Edaravone, it comprises synthetic method and process for purification, is specially:
(a) synthetic: as in alcoholic solvent,, to add non-alcoholic solvent after the reaction again and carry out cooling crystallization, obtain the Edaravone crude product with phenylhydrazine and methyl aceto acetate prepared in reaction Edaravone under 40～90 ℃ and acid catalyst effect.
(b) refining: as the Edaravone dissolving crude product in alcoholic solvent, to be carried out cooling crystallization to wherein adding non-alcoholic solvent, obtain the Edaravone elaboration.
The reaction scheme of present method is as follows:
Be selected from methyl alcohol, ethanol and the Virahol one or more at the alcoholic solvent described in the step (a), be preferably ethanol.Non-alcoholic solvent described in the step (a) is selected from one or more in normal hexane, hexanaphthene, methyl tertiary butyl ether, sherwood oil and the ethyl acetate, is preferably normal hexane or hexanaphthene, and this kind solvent can add below 65 ℃.
Acid catalyst described in the step (a) is selected from one or more in hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, tartrate and the citric acid, is preferably acetic acid and tartrate.The mass volume ratio of phenylhydrazine and alcoholic solvent is 1: 1～1: 10 (g/ml) in the step (a), is preferably 1: 2～1: 5 (g/ml).The mass ratio of phenylhydrazine and acid catalyst is 1: 0.01～1: 0.5 in the step (a), is preferably 1: 0.1～1: 0.2.The temperature of reaction of phenylhydrazine and methyl aceto acetate is 40～90 ℃ in the step (a), is preferably 60～85 ℃.The mass volume ratio of phenylhydrazine described in the step (a) and non-alcoholic solvent is 1: 0.1～1: 5 (g/ml), is preferably 1: 0.1～1: 1 (g/ml).The mol ratio of described phenylhydrazine and methyl aceto acetate is 1: 0.8～0.8: 1.The temperature of cooling crystallization is generally at 0～10 ℃ in the step (a).
Also can further following processing behind step (a) crystallization: isolate crystal, and with described alcoholic solvent and/or the washing of non-alcoholic solvent, last drying under reduced pressure obtains the Edaravone crude product; Wherein said washing preferably adopts gradation to carry out; Described drying under reduced pressure preferably carries out under 1.33～3.33kPa, 80～100 ℃.The purity of the Edaravone crude product that step (a) obtains is more than 99%.
The reaction of step (a) can further be carried out under protection of inert gas.
In one embodiment, step (a) adopts following steps: add ethanol earlier, add phenylhydrazine, methyl aceto acetate and acetic acid under the stirring at room; nitrogen protection is warming up to 75～80 ℃, stops heating behind reaction 1～3h; after continuation is stirred and is cooled to 50～65 ℃; add normal hexane, be cooled to 0～10 ℃, keep temperature stirring and crystallizing 1～3h; filtration under diminished pressure; use ethanol, normal hexane and washing with alcohol filter cake successively, drying under reduced pressure 3～5h obtains the Edaravone crude product.
Be selected from methyl alcohol, ethanol and the Virahol one or more at the alcoholic solvent described in the step (b), be preferably ethanol.Non-alcoholic solvent described in the step (b) is selected from one or more in normal hexane, hexanaphthene, methyl tertiary butyl ether, sherwood oil and the ethyl acetate, is preferably normal hexane, and this kind solvent can add below 65 ℃.
The mass volume ratio of Edaravone crude product described in the step (b) and alcoholic solvent is 1: 1～1: 10 (g/ml), is preferably 1: 2～1: 5 (g/ml).Being dissolved under 60～90 ℃ of protection of inert gas and the temperature of Edaravone crude product carried out in the step (b), and described temperature is preferably 70～85 ℃.The mass volume ratio of Edaravone crude product described in the step (b) and non-alcoholic solvent is 1: 0.1～1: 5 (g/ml), is preferably 1: 0.1～1: 1 (g/ml).
Isolate crystal behind the crystallization in the step (b), and wash with described alcoholic solvent and/or non-alcoholic solvent, last drying under reduced pressure obtains the Edaravone elaboration; Wherein said washing preferably adopts gradation to carry out; Described drying under reduced pressure preferably carries out under 1.33～3.33kPa, 80～100 ℃.The purity of the Edaravone elaboration that step (b) obtains is more than 99.9%.
In one embodiment, step (b) adopts following steps: add ethanol earlier, add the Edaravone crude product under the stirring at room; nitrogen protection is warming up to 75～80 ℃ gradually, and the solid dissolving fully; after stirring is cooled to 50～65 ℃; add normal hexane, be cooled to 0～10 ℃, keep temperature stirring and crystallizing 1～3h; filtration under diminished pressure; use ethanol, normal hexane and washing with alcohol filter cake successively, drying under reduced pressure 3～5h obtains the Edaravone highly finished product.
The present invention is a raw material with phenylhydrazine and methyl aceto acetate, acid as catalyst, prepare high yield (more than 92%, even can reach 95.6%) and the Edaravone of high purity (more than 99.3%), technology is simple, and the reaction conditions gentleness is easy to control, avoided using acetic acid to do problems such as energy consumption waste that solvent brings and equipment corrosion, no three wastes problem, cost is low, is fit to suitability for industrialized production.
Embodiment
Embodiment 1: the preparation of Edaravone
In the four-hole round-bottomed flask of 1L; add 200ml ethanol; add phenylhydrazine 100g (0.9247mol) under the stirring at room successively; methyl aceto acetate 120.3g (0.9247mol) and acetic acid 10ml; nitrogen protection is warming up to 75～80 ℃ gradually, stops heating behind the reaction 1h; after continuation is stirred and is cooled to 60 ℃; add normal hexane 50ml, be cooled to 10 ℃, keep temperature stirring and crystallizing 1h; filtration under diminished pressure; use ethanol 100ml successively; normal hexane 100ml and ethanol 100ml washing leaching cake are 1.33～3.33kpa at pressure, and temperature is under 90 ℃; drying under reduced pressure 3h; obtain crude product Edaravone 151.7g, yield is 94.2%, and it is 99.39% that HPLC detects purity.
Embodiment 2: the preparation of Edaravone
In the four-hole round-bottomed flask of 1L; add 150ml methyl alcohol; add phenylhydrazine 100g (0.9247mol) under the stirring at room successively; methyl aceto acetate 120.3g (0.9247mol) and tartrate 20g; nitrogen protection; be warming up to 75～80 ℃ gradually; stop heating behind the reaction 1h; after continuation is stirred and is cooled to 60 ℃; add methyl tertiary butyl ether 80ml, be cooled to 10 ℃, keep temperature stirring and crystallizing 1h; filtration under diminished pressure; use ethanol 100ml successively; methyl tertiary butyl ether 100ml and ethanol 100ml washing leaching cake are 1.33～3.33kpa at pressure, and temperature is under 90 ℃; drying under reduced pressure 3h; obtain crude product Edaravone 148.4g, yield is 92.1%, and it is 99.55% that HPLC detects purity.
Embodiment 3: the preparation of Edaravone
In the four-hole round-bottomed flask of 5L; add the 1L Virahol; add phenylhydrazine 500g (4.624mol) under the stirring at room successively; methyl aceto acetate 601.7g (4.624mol) and tartrate 50g; nitrogen protection; be warming up to 75～80 ℃ gradually; stop heating behind the reaction 1h; after continuation is stirred and is cooled to 60 ℃; add methyl tertiary butyl ether 300ml, be cooled to 10 ℃, keep temperature stirring and crystallizing 1h; filtration under diminished pressure; use ethanol 500ml successively; methyl tertiary butyl ether 500ml and ethanol 500ml washing leaching cake are 1.33～3.33kpa at pressure, and temperature is under 90 ℃; drying under reduced pressure 3h; obtain crude product Edaravone 753.1g, yield is 93.5%, and it is 99.32% that HPLC detects purity.
Embodiment 4: the preparation of Edaravone
In the four-hole round-bottomed flask of 10L; add 2L ethanol; add phenylhydrazine 1000g (9.247mol) under the stirring at room successively; methyl aceto acetate 1203.4g (9.247mol) and acetic acid 100ml; nitrogen protection is warming up to 75～80 ℃ gradually, stops heating behind the reaction 1h; after continuation is stirred and is cooled to 60 ℃; add normal hexane 300ml, be cooled to 10 ℃, keep temperature stirring and crystallizing 1h; filtration under diminished pressure; use ethanol 1L successively; normal hexane 1L and ethanol 1L washing leaching cake are 1.33～3.33kpa at pressure, and temperature is under 90 ℃; drying under reduced pressure 3h; obtain crude product Edaravone 1540.0g, yield is 95.6%, and it is 99.36% that HPLC detects purity.
Embodiment 5: Edaravone refining
In the four-hole round-bottomed flask of 10L; add 6.2L ethanol; add crude product Edaravone 2482.0g (14.249mol) under the stirring at room; nitrogen protection is warming up to 75～80 ℃ gradually, and the solid dissolving fully; after stirring is cooled to 60 ℃; add normal hexane 1.24L, be cooled to 10 ℃, keep temperature stirring and crystallizing 1h; filtration under diminished pressure; use ethanol 1.38L successively; normal hexane 1.38L and ethanol 1.38L washing leaching cake are 1.33～3.33kpa at pressure, and temperature is under 90 ℃; drying under reduced pressure 5h; obtain highly finished product Edaravone 2256.1g, yield is 90.9%, and it is 99.96% that HPLC detects purity.
1H-NMR(500MHz，DMSO-d
6)δ(ppm)：2.16(s，3H)，3.39(t，2H)，7.12-7.17(m，1H)，7.33-7.38(m，2H)，7.81-7.84(d，2H).
13C-NMR(125MHz，DMSO-d
6)δ(ppm)：16.60，42.38，118.47，124.65，128.44，137.64，156.10，170.28.
MS(EI)：174.2.
Claims (10)
1. the preparation method of an Edaravone, it is characterized in that: in alcoholic solvent, phenylhydrazine and methyl aceto acetate are prepared Edaravone under 40～90 ℃ and acid catalyst effect, add non-alcoholic solvent after the reaction again and carry out cooling crystallization, obtain the Edaravone crude product; Wherein said non-alcoholic solvent is selected from one or more in normal hexane, hexanaphthene, ether, methyl tertiary butyl ether, sherwood oil and the ethyl acetate.
2. the preparation method of Edaravone according to claim 1 is characterized in that: the Edaravone dissolving crude product in alcoholic solvent, is carried out cooling crystallization to wherein adding non-alcoholic solvent, obtain the Edaravone elaboration.
3. the preparation method of Edaravone according to claim 1 and 2, it is characterized in that: described alcoholic solvent is selected from one or more in methyl alcohol, ethanol and the Virahol, is preferably ethanol; Described non-alcoholic solvent is normal hexane or hexanaphthene.
4. the preparation method of Edaravone according to claim 1, it is characterized in that: described acid catalyst is selected from one or more in hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, tartrate and the citric acid.
5. the preparation method of Edaravone according to claim 4, it is characterized in that: described acid catalyst is hydrochloric acid, acetic acid or tartrate.
6. the preparation method of Edaravone according to claim 1, it is characterized in that: the mass volume ratio of described phenylhydrazine and alcoholic solvent is 1: 1～1: 10 (g/ml), is preferably 1: 2～1: 5 (g/ml); The mass ratio of described phenylhydrazine and acid catalyst is 1: 0.01～1: 0.5, is preferably 1: 0.1～1: 0.2; The mass volume ratio of described phenylhydrazine and non-alcoholic solvent is 1: 0.1～1: 5 (g/ml), is preferably 1: 0.1～1: 1 (g/ml); The mol ratio of described phenylhydrazine and methyl aceto acetate is 1: 0.8～0.8: 1.
7. the preparation method of Edaravone according to claim 1, it is characterized in that: the temperature of reaction of described phenylhydrazine and methyl aceto acetate is 60～85 ℃; Isolate crystal behind the crystallization, and wash with described alcoholic solvent and/or non-alcoholic solvent, last drying under reduced pressure obtains the Edaravone crude product; Wherein said washing preferably adopts gradation to carry out; Described drying under reduced pressure preferably carries out under 1.33～3.33kPa, 80～100 ℃.
8. the preparation method of Edaravone according to claim 2, it is characterized in that: the mass volume ratio of described Edaravone crude product and alcoholic solvent is 1: 1～1: 10 (g/ml), is preferably 1: 2～1: 5 (g/ml); The mass volume ratio of described Edaravone crude product and non-alcoholic solvent is 1: 0.1～1: 5 (g/ml), is preferably 1: 0.1～1: 1 (g/ml).
9. the preparation method of Edaravone according to claim 2 is characterized in that: being dissolved under 60～90 ℃ of protection of inert gas and the temperature of described Edaravone crude product carried out, and described temperature is preferably 70～85 ℃.
10. the preparation method of Edaravone according to claim 2 is characterized in that: isolate crystal behind the crystallization, and with described alcoholic solvent and/or the washing of non-alcoholic solvent, last drying under reduced pressure obtains the Edaravone elaboration; Wherein said washing preferably adopts gradation to carry out; Described drying under reduced pressure preferably carries out under 1.33～3.33kPa, 80～100 ℃.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285920A (en) * | 2011-09-21 | 2011-12-21 | 湖南科技大学 | Optimal edaravone synthesis method |
| CN102643234A (en) * | 2012-04-02 | 2012-08-22 | 浙江大学 | Edaravone polymorphic substance and preparation method thereof |
| CN102766097A (en) * | 2012-06-27 | 2012-11-07 | 江苏正大丰海制药有限公司 | Edaravone A-type crystal and preparation method thereof |
| CN103319409A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Edaravone compound, medicinal composition thereof, and preparation methods of compound and composition |
| CN103833640A (en) * | 2012-11-16 | 2014-06-04 | 上海医药工业研究院 | Edaravone crystal, preparation method and application thereof |
| 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 |
| CN109232427A (en) * | 2017-12-15 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Edaravone |
| CN109608398A (en) * | 2019-01-14 | 2019-04-12 | 河南润弘制药股份有限公司 | A kind of preparation method of Edaravone |
| CN111848517A (en) * | 2019-04-30 | 2020-10-30 | 上海医药工业研究院 | Preparation method of edaravone |
| CN114539155A (en) * | 2022-02-15 | 2022-05-27 | 江苏慧聚药业有限公司 | Preparation of edaravone |
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Cited By (17)
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| CN102285920A (en) * | 2011-09-21 | 2011-12-21 | 湖南科技大学 | Optimal edaravone synthesis method |
| CN102285920B (en) * | 2011-09-21 | 2014-07-23 | 湖南科技大学 | Optimal edaravone synthesis method |
| CN102643234A (en) * | 2012-04-02 | 2012-08-22 | 浙江大学 | Edaravone polymorphic substance and preparation method thereof |
| CN102643234B (en) * | 2012-04-02 | 2015-09-30 | 浙江大学 | Edaravone polymorphic substance and preparation method thereof |
| CN102766097B (en) * | 2012-06-27 | 2014-11-05 | 江苏正大丰海制药有限公司 | Edaravone A-type crystal and preparation method thereof |
| CN102766097A (en) * | 2012-06-27 | 2012-11-07 | 江苏正大丰海制药有限公司 | Edaravone A-type crystal and preparation method thereof |
| CN103833640B (en) * | 2012-11-16 | 2016-06-22 | 国药集团国瑞药业有限公司 | A kind of Edaravone crystal, its preparation method and application thereof |
| CN103833640A (en) * | 2012-11-16 | 2014-06-04 | 上海医药工业研究院 | Edaravone crystal, preparation method and application thereof |
| CN103319409A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Edaravone compound, medicinal composition thereof, and preparation methods of compound and composition |
| 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 |
| CN109232427A (en) * | 2017-12-15 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Edaravone |
| CN109608398A (en) * | 2019-01-14 | 2019-04-12 | 河南润弘制药股份有限公司 | A kind of preparation method of Edaravone |
| CN111848517A (en) * | 2019-04-30 | 2020-10-30 | 上海医药工业研究院 | Preparation method of edaravone |
| CN111848517B (en) * | 2019-04-30 | 2023-04-07 | 上海医药工业研究院 | Preparation method of edaravone |
| CN114539155A (en) * | 2022-02-15 | 2022-05-27 | 江苏慧聚药业有限公司 | Preparation of edaravone |
| CN114539155B (en) * | 2022-02-15 | 2024-05-10 | 江苏慧聚药业股份有限公司 | Preparation of edaravone |
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