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A kind of preparation method of edaravone impurity standard product

A technology of edaravone and standard products, which is applied in the field of medicine, can solve the problems of unreported impurity synthesis and content calibration methods, and achieve the effects of low synthesis cost, short synthesis cycle, and simple preparation process

Active Publication Date: 2018-07-10
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there is no report on the synthesis and content calibration method of this impurity

Method used

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  • A kind of preparation method of edaravone impurity standard product
  • A kind of preparation method of edaravone impurity standard product
  • A kind of preparation method of edaravone impurity standard product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1. Put 150ml of chloroform and 10g (57.4mmol) of edaravone into the reaction bottle in sequence. After stirring and dissolving, put in 5g (57.5mmol) of manganese dioxide. Stir and reflux at 65°C for 4 hours; after the reaction, the reaction solution was filtered while hot, and the filtrate was concentrated to dryness at 30-40°C under reduced pressure (vacuum degree ≥ 0.08MPa), to obtain 8.9g of crude impurity product, with a yield of 89.7%.

[0044] 2. Add 100ml of absolute ethanol to 8.9g of crude impurities, stir and reflux at 75-80°C to dissolve, add 0.2g of activated carbon, continue to reflux for 10min, filter while hot, cool the filtrate to 0-10°C, stir and crystallize for 3h, filter , the filter cake was washed with absolute ethanol, and the solid was dried at 40-50°C under reduced pressure (vacuum degree ≥ 0.08MPa) for 6h to obtain 4,4-bis(5-hydroxy-3-methyl-1-phenyl-1H- The pure product of pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one was 7.5g, and the y...

Embodiment 2

[0054] 1. Put 300ml of chloroform and 20g (114.8mmol) of edaravone into the reaction bottle in sequence. After stirring and dissolving, put in 15g (172.5mmol) of manganese dioxide. Stir and reflux at 65°C for 6h; after the reaction, the reaction solution was filtered while hot, and the filtrate was concentrated to dryness at 30-40°C under reduced pressure (vacuum degree ≥ 0.08MPa) to obtain 18.5g of crude impurity product with a yield of 93.2%.

[0055] 2. Add 350ml of absolute ethanol to 18.5g of impurity crude product, stir and reflux at 75-80°C to dissolve, add 0.5g of activated carbon, continue to reflux for 10min, filter while hot, cool the filtrate to 0-10°C, stir and crystallize for 4h, filter , the filter cake was washed with an appropriate amount of absolute ethanol, and the solid was dried at 40-50°C under reduced pressure (vacuum degree ≥ 0.08MPa) for 8 hours to obtain 4,4-bis(5-hydroxy-3-methyl-1-phenyl-1H -Pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one pure ...

Embodiment 3

[0059] 1. Put 400ml of chloroform and 50g (287mmol) of edaravone into the reaction bottle in sequence. After stirring and dissolving, put in 75g (863mmol) of manganese dioxide. Stir and reflux for 8 hours; after the reaction, the reaction solution was filtered while it was hot, and the filtrate was concentrated to dryness at 30-40°C under reduced pressure (vacuum degree ≥ 0.08MPa) to obtain 47.3g of crude impurities.

[0060] Yield 95.3%.

[0061] 2. Add 700ml of absolute ethanol to 47.3g of impurity crude product, stir and reflux at 75-80°C to dissolve, add 4.5g of activated carbon, continue to reflux for 10min, filter while hot, cool the filtrate to 0-10°C, stir and crystallize for 4h, filter , the filter cake was washed with an appropriate amount of absolute ethanol, and the solid was dried at 40-50°C under reduced pressure (vacuum degree ≥ 0.08MPa) for 8 hours to obtain 4,4-bis(5-hydroxy-3-methyl-1-phenyl-1H -Pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one pure produ...

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Abstract

The invention discloses a preparation method of edaravone impurity standard product; the preparation takes edaravone as raw material, and performs catalytic oxidation and purification, so as to obtain 4, 4-bi(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-radical)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-ketone pure product; the pure product content is marked by regular analysis method. The impurity preparation method provided by the invention is easy to obtain raw material, simple and fast in technique, and short in preparation cycle; the marked product content is more than 99.0%. The edaravone provided by the invention can be used as the impurity standard product, and applied to qualitative and quantitative study and detection of edaravone raw materials and the impurities of its preparations.

Description

1. Technical field [0001] The invention relates to a preparation method of a drug impurity standard product, in particular to a preparation method of an edaravone impurity standard product, and belongs to the technical field of medicine. 2. Background technology [0002] Edaravone, whose chemical name is 3-methyl-1-phenyl-2-pyrazolin-5-one, is a neuroprotective agent developed by Mitsubishi Pharmaceutical Co., Ltd. of Japan. Its injection Liquid was listed in Japan in June 2001 (trade name: Specifications: 30mg / 20ml, 15mg / 10ml, 10mg / 5ml). It is clinically used to treat acute cerebral infarction, improve the neurological symptoms caused by acute cerebral infarction, restore the ability to take care of oneself, relieve daily activity obstacles and paralysis caused by acute cerebral infarction. [0003] Edaravone will produce trimer impurities during the synthesis process: 4,4-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-3-methyl -1-phenyl-1H-pyrazol-5(4H)-one, the stru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/26
CPCC07D231/26
Inventor 吴标唐胜国凌林
Owner HEFEI JIUNUO MEDICAL TECH
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