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Edaravone compound synthesized by new method

A compound and route technology, applied in the field of medicine, can solve the problems of slow reaction, low yield, and difficulty in obtaining butanone amide, and achieve the effects of reducing production cost and improving yield

Inactive Publication Date: 2010-09-15
HAINAN MEILAN SMITH KLINE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Regarding the synthetic method of Edaravone, it is reported that some adopt phenylhydrazine and butanone amide to react, but butanone amide is not easy to obtain, and the reaction is slow, so this method has basically been abandoned now; some adopt phenylhydrazine and acetoacetic acid Ethyl ester is prepared by reflux reaction in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN. Ethyl and butyl acetoacetates, Med Prom SSSR, 1961, 15 (1): 42-45), and the obtained The purity of Edaravone is poor, and the yield is not high, only about 70%

Method used

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  • Edaravone compound synthesized by new method

Examples

Experimental program
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Effect test

Embodiment 1

[0023] The synthesis of embodiment 1 Edaravone

[0024] (1) Weigh 13.5g of phenylhydrazine hydrochloride (94mmol), add it to 100ml of water, stir for 0.5 hour, add equimolar sodium hydroxide 3.76g, stir for 0.5 hour;

[0025] (2) Add 11.7g of ethyl acetoacetate (90mmol) dropwise to the above reaction solution, the reaction exotherms, heat up to reflux for 2.5 hours, stop heating, stir and cool to room temperature, filter, and dry to obtain light yellow granular crude product 15.5 g;

[0026] (3) Add 30ml of isopropanol-water solution with a volume ratio of 2:1 to the above crude product, add 2g of activated carbon, reflux for 1 hour, heat filter, cool to room temperature and precipitate a white solid to obtain 14.8g of white crystalline powder, yield It is 90%, mp129°C, and the purity is 99.9%.

Embodiment 2

[0027] The synthesis of embodiment 2 Edaravone

[0028] (1) Weigh 15g of phenylhydrazine hydrochloride (104mmol), add it to 120ml of water, stir for 0.5 hour, add equimolar sodium hydroxide 4.16g, stir for 0.5 hour;

[0029] (2) Add 13g of ethyl acetoacetate (100mmol) dropwise to the above reaction solution, exothermic reaction, heat up to reflux reaction for 2.5 hours, stop heating, stir and cool to room temperature, filter, and obtain 16.7g of light yellow granular crude product after drying ;

[0030] (3) Add 40ml of the above crude product into isopropanol-water solution with a volume ratio of 2:1, add 2.5g of activated carbon, reflux for 1 hour, heat filter, cool to room temperature and precipitate a white solid to obtain 16.1g of white crystalline powder, which is collected The yield is 88.9%, the mp is 128°C, and the purity is 99.9%.

Embodiment 3

[0031] The synthesis of embodiment 3 Edaravone

[0032] (1) Weigh 22g of phenylhydrazine hydrochloride (152mmol), add it to 200ml of water, stir for 0.5 hour, add equimolar sodium hydroxide 6.08g, stir for 0.5 hour;

[0033] (2) Add 19g of ethyl acetoacetate (146mmol) dropwise to the above reaction solution, the reaction exotherms, heat up to reflux for 3 hours, stop heating, stir and cool to room temperature, filter, and dry to obtain 24.8g of light yellow granular crude product ;

[0034] (3) Add 50ml of the above crude product into isopropanol-water solution with a volume ratio of 2:1, add 3g of activated carbon, reflux for 1 hour, heat filter, cool to room temperature and precipitate a white solid to obtain 23.2g of white crystalline powder, yield It is 87.8%, mp128°C, and the purity is 99.9%.

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Abstract

The invention relates to Edaravone synthesized by a new method. The method comprises the following steps of: reacting phenylhydrazine hydrochloride used as initial raw material with sodium hydroxide to generate phenylhydrazine; mixing the phenylhydrazine and ethyl acetoacetate to generate reflux reaction to prepare crude Edaravone; dissolving the crude Edaravone into an isopropanol water solution, adding active carbon for adsorbing and filtering to prepare fine white crystalloid powder. The invention has the advantages of low cost, high product yield and high purity.

Description

technical field [0001] The invention relates to a new route of edaravone compound, which belongs to the technical field of medicine. Background technique [0002] Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one, molecular formula: Molecular formula: C 10 h 10 N 2 O, molecular weight: 174.20, structural formula: [0003] [0004] Edaravone is a brain protectant (free radical scavenger). Clinical studies suggest that N-acetylaspartic acid (NAA) is a specific marker of surviving nerve cells, and its content decreases sharply in the early stage of cerebral infarction. The administration of edaravone to patients in the acute stage of cerebral infarction can inhibit the reduction of local cerebral blood flow around the infarction, and make the NAA content in the brain significantly higher than that of the glycerol control group on the 28th day after the onset. Preclinical studies suggest that intravenous administration of edaravone to rats after ischemia / isch...

Claims

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Application Information

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IPC IPC(8): C07D231/26
Inventor 杨明贵
Owner HAINAN MEILAN SMITH KLINE PHARMA
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