Synthesis process of high-purity edaravone

A synthetic process, edaravone technology, applied in the field of medicine, can solve the problems of dark color, many impurities, high cost, etc., and achieve the effects of improving product purity, shortening reaction time, and saving production costs

Active Publication Date: 2016-11-16
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Synthesis of Edaravone in the prior art requires high-temperature (greater than 75°C) reaction in an acidic environment or without a catalyst. The reaction time is not less than 2 hours. The product has a deep color and many impurities.

Method used

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  • Synthesis process of high-purity edaravone
  • Synthesis process of high-purity edaravone
  • Synthesis process of high-purity edaravone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Take 18kg (138.31mol) of ethyl acetoacetate, add 21L of absolute ethanol to dissolve, control the temperature at 15-25°C, add 14.9kg (137.78mol) of phenylhydrazine dropwise, and keep stirring at 15-25°C for 10min, add hydrogen Sodium oxide 44g (1.1mol), reflux at 80°C for 1h, stir to cool down to 0-10°C, stir and crystallize for 1h, filter, wash the filter cake with ethyl acetate until the filtrate is colorless, and obtain 23kg of wet product of Edaravone, Dissolve the filter cake with 57L of absolute ethanol under reflux, filter, stir the filtrate to cool down to 0-10°C, stir and crystallize for 3h, filter, wash the filter cake with 4L of cold absolute ethanol, and vacuum dry at 60-70°C (≥0.09MPa) for 6h 17.1 kg of white crystalline Edaravone was obtained, the total yield was 71.2%, and the purity was greater than 99.97% (HPLC method).

Embodiment 2

[0044] Take 18kg (138.31mol) of ethyl acetoacetate, add 21L of isopropanol to dissolve, control the temperature at 15-25°C, add 14.9kg (137.78mol) of phenylhydrazine dropwise, keep stirring at 15-25°C for 10min, add hydrogen Sodium oxide 44g (1.1mol), reflux at 85°C for 45min, stir to cool down to 0-10°C, stir and crystallize for 1h, filter, wash the filter cake with ethyl acetate until the filtrate is colorless, and obtain 23.5kg of wet product of Edaravone , the filter cake was dissolved with 58L of absolute ethanol under reflux, filtered, the filtrate was stirred and cooled to 0-10°C, stirred and crystallized for 3h, filtered, the filter cake was washed with 4L of cold absolute ethanol, and vacuum-dried at 60-70°C (≥0.09MPa) After 6 hours, 16.8 kg of white crystalline Edaravone was obtained, with a total yield of 70.0% and a purity greater than 99.97% (HPLC method).

Embodiment 3

[0046] Take 18kg (138.31mol) of ethyl acetoacetate, add 21L of absolute ethanol to dissolve, control the temperature at 15-25°C, add 14.9kg (137.78mol) of phenylhydrazine dropwise, and keep stirring at 15-25°C for 10min, add hydrogen Potassium oxide 62g (1.1mol), reflux at 76°C for 1.5h, stir and cool down to 0-10°C, stir and crystallize for 1h, filter, wash the filter cake with ethyl acetate until the filtrate is colorless, and obtain the wet product of Edaravone 23.3 kg, the filter cake was dissolved with 58L of absolute ethanol under reflux, filtered, the filtrate was stirred and cooled to 0-10°C, stirred and crystallized for 3h, filtered, the filter cake was washed with 4L of cold absolute ethanol, and vacuum-dried at 60-70°C (≥0.09MPa ) 6h, 17.0kg of white crystalline Edaravone was obtained, with a total yield of 70.8% and a purity greater than 99.97% (HPLC method).

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Abstract

The invention discloses a synthesis process of high-purity edaravone. The synthesis process comprises the steps of dissolving ethyl acetoacetate into lower alcohol, adding phenylhydrazine drop by drop under the condition of temperature control, adding a catalytic amount of alkali, carrying out heating reflux cyclization, crystallizing, filtering, washing and refining to obtain the edaravone, wherein the purity of the obtained edaravone is higher than 99.97%. The synthesis process is simple in process, high in yield and pure in product, thus being suitable for industrial production.

Description

1. Technical field [0001] The invention relates to a synthesis method of a known compound, in particular to a synthesis process of high-purity edaravone, which belongs to the technical field of medicine. 2. Background technology [0002] Edaravone (Edaravone, formula (I)), the chemical name is 3-methyl-1-phenyl-2-pyrazolin-5-one, developed by Mitsubishi Chemical Corporation, Japan in June 2001 listed. Edaravone is a free radical scavenger with strong free radical scavenging and anti-peroxidation effects. It is clinically used to improve neurological symptoms, activities of daily living and dysfunction caused by acute cerebral infarction. Edaravone is the first free radical scavenger clinically used to treat acute cerebral infarction, and is the first ischemic neuron protective agent that does not affect the fibrinolytic system. It has high clinical application value and broad market expectation. [0003] The preparation of medicinal edaravone generally adopts the synthesi...

Claims

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Application Information

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IPC IPC(8): C07D231/26
CPCC07D231/26
Inventor 吴标凌林戴一唐胜国
Owner HEFEI JIUNUO MEDICAL TECH
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