Preparation method of brain protective agent and key impurities thereof

A brain protection and impurity technology, which is applied in the preparation of hydrazone, muscular system diseases, neuromuscular system diseases, etc., and can solve the problem of inaccurate control of process conditions such as temperature

Inactive Publication Date: 2021-07-06
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The reason for this impurity is that the control of process conditions such as temp...

Method used

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  • Preparation method of brain protective agent and key impurities thereof
  • Preparation method of brain protective agent and key impurities thereof
  • Preparation method of brain protective agent and key impurities thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Add 108 g of phenylhydrazine to 324 mL of ethanol, add 136.5 g of ethyl acetoacetate at a temperature of -5 to 0 ° C, and react at a temperature of -5 ° C for 1 hour. After the reaction, half of the reaction solution is taken out and added with a mass fraction of 20% The reaction was quenched with 100 mL of sodium bicarbonate solution, extracted with dichloromethane, concentrated under reduced pressure at 35°C to obtain an oil, purified by column chromatography, and dried to obtain 96.59 g of transition state impurities with a yield of 87.7%. LC-MS showed that the [M+H] at 16.658min was 221.11, consistent with the molecular weight of the target product, and determined to be a transition state impurity.

[0038] Raise the temperature of the remaining half of the reaction solution to 60-65°C for 1 hour, quickly add 5.4g of concentrated sulfuric acid solution, raise the temperature to 80-85°C, and react for 3 hours under temperature control. Lavone 78.91g, yield 90.6%....

Embodiment 2

[0042] (1) Add 108 g of phenylhydrazine to 540 mL of isopropanol, add 136.5 g of ethyl acetoacetate at a temperature of -5 to 0 ° C, and react at a temperature of -5 ° C for 1 hour. After the reaction, half of the reaction solution is taken out and added with a mass fraction of Quench the reaction with 100 mL of 20% sodium bicarbonate solution, add dichloromethane for extraction, concentrate under reduced pressure at 35°C to obtain an oil, purify by column chromatography, and dry to obtain 93.50 g of transition state impurities with a yield of 84.9%.

[0043] Raise the temperature of the remaining half of the reaction solution to 60-65°C for 1 hour, quickly add 10.8 g of concentrated sulfuric acid solution, raise the temperature to 80-85°C, and react for 3 hours under temperature control. Lavone 79.35g, yield 91.1%.

[0044] (2) get step (1) gained Edaravone 17.4g to be dissolved in 104mL acetic acid solvent, add 68.0g mass concentration and be 50% hydrogen peroxide, react at ...

Embodiment 3

[0047](1) Add 108 g of phenylhydrazine to 864 mL of ethanol, add 136.5 g of ethyl acetoacetate at temperature control -5 to 0 ° C, and react at temperature -5 ° C for 1 hour. After the reaction, half of the reaction solution is taken out and added with a mass fraction of 20% carbonic acid Quench the reaction with 100 mL of sodium hydrogen solution, add dichloromethane for extraction, and concentrate under reduced pressure at 35°C to obtain an oil, which is purified by column chromatography and dried to obtain 99.76 g of transition state impurities with a yield of 90.4%.

[0048] Raise the temperature of the remaining half of the reaction solution to 60-65°C for 1 hour, quickly add 16.2 g of concentrated sulfuric acid solution, raise the temperature to 80-85°C, and react for 3 hours under temperature control. Lavone 78.04g, yield 89.6%.

[0049] (2) get step (1) gained Edaravone 17.4g to be dissolved in 139mL acetic acid solvent, add 102.0g mass concentration and be 50% hydroge...

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Abstract

The invention relates to a preparation method of a brain protective agent and key impurities thereof. According to the invention, phenylhydrazine and ethyl acetoacetate serve as raw materials, edaravone and three key impurities of edaravone are synthesized in the same route, wherein the three key impurities include a transition-state impurity, edaravone dimer nitrogen oxide and 5-methyl-2-phenyl-4-(propyl-2-iene)-2,4-dihydro-3H-pyrazol-3-one; compared with respective synthesis of edaravone and each impurity, the method has the advantage that time and cost are saved; and experiments prove that the method of preparing edaravone by firstly controlling the process for synthesizing the transition-state impurities and then changing the process are higher in the yield and the purity of edaravone compared with direct synthesis of edaravone.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of a brain protective agent and key impurities thereof. Background technique [0002] Edaravone, whose chemical name is 3-methyl-1-phenyl-2-pyrazolin-5-one, was developed by Japan’s Mitsubishi Tanabe Pharmaceutical Company and was launched in Japan in June 2001. Several generic drugs are on the market. This product is used for the treatment of neurological symptoms related to the acute stage of cerebral infarction; in June 2015, Japan approved a new indication for amyotrophic lateral sclerosis (ALS); in May 2017, it was approved for the treatment of ALS in the United States. [0003] The preparation method of Edaravone is mainly the reaction of phenylhydrazine and methyl ethyl ketone amide or ethyl acetoacetate, and ethyl acetoacetate is easier to react with phenylhydrazine and is easier to obtain, and the price is also cheaper, so phenylhydrazine and acet...

Claims

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Application Information

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IPC IPC(8): C07D231/26A61P25/28A61P21/00C07C249/16C07C251/76
CPCC07D231/26A61P25/28A61P21/00C07C249/16C07C251/76
Inventor 夏军陈相助刘新泉
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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