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Preparation method of edaravone

A technology of Edaravone and transmission equipment, which is applied in the field of preparation of Edaravone, and can solve problems such as easy fluctuations in yield and product quality between batches, affecting the continuous stability of product quality, and limited capacity of reaction containers. , to achieve the effects of easy industrial production, stable product quality and high product purity

Active Publication Date: 2020-10-30
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by the present invention is that, in order to overcome the batch reaction in the industrialized preparation method of existing Edaravone, the production capacity is limited by the size of the reaction vessel, and the operation process is cumbersome; It is easy to produce more impurities, and the yield and product quality between batches are prone to fluctuations, which affects the continuous and stable quality of the final product, which is not conducive to modern industrial production on the whole.

Method used

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  • Preparation method of edaravone
  • Preparation method of edaravone
  • Preparation method of edaravone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Phenylhydrazine (400ml, 4.06mol, 10mL / min) and ethyl acetoacetate (514ml, 4.06mol, 12.85mL / min) were simultaneously pumped into the microchannel via a transfer device (such as a peristaltic pump or a reciprocating plunger pump) In the reactor (HS1 microchannel reactor, purchased from Shandong Haomai Chemical Technology Co., Ltd.), the reaction temperature is 160 ° C, the residence time of the material in the microchannel reactor is 4.8min, and the reactant flows out into water (2L), stirring, The solid was precipitated, filtered, and dried to obtain 695 g of Edaravone, with a yield of 98.3%, and a product purity of 99.0% through HPLC analysis.

[0054] ESI-MS(m / z): 175[M+H] + ; 1 H NMR (400MHz, CDCl 3 )δ: 7.83(d,2H), 7.37(t,2H), 7.15(t,1H), 3.34(s,2H), 2.11(s,3H); melting point: 127.0~128.1℃.

Embodiment 2

[0056] Phenylhydrazine (400mL, 4.06mol, 10mL / min), ethyl acetoacetate (514mL, 4.06mol, 12.85mL / min) and acetic acid (23.22mL, 0.406mol, 0.58mL / min) were simultaneously pumped into to the tubular reactor ( PR37 reactor, purchased from Ehrfeld Mikrotechnik GmbH (Ehrfeld company)), the reaction temperature is 142 ° C, the residence time of the material in the tubular reactor is 4.8min, and the reactant flows out into ethyl acetate (0.5L), stirring, The solid was precipitated, filtered, and dried to obtain 701 g of Edaravone, with a yield of 99.1%, and a product purity of 99.98% through HPLC analysis.

[0057] ESI-MS(m / z): 175[M+H] + ; 1 H NMR (400MHz, CDCl 3 )δ: 7.84(d,2H), 7.38(t,2H), 7.16(t,1H), 3.33(s,2H), 2.11(s,3H); melting point: 128.0~129.2℃.

Embodiment 3

[0059] Phenylhydrazine (400mL, 4.06mol, 20mL / min), ethyl acetoacetate (540mL, 4.26mol, 27mL / min) and acetic acid (23.22mL, 0.406mol, 0.58mL / min) were simultaneously pumped into the Tubular reactor ( The PR37 reactor is purchased from Ehrfeld Mikrotechnik GmbH (Ehrfeld Mikrotechnik GmbH (Ehrfeld company)), the reaction temperature is 147 ° C, the residence time of the material in the tubular reactor is 2.3min, and the reactant flows out into water (2L), stirring, and solids are precipitated. Filtration and drying gave 705 g of Edaravone with a yield of 99.7%, and the product purity was 99.1% through HPLC analysis.

[0060] ESI-MS(m / z): 175[M+H] + ; 1 H NMR (400MHz, CDCl 3 )δ: 7.83(d,2H), 7.38(t,2H), 7.16(t,1H), 3.34(s,2H), 2.11(s,3H); melting point: 127.8~128.8℃.

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Abstract

The invention discloses a preparation method of edaravone. The preparation method comprises the following steps: in the presence or absence of a solvent, phenylhydrazine and ethyl acetoacetate are subjected to a cyclization reaction in a continuous flow reactor, and the molar ratio of phenylhydrazine to ethyl acetoacetate in the continuous flow reactor is (0.8-1.2): 1, wherein the cyclization reaction is carried out in the presence of protonic acid or in the absence of protonic acid. The preparation method disclosed by the invention can realize continuous, efficient, safe, energy-saving and accurately-controlled modern industrial production. The method has the advantages of mild process conditions, fast reaction, safety, reliability, simple operation, low operation cost, substantial reduction of the generation of by-products, almost quantitative completion of the reaction, high purity of the product obtained through the reaction, elimination of the inter-batch yield and the fluctuationof the product quality in the intermittent reaction kettle operation, and suitableness for the requirements of modern industrial production.

Description

technical field [0001] The invention relates to a preparation method of Edaravone. Background technique [0002] Edaravone (Edaravone), chemical name is 3-methyl-1-phenyl-2-pyrazolin-5-one, and its structural formula is as shown in formula (I): [0003] [0004] Edaravone is a brain protectant developed by Japan's Mitsubishi Pharmaceutical Company, i.e. a free radical scavenger. Clinically, it is mainly used to improve neurological symptoms, activities of daily living and dysfunction caused by acute cerebral infarction. [0005] Studies on the mechanism of action of Edaravone show that it can scavenge free radicals and inhibit lipid peroxidation, thereby inhibiting the oxidative damage of brain cells, vascular endothelial cells, and nerve cells. Preclinical studies have shown that the use of edaravone can prevent the progression of cerebral edema and cerebral infarction, relieve the accompanying neurological symptoms, and inhibit delayed neuronal death. The administrat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/26
CPCC07D231/26
Inventor 裘鹏程陈一波李承明张福利
Owner SHANGHAI INST OF PHARMA IND CO LTD