Description:An improved process for the preparation of Edaravone.

Field of the Invention

The present invention relates to an improved process for the preparation of Edaravone, having the chemical structural of Formula I.

Background of the Invention

Edaravone is used for the treatment of amyotrophic lateral sclerosis (ALS). Edaravone was approved by the U.S. Food and Drug administration (FDA) on May 5, 2017. Edaravone is a member of the substituted 2-pyrazolin-5-one class, has the chemical name 3-methyl-1-phenyl-2-pyrazolin-5-one. It was developed and marketed as Radicava by Mitsubishi Tanabe Pharma Corp. The molecular formula is C10H10N2O. The structural Formula is:

Edaravone is first disclosed in Justus Liebigs Annalen der Chemie 1889, 255, 230-251 further its process for preparation is also disclosed in US 2017815 A, US 4857542 A, US 4906644 A, US2006135588 A2, IN 305627, IN 1792/MUM/2017, IN 201741044266, IN 201941005182 these process leads to the formation of high impurities results less yield and additional purification techniques required to get pure Edaravone.

In view of the above, there is a significant need to develop a cost-effective, stable, commercially viable, large scale and robust processes to enable improved technology for production of pure Edaravone of Formula I with good yield.

Summary of the Invention

The present invention provides an improved process for the preparation of Edaravone with better purity and good yield.

The main embodiment of the present invention provides an improved process for the preparation of Edaravone comprising the steps of:

i) reacting the phenyl hydrazine with ethyl acetoacetate in methanol and water as solvent, triethylamine as base to obtain a reaction mass containing Edaravone;
ii) isolating Edaravone from the reaction mass obtained in step (i);
iii) optionally, purifying the Edaravone.

Detailed Description of the Invention

Accordingly, the present invention relates an improved process for the preparation of Edaravone by reacting phenyl hydrazine with ethylacetoacetate in methanol, water as solvent, triethylamine as base followed by purification to get Edaravone. The schematic description of the process is as shown in Scheme I.

In step-i), reacting the phenyl hydrazine with ethyl acetoacetate in methanol, water and triethylamine to obtain Ethyl (3E)-3-(2-phenylhydrazine-1-ylidene)-butanoate as in situ compound is washed with purified water followed Ethyl acetate to obtain a reaction mass containing Edaravone.

The reaction temperature may range from 50 °C to 60 °C and preferably at a temperature in the range from 55°C to 60 °C. The duration of the reaction may range from 3 to 5 hours, preferably for a period of 4 hours.

In step ii), isolating the Edaravone from reaction mass by using Methanol and Ethyl acetate.

The reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 70 °C. The duration of the reaction may range from 1 to 2 hours, preferably for a period of 30 minutes.

In step iii), purifying the crude Edaravone by using Methanol to obtain pure Edaravone.
The reaction temperature may range from 55 °C to 70 °C and preferably at a temperature in the range from 60 °C to 65 °C. The duration of the reaction may range from 1 to 2 hours, preferably for a period of 30 minutes.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

EXPERIMENTAL PORTION

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example 1: Process for the preparation of Edaravone.

Charge Methanol (12.5 L), Purified water (12.5 L), Phenyl hydrazine, Triethyl amine (0.7 Kg) and Ethyl acetoacetate (15.75 Kg) into reactor at 25-35°C. Maintain the contents of reactor at 40-45°C for 1 hour. Heat the contents of reactor to 50-55°C and maintain the contents of reactor at 50-55°C for 4 hours. Monitor the reaction progress by using HPLC, after completion of reaction cool the contents of reactor to 25-35 °C and maintain for 1 hour. Load the material into centrifuge spin dry for complete removal of mother liquid. Wash the material with purified water (12.5 L) spin dry for complete removal of mother liquid. Wash the material with chilled Ethyl acetate (12.5 L) spin dry for complete removal of mother liquid. Charge Methanol (15.75 L) into reactor at 25-35 °C heat the contents of reactor to 60-70°C (Reflux temperature). Maintain for 30 minutes. Cool the contents of reactor to 10-15°C and maintain for 2 hours. Load the material into centrifuge spin dry for complete removal of mother liquid. Wash the material with chilled Ethyl acetate (12.5 L) spin dry for complete removal of mother liquid. Charge Ethyl acetate (12.5 L) into reactor at 25-35°C. Maintain the contents of reactor at 25-35°C for 30 minutes. Cool the contents of reactor to 10-15 °C and maintain for 1 hour. Load the material into centrifuge. Spin dry for complete removal of mother liquid. Wash the material with chilled Ethyl acetate (18.75 L). Spin dry for complete removal of mother liquid. Unload the crude Edaravone.

Example 2: Purification of Edaravone

Charge Methanol (22.5 L) and crude Edaravone into reactor at 25-30 °C. Heat the contents reactor to 60-65 °C maintain the contents of reactor at 60-65 °C for 30 minutes. Slowly cool the contents of reactor to 10-15 °C and maintain for 1hour. Load the material into centrifuge. Spin dry for complete removal of mother liquid. Wash the material with Chilled Methanol (7.5 L). Spin dry for complete removal of mother liquid. Unload and dry the compound in a vacuum dryer to obtain pure Edaravone.

Dated this 3rd day of February 2023.
, Claims:
1. An improved process for the preparation of Edaravone compound of Formula I

wherein the process comprises:
i) reacting the phenyl hydrazine with ethyl acetoacetate in methanol and water as solvent, triethylamine as base to obtain a reaction mass containing Edaravone;
ii) isolating Edaravone from the reaction mass obtained in step (i);
iii) optionally, purifying the Edaravone.

2. The process as claimed in claim 1, wherein isolation of Edaravone from reaction mass using Methanol followed by Ethyl acetate.

3. The process as claimed in claim 1, wherein purification of Edaravone in Methanol.