DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201941005182 filed on February 09, 2019; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Edaravone that is simple and economically significant. This improved process also includes purification of Edaravone.

BACKGROUND OF THE INVENTION

Edaravone is chemically known as 3-methyl-1-phenyl-2-pyrazolin-5-one, used for the treatment of amyotrophic lateral sclerosis in USA and Japan.

The US Patent No. 2017815 discloses the preparation of Edaravone from the condensation reaction of phenylhydrazine with ethyl acetoacetate as disclosed below.

The applicants of the US Patent No. 2017815 employ benzene or toluene during the condensation. The continuous removal of water formed during the reaction increases the efficiency of this reaction. The continuous removal of water is done by distilling the solvent under reduced pressure during the reaction as disclosed in this Patent.
The US Patent No. 4857542 disclose the preparation of Edaravone from the condensation reaction of phenyl hydrazine with ethyl acetoacetate in ethanol without distillation yielded a high impurities results less yield.

The US Patent No. 4906644 discloses the reaction of the condensation reaction of phenyl hydrazine with ethyl acetoacetate in presence of acid or bases.

The Indian Patent No. 305627 discloses the preparation of Edaravone from phenyl hydrazine or its salts with ethyl acetoacetate in alcohol solvents, then distillation of alcohol solvents further co-distillation with solvent I (chlorinated solvents such as chloroform, dichloromethane) and isolation with (nonpolar solvents such as cyclohexane, hexane) results less yield.

There are some impurities generated during the preparation of Edaravone, hence it is essential to control the impurities during the preparation or during the work-up procedures after the completion of the reaction to obtain the product with desired purity.

Besides the availability of different methods for the preparation Edaravone in state of the art, there is a need for an improved process for the preparation of Edaravone that is economically significant.

OBJECT OF THE INVENTION

The main object of the invention is to provide an improved process for the preparation of Edaravone.

Another object of the invention is to provide a process for the purification of Edaravone.

SUMMARY OF THE INVENTION

The primary aspect of the present invention is to provide an improved process for the preparation of Edaravone with better purity.

One aspect of the present invention is to provide an improved process for the preparation of Edaravone comprising the steps of:
(a) reacting phenyl hydrazine or its acid addition salts with the ethylacetoacetate in ethyl acetate as solvent to obtain a reaction mass containing Edaravone;
(b) optionally, charcoalizing the reaction mass obtained in step (a);
(c) isolating Edaravone from the reaction mass obtained in step (a) or step (b) without distilling ethyl acetate under reduced pressure; and
(d) optionally, purifying the Edaravone.

In some embodiment, the step (a) of the above described process for the preparation of Edaravone is carried out in the presence of base, preferably sodium hydroxide. In some other embodiment, step (a) of the above described process for the preparation of Edaravone is carried out in the presence of acid, preferably organic acid, more preferably acetic acid.

In some other embodiment, the step (d) of the above described process for the preparation of Edaravore is carried out by crystallization from ethyl acetate, optionally, followed by recrystallization from alcoholic solvent or its mixture, preferably ethanol.

Another aspect of the invention is to provide a process for the purification of Edaravone comprising the steps of:
(a) providing a solution of Edaravone in ethyl acetate;
(b) cooling the solution of Edaravone provided in step (a);
(c) isolating Edaravone from the cooled solution obtained in step (b);
(d) optionally, dissolving the Edaravone obtained in step (c) in alcoholic solvent or its mixture thereof, and isolating the crystalline Edaravone.

In some embodiment, the step (a) of the above described process for the purification of Edaravone is carried out by dissolving the Edaravone in ethylacetate by heating.

In some other embodiment, the isolation in step (c) of the above described process for the purification of Edaravone is carried out by filtration of the crystallized Edaravone.

In some embodiment, the step (d) is carried out by crystallization from alcoholic solvent or mixture thereof, preferably ethanol, followed by filtration of crystallized Edaravone.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to provide an improved process for the preparation of Edaravone that is simple and economically significant with better purity.

One aspect of the present invention is to provide an improved process for the preparation of Edaravone comprising the steps of:
(a) reacting phenyl hydrazine or its acid addition salts with the ethylacetoacetate in ethyl acetate as solvent to obtain a reaction mass containing Edaravone;
(b) optionally, charcoalizing the reaction mass obtained in step (a);
(c) isolating Edaravone from the reaction mass obtained in step (a) or step (b) without distilling ethyl acetate under reduced pressure; and
(d) optionally, purifying the Edaravone.

In some embodiment of the present invention, the step (a) in the above described process for the preparation of Edaravone is carried out in the presence of base selected from organic base or inorganic base; inorganic base may be selected from alkali and alkaline earth metal hydroxides, carbonates and bicarbonates; and organic base is selected from the group comprising diisopropyl amine, diisobutyl amine, triethylamine, diethylamine, dicyclohexylamine, n-butylamine, diisopropyl ethylamine, pyridine and the like.

In some embodiment of the present invention, the step (a) in the above described process for the preparation of Edaravone is carried out in the presence of sodium hydroxide.

In some embodiment of the present invention, the step (a) in the above described process for the preparation of Edaravone is carried out in the presence of acid selected from hydrochloric acid, sulphuric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid and the like.

In some embodiment of the present invention, the step (a) in the above described process for the preparation of Edaravone is carried out in the presence of organic acid like acetic acid.

The inventors of the present invention, tried different solvents for the reaction of phenyl hydrazine or its acid addition salts with the ethylacetoacetate in presence of catalytic amount of base or acid for reducing the impurity formation and for providing simple and economical process.

Surprisingly, the inventors of the present invention found a better yield having less impurities during the reaction of phenyl hydrazine or its acid addition salts with the ethylacetoacetate by the use of ethylacetate solvent without distilling the reaction solvent (ethylacetate) makes workup procedure easy and simple.

In some embodiment of the present invention, charcoalizing in step (b) of the above described process for the preparation of Edaravone is carried out at temperature of about 60°C after reaction completion.

In some embodiment of the present invention, isolation in step (c) in the above described process for the preparation of Edaravone is carried out by cooling to temperature of about 5°C without distilling the solvent (ethyl acetate) under reduced pressure.

In some embodiment of the present invention, purification in step (d) in the above described process for the preparation of Edaravone is carried out by crystallization or any other conventional techniques. The crystallization is carried out in ethyl acetate solvent, optionally, followed by recrystallization from any alcoholic solvent or mixture thereof, preferably ethanol.

Another aspect of the invention is to provide a process for the purification of Edaravone comprising the steps of:
(a) providing a solution of Edaravone in ethyl acetate;
(b) cooling the solution of Edaravone provided in step (a);
(c) isolating Edaravone from the cooled solution obtained in step (b);
(d) optionally, dissolving the Edaravone obtained in step (c) in alcoholic solvent or its mixture thereof, facilitating crystallization and isolating the crystalline Edaravone.

In some embodiment of the present invention, step (a) in the above described process for purification of Edaravone is carried out by dissolving the Edaravone in ethylacetate by heating.

In some embodiment of the present invention, step (b) in the above described process for purification of Edaravone is carried out by cooling to temperature of about 5°C without distilling the solvent (ethyl acetate) under reduced pressure.

In some embodiment of the present invention, isolation in step (c) of the above described process for purification of Edaravone is carried out by filtration of the crystallized Edaravone.

In some embodiment of the present invention, step (d) in the above described process for purification of Edaravone is carried out by crystallization from any alcoholic solvent or mixture thereof, preferably ethanol, followed by filtration of the crystallized Edaravone.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of Edaravone:
To a mixture of phenyl hydrazine (200 g) and ethyl acetoacetate (122.75 g) in ethyl acetate (400 ml), sodium hydroxide powder (0.296 g) was added and stirred at 75°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was charcoalized with activated carbon (5 g) at 60°C and filtered. The filtrate was gradually cooled to 30°C and maintained for 30 minutes, then cooled to 5°C. The cooled reaction mass was maintained till the crystallisation is complete. The formed solid was filtered; washed with chilled ethyl acetate (200 ml); then washed with water (500 ml) and dried to obtain the titled compound. Yield: 210 g; Purity: 99.02%.

Example-2: Purification of Edaravone: A suspension of wet crude Edaravone (100 g) in ethanol (300 ml) was heated to 70°C for 75 minutes to obtain a clear yellow solution. The obtained yellow solution was filtered through micron filter. The filtrate was cooled gradually to 30°C and maintained for 45 minutes, then solution was cooled to 5°C till the crystallization of the product is complete. The resulting product was then filtered, washed with ethanol (100 ml) and dried. Yield: 90 g; Purity: 99.94%.

Example-3: Preparation of Edaravone:
To a mixture of phenyl hydrazine (200 g) and ethyl acetoacetate (122.75 g) in ethyl acetate (ml), acetic acid (2.80 g) was added and stirred at 75°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was charcoalized with activated carbon (5 g) at 60°C and filtered. The filtrate was gradually cooled to 30°C and maintained for 30 minutes, then cooled to 5°C. The cooled reaction mass was maintained till the crystallisation is complete. The formed solid was filtered; washed with chilled ethyl acetate (200 ml). Then the resulted wet solid was recrystallized with ethanol and dried to obtain the titled compound. Yield: 160 g; Purity: 99.00%.

Example-4: Purification of Edaravone:
A suspension of wet crude Edaravone (100 g) in ethylacetate (500 ml) was heated at 70°C then charcoalized with activated carbon (5 g) at not less than 65°C and filtered. The obtained filtrate was gradually cooled to 30°C and maintained for 30 minutes, then cooled to 5°C. The cooled reaction mass was maintained till the solid formation is complete. The obtained solid was filtered; washed with chilled ethylacetate (100 ml). The resulted wet solid was suspended with ethanol (300 ml) was heated to 70°C for 75 minutes to obtain a clear yellow solution. The obtained yellow solution was filtered through micron filter. The filtrate was cooled gradually to 30°C and maintained for 45 minutes, then further cooled to 5°C till the crystallization of the product is complete. The resulting product was then filtered, washed with ethanol (100 ml) and dried. Yield: 80 g; Purity: 99.96%.
,CLAIMS:
1. A process for the preparation of Edaravone comprising the steps of:
(a) reacting phenyl hydrazine or its acid addition salts with the ethylacetoacetate in ethyl acetate as solvent to obtain a reaction mass containing Edaravone;
(b) optionally, charcoalizing the reaction mass obtained in step (a);
(c) isolating Edaravone from the reaction mass obtained in step (a) or step (b) without distilling ethyl acetate under reduced pressure; and
(d) optionally, purifying the Edaravone.

2. The process as claimed in claim 1, wherein step (a) is carried out in the presence of base, preferably sodium hydroxide.

3. The process as claimed in claim 1, wherein step (a) is carried out in the presence of acid, preferably organic acid, more preferably acetic acid.

4. The process as claimed in claim 1, wherein step (d) is carried out by crystallization from ethyl acetate, optionally, followed by recrystallization from alcoholic solvent or mixture thereof, preferably ethanol.

5. A process for the purification of Edaravone comprising the steps of:
(a) providing a solution of Edaravone in ethyl acetate;
(b) cooling the solution of Edaravone provided in step (a);
(c) isolating Edaravone from the cooled solution obtained in step (b);
(d) optionally, dissolving the Edaravone obtained in step (c) in alcoholic solvent or its mixture thereof, and isolating the crystalline Edaravone.

6. The process as claimed in claim 5, wherein step (a) is carried out by dissolving the Edaravone in ethylacetate by heating.

7. The process as claimed in claim 5, wherein step (c) is carried out by filtration of the crystallized Edaravone.

8. The process as claimed in claim 5, wherein step (d) is carried out by crystallization from alcoholic solvent or mixture thereof, preferably ethanol, followed by filtration of the crystallized Edaravone.