FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
Title: “An improved process for the preparation of
Edaravone of formula (X)”
Applicants: SUMAR BIOTECH LLP
Address: Plot No.: 112, 113, 114, G.I.D.C. Estate, Tal:
Gozaria, Dist: Mehsana-382825, Gujarat, India.
Nationality: An Indian Company
The following specification describes the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Edaravone of formula (X). More particularly, the present invention relates to a sustainable and eco-friendly synthesis of Edaravone using phenyl hydrazine hydrochloride of formula (I), ethyl acetoacetate (II), and water, with Baker’s yeast (Saccharomyces cerevisiae) serving as a biocatalyst. This biocatalytic route offers a green alternative by operating under mild reaction conditions and minimizing harmful by-products.
BACKGROUND OF THE INVENTION
Edaravone of formula (X) is a small-molecule antioxidant that has garnered significant attention for its therapeutic benefits, particularly in the treatment of neurodegenerative diseases and acute neurological disorders.
Formula (X) It is first approved in Japan for treating ischemic stroke and later gained recognition for its efficacy in slowing the progression of amyotrophic lateral sclerosis (ALS). Edaravone of formula (X) scavenges reactive oxygen species (ROS), thereby protecting cells from oxidative stress, a key factor in neuronal damage. Due to its pharmacological significance, developing sustainable and efficient methods for synthesizing Edaravone of formula (X) is of considerable interest.
It is also known by its IUPAC name (3-methyl-1-phenyl-2-pyrazolin-5-one).
There are number of processes available to prepare Edaravone of formul (X).

Edaravone is disclosed first in patent US4857542 filed by Mitsubishi Kasei Corp. US4857542 has disclosed Edaravone structure, demonstrated that disorder has effective prevention and treatment to the recycle system, has good effect as lipid peroxidation inhibitor and disordered brain function treatment especially. US4857542 has disclosed phenyl hydrazine and methyl acetoacetate back flow reaction in dehydrated alcohol, makes Edaravone, and yield is 65%.
WO2006/71730 filed by Astrazeneca Ab and Nps Pharmaceuticals, Inc has disclosed a process for the preparation of Edaravone of formula (X) wherein phenyl hydrazine and methyl acetoacetate is reacted in presence of acetic acid at 50℃ followed by extracting it with ethyl acetate to give Edaravone of formula (X) in 86% yield. Because such technology that the acetic acid boiling point, adopts than higher and acid more intense can cause huge energy consumption iste and equipment corrosion, is not suitable for suitability for industrialized production.
CN102180834A has described a process for the preparation of Edaravone of formula (X) as per scheme-1, the said process comprises the steps: reacting phenyl hydrazine with ethyl acetoacetate in an alcohol solvent under the action of an acid catalyst to prepare the edaravone; and after the reaction, adding a non-alcohol solvent to cool and crystallize to obtain the edaravone crude product.
Scheme-1:
Acid catalyst described in the process is selected from one or more in hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, tartrate and the citric acid.
Traditional synthesis routes for Edaravone involve multi-step processes that often utilize harsh chemicals, toxic reagents, and environmentally unfriendly solvents. These methods can also demand high energy inputs and result in low atom economy. The growing emphasis on green chemistry and sustainable practices necessitates the exploration of eco-friendly alternatives for pharmaceutical synthesis.
There is a demand of providing a simple, easy to operate, industry & economically viable and environment friendly process for the preparation of Edaravone of formula (X).

OBJECTS OF THE INVENTION
Accordingly, the main object of the present invention is to overcome the problems faced by the prior art processes in the preparation of Edaravone of formula (X).
There is an object of the present invention to provide a simple, environment friendly, robust, easy to operate, industry & economically viable and single step environment friendly process for the preparation of Edaravone of formula (X).
It is also an object to provide a process for the preparation of Edaravone of formula (X) from from phenyl hydrazine hydrochloride of formula (I) and ethyl acetoacetate of formula (II) using baker’s yeast in water as solvent that provides increased yield of of formula (X) from phenyl hydrazine hydrochloride of formula (I) and ethyl acetoacetate of formula (II).
It is also an object to provide a process for the purification of Edaravone of formula (X) using organic solvent and obtaining Edaravone of formula (X) with improved quality having lesser amounts of impurities in the final product.
BRIEF DESCRIPTION OF DRAWINGS
Table-1: Experimental data on the process for the preparation of crude edaravone of formula (X).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Edaravone of formula (X). More particularly, the present invention relates to a sustainable and eco-friendly synthesis of Edaravone using phenyl hydrazine hydrochloride of formula (I), ethyl acetoacetate (II), and water, with Baker’s yeast (Saccharomyces cerevisiae) serving as a biocatalyst.
Formula (I) Formula (II) Formula (X)
Proposed Route of synthesis for the preparation of Edaravone of formula (X) is shown in scheme-2 as follows:

Scheme-2: Route of Synthesis for Preparation of Edaravone of formula (X):
The present invention provides a simple, environment friendly, robust, easy to operate, industry & economically viable and single step process for the preparation of Edaravone of formula (X). The inventors have proposed a novel, sustainable approach to the synthesis of Edaravone of formula (X) by employing phenyl hydrazine hydrochloride (I) and ethyl acetoacetate (II) as key starting materials.
The novelty of the present invention lies in to 2 major aspects i.e. (i)
carrying out reaction in water as solvent and (ii) the use of Baker’s
yeast (Saccharomyces cerevisiae).
Use of water avoids the use of environment unfriendly and harmful
organic solvents in the reaction.
Use of Baker’s yeast (Saccharomyces cerevisiae) as a biocatalyst in the
process of the present invention offers several advantages over
environment unfriendly and harmful conventional chemical catalysts
such as inorganic or organic acids. Biocatalysis enables reactions
under mild conditions, reducing the need for high temperatures or
pressures, and minimizes the generation of toxic by-products.
Furthermore, Baker’s yeast is readily available, inexpensive,
biodegradable, and aligns with the principles of green chemistry.
The biocatalytic approach presented in the present invention aims to
not only improve the efficiency and environmental profile of Edaravone

(X) synthesis but also demonstrate the feasibility of integrating biological systems into mainstream chemical processes. By utilizing readily accessible reagents and a benign catalyst, this method contributes to the advancement of sustainable synthetic practices in pharmaceutical chemistry.
The present inventors have comprehensively and successfully investigated the possibility of developing a process for the preparation of Edaravone of formula (X).
According to the present invention, a process for the preparation of Edaravone of formula (X) is provided, the said process comprises:
i. Dissolving 1 mole ratio of phenyl hydrazine hydrochloride of
formula (I) in 1 to 10 volumes of water; ii. Adding 2 to 2.5 mole ratio of ethyl acetoacetate of formula (II) in
step-i at a temperature between 00C to 350C; iii. Adding 3 to 5 gms of baker’s yeast, 5 to 10% of aqueous sodium
hydroxide solution in step-ii and facilitating condensation
reaction at a pH between 4 to 5 and at a room temperature for
15-24 hours; iv. Filtering the reaction mass of step-iii to remove baker’s yeast
and obtaining step-iv in the form of aqueous solution; v. Extracting aqueous solution of step-iv with organic solvent
followed by removal of the said organic solvent to get crude
edaravone of formula (X); vi. Conducting purification step of step-v using organic solvent to
obtain pure edaravone of formula (X).
EXAMPLES OF THE PRESENT INVENTION
Materials:
All materials are commercially available in the market including:
Phenyl hydrazine hydrochloride (I)
Ethyl acetoacetate (II)
Baker’s yeast
The process for the preparation of Edaravone (X) is carried out using
the following materials.
Phenyl hydrazine hydrochloride (I) and ethyl acetoacetate (II) are
employed as key starting reagents. Baker’s yeast is utilized as a
biocatalyst to facilitate the reaction under mild conditions. Water is
used as the reaction medium, ensuring a sustainable and eco-friendly
process. Aqueous solution of sodium hydroxide is employed for pH
adjustment to optimize the enzymatic activity of the yeast.

For product extraction and purification, organic solvent selected from methylene dichloride (MDC), ethyl acetate or methyl ethyl ketone (MEK) is used as a solvent, ensuring effective separation of the product from the reaction mixture. Additionally, distilled or purified water is utilized for rinsing and washing during the purification steps.
All chemicals used are of analytical grade to ensure reliable results.
General process:
Crude Edaravone of formula (X):
In a 250 mL round-bottom flask, phenyl hydrazine hydrochloride (I) is dissolved in water to prepare the reaction mixture. To this solution, ethyl acetoacetate (II) is added gradually at a temperature between 00C to 350C with continuous stirring to ensure uniform mixing. Next, Baker's yeast is introduced as a biocatalyst, facilitating the condensation reaction between the reagents.
The reaction mixture is then stirred for 15 to 24 hours at a room temperature, preferably between 150C to 370C. This temperature is selected to optimize yeast enzymatic activity without causing enzyme denaturation. During the reaction, the pH of the solution is monitored and adjusted to 4–5, using aqueous solution of sodium hydroxide as needed, to maintain yeast viability and ensure efficient catalysis.
After completion of the reaction, the yeast biomass is removed by filtration, and the supernatant containing the product is collected. Extraction of Edaravone is performed by adding organic solvent selected from methylene dichloride (MDC) or ethyl acetate or methyl ethyl ketone (MEK) to the supernatant, followed by vigorous shaking to facilitate phase separation. The organic layer containing the product is separated, ished with distilled water to remove residual aqueous impurities, and dried over anhydrous sodium sulfate to eliminate moisture.
The crude product is obtained by evaporating the organic solvent under reduced pressure using a rotary evaporator. Crude edaravone (X) may be dried in vacuum oven at 30-500C and taken for further purification.
According to the above process,
In step-i, 1 mole ratio of phenyl hydrazine hydrochloride (I) is taken for
the reaction purpose and distilled or purified water as a solvent in
amount between 1 to 10 volume is taken for the reaction purpose.
In step-ii, ethyl acetoacetate (II) is taken in a mole ratio between 2 to
2.5.

In step-iii, baker’s yeast is used in amount between 3 to 5 gms per 1
mole ratio of phenyl hydrazine hydrochloride (I). Further, 5 to 10% of
aqueous solution of sodium hydroxide is used to adjust pH between 4
to 5.
For the step-i and ii, temperature is kept between 00C to 350C while
for step-iii, temperature is kept at a room temperature, preferably
between 150C to 370C.
In step-v, organic solvent selected from methylene dichloride (MDC),
ethyl acetate or methyl ethyl ketone (MEK) is used as solvent. Organic
solvent is taken 2 to 10 volumes compared to water used in the
reaction and as per the requirement of the process.
Table-1 (Drawings sheet No. 1) shows experimental data on the process for the preparation of crude edaravone of formula (X).
Purification of crude Edaravone of formula (X):
For further purification, the crude product is dissolved in organic solvent at a temperature between 400C to 700C and allowed to cool gradually to room temperature, followed by additional cooling in an ice bath to attain temperature between 00C to 100C and to promote crystal formation. The crystallized product is collected by filtration and ished with cold organic solvent. Finally, the purified product is dried under vacuum or in a desiccator to obtain the final Edaravone. The final edaravone of formula (X) obtained with the said process is having HPLC purity more than 99.5%.
In step-vi, purification is carried out in organic solvent at a temperature between 400C to 700C which may be kept as per the boiling point of organic solvent followed by cooling it to 00C to 100C and filtering and washing it with organic solvent to give pure edaravone of formula (X).
In the above purification step, methylene dichloride (MDC), ethyl acetate or methyl ethyl ketone (MEK) is used as organic solvent. Organic solvent is taken 2 to 15 volumes compared to weight of crude edaravone o formula (X).
If further purification is necessary, silica gel chromatography using organic solvent selected from methylene dichloride (MDC), ethyl acetate or methyl ethyl ketone (MEK) is considered to achieve a high-purity product.
Table-2 shows experimental data on the process for the purification of crude edaravone and obtaining pure edaravone of formula (X).

Table-2:

Experiment of
Crude Edaravone (X) Organic Solvent for purification HPLC (%)
Edaravone
(X) (pure) (Yield w/w)
EXP 01 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 02 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 03 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 04 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 05 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 06 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 07 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 08 Methyl ethyl ketone (MEK) 99.7 0.6
EXP 09 Methylene Dichloride (MDC) 99.8 0.7
EXP 10 Methylene Dichloride (MDC) 99.8 0.7
EXP 11 Methylene Dichloride (MDC) 99.8 0.7
EXP 12 Methylene Dichloride (MDC) 99.8 0.7
EXP 13 Methylene Dichloride (MDC) 99.8 0.7
EXP 14 Methylene Dichloride (MDC) 99.8 0.7
EXP 15 Methylene Dichloride (MDC) 99.8 0.7
EXP 16 Methylene Dichloride (MDC) 99.8 0.7
EXP 17 Methylene Dichloride (MDC) 99.8 0.7
EXP 18 Methylene Dichloride (MDC) 99.8 0.7
EXP 19 Ethyl acetate 99.9 0.8
EXP 20 Ethyl acetate 99.9 0.8
EXP 21 Ethyl acetate 99.9 0.8
EXP 22 Ethyl acetate 99.9 0.8
EXP 23 Ethyl acetate 99.9 0.8
EXP 24 Ethyl acetate 99.9 0.8
EXP 25 Ethyl acetate 99.9 0.8
EXP 26 Ethyl acetate 99.9 0.8

EXP 27 Ethyl acetate 99.9 0.8
EXP 28 Ethyl acetate 99.9 0.8
ADVANTAGES OF THE PRESENT INVENTION
1. The process of the present invention is a simple, environment friendly, robust, easy to operate, industry & economically viable process.
2. The said process provides edaravone of formula (X) with improved quality having lesser amounts of impurities in the final product.

We claim:
1. A process for the preparation of Edaravone of formula (X)
which comprises: i. Dissolving 1 mole ratio of phenyl hydrazine hydrochloride of formula (I) in 1 to 10 volumes of water; ii. Adding 2 to 2.5 mole ratio of ethyl acetoacetate of formula (II) in step-i at a temperature between 00C to 350C;
iii. Adding 3 to 5 gms of baker’s yeast, 5 to 10% of aqueous
sodium hydroxide solution in step-ii and facilitating
condensation reaction at a pH between 4 to 5 and at a
room temperature for 15-24 hours; iv. Filtering the reaction mass of step-iii to remove baker’s
yeast and obtaining step-iv in the form of aqueous
solution; v. Extracting aqueous solution of step-iv with organic
solvent followed by removal of the said organic solvent
to get crude edaravone of formula (X); vi. Conducting purification step of step-v using organic
solvent to obtain pure edaravone of formula (X).
2. The process as claimed in claim-1 wherein in step-i, water is selected from distilled or purified water.
3. The process as claimed in claim-1 wherein in step-vi, crude edaravone (X) of step-v is dissolved in organic solvent at a temperature between 400C to 700C followed by cooling it to 00C to 100C, filtering and washing it with organic solvent to give pure edaravone of formula (X).
4. The process as claimed in claim-1 wherein in step-v & vi, organic solvent is selected from methylene dichloride (MDC), methyl ethyl ketone (MEK) or ethyl acetate.