FORM 2
THE PATENT ACT, 1970 (39 of 1970) &
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF REBAMIPIDE"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.

AN IMPROVED PROCESS FOR THE PREPARATION OF REBAMIPIDE
Technical field of the invention
The present invention relates to an improved process for preparation of Rebamipide compound represented by compound of structural formula I through formation of compound represented by structural formula II i.e. α-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester,

Background of the invention
Rebamipide is chemically known as 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid and was first disclosed in U.S. Pat. No. 4,578,381 (hereafter referred to as US'381) and is represented by compound of structural formula I.

Rebamipide is well tolerated and effective drug used for treatment of peptic ulcers, acute gastritis or gastric mucosa lesion affected in acute exacerbation of chronic gastritis.

U.S. Pat. No. 4,578,331 describes a process for the preparation of Rebamipide compound represented by structural formula I as depicted below in Scheme I wherein ethyl 2-acetamido-2-carboethoxy-3-[2(lH)-quinolinon-4-yl]propionate compound represented by structural formula III is hydrolyzed with 20% hydrochloric acid to obtain 2-amino-3-[2(lH)-quinolinon-4-yl] propionic acid hydrochloride compound represented by structural formula IV, which on condensation with 4-chlorobenzoylchloride compound represented by structural formula V gives Rebamipide compound represented by structural formula I.

U.S. Patent. No. 6,680,386 discloses another process for preparation of Rebamipide compound represented by structural formula I as depicted below in Scheme II wherein diethyl benzamidomalonate compound represented by structural formula VI on reaction with 4-(Bromomethyl)-lH-quinolin-2-one compound represented by structural formula VII in presence

of sodium ethoxide in ethanol at room temperature for 16 hours provided di-ester compound represented by structural formula VIII which on hydrolysis and subsequently decarboxylation results in Rebamipide compound represented by structural formula I.

U.S. Patent. No. 8,338,635 discloses a method of synthesis of half ester compound represented by structural formula X by reacting di-ester compound represented by structural formula IX with base followed by acidification. This preparation process can be expressed by the scheme III:


The aforementioned prior art processes provides Rebamipide compound represented by structural formula I requires long reaction hours, high basic condition and high temperature which ultimately promotes formation of impurities and affecting purity of Rebamipide compound represented by structural formula I.
Accordingly there is a need in the art to develop a simple, environment friendly & improved process of preparing Rebamipide compound represented by structural formula I.
Object of the invention
i) The main object of the present invention is to provide an improved process for
preparation of Rebamipide compound represented by structural Formula I, in high yield and purity.

i) Another object of present invention is to provide an improved process for preparation
of Rebamipide compound represented by structural Formula I, through formation of compound represented by structural formula II i.e. a-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester.
ii) Yet another object of present invention is to provide simple, economic, environment
friendly and industrially viable process for the preparation of Rebamipide compound represented by structural Formula I.
Summary of the invention
A first aspect of the present invention is to provide an improved process for preparation of Rebamipide compound represented by structural Formula I by using compound represented by

structural formula II i.e. α-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester.

Another aspect of the present invention is to provide an improved process for preparation of Rebamipide compound represented by structural Formula I comprising the steps of:
a) reacting compound represented by structural formula VI with 4-(bromomethyl)-lH-quinolin-2-one compound represented by structural formula VII to obtain the compound α-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester represented
by structural formula II.

b) hydrolyzing the compound represented by structural formula II in presence of alkali base followed by acidification to obtain compound Rebamipide represented by structural formula I.


Detailed Description of the invention
The reaction of diethyl benzamidomalonate represented by structural formula VI with a base may be carried out in a polar solvent selected from the group comprising of dimethylformamide, dimethylsulfoxide or tetrahydrofuran or alcoholic solvent of mixture(s) thereof.
The examples of inorganic base may include but not limited to sodium hydroxide, potassium hydroxide or lithium hydroxide.
The ratio of base to diethyl benzamidomalonate represented by structural formula VI may be between 0.75 to 2.5.
A compound represented by structural formula VI may be reacted with 4-(bromomethyl)-1H-quinolin-2-one compound represented by structural formula VII to obtain compound represented by structural formula VIII.
The reaction of compound represented by structural formula VI with 4-(bromomethyl)-lH-quinolin-2-one compound represented by structural formula VII may be carried out at a temperature in the range of 25°C to 150°C.
The reaction of compound represented by structural formula VI with 4-(bromomethyl)-lH-quinolin-2-one compound represented by structural formula VII may be carried out for duration of 1 hours to 10 hours.

The reaction is also carried out by using alkali halide viz. sodium chloride, sodium bromide and sodium iodide. The mole ratio of alkali halide may be between 1 to 5.
The compound represented by structural formula II may be isolated by quenching the reaction mixture with water.
The hydrolysis of compound represented by structural formula II may be carried out in the presence of an inorganic base.
The examples of inorganic base may include but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium bicarbonate or sodium bicarbonate.
The hydrolysis of α-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester of structural formula II may be carried out in an alcoholic solvent or/and aqueous solution or and mixture(s) thereof.
The examples of alcohol solvent may be selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butyl alcohol or mixture(s) thereof and water or mixture(s) thereof.
The hydrolysis of compound of structural formula II may be carried out at a temperature in the range of 40°C to 120°C for a period of 30 minutes to 4 hours.
The acidification of the compound represented by structural formula XI with an acid, in a solvent to obtain a compound represented by structural formula I.
The examples of inorganic acid may include but not limited to hydrochloric acid, Sulphuric acid, acetic acid or mixture(s) thereof.

The Rebamipide compound represented by structural Formula I may be isolated by the combination of one or more steps of quenching the reaction mixture with hydrochloride acid, stirring, filtering precipitation, washing, drying or combination thereof.
In the following examples, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of α-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester compound represented by structural formula II.
A solution of diethyl benzamidomalonate compound represented by structural formula VI (34.5 gm) in dimethyl formamide (250 ml) was added sodium hydroxide (5 gm). The 4-bromomethyl-1H-quinolin-2-one compound represented by structural formula VII (25 gm) was added into the reaction mixture and heated at 135-150°C for 8-10 hours. The reaction mixture is cooled and quenched with water (100 ml). The precipitate obtained was filtered, washed with water (2X25 ml) and dried to get α-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester compound represented by structural formula II, Yield: 37.6 gm (90%).
Example: 2. Preparation of α-[(4-Chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester compound represented by structural formula II.
A solution of diethyl benzamidomalonate compound represented by structural formula VI (14 gm) in dimethyl formamide (100 ml) was added sodium hydroxide (2.2 gm). The 4-bromomethyl-lH-quinolin-2-one compound represented by structural formula VII (10 gm) was added into the reaction mixture and added sodium chloride (2.46 gm) resulting reaction mixture was heated at 135-150°C for 8-10 hours. The reaction mixture is cooled and quenched with water (50 ml). The precipitate obtained was filtered, washed with water (2X10 ml) and dried to get a-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester compound represented by structural formula II. Yield: 15.5 gm (92.5%).

Example 3: Preparation of 2-(4-chlorobenzoylamino)-3-[2-(lH)-quinolinon-4-yl] propionic acid compound represented by structural formula I (Rebapimide).
A solution of potassium hydroxide (1.96 gm) in water (40 ml) added n-butanol (40 ml) and a-[(4-Chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester compound represented by structural formula II (10 gm) and resulting reaction mixture was heated slowly and raised the temperature at 40°C to 120°C for 2 hour. The concentrated hydrochloric acid (4.0 ml) was added into the precooled reaction mixture. The precipitate obtained was filtered, washed with water (2X10 ml) and dried at 90-95°C for 4 hours to get 2-(4-chlorobenzoylamino)-3-[2-(lH)-quinolinon-4-yl] propionic acid compound represented by structural formula I. Yield: 7.5 gm (80.66%).
Purity: 99.8% (By HPLC)

WE CLAIM:
1. An improved process for preparation of Rebamipide compound represented by structural Formula I comprising the steps of:
a) reacting compound represented by structural formula VI with 4-(bromomethyl)-lH-quinolin-2-one compound represented by structural formula VII to obtain compound represented by structural formula II.

b) hydrolyzing the compound represented by structural formula II in presence of alkali base to followed by acidification to obtain compound Rebamipide represented by structural formula I.


2. An improved process for preparation of Rebamipide compound represented by structural formula I by using compound a-[(4-chlorobenzoyl)amino]-l,2-dihydro-2-oxo-4-quinoline propionic acid ethyl ester represented by structural formula II.

3. The process as claimed in claim 1, wherein the inorganic base used in step a) is selected from the group comprising of sodium hydroxide, potassium hydroxide or lithium hydroxide.
4. The process as claimed in claim 1, wherein the solvent used in step a) is selected from the group comprising of dimethylformamide, dimethylsulfoxide or tetrahydrofuran, alcoholic solvent or mixture(s) thereof.
5. The process as claimed in claim 1, wherein the reaction of compound represented by structural formula VI with 4-(bromomethyl)-1H-quinolin-2-one compound represented by structural formula VII is carried out at a temperature in the range of 25°C to 150°C for a period of 1 hours to 10 hours.
6. The process as claimed in claim 1, wherein hydrolysis of compound represented by structural formula II is carried out in the presence of inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium bicarbonate or sodium bicarbonate of mixture(s) thereof.
7. The process as claimed in claim 1, wherein hydrolysis of compound represented by structural formula II is carried out in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butyl alcohol or mixture(s) thereof.

8. A process as claimed in claim 1, wherein hydrolysis of compound represented by structural formula II is carried out at a temperature in the range of 40°C to 65°C for a period of 30 minutes to 4 hours.
9. A process as claimed in claim 1, wherein acidification of compound is carried out in the presence of acid such as hydrochloric acid, Sulphuric acid, acetic acid or mixture(s) thereof.