DESC:TECHNICAL FIELD

The invention relates to an improved process for preparing Rebamipide. More particularly, the invention relates to an improved process for preparing Rebamipide with high purity and high yield. The Rebamipide is used as a medicament for treating gastric ulcer and the like.

BACKGROUND OF THE INVENTION

The chemical name of Rebamipide is 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolon-4-yl] propionic acid represented by following formula (I). It is a medicament that has a potent effect on the treatment of gastric ulcer, acute gastritis, or gastric mucosa lesion affected in acute exacerbation of chronic gastritis.

JP-A-60-19767 discloses a process for the preparation of Rebamipide which comprises reacting bromomethylcarbostyril compound of formula (II) with diethylacetamidomalonate compound of formula (III) in the presence of a base such as sodium ethoxide to give carbostyrilmalonate compound of formula (IV).The compound of formula (IV) is hydrolysed and decarboxylated in the presence of a mineral acid such as hydrochloric acid to prepare carbostyril amino acid compound of formula (V) and the resultant compound is acylated with 4-chlorobenzoyl chloride of formula (VI) to prepare the desired Rebamipide of the formula (I). This process is depicted in Scheme-1

Scheme-1

The above starting material, bromomethylcarbostyril compound of formula (II) can be prepared by brominating acetoacetanilide of formula (VII) with bromine in the presence of N-bromosuccinimide to give a compound of the formula (VIII) followed by ring-closure reaction with condensing agent such as concentrated sulphuric acid to provide the compound of formula (II). However the product (II) is associated with 6-bromocarbostyril compound of formula (IX) which is an impurity and which is formed during the bromination of acetoacetanilide. This process is depicted in Scheme-2

Scheme-2

On transforming the bromomethylcarbostyril compound of formula (II) to Rebamipide of formula (I) according to scheme-1, the above impurity present in the bromomethylcarbostyril of formula (II) i.e. 6-bromocarbostyril compound of formula (IX) is reacted in the same manner as bromomethylcarbostyril compound of formula (II) as shown in the following scheme-3, to give the corresponding 6-bromo analogue compounds of formula (X) and compound of formula (XI) and thereby the compound of formula (XII) is always associated as an impurity with the desired Rebamipide compound of formula (I). The process is depicted in Scheme-3.

Scheme-3

JP 3911008 B2 discloses the process for preparing Rebamipide of the formula (I) which comprises of performing a carbostyril amino acid compound of formula (V) or a salt thereof containing a 6-bromocarbostyril amino acid compound of formula (XI) as an impurity to a reduction treatment in the presence of hydrogen and a catalyst in a basic aqueous solution, thereby selectively converting the impurity of formula (XI) to the carbostyril amino acid compound of formula (V); and then reacting the carbostyril amino acid compound (V) with 4-chlorobenzoyl chloride in a basic aqueous solution to give Rebamipide of formula (I) as shown in scheme-4.

Scheme-4

JP 3892894 B2 discloses a process for preparing Rebamipide (I) which comprises subjecting a compound of the formula (IV) to the following step (a), or steps (a) and (b) to prepare a compound of the formula (V) and furthermore subjecting the compound of formula (V) to the step (c).
a) heating the compound of formula (IV) in the presence of normal octanol or acetophenone under acidic condition;
b) removing a material by-produced at the step (a)
c) reacting the compound of formula (V) with 4-chlorobenzoyl chloride under basic condition to obtain Rebamipide (I).

The above described process is depicted as follows in scheme-5

Scheme-5

In all the above mentioned prior-art processes it is difficult to prepare Rebamipide in high purity with high yield, since the removal of bromo impurity is really challenging, and the impurity is not completely removed by conventional purification process such as recrystallization or washing with solvent. Further the prior art process reported to remove this impurity uses flammable gas like hydrogen under pressure which is commercially not safe to operate. Hence there is a need to develop an alternate process which avoids the use of highly flammable hydrogen under pressure for the removal of the 6-bromocarbostyril compound of formula (IX) which is present in bromomethylcarbostyril compound of formula (II).

Despite this, there are unsolved drawbacks in these prior art procedures such as the use of hydrogen gas which is highly flammable as well as the use of high boiling solvents like octanol or acetophenone which is required to avoid frothing during decarboxylation. So far the most suitable on commercial scale and efficient method for removing the bromo impurity without the use of hydrogen and high boiling solvents has not yet been proposed.

Hence, it would be desirable to provide a highly effective purification method without loss of desired compound by converting the contaminated bromo impurity, which is hardly removed by a conventional purification method, into the desired compound by selective reduction in an appropriate stage and thereby the purity of the active pharmaceutical ingredient can be enhanced. Accordingly, the method of the invention might be advantageously used in the industrial process for preparing Rebamipide which is used as a medicament in which higher purity is required.

According to the method of the invention, the desired compound can be easily produced on industrial scale by easy operations without the use of hydrogen as well as high boiling solvents.

Thus the present inventors have extensively studied the effectiveness of reduction without hydrogen on the appropriate stage to remove the contaminated bromo impurity which also avoids the excess frothing during decarboxylation and found that the desired Rebamipide could be prepared with high purity and high yield.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide an improved process for preparation of Rebamipide with high yield and high purity.

Another object of the invention is to provide a method of reducing the bromo impurity in the absence of highly flammable hydrogen.
Yet another object of the invention is to provide a method of converting the undesired bromo impurity into desired product in the process for preparing Rebamipide.

Yet another object of the invention is the use of ester solvent in bromination of acetoacetanilide for reducing the bromo impurity in the initial stage of Rebamipide preparation.

A further object of the invention is to provide a process for the preparation of Rebamipide by avoiding the use of high boiling solvents like octanol and acetophenone.

SUMMARY OF THE INVENTION

Accordingly, in one aspect the invention provides an improved process for the preparation of pure Rebamipide compound of formula (I)

which comprises the steps of:
a) subjecting carbostyrildiacid or its ester or its salts compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa) in the absence of hydrogen to reduction treatment in the presence of catalyst in basic aqueous solution there by selectively converting the bromo impurity (IVa) to transform into carbostyrildiacid compound of formula (IV) or its ester or its salts

wherein R1 represent Hydrogen, lower alkyl selected from methyl, ethyl, and propyl, the alkali salts of the compound of formula-IV are selected from lithium, sodium, and potassium;
b) converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V);

c) converting the carbostyril amino acid compound of formula (V) into Rebamipide of formula (I) by conventional method.

In another aspect the invention provides an improved process for the preparation of amino acid compound of formula (V)

which comprises the steps of:
(a) subjecting carbostyrildiacid or its ester or its salts compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa) in the absence of hydrogen to reduction treatment in the presence of catalyst in basic aqueous solution there by selectively converting the bromo impurity (IVa) to transform into carbostyrildiacid compound of formula (IV) or its ester or its salts

wherein R1 represent Hydrogen, lower alkyl selected from methyl, ethyl, and propyl, the alkali salts of the compound of formula-IV are selected from lithium, sodium, and potassium;

(b) converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V)
.

In another aspect, the invention provides an improved process for the preparation of bromo compound of formula (VIII)

which comprises the step of:
brominating acetoacetanilide with conventional reagent in ester solvent selected from methyl acetate, ethyl acetate and isopropyl acetate.

This bromo compound of formula (VIII) is employed for the process for the preparing of Rebmipide (I).

DETAILED DESCRIPTION OF THE INVENTION

The first embodiment of the present invention relates to a process for the preparation of Rebamipide (I) which comprises following steps:

a) subjecting carbostyrildiacid or its ester or its salt compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa) in the absence of hydrogen to reduction treatment in the presence of catalyst in basic aqueous solution there by selectively converting the bromo impurity (IVa) into carbostyrildiacid compound of formula (IV) or its ester or its salts

wherein R1 represent Hydrogen, lower alkyl selected from methyl, ethyl, and propyl, the alkali salts of the compound of formula-IV are selected from lithium, sodium, and potassium;
b) converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V);

c) converting the carbostyril amino acid compound of formula (V) into Rebamipide of formula (I) by conventional method.
The method of the invention is shown in the following scheme-6

Scheme-6

The catalyst employed in the step-(a) of the process for the preparation of Rebamipide (I) is selected from the group comprising palladium catalyst and nickel catalysts, preferably Raney nickel.

The base employed in the step-(a) of the process for the preparation of Rebamipide (I) is selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, preferably sodium hydroxide.

The second embodiment of the present invention relates to an improved process for the preparation of amino acid compound of formula (V)

which comprises:
a). subjecting carbostyrildiacid or its ester or its salts compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa) in the absence of hydrogen to reduction treatment in the presence of catalyst in basic aqueous solution there by selectively converting the bromo impurity (IVa) into carbostyrildiacid and/or its ester and/or its salts compound of formula (IV)

wherein R1 represent Hydrogen, lower alkyl selected from methyl, ethyl, and propyl, the alkali salts of the compound of formula-IV are selected from lithium, sodium, and potassium;

b).converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V)
.

The inventors of the present invention performed many experiments for removal of bromo impurity at different stages with and without the use of hydrogen at different reaction conditions. It was found that carbostyrildiacid or its ester or its salts compound of formula (IV) containing the 6-bromo carbostyrilanalog compound of formula (IVa) in the absence of hydrogen to reduction treatment in the presence of catalyst in basic aqueous solution selectively converts the bromo impurity to carbostyrildiacid effectively. The carbostyrildiacid or its ester or its salts compound of formula (IV) may be employed for the preparation of Rebamipide.

Table-1: Comparison of Prior art process & the Present invention process

Process Hydrogen source % of Bromo impurity
Prior art process
IN 4286/DELNP/2006
(US 7,718,805)
Example-1 2 atm of hydrogen Not detected
No hydrogen pressure 0.17%
Present invention process No hydrogen pressure Not detected

The third embodiment of the invention provides a process for the preparation of compound of formula (IV) which comprises of the following steps of:
a) brominating acetoacetanilide in ester solvent to obtain 4-bromo-3-oxo-N-phenyl-butyramide of formula VIII;

b) cyclizing the compound of formula VIII obtained in step (a) compound by conventional method to obtain 4-Bromomethyl-1H-quinolin-2-one of formula II with an impurity of the compound of formula IX;
c) optionally reacting compounds resulted in step (b) with diethylacetamidomalonate to obtain diester intermediates of formula (IV).

The disaster intermediate of formula IV may be used in the process for preparing Rebamipide (I).

The method of the invention as described in the third embodiment is shown in the following scheme-7

Scheme-7

R1depicted in the aforementioned scheme is selected from hydrogen, lower alkyl selected from methyl, ethyl, and propyl.

The ester solvent employed in step (a) for the process for the preparation of compound of formula (IV) is selected from the group comprising ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate, propyl acetate and the likes preferably ethyl acetate and isopropyl acetate.

The inventors of the present invention unexpectedly found that ester solvent employed in step (a) for the process for the preparation of compound of formula (IV)bromo compound of formula (VIII) results in precipitation or crystallization of the compound of formula-VIII thereby avoiding the usual workup to isolate the product.

The present invention is described by the following examples, which are for illustrative purpose only and should not be construed so as to limit the scope of the invention in any manner.

Example -1: Preparation of 4-Bromo-3-oxo-N-phenyl-butyramide (Formula VII)
Method-A: To a solution of acetoacetanilide (200 g) in ethyl acetate, was added dropwise 190g of Bromine in ethyl acetate and stirred at room temperature for 4 hours. Excess bromine was quenched by the addition of aqueous sodium bisulphite solution. The precipitated product was filtered off and washed with water followed by ethyl acetate. Drying the product under vacuum afforded, 4-Bromo-3-oxo-N-phenyl-butyramide. (Yield: 80%, purity by HPLC: 96%)

Method-B: To a solution of acetoacetanilide (200 g) in isopropyl acetate, was added dropwise190g of Bromine in isopropyl acetate and stirred at room temperature for 4 hours. Excess bromine was quenched by the addition of aqueous sodium bisulphite solution. The precipitated product was filtered off and washed with water followed by ethyl acetate. Drying the product under vacuum afforded, 4-Bromo-3-oxo-N-phenyl-butyramide. (Yield: 85%, purity by HPLC: 96%)

Method-C: To a solution of acetoacetanilide (200 g) in butyl acetate, was added dropwise190g of Bromine in butyl acetate and stirred at room temperature for 4 hours. Excess bromine was quenched by the addition of aqueous sodium bisulphite solution. The precipitated product was filtered off and washed with water followed by ethyl acetate. Drying the product under vacuum afforded, 4-Bromo-3-oxo-N-phenyl-butyramide. (Yield: 82%, purity by HPLC: 96%)

Example -2: Preparation of 4-Bromomethyl-1H-quinolin-2-one (Formula II)
To a solution of 200 g of 4-Bromo-3-oxo-N-phenyl-butyramide in 600 ml of concentrated sulfuric acid was heated under stirring for 1 hour at 80°C. The reaction mass was diluted with DM water and stirred at room temperature for additional 1 hour. The precipitated product was filtered and washed with water followed by methanol. The product was dried under vacuum to afford 4-Bromomethyl-1H-quinolin-2-one. (Yield: 90%, purity by HPLC: 96%)

Example -3: Preparation of Acetylamino-2-(2-oxo-1,2-Dihydro-Quinolin-4-yl methyl)-malonic acid dimethyl ester (Formula IV)
To a solution of 9.375g of sodium in 625 ml of methanol, was added 125g of diethylacetamidomalonate and heated the reaction mass at 40-45°C for 1 hour under nitrogen atmosphere. 125 g of 4-Bromomethyl-1H-quinolin-2-one was added at 40-45°C under nitrogen atmosphere. The reaction mass was heated and stirred for 1 hour at about 65-70°C under nitrogen atmosphere. The reaction mass was cooled and neutralized with acetic acid. Excess of methanol was removed under vacuum at 50±2°C and diluted with water. The precipitated product was filtered under vacuum and washed with water followed by ethanol. The product was dried under vacuum to afford Acetylamino-2-(2-oxo-1,2-Dihydro-Quinolin-4-yl methyl)-malonic acid dimethyl ester (Yield: 75%, purity by HPLC: 96%)

Example -4: Preparation of 2-Amino-3-(2-oxo-1,2-Dihydro-quinolin-4-yl)-propionic acid hydrochloride dihydrate (Formula V)
To a solution of sodium hydroxide in water were added Acetylamino-2-(2-oxo-1,2-Dihydro-Quinolin-4-yl methyl)-malonic acid alkyl ester intermediate and Raney nickel. The reaction mass was stirred at 40-60 °C. The reaction mass was filtered and to the clear filtrate concentrated hydrochloric acid was added and stirred at room temperature. The reaction mass was heated and stirred at about 80±90°C.The temperature was raised slowly and stirred at about 100±2°C. After completion of the reaction, cooled and stirred to crystallize the product. The product was filtered and washed with water followed by acetone. The product was dried under vacuum to afford 2-Amino-3-(2-oxo-1,2-Dihydro-quinolin-4-yl)-propionic acid hydrochloride dihydrate.(Yield: 90%, purity by HPLC: 99%)

Example -5: Preparation of Rebamipide (Formula I)
To a solution of sodium hydroxide in water was added 2-Amino-3-(2-oxo-1,2-Dihydro-quinolin-4-yl)-propionic acid hydrochloride dihydrate and cooled. To the reaction mass was added4-chloro benzoyl chloride at 0-5°C. The reaction mass was stirred for reaction completion. The reaction mass pH was adjusted to acidic by using 5% HCl. The precipitated product was filtered and washed with water followed by slurry washed with acetone and methanol. Drying the solid under vacuum at about 60°C to give crude Rebamipide compound of formula I. (Yield: 90%, purity by HPLC: 99%)

Example -6: Purification of Rebamipide (Formula I)
To a solution of 11.56 g of sodium hydroxide in 595 ml of methanol, was added 85 g of crude Rebamipide, and stirred at room temperature. The product was filtered and slurry washed with methanol. This solid was suspended on 1:1 mixture of water and methanol was heated at about 65-70°C to form a clear solution. The clear solution was filtered at hot condition. To the clear filtrate was 42.5 g of acetic acid at 60-65 °C drop by drop and stirred at room temperature. The product was filtered and washed with water followed by slurry washed with methanol. Drying the solid under vacuum at about 60-65°C for afforded pure Rebamipide compound of formula I. (Yield: 90%, purity by HPLC: 99%)

,CLAIMS:We Claim
1. An improved process for the preparation of Rebamipide compound of formula (I)

comprising the steps of:
a) subjecting carbostyrildiacid and/or its ester and/or its salts compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa), in the absence of hydrogen, to reduction treatment in the presence of catalyst in basic aqueous solution, there by selectively converting the bromo impurity (IVa) into carbostyrildiacid and/or its ester and/or its salts compound of formula (IV)

wherein R1 represent Hydrogen, lower alkyl selected from methyl, ethyl, and propyl, alkali metals selected from lithium, sodium, and potassium;
b) converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V);

c) converting the carbostyril amino acid compound of formula (V) into Rebamipide of formula (I).

2. A process as claimed in claim 1, wherein said catalyst employed in the step-(a) is selected from palladium catalyst and nickel catalyst, preferably Raney nickel.

3. A process as claimed in claim 1, wherein said base employed in the step-(a) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, preferably sodium hydroxide.

4. An improved process for the preparation of amino acid compound of formula (V)

comprising the steps of:
a). subjecting carbostyrildiacid and/or its ester and/or its salts compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa), in the absence of hydrogen, to reduction treatment, in the presence of catalyst in basic aqueous solution, there by selectively converting the bromo impurity(IVa) into carbostyrildiacid and/or its ester and/or its salts compound of formula (IV)

wherein R1 represent Hydrogen, lower alkyl selected from methyl, ethyl, and propyl, alkali metals selected from lithium, sodium, and potassium;
b). converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V).

5. An improved process for the preparation of amino acid compound of formula (V)

comprising the steps of:
a). subjecting carbostyrildiacid or its salts compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa), in the absence of hydrogen, to reduction treatment, in the presence of catalyst in basic aqueous solution there by selectively converting the bromo impurity (IVa) into carbostyrildiacid or its salts compound of formula (IV)

wherein R1 represent Hydrogen, alkali metals selected from lithium, sodium, and potassium;
b). converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V).

6. An improved process for the preparation of amino acid compound of formula (V)

comprising the steps of:
a). subjecting carbostyrildiacid sodium salt compound of formula (IV) containing 6-bromo carbostyril analog compound of formula (IVa), in the absence of hydrogen, to reduction treatment, in the presence of catalyst in basic aqueous solution there by selectively converting the bromo impurity (IVa) into carbostyrildiacid sodium salt compound of formula (IV)

wherein R1 represent sodium;
b). converting the product obtained in stage (a) to carbostyril amino acid compound of formula (V).

7. An improved process for the preparation of bromo compound of formula (VIII)

comprising the steps of:
a). brominating acetoacetanilide with brominating reagent in ester solvent selected from methyl acetate, ethyl acetate and isopropyl acetate;

b) optionally converting the product obtained in step (a) into Rebamipide (I).