DESC:Field Of The Invention
The present invention relates to a novel process for the preparation of Brivaracetam having the structural formula (I).

The present invention also relates to a novel compound of formula (IV).

wherein X is a halogen and R is alkyl, cycloalkyl, alkoxy, aryloxy, aryl or alkylaryl.

The present invention also relates to process for the preparation of compound of Formula (IV) and its use in the preparation of Brivaracetam of formula (I).

Back Ground Of The Invention
Brivaracetam is a chemical analog of Levetiracetam, marketed under the brand name of BRIVIACT for the adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. Brivaracetam is considered as one of the most promising third generation anti-epileptic drugs due to its improved safety profile and possibility to be used for wider range of epilepsy.

Brivaracetam is a diastereomer and chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide and is represented by general Formula I.

Brivaracetam and process for its preparation is first disclosed in US 6911461 B2. The reported process utilizes preparative HPLC for chiral resolution of isomers which makes it difficult for bulk manufacturing as well as it effects the overall yield making the process uneconomical.

Various synthetic routes for Brivaracetam were disclosed in the prior art references US 7122682, US 7629474, US 8076493, US 8338621, US 8957226, CN 106748748 A, CN 108503573 A WO 2016191435 A1 and IN 201641030239. The reported processes for the preparation of Brivaracetam suffer from many disadvantages which includes difficulty in achieving desired chiral purity, tedious and cumbersome work up procedures, multiple crystallizations or isolation steps, column chromatographic separations and purifications etc. All these disadvantages effect the overall yield as well as the quality of the final product.

In view of all these disadvantages, there is a significant need to develop a cost effective, commercially viable process for the preparation of highly pure Brivaracetam with good yield.

Summary Of The Invention
The present invention provides a cost effective, novel and an efficient process for the preparation of Brivaracetam with higher yields and purity.

In one aspect, the present invention provides a process for the preparation of Brivaracetam compound of formula-I.

which comprises:
a) ring opening of compound of formula-II

with halogenating agent to obtain compound of formula-III;

wherein X is a halogen;
b) acylating the compound of formula-III with an acylating agent in a solvent in the presence of base to give compound of formula-IV;

wherein X is as defined above and R is alkyl, cycloalkyl, alkoxy, aryloxy, aryl or alkylaryl.
c) condensation of compound of formula-IV with amide derivative of formula-V or its salt

in a solvent in the presence of a base and to obtain compound of formula-VI;

wherein X is as defined above;
d) cyclization of compound of formula-VI in a solvent in the presence of a base to obtain Brivaracetam of formula-I.

In another aspect, the present invention provides a process for the preparation of Brivaracetam compound of formula-I.

which comprises:
a) ring opening of compound of formula-II

with halogenating agent to obtain compound of formula-III;

wherein X is a halogen;
b) acylating the compound of formula-III with ethylchloroformate in a solvent in the presence of base to give compound of formula-IVa;

wherein X is as defined above;
c) condensation of compound of formula-IVa with amide derivative of formula-V or its salt

in a solvent in the presence of a base to obtain compound of formula-VI;

wherein X is as defined above;
d) cyclization of compound of formula-VI in a solvent in the presence of a base to obtain Brivaracetam of formula-I.

In yet another aspect, the present invention provides a process for the preparation of Brivaracetam compound of formula-I.

which comprises:
a) ring opening of compound of formula-II

with halogenating agent to obtain compound of formula-III;

wherein X is a halogen;
b) acylating the compound of formula-III with pivaloyl chloride in a solvent in the presence of base to give compound of formula-IVb;

wherein X is as defined above;
c) condensation of compound of formula-IVb with amide derivative of formula-V or its salt

in a solvent in the presence of a base and to obtain compound of formula-VI;

wherein X is as defined above;
d) cyclization of compound of formula-VI in a solvent in the presence of a base to obtain Brivaracetam of formula-I.

In yet another aspect the present invention provides a novel compound of formula-IV.

wherein X is a halogen and R is alkyl, cycloalkyl, alkoxy, aryloxy, aryl or alkylaryl.

In yet another aspect the present invention provides a novel intermediate compound of formula-IVc.

In yet another embodiment the present invention provides a novel intermediate compound of formula-IVd.

In yet another aspect, the present invention provides a process for the preparation of intermediate compound of formula-IVc.

which comprises:
a) ring opening of compound of formula-II

with brominating agent in a solvent to obtain compound of formula-IIIa;

b) acylating the compound of formula-IIIa with ethylchloroformate in a solvent in the presence of base to give compound of formula-IVc.

In yet another embodiment, the present invention provides a process for the preparation of intermediate compound of formula-IVd.

which comprises:
a) ring opening of compound of formula-II

with brominating agent in a solvent to obtain compound of formula-IIIa;

b) acylating the compound of formula-IIIa with pivaloyl chloride in a solvent in the presence of base to give compound of formula-IVd.

Detailed Description Of The Invention

Accordingly, the present invention provides the novel process for the preparation of Brivaracetam of compound of formula-I.

The main embodiment of the present invention provides an improved process for the preparation of Brivaracetam of formula (I) as shown in the scheme-I given below.

Scheme-I

In stage-1, the compound of formula-II is reacted with a halogenating agent followed by heating the resulting reaction mixture to reflux temperature. Stirred the resulting reaction mixture until the completion of the reaction and cooled to room temperature. The obtained crude was dissolved in an organic solvent and water. Both the aqueous and organic layers were separated. Aqueous layer was extracted with an organic solvent. Distilled off the solvent from the obtained organic layer to obtain compound of formula-III.

Halogenating agent is selected from the group consisting of thionyl bromide, boron tribromide, Hydrobromic acid in water, Hydrobromic acid in acetic acid, thionyl chloride, HCl in water, HCl in acetic acid and the like. Preferably Hydrobromic acid in acetic acid.

The reaction temperature may range from 40-65 °C and preferably at a temperature in the range from 55-55 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 7-8 hours.

Solvent used for extractions in the reaction is selected from the group consisting of chlorinated solvents such as dichloromethane; ester solvents such as ethyl acetate; aromatic organic solvents such as toluene. Preferably toluene.

In stage-2, the compound of formula-III is reacted with an acylating agent in a solvent in the presence of a base in cooling conditions and stirred the resulting reaction mixture until the completion of the reaction. The obtained reaction mass i.e, the compound of Formula IV is reacted with compound of formula-V or its salt in a solvent in the presence of a base. Stirred the reaction mixture and filtered the resulting reaction mixture. Distilled off the solvent under reduced pressure from the obtained filtrate to obtain compound of formula-V.

Acylating agent is selected from the group consisting of methyl chloroformate, ethyl chloroformate, pivaloyl chloride and the like.

The reaction temperature may range from 0-10 °C and preferably at a temperature in the range from 0-5 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 7-8 hours.

Solvent used in the reaction is selected from the group consisting of acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, dichloromethane, chlorobenzene, chloroform, toluene, xylene, benzene, ethyl acetate, methyl acetate, propyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran or the mixture of solvents thereof. Preferably, tetrahydrofuran.
Base used in the reaction is selected from the group consisting of dimethylaminopyridine, triethylamine, diisopropylethylamine, diethyl amine, ammonia and the like. Preferably triethylamine.

In stage-3, the crude obtained from stage-2 was dissolved in an organic solvent and cooled to -5 to 0ºC followed by slow addition of base to the reaction mass in the cooling conditions. Stirred the reaction mixture until the completion of the reaction and isolated Brivaracetam of formula (I).

Solvent used in the reaction is selected from the group consisting of dichloromethane, chlorobenzene, chloroform or the mixture of solvents thereof. Preferably, dichloromethane.

The reaction temperature may range from -5 to 0ºC. The duration of the reaction may range from 2-6 hours, preferably for a period of 4 hours.

Base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, caesium carbonate, caesium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and the like. Preferably potassium hydroxide.

In another embodiment the present invention provides an improved process for the preparation of Brivaracetam of formula (I) as shown in the scheme-II given below.

Scheme-II

In stage-1, the compound of formula-II is reacted with halogenating agent followed by heating the resulting reaction mixture to reflux temperature. Stirred the resulting reaction mixture until the completion of the reaction and cooled to room temperature. The obtained crude was dissolved in an organic solvent and water. Both the aqueous and organic layers were separated. Aqueous layer was extracted with an organic solvent. Distilled off the solvent from the obtained organic layer to obtain compound of formula-III.

Halogenating agent is selected from the group consisting of thionyl bromide, boron tribromide, hydrobromic acid in water, hydrobromic acid in acetic acid, thionyl chloride, HCl in water, HCl in acetic acid and the like. Preferably hydrobromic acid in acetic acid.

The reaction temperature may range from 40-65 °C and preferably at a temperature in the range from 55-55 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 7-8 hours.

Solvent used for extractions in the reaction is selected from the group consisting of chlorinated solvents such as dichloromethane; ester solvents such as ethyl acetate; aromatic organic solvents such as toluene. Preferably toluene.

In stage-2, the compound of formula-III is reacted with ethyl chloroformate in a solvent in the presence of a base in cooling conditions and stirred the resulting reaction mixture until the completion of the reaction. The obtained reaction mass i.e, the compound of formula IV-a is reacted with compound of formula-V or its salt in a solvent in the presence of a base. Stirred the reaction mixture and filtered the resulting reaction mixture. Distilled off the solvent under reduced pressure from the obtained filtrate to obtain compound of formula-VI.

The reaction temperature may range from 0-10 °C and preferably at a temperature in the range from 0-5 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 7-8 hours.

Solvent used in the reaction is selected from the group consisting of acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, dichloromethane, chlorobenzene, chloroform, toluene, xylene, benzene, ethyl acetate, methyl acetate, propyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran or the mixture of solvents thereof. Preferably, tetrahydrofuran.

Base used in the reaction is selected from the group consisting of dimethylaminopyridine, triethylamine, diisopropylethylamine, diethyl amine, ammonia and the like. Preferably triethylamine.

In stage-3, the crude obtained from stage-2 was dissolved in an organic solvent and cooled to -5 to 0 ºC followed by slow addition of base to the reaction mass in the cooling conditions. Stirred the reaction mixture until the completion of the reaction and isolated Brivaracetam of formula (I).

Solvent used in the reaction is selected from the group consisting of dichloromethane, chlorobenzene, chloroform or the mixture of solvents thereof. Preferably, dichloromethane.

The reaction temperature may range from -5 to 0 ºC. The duration of the reaction may range from 2-6 hours, preferably for a period of 4 hours.

Base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, caesium carbonate, caesium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and the like. Preferably potassium hydroxide.

In yet another embodiment the present invention provides an another improved process for the preparation of Brivaracetam of formula (I) as shown in the scheme-III given below:

Scheme-III
In stage-1, the compound of formula-II is reacted with halogenating agent followed by heating the resulting reaction mixture to reflux temperature. Stirred the resulting reaction mixture until the completion of the reaction and cooled to room temperature. The obtained crude was dissolved in an organic solvent and water. Both the aqueous and organic layers were separated. Aqueous layer was extracted with an organic solvent. Distilled off the solvent from the obtained organic layer to obtain compound of formula-III.

Halogenating agent is selected from the group consisting of thionyl bromide, boron tribromide, hydrobromic acid in water, hydrobromic acid in acetic acid, thionyl chloride, HCl in water, HCl in acetic acid and the like. Preferably hydrobromic acid in acetic acid.

The reaction temperature may range from 40-65 °C and preferably at a temperature in the range from 55-55 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 7-8 hours.

Solvent used for extractions in the reaction is selected from the group consisting of chlorinated solvents such as dichloromethane; ester solvents such as ethyl acetate; aromatic organic solvents such as toluene. Preferably toluene.

In stage-2, the compound of formula-III is reacted with pivaloyl chloride in a solvent in the presence of a base in cooling conditions and stirred the resulting reaction mixture until the completion of the reaction. The obtained reaction mass i.e, the compound of formula IV-b is reacted with compound of formula-V or its salt in a solvent in the presence of a base. Stirred the reaction mixture and filtered the resulting reaction mixture. Distilled off the solvent under reduced pressure from the obtained filtrate to obtain compound of formula-VI.

The reaction temperature may range from 0-10 °C and preferably at a temperature in the range from 0-5 °C. The duration of the reaction may range from 5-10 hours, preferably for a period of 7-8 hours.

Solvent used in the reaction is selected from the group consisting of acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, dichloromethane, chlorobenzene, chloroform, toluene, xylene, benzene, ethyl acetate, methyl acetate, propyl acetate, diethyl ether, tert-butyl methyl ether, tetrahydrofuran or the mixture of solvents thereof. Preferably, tetrahydrofuran.

Base used in the reaction is selected from the group consisting of dimethylaminopyridine, triethylamine, diisopropylethylamine, diethyl amine, ammonia and the like. Preferably triethylamine.

In stage-3, the crude obtained from stage-2 was dissolved in an organic solvent and cooled to -5 to 0ºC followed by slow addition of base to the reaction mass in the cooling conditions. Stirred the reaction mixture until the completion of the reaction and isolated Brivaracetam of formula (I).

Solvent used in the reaction is selected from the group consisting of dichloromethane, chlorobenzene, chloroform or the mixture of solvents thereof. Preferably, dichloromethane.

The reaction temperature may range from -5 to 0ºC. The duration of the reaction may range from 2-6 hours, preferably for a period of 4 hours.

Base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, caesium carbonate, caesium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and the like. Preferably potassium hydroxide.

In yet another preferred embodiment, the present invention provides a novel compound of formula-IV.

wherein X is selected from chloro, fluoro, bromo and iodo; R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, benzoxy, cyclopropyl, cyclobutyl, cycloheptyl, phenyl, naphthyl, tosyl, benzyl and the like.

In yet another preferred embodiment, the present invention provides a novel compound of formula-IVc.

In yet another preferred embodiment the present invention provides a novel compound of formula-IVd.

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 Brivaracetam
Stage-1: Synthesis of (R)-3-(bromomethyl)hexanoic acid (III)
To a mixture of (R)-Dihydro-4-propyl-2(3H)-furanone (II) (1 weight) and acetic acid (1.0 volumes) was added hydrobromic acid in acetic acid (2.5 volumes) at room temperature and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to 50-55 ºC temperature and stirred for 8 hours at the same temperature. The obtained reaction mass was cooled to room temperature and toluene (5 volumes) was added. Water (1 volumes) was added and stirred the biphasic reaction mass. The layers were separated and aqueous layer was extracted with toluene (2.0 volumes). The combined organic layers were washed with water (2.0 volumes), brine solution, separated and distilled under reduced pressure to get Stage-1 compound.
Yield: (80%).

Stage-2: Synthesis of (R)-3-bromomethyl-hexanoic acid-[(S)-1-carbamoyl-propyl]-amide (VI)
A mixture of Stage-1 compound (1.0 equivalents), triethylamine (1.5 equivalents) and tetrahydrofuran (10.0 volumes) were cooled to 0 °C. Ethyl chloroformate (1.1 equivalents) was added slowly to the reaction mass and stirred for 2 hours at the same temperature. The reaction mass thus obtained was added to a mixture of (S)-2-aminobutyramide hydrochloride (1.1 equivalents) in tetrahydrofuran (10.0 volumes) and triethylamine (1.1 equivalents) at 0-5 ºC and stirred for 8 hours at 25-30 ºC. Filtered the reaction mass through celite bed and concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (5.0 volumes) and washed with water, brine solution. The organic volatiles were distilled under reduced pressure to get Stage-2 compound.
Yield: (70%).

Stage-3: Synthesis of Brivaracetam
Mixture of Stage-2 compound (1.0 equivalent), sodium sulphate (2.0 equivalents) and dichloromethane (10.0 v) was cooled to -5-0 °C, potassium hydroxide (1.5 equivalents) was added slowly and stirred for 4 hours at -5-0 ºC. After completion of the reaction, the reaction mass was filtered through celite bed and concentrated. The residue obtained was recrystallized in diisopropyl ether (5.0 volumes), the obtained organic layer was washed with water, brine solution. The organic volatiles were distilled under reduced pressure to get Stage-3 compound.
Yield: (70%).

Example-2: Process for the preparation of Brivaracetam
Stage-1: Synthesis of (R)-3-(bromomethyl)hexanoic acid (III)
To a mixture of (R)-Dihydro-4-propyl-2(3H)-furanone (II) (1 weight) and acetic acid (1.0 volumes) was added hydrobromic acid in acetic acid (2.5 volumes) at room temperature and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to 50-55 ºC temperature and stirred for 8 hours at the same temperature. The obtained reaction mass was cooled to room temperature and toluene (5 volumes) was added. Water (1 volumes) was added and stirred the biphasic reaction mass. The layers were separated and aqueous layer was extracted with toluene (2.0 volumes). The combined organic layers were washed with water (2.0 volumes), brine solution, separated and distilled under reduced pressure to get Stage-1 compound.
Yield: (80%).

Stage-2: Synthesis of (R)-3-bromomethyl-hexanoic acid-[(S)-1-carbamoyl-propyl]-amide (VI)
A mixture of Stage-1 compound (1.0 equivalent), triethylamine (1.5 equivalents) and tetrahydrofuran (10.0 volumes) were cooled to 0 °C. Pivaloyl chloride (1.1 equivalents) was added slowly to the reaction mass and stirred for 2 hours at the same temperature. The reaction mass thus obtained was added to a mixture of (S)-2-aminobutyramide hydrochloride (1.1 equivalents) in tetrahydrofuran (10.0 volumes) and triethylamine (1.2 equivalents) at 0-5 ºC and stirred for 8 hours at 25-30 ºC. Filtered the reaction mass through celite bed and concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (5.0 volumes) and washed with water, brine solution. The organic volatiles were distilled under reduced pressure to get Stage-2 compound.
Yield: (70%).

Stage-3: Synthesis of Brivaracetam
Mixture of Stage-2 compound (1.0 equivalents), sodium sulphate (2.0 equivalents) and dichloromethane (10.0 volumes) was cooled to -5-0 °C, potassium hydroxide (1.5 equivalents) was added slowly and stirred for 4 hours at -5-0 ºC. After completion of the reaction, the reaction mass was filtered through celite bed and concentrated. The residue obtained was recrystallized in diisopropyl ether (5.0 volumes), the obtained organic layer was washed with water, brine solution. The organic volatiles were distilled under reduced pressure to get Stage-3 compound.
Yield: (70%).
,CLAIMS:

1. Novel compound of formula-IV

wherein X is a halogen and R is alkyl, cycloalkyl, alkoxy, aryloxy, aryl or alkyl aryl.

2. Novel compound of formula-IVc

3. Novel intermediate compound of formula-IVd

4. A process for the preparation of Brivaracetam compound of formula-I.

which comprises:
a) ring opening of compound of formula-II

with halogenating agent to obtain compound of formula-III;

wherein X is a halogen;
b) acylating the compound of formula-III with an acylating agent in a solvent in the presence of base to give compound of formula-IV;

wherein X is as defined above and R is alkyl, cycloalkyl, alkoxy, aryloxy, aryl or alkyl aryl.
c) condensation of compound of formula-IV with amide derivative of formula-V or its salt

in a solvent in the presence of a base and to obtain compound of formula-VI;

wherein X is as defined above;
d) cyclization of compound of formula-VI in a solvent in the presence of a base to obtain Brivaracetam of formula-I.

5. A process for the preparation of Brivaracetam compound of formula-I.

which comprises:
a) ring opening of compound of formula-II

with halogenating agent in a solvent to obtain compound of formula-III;

wherein X is a halogen;
b) acylating the compound of formula-III with ethyl chloroformate in a solvent in the presence of base to give compound of formula-IVa;

wherein X is as defined above;
c) condensation of compound of formula-IVa with amide derivative of formula-V or its salt

in a solvent in the presence of a base to obtain compound of formula-VI;

wherein X is as defined above;
d) cyclization of compound of formula-VI in a solvent in the presence of a base to obtain Brivaracetam of formula-I.

6. A process for the preparation of Brivaracetam compound of formula-I.

which comprises:
a) ring opening of compound of formula-II

with halogenating agent in a solvent to obtain compound of formula-III;

wherein X is a halogen;
b) acylating the compound of formula-III with pivaloyl chloride in a solvent in the presence of base to give compound of formula-IVb;

wherein X is as defined above;
c) condensation of compound of formula-IVb with amide derivative of formula-V or its salt

in a solvent in the presence of a base and to obtain compound of formula-VI;

wherein X is as defined above;
d) cyclization of compound of formula-VI in a solvent in the presence of a base to obtain Brivaracetam of formula-I.

7. A process for the preparation of intermediate compound of formula-IVc

which comprises:
a) ring opening of compound of formula-II

with brominating agent in a solvent to obtain compound of formula-IIIa;

b) acylating the compound of formula-IIIa with ethylchloroformate in a solvent in the presence of base to give compound of formula-IVc.

8. A process for the preparation of intermediate compound of formula-IVd

which comprises:
a) ring opening of compound of formula-II

with brominating agent in a solvent to obtain compound of formula-IIIa;

b) acylating the compound of formula-IIIa with pivaloyl chloride in a solvent in the presence of base to give compound of formula-IVd.