DESC:Field of The Invention
The present invention relates to an improved process for the preparation of Brivaracetam having the structural 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 like US 7122682, US 7629474, US 8076493, US 8338621, US 8957226, 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 embodiment, 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 thionyl chloride in methanol to obtain compound of formula-III;

b) condensation of compound of formula-III with amide derivative of formula-IV

in presence of a base and optionally a phase transfer catalyst to obtain compound of formula-V;

c) cyclization of compound of formula-V in an organic solvent to obtain Brivaracetam of formula-I.

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

which comprises:
a) condensation of compound of formula-II

with ester derivative of compound of formula-VI

to obtain compound of formula-IX;

b) protection of compound of formula-IX with a hydroxy protecting agent in the presence of base to obtain compound of formula-X;

c) cyclization of compound of formula-X in an organic solvent to obtain compound of formula-VIII;

d) aminolysis of compound of formula-VIII with an aminating agent to obtain Brivaracetam of formula-I.

In yet another embodiment, 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 thionyl chloride in methanol to obtain compound of formula-III;

b) condensation of compound of formula-III with a compound of formula-XV

in a presence of a base and a catalyst to obtain compound of formula-XVI;

c) reduction followed by cyclization of compound of formula-XVI in the presence of reducing agent and solvent to obtain Brivaracetam of formula-I.

In yet another embodiment, 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 thionyl chloride in methanol to obtain compound of formula-III;

b) condensation of compound of formula-III with a compound of formula-XV

in a presence of a base and a catalyst to obtain compound of formula-XVI;

c) reduction of compound of formula-XVI in the presence of reducing agent and a solvent to obtain compound of Formula XVII.

d) cyclization of compound of formula-XVII in an organic solvent to obtain Brivaracetam of formula-I.

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 step-1, the compound of formula-II is reacted with thionyl chloride in the presence of methanol followed by heating the resulting reaction mixture to reflux temperature. Stirred the resulting reaction mixture and evaporated the solvent from the reaction mixture. The obtained crude was dissolved in water and basified the resulting reaction mixture with aqueous sodium bicarbonate solution. 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.

The reaction temperature may range from 40-65°C and preferably at a temperature in the range from 55-65°C. The duration of the reaction may range from 12-18 hours, preferably for a period of 14-16 hours.

The amount of thionyl chloride used in the reaction may be in the range of 1.0 to 3.0 molar equivalents and preferably 1.6 to 2.2 molar equivalents.

Solvent used for extractions in the reaction is selected from chlorinated solvents such as dichloromethane; ester solvents such as ethyl acetate; aromatic organic solvents such as toluene. Preferably dichloromethane.
In step-2, the compound of formula-III is condensed with compound of formula-IV in the presence of a base, organic solvent and a phase transfer catalyst or optionally nucleophilic agent. 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.

The reaction temperature may range from 75-95°C and preferably at a temperature in the range from 80-90°C. The duration of the reaction may range from 20-30 hours, preferably for a period of 22-26 hours.

The phase transfer catalyst used in the reaction is selected from tetra-N-butyl ammonium bromide and tetra-N-butyl ammonium iodide. Preferably, tetra-N-butyl ammonium iodide.
The nucleophic agent used in the reaction is selected from sodium iodide, sodium methoxide, preferably using sodium iodide.

The amount of tetra-N-butyl ammonium iodide used in the reaction may be in the range of 0.1 to 1.0 molar equivalents and preferably 0.2 to 0.4 molar equivalents.

Solvent used in the reaction is selected from ester solvents such as ethyl acetate and isopropyl acetate. Preferably, isopropyl acetate.

Base used in the reaction is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate. Preferably, sodium carbonate.

The amount of sodium carbonate used in the reaction may be in the range of 1.0 to 3.0 molar equivalents and preferably 1.5 to 2.0 molar equivalents.

The crude obtained from step-2 was dissolved in toluene and heated to reflux temperature. Stirred the reaction mixture and evaporated the solvent from the resulting reaction mixture. The obtained reaction mixture was dissolved in ethyl acetate. Unwanted solid was separated by filtration and volatiles were evaporated from the obtained filtrate to get pure Brivaracetam.

The reaction temperature may range from 90-120°C and preferably at a temperature in the range from 100-110°C. The duration of the reaction may range from 20-30 hours, preferably for a period of 22-26 hours.

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 step-1, the compound of formula-II is condensed with compound of formula-VI and the resulting reaction mixture was heated. The reaction mixture was stirred for a period of time. After consumption of starting material, base and dichloromethane were added to the resulting reaction mixture. Hydroxy protecting agent was added to the reaction mixture followed by washing with aqueous sodium bicarbonate solution. Volatiles were removed under reduced pressure to obtain compound of formula-VIII.

The reaction temperature may range from 140-170°C and preferably at a temperature in the range from 160-165°C. The duration of the reaction may range from 30-60 hours, preferably for a period of 45-48 hours.
Base used in the reaction is selected from an organic base such as triethyl amine, diisopropyl amine, pyridine, N-methyl pyrrolidone, 4-dimethyl amino pyridine or inorganic base such as alkali metal hydroxides and alkali metal carbonates. Preferably triethyl amine.

The amount of triethylamine used in the reaction may be in the range of 2.0 to 4.0 molar equivalents and preferably 2.5 to 3.0 molar equivalents.

The hydroxy protecting group used in the reaction is selected from para toluene sulfonyl, benzyloxy carbonyl, methoxy carbonyl and tert-butoxy carbonyl. Preferably tosyl group.

The amount of tosyl chloride used in the reaction may be in the range of 0.5 to 2 molar equivalents and preferably 1 to 1.2 molar equivalents.

In step-2, the compound of formula-VIII is treated with an ammonia source in an organic solvent followed by removal of volatiles under reduced pressure and finally recrystallization to get pure Brivaracetam.

The reaction temperature may range from 15-30°C and preferably at a temperature in the range from 18-22°C.

Ammonia source used in the reaction is selected from ammonia gas, ammonium hydroxide and ammonium chloride. Preferably, ammonia gas.

Solvent used in the reaction is selected from ester solvents, chloro solvents, alcohol solvents. Preferably, methanol.

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 step-1, the compound of formula-II is reacted with thionyl chloride in the presence of methanol followed by heating the resulting reaction mixture to reflux temperature. Stirred the resulting reaction mixture and evaporated the solvent from the reaction mixture. The obtained crude was dissolved in water and basified the resulting reaction mixture with aqueous sodium bicarbonate solution. 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.

Solvent used in the reaction is selected from ester solvents, chloro solvents, alcohol solvents, polar solvents, hydrocarbon solvents, nitrile solvents, ether solvents. Preferably using dichloromethane.

The reaction temperature may range from 40-65°C and preferably at a temperature in the range from 55-65°C. The duration of the reaction may range from 12-18 hours, preferably for a period of 14-15 hours. The amount of thionyl chloride used in the reaction may be in the range of 1.0 to 3.0 molar equivalents and preferably 1.6 to 2.2 molar equivalents.

In step-2, compound of formula-III is condensed with compound of formula-XV in presence of phase transfer catalyst optionally nucleophilic reagent to obtain compound of formula-XVI.

The reaction temperature may range from 70-95°C and preferably at a temperature in the range from 75-85°C. The duration of the reaction may range from 15-30 hours, preferably for a period of 20-24 hours.

The phase transfer catalyst used in the reaction is selected from tetra-N-butyl ammonium bromide and tetra-N-butyl ammonium iodide. Preferably, tetra-N-butyl ammonium iodide.

The nucleophic agent used in the reaction is selected from sodium iodide, sodium methoxide, preferably using sodium iodide.

The amount of tetra-N-butyl ammonium iodide used in the reaction may be in the range of 0.1 to 1.0 molar equivalents and preferably 0.2 to 0.4 molar equivalents.

The nucleophic agent used in the reaction is selected from sodium iodide, sodium methoxide, preferably sodium iodide.

The amount of sodium iodide used in the reaction may be in the range of 0.1 to molar equivalents and preferably 0.1 to 0.5 molar equivalents.

In step-3, compound of formula-XVI is reduced to compound of formula-XVIII using a reducing agent in an organic solvent. The resulting compound of formula-XVIII is cyclized in presence of an organic solvent to obtain Brivaracetam.

The reducing agent used in the reaction is selected from metal catalysts like palladium on carbon, raney nickel, preferably palladium on carbon.

The reaction temperature may range from 70-95°C and preferably at a temperature in the range from 75-85°C. The duration of the reaction may range from 15-30 hours, preferably for a period of 20-24 hours.

In step-4, compound of formula-XVI is reduced to compound of formula-XVIII directly using a reducing agent in an organic solvent to obtain Brivaracetam.

The reducing agent used in the reaction is selected from metal catalysts like palladium on carbon, raney nickel, preferably palladium on carbon.

The reaction temperature may range from 70-95°C and preferably at a temperature in the range from 75-85°C. The duration of the reaction may range from 15-30 hours, preferably for a period of 20-24 hours.

Solvent used for in the reaction is selected from alcoholic solvents such as methanol, ethanol and isopropanol, preferably using isopropanol.

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 methyl (3R)-3-(chloromethyl)hexanoate
To a mixture of (R)-Dihydro-4-propyl-2(3H)-furanone (1 eq.) and methanol (5.0 vol) was added thionyl chloride (2.0 eq.) drop wise at 15-20°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to reflux temperature and stirred for 14-15 hours at the same temperature. Volatiles were removed under reduced pressure. Water was added to the obtained crude and basified with aqueous sodium bicarbonate solution. Both the aqueous and organic layers were separated and aqueous layer was extracted with dichloromethane. Volatiles were removed from the organic layer under reduced pressure to get the title compound.
Yield: 85 %

Stage-2: Synthesis of methyl (3R)-3-({[(1S)-1-carbamoyl propyl] amino}methyl)hexanoate
Compound obtained in stage-1 was added to a mixture of (S)-2-aminobutyramide, tetra butyl ammonium iodide, isopropyl acetate and sodium carbonate at 25-30°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to reflux temperature and stirred for 24 hours at the same temperature. Filtered the reaction mixture through celite bed and volatiles were removed under pressure from the obtained filtrate to get the title compound.

Stage-3: Synthesis of Brivaracetam
Toluene was added to the resulting crude obtained in stage-2 and stirred for 10 minutes for clear dissolution. The resulting reaction mixture was heated to reflux temperature and stirred for 24 hours at the same temperature. Volatiles were removed under reduced pressure. The obtained crude was dissolved in ethyl acetate and stirred for 60 minutes at the same temperature. Unwanted solid was separated by filtration and volatiles were removed under reduced pressure from the obtained filtrate to get the title compound. Yield: 70 %

Example-2: Process for the preparation of Brivaracetam
Stage-1: Synthesis of methyl (3R)-3-(chloromethyl)hexanoate
To a mixture of (R)-Dihydro-4-propyl-2(3H)-furanone (1 eq.) and methanol (5.0 vol) was added thionyl chloride (2.0 eq.) drop wise at 15-20°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to reflux temperature and stirred for 14-15 hours at the same temperature. Volatiles were removed under reduced pressure. Water was added to the obtained crude and basified with aqueous sodium bicarbonate solution. Both the aqueous and organic layers were separated and aqueous layer was extracted with dichloromethane. Volatiles were removed from the organic layer under reduced pressure to get the title compound.
Yield: 85 %

Stage-2: Synthesis of methyl (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanoate
Compound obtained in stage-1 was added to a mixture of methyl(S)-2-amino butanoate, sodium iodide, sodium carbonate and isopropyl acetate at 25-30°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to reflux temperature and stirred for 24 hours at the same temperature. Filtered the reaction mixture through celite bed and volatiles were removed under reduced pressure from the obtained filtrate.

The obtained crude was dissolved in toluene. The reaction mixture was heated to reflux temperature and stirred for 24 hours at the same temperature. Volatiles were removed under reduced pressure from the reaction mixture. The resulting crude was dissolved in ethyl acetate and stirred for 60 minutes at the same temperature. Unwanted solids were separated by filtration and volatiles were removed under reduced pressure form the obtained filtrate to get the title compound. Yield: 70 %

Alternative synthesis of methyl (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanoate
Compound obtained in stage-1 was added to a mixture of methyl(S)-2-amino butanoate, sodium iodide, sodium carbonate and dimethyl formamide at 25-30°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to 110-120°C and stirred for 24 hours at the same temperature. Filtered the reaction mixture through celite bed and water was added to the obtained filtrate. The resulting reaction mixture was extracted with methyl tert-butyl ether. Volatiles were removed under reduced pressure from the obtained organic layer to get the title compound. Yield: 70 %

Stage-3: Synthesis of Brivaracetam
Compound obtained in stage-2 was suspended in methanol at 25-30°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was purged with 3 bars of ammonia gas. After consumption of the starting material, carefully ventilate ammonia gas. Volatiles were removed under reduced pressure from the reaction mixture and the obtained crude was recrystallized in diisopropyl ether to get the title compound. Yield: 80 %

Example-3: Process for the preparation of Brivaracetam
Stage-1: Synthesis of methyl (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanoate
A mixture of (R)-dihydro-4-propyl-2(3H)-furanone and methyl(S)-2-aminobutanoate was stirred for 48 hours at 160-165°C. After consumption of starting material, dichloromethane and triethylamine were added to the resulting reaction mixture at 25-30°C. Cooled the reaction mixture to 0°C. Tosyl chloride was added to the obtained reaction mixture at 0-5°C and stirred for 3 hours at 25-30°C. The resulting reaction mixture was washed with aqueous sodium bicarbonate solution. Both the aqueous and organic layers were separated. Volatiles were removed under reduced pressure from the organic layer to get the title compound.
Yield: 50 %

Stage-2: Synthesis of Brivaracetam
Compound obtained in stage-1 was suspended in methanol at 25-30°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was purged with 3 bars of ammonia gas. After consumption of the starting material, carefully ventilate ammonia gas. Volatiles were removed under reduced pressure from the reaction mixture and the obtained crude was recrystallized in diisopropyl ether to get the title compound. Yield: 80 %

Example-4: Process for the preparation of Brivaracetam
Stage-1: Synthesis of (3R)-3-(bromomethyl) hexanoic acid
A mixture of (R)-dihydro-4-propylfuran-2(3H)-one in acetic acid and hydro bromic acid in acetic acid was stirred for 10 minutes at 25-30°C. The resulting reaction mixture was heated to 50-55°C and stirred for 8 hours at the same temperature. Water and toluene were added to the obtained reaction mixture and stirred for 10 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with toluene. Combine the organic layers and washed with water. Volatiles were removed under reduced pressure from the obtained organic layer to get the title compound. Yield: 80 %

Stage-2: Synthesis of (3R)-3-(bromomethyl)-N-[(1S)-1-carbamoylpropyl]hexanamide
The compound obtained in stage-1 was added to a mixture of triethylamine and tetrahydrofuran at 25-30°C. Cooled the resulting reaction mixture to 0-5°C. Ethyl chloroformate was slowly added to the reaction mixture at 0-5°C and stirred for 2 hours at the same temperature. The resulting reaction mixture was added to a solution of 2-amino butyramide hydrochloride in tetrahydrofuran and triethylamine at 25-30°C. The reaction mixture was stirred for 8 hours at 25-30°C. Filtered the reaction mixture through celite bed and volatiles were removed under reduced pressure from the obtained filtrate. The obtained crude was dissolved in dichloromethane and the resulting reaction mixture was washed with water followed by brine solution. Both the organic and aqueous layers were separated. Volatiles were removed from the organic layer under reduced pressure to get the title compound. Yield: 70 %

Stage-3: Synthesis of Brivaracetam
The compound obtained in stage-2 was suspended in a mixture of sodium sulphate and dichloromethane at 25-30°C. The resulting reaction mixture was cooled to 0°C. Potassium hydroxide flakes were slowly added to the reaction mixture and stirred for 4 hours at the same temperature. Filtered the reaction mixture through celite bed and volatiles were removed under reduced pressure from the obtained filtrate. Diisopropyl ether and dichloromethane were added to the obtained crude at 25-30°C and stirred for 10 minutes at the same temperature. Volatiles were removed under reduced pressure from the reaction mixture to get the title compound.
Yield: 70 %

Example-5: Process for the preparation of Brivaracetam
Stage-1: Synthesis of methyl (3R)-3-(chloromethyl)hexanoate
Thionyl chloride (2.0 eq.) was added drop wise to a mixture of (R)-Dihydro-4-propyl-2(3H)-furanone (1 eq.) and methanol (5.0 vol) at 15-20°C and stirred for 10 minutes at the same temperature. The resulting reaction mixture was heated to reflux temperature and stirred for 14-15 hours at the same temperature. Volatiles were removed under reduced pressure. Water was added to the obtained crude and basified with aqueous sodium bicarbonate solution. Both the aqueous and organic layers were separated and aqueous layer was extracted with dichloromethane. Volatiles were removed from the organic layer under reduced pressure to get the title compound. Yield: 85 %

Stage-2: Synthesis of compound of formula-XVI
The compound obtained in stage-1 was added to a mixture of (2S)-2-(benzylamino) butanamide (1.2 eq.), sodium iodide (0.1 eq.) and sodium carbonate (2.0 eq) in isopropanol at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 24 hours at the same temperature. Filtered the reaction mixture through celite bed and volatiles were evaporated under reduced pressure from the obtained filtrate. The obtained crude was recrystallized in diisopropyl ether to get the title compound. Yield: 80 %

Stage-3: Synthesis of compound of formula-XVII
The compound obtained in stage-2 was added to a mixture of 10 % palladium on carbon and methanol an autoclave at 25-30°C. The reaction mixture was pressurized with hydrogen gas. Heated the reaction mixture to 80-85°C and stirred for 6 hours at the same temperature. After completion of the reaction, filtered the reaction mixture through celite bed and volatiles were evaporated under reduced pressure from the obtained filtrate to get the title compound.

Example-6: Alternative process for the preparation of Brivaracetam:
Compound of formula-XVI was added to a mixture of 10 % palladium on carbon and methanol an autoclave at 25-30°C. The reaction mixture was pressurized with hydrogen gas. Heated the reaction mixture to 80-85°C and stirred for 6 hours at the same temperature. After completion of the reaction, filtered the reaction mixture through celite bed and volatiles were evaporated under reduced pressure from the obtained filtrate. The resulting crude was dissolved in toluene and heated the reaction mixture to 110-120°C and stirred for 24 hours at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure. The obtained residue was dissolved in ethyl acetate and stirred for 60 minutes at the same temperature. Unwanted solids were separated by filtration and volatiles were evaporated under reduced pressure from the obtained filtrate to get the title compound. Yield: 70 %

Example-7: Process for the preparation of Brivaracetam:
Stage-1: Synthesis of sodium (3R)-3-(hydroxymethyl)hexanoate

(R)-Dihydro-4-propyl-2(3H)-furanone was added to a mixture of ethanol and sodium hydroxide at 25-30°C. The reaction mixture was stirred for 4 hours at the same temperature. Volatiles were evaporated under reduced pressure from the reaction mixture. The obtained crude was dissolved in N, N-dimethylformamide and cooled the resulting reaction mixture to 0-5°C. Methyl iodide was slowly added to the reaction mixture at 0-5°C and stirred for 20 hours at the same temperature. Water and ethyl acetate were added to the reaction mixture. Both the organic and aqueous layers were separated and organic layer was washed with brine solution. Volatiles were removed under reduced pressure from the obtained organic layer to get the title compound.
Yield: 80 %

Stage-2: Synthesis of methyl (3R)-3-(hydroxymethyl)hexanoate

The compound obtained in stage-1 was added to a mixture of sodium acetate, TEMPO and dichloromethane at 25-30°C and stirred for 30 minutes at the same temperature. Trichloroisocyanuric acid was added to the reaction temperature at 0-5°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dichloromethane. Both the organic and aqueous layers were separated and organic layer was washed with aqueous sodium carbonate solution. The reaction mixture was used to the next step directly.

Stage-3: Synthesis of Brivaracetam
The reaction mixture obtained in stage-2 was added to a mixture of (2S)-2-amino butanamide and acetic acid at 25-30°C and stirred for 30 minutes at the same temperature. Sodium triacetoxy borohydride was added to the reaction mixture at 25-30°C and stirred for 5 hours at the same temperature. The resulting reaction mixture was washed with aqueous sodium carbonate and extracted with dichloromethane. Both the organic and aqueous layers were separated and organic layer was washed with water followed by brine solution. Volatiles were removed from the organic layer under reduced pressure to get the title compound.
Yield: 70 %.
,CLAIMS:We Claim:
1. An improved process for the preparation of Brivaracetam of formula-I

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

with thionyl chloride in methanol to obtain compound of formula-III;

b) reacting compound of formula-III with amide derivative of formula-IV

in the presence of a base and optionally phase transfer catalyst to obtain compound of formula-V;

c) cyclization of compound of formula-V in an organic solvent to obtain Brivaracetam of formula-I.

2. The process as claimed in claim 1, wherein the said phase transfer catalyst is selected from tetra-N-butyl ammonium bromide or tetra-N-butyl ammonium iodide.

3. An improved process for the preparation of Brivaracetam of formula-I

which comprises:
a) condensation of compound of formula-II

with ester derivative of compound of formula-VI

to obtain compound of formula-IX;

b) protecting compound of formula-IX with a hydroxy protecting group in presence of base to obtain compound of formula-X;


c) cyclization of compound of formula-X in an organic solvent to obtain compound of formula-VIII;

d) aminolysis of compound of formula-VIII with an aminating agent to obtain Brivaracetam of formula-I.

4. The process as claimed in claims 3, wherein the said aminating agent is selected from ammonia gas, ammonium hydroxide or ammonium chloride.

5. The process as claimed in claim 3, wherein said hydroxy protecting group is selected from para toluene sulfonyl (OTs), benzyloxy carbonyl (Cbz), methoxycarbonyl, ethoxy carbonyl, tert-butyloxycarbonyl (Boc), p-methoxybenzyl or tetrahydropyran.

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

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

with thionyl chloride in methanol to obtain compound of formula-III;

b) treatment of compound of formula-III with a compound of formula-XV

in a presence of a base and a catalyst to obtain compound of formula-XVI;

c) reduction followed by cyclization of compound of formula-XVI in a solvent in the presence of reducing agent to obtain Brivaracetam of formula-I.

7. The process as claimed in claim 6, wherein said reduction carried out by using palladium on carbon.

8. An improved process for the preparation of Brivaracetam compound of formula-I.

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

with thionyl chloride in methanol to obtain compound of formula-III;

b) treatment of compound of formula-III with a compound of formula-XV

in a presence of a base and a catalyst to obtain compound of formula-XVI;

c) reduction of compound of formula-XVI in a solvent in the presence of reducing agent to obtain compound of Formula XVII.

d) cyclization of compound of formula-XVII in an organic solvent to obtain Brivaracetam of formula-I.

9. The process as claimed in claims 1, 3, 6 and 8, wherein the said base is selected from inorganic base alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate; or organic bases such as triethylamine (TEA), diisopropylethylamine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), diisobutylamine (DIBA), piperidine, pyridine, 4- dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), N-methyl pyrrolidone (NMP).

10. The process as claimed in claims 1, 3, 6 and 8, wherein said the organic solvent is selected from aromatic hydrocarbon solvents such as toluene, xylene; chlorinated solvents such as dichloromethane; alcoholic solvents such as methanol, ethanol, isopropanol; ether solvents such as tetrahydrofuran or nitrile solvents such as acetonitrile.