DESC:FIELD OF INVENTION:
The present invention relates to an improved and industrially feasible process for the preparation of Brivaracetam.

BACKGROUND OF THE INVENTION:
(2S)-2-((4R) -2- oxo-4-n-propyl-1-pyrrolidinyl) butanamide, generally known as Brivaracetam, is an anticonvulsant drug useful in the treatment of partial onset seizures in patients 16 years of age and older with epilepsy. The compound has following chemical structure:

Brivaracetam preparation and use as pharmaceuticals are described in International Patent Application Publication No. WO01/062726, in particular suitable for the treatment of neurological disorders, particularly (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl) butanamide is also disclosed.
The synthetic scheme exemplified in above reference is given in Scheme 1:

Scheme-1
The reported process utilizes preparative HPLC for isomer separation.
Apart from the above, US Patents US7122682 B2, US7629474 B2, US8076493 B2, US8338621 B2 and US8957226 B2 also described processes for the preparation of Brivaracetam.
The processes for the preparation of Brivaracetam described in the above mentioned patents suffer from many disadvantages which includes difficulty in achieving desired purity, tedious and cumbersome work up procedures, high temperature and longer time reaction, multiple crystallizations or isolation steps, use of excess reagents and solvents etc. All these disadvantages affect the overall yield as well as the quality of the final product.
Based on the above discussed facts there is a need for an improved process for the preparation of Brivaracetam with high purity and yield which overcome the drawback of prior publications. The present inventors have found an efficient process for the preparation of Brivaracetam which offers the following advantages over the prior publications such as simple scalable procedures suitable for large scale production, high yields and less effluent.

SUMMARY OF THE INVENTION:
In one aspect, the present invention relates to an improved process for preparation of Brivaracetam with good yield and high purity.

In another aspect, the present invention relates to a process for preparation of Brivaracetam intermediate.

In another aspect, the present invention relates to a novel intermediate compound of Brivaracetam.

In another aspect, the present invention relates to a use of novel intermediate compound in the preparation of Brivaracetam and its pharmaceutically acceptable salts thereof.

FIGURES:
Fig 1: Illustrated schematic representation of the present invention.

DETAILED DESCRIPTION OF THE INVENTION:
According to one aspect, the present invention provides an improved process for the preparation of Brivaracetam comprising the steps of:
a) condensation reaction of valeraldehyde and glycolic acid in the presence of a base to obtain n-propyl hydroxyfuranone of formula II;

b) reductive amination and cyclization of n-propyl hydroxyfuranone of formula II with (S)-2-aminobutanoic acid to obtain (2S)-2-(2-oxo-4-propyl-2, 5-dihydro-1H-pyrrol-1-yl) butanoic acid of formula III;

c) reduction of double bond of (2S)-2-(2-oxo-4-propyl-2, 5-dihydro-1H-pyrrol-1-yl) butanoic acid to obtain (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid of formula IV;

d) reacting (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid of formula IV with R-CO-X in the presence of a base to get compound of the formula V which can optionally be isolated;

wherein R is selected from C1-C6 alkyl group either straight chain or branched and X is selected from halogen; and

e) reacting compound of formula V with ammonium source to obtain Brivaracetam.

The base employed in process step a) include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (?, ?-diisopropylethylamine), N-methylpiperidine, N-methylmorpholine alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc.; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc.; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc.; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide

The step b) reaction can be carried out under reductive amination conditions. The reaction may be carried out in an inert solvent, in the presence of a reducing agent and acid. Reducing agents such as NaBH3CN, NaBH4, NaBH(OAc) 3 etc. and all other reagents known in the art, acid such as acetic acid.

The reduction of the double bond in step c) can be carried out in the presence of metal based catalyst such as Pd, Pt, Ir, Fe, Zn. Ni.

The reaction step d) can be carried out in the presence of solvent and base.

The solvent of step d ) can be selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, formic acid, acetic acid, propionic acid or mixtures thereof.

The base of step d) include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (?, ?-diisopropylethylamine), N-methylpiperidine, N-methylmorpholine alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc.; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc.; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc.; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide

The intermediate compound of formula V obtained in reaction step d) can be formed in situ or it can be isolated.

The ammonium source used in step e) can be selected liquid ammonia, gaseous ammonia and ammonium salts like ammonium chloride.
According to another aspect the present invention provides a process for the preparation of intermediate compound of formula (V);

wherein R is C1-C6 alkyl group either straight chain or branched; comprising reaction of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid of formula IV with R-CO-X to get compound of the formula V; wherein R is selected from C1-C6 alkyl group either straight chain or branched and X is selected from halogen.

In one embodiment, the reaction can be carried out in the presence of solvent and base.

The solvent can be selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, formic acid, acetic acid, propionic acid or mixtures thereof.

The base include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (?, ?-diisopropylethylamine), N-methylpiperidine, N-methylmorpholine alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc.; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc.; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc.; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide.

In another aspect, Brivaracetam can be purified by chromatographic or crystallization techniques like chiral chromatography, preparative high performance liquid chromatography, Simulated Moving Bed chromatography, (SMB), Batch Elution Chromatography, multi column chromatography (MCC), dynamic crystallization etc. The HPLC purity of the Brivaracetam achieved by the present invention is not less than 95%, preferably more than 99 % and most preferably more than 99.5%.

Examples:
1. Preparation of 5-hydroxy-4-propyl furan -2(5H)-one (II):
0.1kg of Morpholine was added in 0.4L cyclohexane and stirred at 0-5°C, to it was added 0.16kg 50% aq.glycolic acid dropwise. The reaction mass was brought to room temperature and stirred for around 1-2 hrs.0.1 kg of valeraldehyde was added to reaction mass and heated to 40°C. Reaction mass was monitored and cooled to room temperature, 0.2L of conc. HCl was added and stirred for 2-4hrs. Organic layer and aqueous layer was separated , aqueous layer was washed with cyclohexane , to the aqueous layer was added around 0.3 L of DCM , to reaction mass slowly sodium bicarbonate was added to stirred for 30-40 mins and layers were separated. Organic layer was distilled out to get the desired product.

Yield: 1.4 kg

2. Preparation of (2S)-2-(2-oxo-4-propyl-2, 5-dihydro-1H-pyrrol-1-yl) butanoic acid (III):
0.075kg of (S)-2-Amino butyric acid was added to 0.75 L of methanol, the reaction mixture was cooled to 0-5°C; to it was added 0.04 kg sodium methoxide lot wise at 0-5°C and reaction mixture was brought to 15-20°C. 0.1kg of 5-hydroxy-4-propyl furan -2(5H)-one in 0.75ml of methanol was added to reaction mass dropwise and reaction mixture was stirred at room temperature for about 3-5hrs. Further the reaction mass was cooled to 0-5°C and 0.025kg of sodium borohydride was added lot wise and reaction mass was stirred for 1-2hrs mins at room temperature. 0.14kg of acetic acid was added to reaction mass, raised the temperature to 60-70°C and stirred for overnight. After completion of the reaction, methanol was distilled out, 1.5 L of DCM, saturated brine was added to reaction mass and allowed to stir. The layers were separated, organic layer was distilled under vacuum. 0.3 L of cyclohexane was added, heated to 40-45°C, reaction mixture was gradually cooled to 10-15°C under stirred ; solid obtained was filtered washed with cyclohexane and dried under vacuum to get desired product.
Yield: 1.2 kg

3. Preparation of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid (IV):
0.1kg of (2S)-2-(2-oxo-4-propyl-2, 5-dihydro-1H-pyrrol-1-yl) butanoic acid was added in 1L of ethanol, the reaction mass was cooled to 10-20°C, and 0.01kg of 10% Pd/C (50% wet) was added purged with hydrogen gas . The reaction mass was stirred at room temperature for about 2-3 hours , after completion of the reaction, reaction mass was filtered over celite bed and washed with ethanol. The filtrate was distilled under vacuum, 0. 3L of 10% 2-methyl THF in heptane was added, heated the reaction mas to 40-45°C, further allowed to cool reaction mass to 10-15°C under stirred, solid obtained was filtered and washed with n-heptane , solid was dried under vacuum to get the desired product.
Yield: 0.9kg (90%)

4. Preparation of Crude Brivaracetam:
25 gm of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid was added to 250ml of DCM in the round bottom flask and cooled to 0-5°C, 24.5ml of triethylamine was added to the reaction mass stirred at 0-5°C for 15-20mins. Further 20.20ml of pivaloyl chloride was added slowly and reaction was allowed to stir for 2hrs at 5-15°C. After completion of the reaction, it reaction mixture was cooled to 0-5°C and 31.3g of ammonium chloride was added in one lot and stirred for 10 minutes. 32.7 ml of triethylamine was added to the reaction mixture and the reaction was stirred for two hours at 5-10°C. Water was added to the reaction mass and stirred at room temperature. Organic and water layer were separated. The organic layer was washed with 10% HCl, distilled out the organic layer. 100ml of DIPE was added and stirred at room temperature, the solid was filtered and dried under vacuum to get 17.5gm of crude Brivaracetam.
Yield: 17.5gm (0.7w/w)
HPLC results: 84.07%, Diastereomer: 14.55%

6. Purification of Brivaracetam by preparative HPLC.
Chiral purification of Brivaracetam was done by preparative HPLC using chiral pak IC.
Mobile phase: DCM and IPA
100gm of crude Brivaracetam (containing 12-15% of undesired diastereomer) was dissolved in DCM and IPA. This solution was injected with fixed volume on the preparative column. Feed solution was injected in staking mode with continuous flow of mobile phase with desired flow rate. The eluted fractions were collected and HPLC purity was checked. The fractions with desired purity were collected and distilled off. Distilled mass was diluted with isopropyl acetate and cooled to subzero temperature. The solid obtained was filtered, washed with pre-cooled isopropyl acetate and dried under vacuum.
Yield: 65-70 gm
HPLC Purity: > 99%
,CLAIMS:1. An improved process for the preparation of Brivaracetam comprising the steps of:
a) condensation reaction of valeraldehyde and glycolic acid in the presence of a base to obtain n-propyl hydroxyfuranone of formula II;

b) reductive amination and cyclization of n-propyl hydroxyfuranone of formula II with (S)-2-aminobutanoic acid to obtain (2S)-2-(2-oxo-4-propyl-2, 5-dihydro-1H-pyrrol-1-yl) butanoic acid of formula III;

c) reduction of double bond of (2S)-2-(2-oxo-4-propyl-2, 5-dihydro-1H-pyrrol-1-yl) butanoic acid to obtain (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid of formula IV;

d) reacting (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl) butanoic acid of formula IV with R-CO-X in the presence of a base to get compound of the formula V which can optionally be isolated;

wherein R is selected from C1-C6 alkyl group either straight chain or branched; and
e) reacting compound of formula V with ammonium source to obtain Brivaracetam; and
f) optionally purifying Brivaracetam.

2. The process according to claim 1, base employed in step a)include pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (?, ?-diisopropylethylamine), N-methylpiperidine, N-methylmorpholine alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc.; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc.; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc.; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide.

3. The process according to claim 1, reducing agent employed in step b) NaBH3CN, NaBH4, NaBH(OAc)3 and acid such as acetic acid.

4. The process according to claim 1 the reduction of the double bond in step c) be carried out in the presence of metal based catalyst such as Pd, Pt, Ir, Fe, Zn. Ni.

5. The process according to claim 1, the base employed in step d) is selected from pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (?,?-diisopropylethylamine),N-methylpiperidine, N-methylmorpholine and like. Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc.; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc.; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc.; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide.

6. The process according to claim 1, ammonia source employed in step e) include liquid ammonia, ammonium chloride and gaseous ammonia.

7. The process according to claim 1, purification of Brivaracetam in step f) is carried out by preparative HPLC.

8. A process for preparation of compound of formula V comprising:
a) reacting compound of formula IV with acid halide in the presence of base to obtain a compound of formula V

Wherein R is C1-6 alkyl group, X is halogen.

9. The process according to claim 8, wherein acid halide used more preferably acid chloride.

10. The process according to claim 9, the base employed in step a) is selected from pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (?, ?-diisopropylethylamine), N-methylpiperidine, N-methylmorpholine and like. Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc.; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc.; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc.; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide.