The present invention relates to process for the preparation of brivaracetam. The present invention
further relates to process for preparation of intermediate compounds and their use in the
preparation of brivaracetam. ^
BACKGROUND OF THE INVENTION
Brivaracetam, an analogue of levetiracetam, chemically known as (2S)-2-[(4i?)-2-oxo-4-propyltetrahydro-l#-pyrrol-l-yl] butanamide having structure of Formula (I),

O (I)
Brivaracetam marketed under the brand name BRIVIACT, has been found to display a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect. BRIVIACT is indicated as adjunctive therapy in the treatment of partial onset seizures in patients 16 years of age and older with epilepsy.
Several processes for the preparation of brivaracetam are known in the prior arts. For example, U.S. Patent No. 6,784,197 discloses the process for the preparation of brivaracetam which involves a reductive arhination step using (^)-2-aminobutyramide yielding the unsaturated intermediate (lb) followed by hydrogenolysis step using ammonium formate yielding the diastereomers (la) and (I), as shown in the following Scheme-1:



PhMe, NaBH4, H20 X, . HCOONH4
AcOH / Y. Pd/C

H20
NH2 £ ■ \^^/NH2 \^\^NH2
O .0 . 0
(0
Scheme-I

The above method of Scheme-I further involves separation of two diastereomers using chiral HPLC.
U.S. Patent No. 7,629,474 discloses process for preparation of brivaracetam which is shown in following Scheme-II:
H+ HA.OH -w W ' 6-HCI

O 6 HCI, H20 HO^f/^O
NH2
O cT^NH \ ' f^VNH2^

■'■■ 0.
Scheme-II
The above method of Scheme-II further involves separation of two diastereomers using chiral chromatography.
U.S. Patent No. 8,957,226 discloses process for preparation of brivaracetam as shown in following Scheme-Ill:
, . ^ O. . °2N^ Q RaneyNi
CH3N02 /\ JL A MeQH )—v Chiral HPLC
H
Br V_ \ . :
.OMe ■'- N—,
^'r\ ' o 0*«Aq NH3 r\ chiral HPLC r

H >S<^0 \ >\ .NH2 \^^/NH2
°\ 0 0
. (I)
Scheme-Ill J
U.S. Patent No. 8,331,621 discloses process for preparation of (5)-2-[4-propyl-2-oxopyrrolidin-
l-yl]butyramide which is shown in following Scheme-IV: , .

O^^OMe

Br ' " H2N^^r0Me
OMe + -HCI J p ' '

ryrrx

OMe


(S)-2-[4-propyN2-oxopyrro!idin-
1-yl]butyramide
Scheme-IV
Kenda et al (Journal of Medicinal Chemistry, 2004, 47, 530-549) reported process for preparation of brivaracetam which involves the same problem of purification using chiral HPLC. The Scheme* V is as follows: *


O SOCI2
,MgBr

•Q-

' Cul, TMSCI dry Et20

TMSI |
CH2CI2

OH

O
NH-
Chiral HPLC
O
NH2

O NH2
CI

N

-"Q-o
.NH-

O

(I)

O

Scheme-V
Thus, there is a need to develop a process for preparation of brivaracetam that can be adapted to industrial scale production. The inventors have developed simple process for preparation of brivaracetam with high chiral purity, greater yield, cost effective and eco-friendly manner to obviate one or more of the problems associated with prior art processes.
SUMMARY OF THE INVENTION
One aspect of the present invention provides an improved process for preparation of the brivaracetam or pharmaceutically acceptable salt thereof, which obviates the need of chiral chromatography for the purification.
In another aspect the present invention provides an improved process for preparation of the brivaracetam or pharmaceutically acceptable salt thereof, wherein chiral purity of brivaracetam

thus obtained is more than about 99.90%, preferably more than about 99.95%, more preferably
more "than about 99.97%. ./
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutical^ acceptable salt thereof, comprising the steps of:
a) converting (iS)-3-(2-arnino-2-oxoethyl)hexanoic acid of formula (II) to (i?)-3-((((S)-l-carboxypropyl)amino)methyI)hexanoic acid of formula (III);
b) converting (J?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanbic acid of formula (III) obtained in step (a) to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof; and
c) optionally, purifying the brivaracetam of formula (IA) obtained in step (b) by using purification method to obtain brivaracetam of formula (I) or pharmaceutically acceptable salt thereof, wherein purification method is not purification by chiral chromatography.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-VI, comprising the steps of;
a) converting (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (II) to (R)-3-(aminomethyl)hexanoic acid of formula (IIA);
b) reacting (i?)-3-(aminomethyl)hexanoic acid of formula (IIA) obtained in step (a) with compound of formula (IIB) to obtain (R)-3-((((S)-l-carboxyprppyl)amino)methyl)hexan6ic acid of formula (III);'
c) converting (i?)-3-((((5)-l-carboxypropyl)amino)methy])hexanoic acid of formula (III) obtained in step (b) to compound of formula (IIIA);
d) converting-compound of formulai (IIIA) obtained in step (c) to compound of formula (IIIB);
e) converting compound of formula (IIIB) obtained in step (d) to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof; and
f) optionally, purifying the brivaracetam ^of formula (IA) obtained in step (e) by using purification method to obtain brivaracetam of formula (I) or pharmaceutically acceptable salt thereof, wherein purification method is hot purification by chiral chromatography.

In anothei" aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-VII, comprising the steps of:
a) converting (5f)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (II) to (R)-3-(aminomethyl)hexanoic acid of formula (IIA);
b) reacting (i?)-3-(amiriomethyl)hl-carboxypropyl)amino)rnethyl)hexanoic acid of formula (III);

g) converting (i?)-3-((((5)-l-carboxypropyI)amino)methyl)hexanoic acid of formula (III)
obtained in step (f) to compound of formula (IIIA); h) converting compound of formula (IIIA) obtained in step (g) to compound of formula (IIIB); i) v converting compound of formula (IIIB) obtained in step (h) to brivaracetam of formula
(IA) or pharmaceutically acceptable salt thereof; and
j ■ m . ...
j) optionally, purifying the brivaracetam of formula (IA) obtained in step (i) by using
purification method to obtain brivaracetam of formula (I) or pharmaceutically salt thereof,
wherejn purification method is not purification by chiral chromatography. ■ ■. ,
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-X, comprising the steps of conversion of compound of Formula (III) to compound of Formula (IIIB), wherein R2 is Hydrogen. Optionally, compound of formula IIIB, wherein R2 is Hydrogen, may first be converted to an ester followed by amidation.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, comprising the steps of reacting compound (&)-3-(aminomethyl)hexanoic acid of formula of formula (IIA) with (i?)-2-bromobutyric acid of formula (IIB') in presence of base to obtain (^)-3-((((5)-l-carboxypropyl)artiino)methyl)hexanoic acid of formula (III), wherein the addition of base, is carried out in one or more lots.
In another aspect, present invention provides process for preparation of brivaracetam wherein (5)-3-(2-amin6-2-oxoethyl)hexanoic acid of formula (II) is used as an intermediate compound.
In another aspect, present invention provides purification of compound (7?)-3-((((S)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) by using any suitable purification method known in the literature.
In another aspect, present invention provides brivaracetam characterized by X-ray diffraction (XRD) spectrum as shown in Figure-1.
In another aspect, present invention provides brivaracetam characterized "by Differential Scanning Calorimetric (DSC) thermogram as shown in Figure-2.

In another aspect, present invention provides a pharmaceutical composition, comprising brivaracetam or a pharmaceutical^ acceptable salt thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.
In another aspect, brivaracetam prepared by the processes of the present invention possess the relative particle size distribution, wherein the 10th volume percentile particle size D (0.1) is less than about 50 |xm, preferably less than about 40 (xm, the 50th, volume percentile particle size D (0.5) is less than about 150 [im, preferably less than about 100 |j,m, and the 90th volume percentile particle size D (0.9) isjess than about 400 urn, preferably less than about 300 |im.
BRIEF DESCRIPTION OF DRAWINGS
Figure-1: Illustrates the XRD pattern of brivaracetam obtained according to example no. 5
Figure-2: Illustrates the DSC thermogram of brivaracetam obtained according to example no. 5
-j . ■ •
DETAIL DESCRIPTION OF THE INVENTION
One aspect of the present invention provides an improved process for preparation process for preparation of the brivaracetam or pharmaceutically acceptable salt thereof, which obviates the need of chiral chromatography for the purification.
In another aspect the present invention provides an improved process for preparation of the brivaracetam or pharmaceutically acceptable salt thereof, wherein chiral purity of brivaracetam thus obtained is more than about 99.90%, preferably more than about 99.95%, more preferably more than about 99.97%.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, comprising the steps of:.
a) converting (5)-3-(2-amino-2-oxoethyI)hexanoic acid of formula (II) to (R)-3-((((S)-\-carboxypropyl)aminb)methyl)hexanoic acid of formula (III);

b) converting (i?)-3-((((iS)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III)
. obtained in step (a) to brivaracetam of formula (IA) or pharmaceutical^ acceptable salt
thereof; and
c) optionally, purifying the brivaracetam of formula (IA) obtained in step (b) by using
purification method to; obtain brivaracetam of formula (I) or pharmaceutically salt thereof,
wherein purification method is not purification by chiral chromatography.
In step (a) of the aforementioned process, conversion of (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (II) to (7?)-3-((((iS)-l-carboxypropyl)arhino)methyl)hexanoic acid of formula (III) proceed through an intermediate compound (i?)-3-(aminomethyl)hexanoic acid of formula (IIA), -which may be used in-situ for the next step or can be isolated.and optionally purified before conversion to compound of formula (III).
In step (a) of the aforementioned process conversion of compound of formula (II) to compound of formula (IIA) is carried out by using one or more suitable bases and halogen source. Suitable base is selected from the group comprising of hydroxides of alkali or alkaline earth metals such as sodium, hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or the like, preferably sodium hydroxide.
Suitable halogen source is selected from the group comprising of sodium hypochlorite, sodium
hypobromite, chlorine, bromine, or the like, preferably sodium hypochlorite; and subsequently,
carrying out the coupling by using compound of formula (IIB), preferably (i?)-2-bromobutyfic
acid. ° -
Moreover, in step (a) of the aforementioned process, coupling of compound of formula (IIA) with
• , '
compound of formula (IIB) is carried out by using one or more suitable solvents and one or more
suitable bases. Suitable solvent is selected from the group comprising of alcohol solvents, such as
methanol, ethanol, propanol, isopropanol, butanol or the like; ether solvent such as
tetrahydrofuran, dioxane, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, methyl tert-
butyl ether (MTBE), halogenated hydrocarbon solvent, such as dichloromethane, chloroform,
carvbon tetrachloride, or the like; hydrocarbon solvent such as toluene, xylene or benzene, or the
like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone,
or the like; or water, or mixture thereof, preferably water.

Suitable base is selected from the group comprising of hydrides, such as sodium hydride or
potassium hydride, or the like; alkali metal hydroxides, such as lithium hydroxide, sodium
hydroxide, potassium hydroxide, or the like;:alkaline earth metal hydroxides, such as barium
hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali
metal carbonates, sjjch as sodium carbonate, potassium carbonate, lithium carbonate, cesium
carbonate, or the likej alkaline earth metal carbonates, such as magnesium carbonate, calcium
carbonate, or the like; alkali metal bicarbonates, such as sodium bicarbonate, potassium
bicarbonate, or the like; organic bases, such as triethylamine, tributylamine, iV-methylmorphoIine,
Af,Af-diisopropyIethylamine, 7V-methylpyrrolidine, pyridine, or the like, preferably potassium
hydroxide. '
In step (b) of the aforementioned process, conversion of (i?)-3-((((5)-1 -carboxypropyl)amirio)methyl)hexanoic acid of formula (III) to brivaracetam of formula (I) or pharmaceutically salt thereof may proceed through intermediate compounds (IIIA) and/or (IIIB).
In step (b) of the aforementioned process, conversion of (i?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) to brivaracetam of formula (I) or pharmaceutically salt thereof optionally involves isolation and optionally purification of intermediate compound (IIIA) and/or (IIIB).
Further, cyclization in the step (b) of the aforementioned process may be carried out by using suitable catalyst selected from the group comprising of 4-(dimethylamino)pyridine, 2-hydroxy pyridine or the like, preferably 2-hydroxy pyridine.
Furthermore, step (b) of the aforementioned process, wherein butanamide side chain can be obtained from converting respective acid/ester by using suitable ammonia source selected from ammonia solution or,ammonia gas, or the like, preferably ammonia "solution and ammonia gas.
In the step "(b) of the aforementioned process conversion of compound of formula (III) to compound of formula (IIIA) may be carried out by using any suitable ester forming agent such as one or more suitable acids in presence of suitable alkyl source, (i) Suitable acid(s) is selected from the group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, or the like, preferably sulphuric acid, and (ii) one or

more suitable ester forming agents is selected from the group comprising of alcohol solvents, such
as methanol, ethanol, propanol, isopropanol, butanol or the like; or mixture thereof, preferably
methanol. '*'-■.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutical^ acceptable salt thereof, as shown in Scheme-VI, comprising the steps of:
a) converting (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (II) to (K)-3-(aminomethyl)hexanoic acid of formula (HA);
b) reacting (^)-3-(aminomethyl)hexanoic acid of formula (IIA) obtained in step (a) with compound of formula (IIB) to obtain (i?)-3-((((S)-l -carboxypropyl)amino)methyl) hexanoic acid of formula (III);
c) converting (i?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) obtained in step (b) to compound of formula (IIIA);
d) converting compound of formula (IIIA) obtained in step (c).to compound of formula (NIB);
e) converting compound of formula (IHB) obtained in step (d) to brivaracetam of formula (IA) or pharmaceutical^ acceptable salt thereof; and
f) optionally, purifying the brivaracetam of formula (IA) obtain in step (b) by using purification method to obtain brivaracetam. of formula (I) or pharmaceutical^ salt thereof,
^ wherein purification method is not purification by chiral chromatography.

COOH
(IIIA)
(I)
(IA)
Scheme-VI
A wherein Ri and R2 independently represents Oi-Ce alkyl, LG represents suitable leaving^group selected from halogen, tosylate, mesylate or the like.

In aforementioned process any intermediate at any stage, with or without isolation, may be used to proceed further, for preparation of brivaracetam.
*
Step a) of the aforementioned process is carried out by using (i) suitable base selected from the group comprising of hydroxides of alkali or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or the like, preferably sodium hydroxide, and (ii) suitable halogen source selected from the group comprising of sodium hypochlorite, sodium hypobromite, chlorine, bromine, or the like, preferably sodium hypochlorite.
Step b) of the aforementioned process is carried out by using suitable base selected from the group comprising of hydrides, such as sodium hydride or potassium hydride, or the like; alkali metal -hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; alkaline earth metal hydroxides, such-as barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as sodium carbonate, potassium* carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, or the like; organic bases, such as triethylamine, tributylamine, Af-methylmorpholine, A^,A^-diisopropylethylamine, N-methylpyrrolidine, pyridine, or the like, preferably potassium hydroxide.
Further, step b) of the aforementioned is carried out by using suitable solvent selected from the group comprising of alcohol solvents, such: as methanol, ethanol, propanol, isopropanol, butanol or the like; ether solvent such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, methyl tert-buty\ ether (MTBE), halogenated hydrocarbon solvent, such as dichloromethane, chloroform, carbon tetrachloride, or the -like; hydrocarbon solvent such as toluene, xylene or benzene, or the like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, or the like; or water, or mixture thereof, preferably water.
Step c) of the aforementioned process is carried out by using (i) one Or more suitable acids selected from the j*roup comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, or the like, preferably sulphuric acid, and (ii) one or more suitable ester forming agents selected from the group comprising of alcohol solvents, such

as methanol, ethanol, propariol, isopropanol, butahol or the like; or mixture thereof, preferably methanol.
Step d) of the aforementioned process is carried out by using suitable catalyst selected from the group comprising of 4-(dimethylamino)pyridine, 2-hydroxy pyridine or the like, preferably 2-hydroxy pyridine:
Step e) of the aforementioned process is carried out by using suitable ammonia source selected from ammonia solution, ammonia gas, or the like, preferably ammonia solution and ammonia gas.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-VII, comprising the steps of:
a) converting (S)-3-(2-arnino-2-oxoethyI)hexarioic acid of^ formula (II) to (#)-3-(aminomethyl)hexanoic acid of formula (IIA);
b) reacting (i?)-3-(aminomethyI)hexanoic acid of formula (IIA) obtained in step (a) with (R)-2-bromobutyric acid of formula (IIB') to obtain (i?)-3-((((5)-l-carboxypropyl)amino)methyi)hexanoic acid of formula (III);
c)- converting (7?)-3-((((5)-l-:carboxypropyl)amino)methyl)hexanoic acid of formula (III) obtained in step _ (b) to methyl (^)-3-((((S)-l-methoxy-l-oxobutan-2-yl)amino)methyl)hexanoate of formula (IIIA');
d) converting methyl (7?)-3-((((5)-l-methoxy-l-oxobutan-2-yI)amino)methyl)hexanoate of
formula (IIIA') obtained in step (c) to methyl (S)-2-((i?)^2-oxo-4-propylpyrrolidin-l-
yl)butanoate of formula (IIIB');
* -
e) converting methyl (iS)-2-((7?)-2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB9)-obtained in step (d) to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof; and
f) optionally, purifying the brivaracetam of formula (IA) obtained in step (e) by using purification method to obtain brivaracetam of formula (I) or pharmaceutically acceptable salt thereof, wherein purification method is not purification by chiral chromatography.

COOH -

Scheme-VII
In aforementioned process any intermediate at any stage with or without isolation may be used to proceed further, for preparation of brivaracetam.
Step a) of the aforementioned process is carried out by using suitable base "selected from the group comprising of hydroxides of alkali or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or the like, preferably sodium hydroxide, and suitable halogen source selected from the group comprising of sodium hypochlorite, sodium hypobromite, chlorine, bromine, or the like, preferably sodium hypochlorite.
Step b) of the aforementioned process is carried out by using suitable base selected from the group comprising of hydrides, such as sodium hydride or potassium hydride, or the like; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; alkaline earth metal hydroxides, such as barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium, carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, or the like; organic bases, such as triethylamine, tributylamine, ./V-methylmorpholine, AyV-diisopropylethylamine, N-methylpyrrolidine, pyridine, or the like, preferably potassium hydroxide.
Further, step b) of the aforementioned is carried put by using suitable solvent selected from the group comprising of alcohol solvents, such as methanol, ethanol, propanol, isopropanol, butanol or the like; ether solvent such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, methyl tert-buty\ ether (MTBE), halogenated hydrocarbon solvent,,such as

dichloromethane, chloroform, carbon tetrachloride, or the like; hydrocarbon solvent such as toluene, xylene or benzene, or the like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, or the like; or water, or mixture thereof, preferably water.
Step c) of the aforementioned process is carried out by using (i) one or more suitable acids selected from the group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, or the like, preferably sulphuric acid, and (ii) one or more suitable ester forming agents selected from the group comprising of alcohol solvents, such as methanol, ethanol, propanol, isopropanol, butanol or the like; or mixture thereof, preferably methanol.
Step d) of the aforementioned process is carried out by using suitable catalyst selected from the group comprising of 4-(dimethylamino)pyridine, 2-hydroxy pyridine or the like, preferably 2-hydroxy pyridine.
Step e) of the aforementioned process is carried out by using suitable ammonia source selected from ammonium solution, ammonia gas, or the like, preferably ammonia solution and ammonia gas.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-VIII, comprising the steps of:
a) converting (7?)-3-((((5)-l-carboxypropyl)arnino)methyl)hexanoicacid of formula (III) to compound of formuIa-(IIIA); '■ -
b) converting compound of formula (IIIA) obtained instep (a) to compound of formula (IIIB);
c) converting compound of formula (IIIB) obtained in step (b) to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof; and
d) optionally, purifying the brivaracetam of formula (IA) obtained in step (c) by using purification method to obtain brivaracetam of formula (I) or pharmaceutically acceptable salt thereof, wherein purification method is not purification by chiral chromatography.

.COOH /COORT

Purification / V.
N ~ ~- \^°
NH2 \>\.NH2
O
0) Scheme-VIII
wherein Ri and R2 independently represents H or CirCe alkyl.

In aforementioned process any intermediate at any stage with or without isolation may be used to proceed further, for preparation of brivaracetam.

Step a) of the aforementioned process is carried out by using (i) one or more suitable acids selected from the group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, orthe like, preferably sulphuric acid, and (ii) one or more suitable ester forming agents selected from the group comprising of alcohol solvents, such as methanol, ethanol, propanol, isopropanol, butanol of the like; or mixture thereof.

Step b) of the aforementioned process is carried out by using suitable catalyst selected from the
group comprising of 4-(dimethylamino)pyridine, 2-hydroxy pyridine or the like, preferably 2-
hydroxy pyridine. '*"

Step c) of the aforementioned process is carried out by using suitable ammonia source selected from ammonium solution, ammonia gas, or the like, preferably ammonia solution and ammonia
gas. ...

In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-IX, comprising the steps of:

a) converting (7?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) to methyl (R)-3-((((S)~ 1 -methpxy-1 -oxobutan-2-y I)amino)methyl)hexanoate of formula (IIIA');
b) converting methyl (7?)-3-((((5)-l-methoxy-l-oxobutan-2-yl)amino)methyl)hexanoate of formula (IIIA') obtained instep (a) to methyl (5)-2-((i?)-2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB');
c) converting methyl (5)-2-((i?)-2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB') obtained in step (b) to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof; and
d) optionally, purifying the brivaracetam of formula (IA) obtain in step (c) by using purification method to obtain brivaracetam of formula (I) or pharmaceutically acceptable salt thereof, wherein purification method is not purification by chiral chromatography.

./ \^_ /V_ Purification / S ° ~ S ° ~ "' %^°

O. 6
(IIIB1)
(IA) (I)
Scheme-IX

O

In aforementioned process any intermediate at any stage with or without isolation may be used to proceed further, for preparation of brivaracetam.
Step a) of the aforementioned process is carried out by using suitable acid selected from the group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, or the like,,preferably sulphuric acid, and suitable ester forming agent selected from the group comprising of alcohol solvents, such as methanol, ethanol, propanol, isopropanol, butanol or the like; or mixture thereof.

Step b) of the aforementioned process is carried out by using suitable catalyst selected from the group comprising of 4-(dimethylamino)pyridine, 2-hydroxy pyridine or the like, preferably 2-hydroxy pyridine.
Step c) of the aforementioned process is carried out by using suitable ammonia source selected from ammonium solution, ammonia gas, or the like, preferably ammonia solution and ammonia gas.
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-X, comprising the steps of:
a) treating 3-propylgIutaric acid of formula (IV) with suitable reagent to obtain 4-propy!dihydro-2//-pyran-2,6(3//)-dione of formula (V);
b) converting 4-propyldihydro-2//-pyran-2,6(3#)-dione of formula (V) obtained in step (a) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (VI);
c) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (VI) obtained in step (b) with suitable resolving agent to obtain compound of formula (VII);
d) converting the compound of formula (VII) obtained in step (c) to compound (5)-3-(2-amino-2~-oxbethyl)hexanoic acid of formula (II);
e) converting (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (II) obtained in step (d) to (7?)-3-(aminomethyl)hexanqic acid of formula (IIA); ~ . . -
f) reacting (7?)-3-(aminomethyl)hexanoic acid of formula (IIA) obtained in step (e) with compound of v formula : (IIB) to obtain (#)-3-((((S)-l-carbbxypropyl)amino)methyl)hexanoic acid of formula (III);
g) converting (7?)-3-((((iS)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) obtained in step (f) to compound of formula (IIIA); ,
h) converting compound of formula (IIIA) obtained instep (g) to compound of formula (IIIB);
i) converting compound of formula (IIIB) obtained in step (h) to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof; and
j) optionally, purifying the brivaracetam of formula (IA) obtained in step (i) by using purification method to obtain brivaracetam of formula (I) or pharmaceutically acceptable salt thereof, wherein purification method is not purification by chiral chromatography.

In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Schefne-X, comprising the steps of conversion of compound of Formula (III) to compound of Formula (IIIB), wherein R2 is Hydrogen. Optionally, compound of formula IIIB, wherein R2 is Hydrogen, may first be converted to an ester followed by amidation.

COOH COOH

CTtDH Resolving group (VII)
COOH

Scheme-X
wherein Ri and R2 independently represents Ci-Ce alkyl, LG represents suitable leaving group selected from halogen, tosylate, mesylate or the like, and resolving group selected from either (R) or (S) of the enantiomer of l-(l-naphthyl)ethylamine, l-(2-naphthyI)ethy!amine, jV-benzyl phenylethylamine, 1-phenylethylamine or the like.
In aforementioned process, any intermediate at any stage with or without isolation may be used to proceed further, for preparation of brivaracetam.
Step a) of the aforementioned process is carried out in a suitable reagent selected from acetic anhydride, acetyl chloride or the like, preferablyacetic anhydride.
Step b) of the aforementioned process is carried out by using ammonia, aqueous ammonia or the
like. .
Step c) of the aforementioned process is carried out by using suitable resolving agent selected from the group comprising of either (R) or (5) of the enantiomer of 1- or 2-naphthyl ethyl amine, TV-

benzyl phenylethylamine, 1-phenylethylamine or the like, in presence of a suitable solvent or mixture of solvents.
Step e). of the aforementioned process is carried out by using (i) suitable base selected from the group comprising of hydroxides of alkali or alkaline earth metals such as- sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or the like, preferably.sodium hydroxide, and (ii) suitable halogen source selected from the group comprising of sodium hypochlorite, sodium hypobromite, chlorine, bromine, or the like, preferably sodium hypochlorite. The product obtained at this stage may be purified further to improve chemical purity and/or chiral purity.
Step f) of the aforementioned process is carried out by using suitable base selected from the group comprising of hydrides, such as sodium hydride or potassium hydride, or the like; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; alkaline earth metal' hydroxides, such as barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, or the like; organic bases, such as triethylamine, tributylamine, Af-methylmorpholine,- TV^Af-diisopropylethylamine, N-methylpyrrolidine, pyridine^ or the like,,preferably potassium hydroxide.
Further, step f) of the aforementioned is carried out by using suitable solvent selected from the group comprising of alcohol solvents, such as methanol, ethanol, propanol, isopropanol, butanol or.the like; ether solvent such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, methyl tert-buty\ ether (MTBE), halogenated hydrocarbon solvent, such as dichloromethane, chloroform, carbon tetrachloride, or the like; hydrocarbon solvent such as toluene, xylene or benzene, or the like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutylketone, or the like; or water, or mixture thereof, preferably water.
Step g) of the aforementioned process is carried out by using (i) one or more suitable acids selected from the group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid, or the like, preferably sulphuric acid, and (ii) one

or more suitable ester forming agents selected from the group comprising of alcohol solvents, such as methanol, ethanol, propanoic isopropanol, butanol or the like; or mixture thereof.
Step h).of the aforementioned process is carried out by using suitable catalyst selected from the .group comprising of 4-(dimethylamino)pyridine, 2-hydroxy pyridine or the like, preferably 2-hydroxy pyridine.
Step i) of the aforementioned process is^carried out by using suitable ammonia source selected l from ammonia solution, ammonia gas, or the like, preferably ammonia solution and ammonia gas.
The product obtained at this stage may be purified further to improve chemical purity and/or chiral purity.
In.another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutical ly acceptable salt thereof, comprising the steps of reacting compound (i?)-3-(aminomethyl)hexanoic acid of formula of formula (IIA) with (7?)-2-bromobutyric acid of formula (IIB') in presence of base to obtain (i?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III), wherein the addition of base is carried out in one or more lots.
In another aspect, present invention provides process for preparation of brivaracetam wherein (S)-3-(2-amirio-2-oxoethyl)hexanoic acid of formula (II) used as an intermediate compound.
In another aspect, present invention provides purification of (i?)-3-((((S)-l-carboxypropyl)amino)methyI)hexanoic acid of formula (III) using any suitable purification method known in the literature..
In present invention, any step of the schemes referred above may be carried out by using one or more suitable solvent selected from the. group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons, ethers,~amides, dialkylsulfoxides, hydrocarbons, water or the mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Alcohols are selected from the group comprising of methanol, ethanol, w-propanol,'isopropanol, w-butanol and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like.

Halogenated hydrocarbons are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and-the like. Ethers are selected, from the group comprising of diethyl ether, cyclopentyl methyl ether, methyl tert-buty\ ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the group comprising of Af,Af-dimethylformamide (DMF), A^,A^-dimethylacetamide.(DMA), A^-methylformamide," N-' methylpyrrolidone and the like. Dialkyl sulfoxides are selected from the group comprising of dimethylsulfoxide^diethylsulfoxide, dibutylsulfoxide and the like. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene,- xylene and the like. The resolution step as referred above may preferably be carried out using solvent such as chloroform, ethanol, acetone, toluene, Zso-propyl alcohol, methanol, acetonitrile, ethyl acetate and combination thereof or the like.
In another aspect, the present invention provides brivaracetam characterized by X-ray diffraction (XRD) spectrum as shown in Figure-1.
In another aspect, the present invention provides brivaracetam characterized by Differential Scanning Calorimetric (DSC) thermogram as shown in Figure-2.
In another aspect, the present invention provides a pharmaceutical composition, comprising brivaracetam or a pharmaceutical jy acceptable salt thereof prepared by the processes of the present invention and at least one -pharmaceutical^ acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.
In another aspect, brivaracetam prepared by the processes of the present invention possess the relative particle size distribution, wherein the 10th volume percentile particle size D (0.1) is.less" than about 50"(im, preferably less than about 40 jam,, the 50th volume percentile particle size D (0.5) is less than about 150 pm, preferably less than about 100 jinvand the 90th volume percentile particle size.D (0.9) is less than about 400 (im, preferably less than about 300 Jim.
In any process of the present invention, any intermediate at any stage with or without isolation may be purified by using purification method known in the literature.

As used herein, the suitable leaving group includes chloro, bromo, iodo and the like; mesyl, tbsyl,
nosyl and the like. ' "
As used herein, the pharmaceutical^ acceptable salts includes acid addition salts formed with inorganic acids or with organic acids. The inorganic acids maybe selected from hydrochloric acid, hydrobrornic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, and the like; organic acids may be selected from acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, hydroxyacetic acid, propanoic acid, pyruvic acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonie acid, benzenesulfonic acid, j9-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid and the like.
As used herein, the purification method improves the chemical purity and/or chiral purity, includes salt formation, acid-base treatment, precipitation, crystallization using solvent, distillation, filtration and the like. The best mode of carrying out invention is illustrated by the below mentioned examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
Examplerl: Preparation of 3-(2-amino-2-oxoethyI)hexanbic acid
3-Propyl glutaric acid (250g, 1.43mol) and acetic anhydride (270g, 2.64mol) were Combined and placed under reflux for 6h. The mixture was distilled under vacuum at 100°C followed by degassing for 30min. The residue 3-pfopylglutaric anhydride was dissolved in methyl tert-b\ity\ ether (250 ml) and slowly adjusted the pH to 8-9 by aqueous ammonia (290ml) at 0-10°C and water (375ml, 1.5V) was added at temperature of 25°C or less. The mixture was stirred for 5h, and the layers were separated. In the aqueous layer hydrochloric acid (235ml) was added to adjust the pH of 1-2. The mixture was stirred at 25-30°C for 2h followed by stirring at 0-5 °C for 2h and filtered. The solid was washed with water (250ml x 2) and dried under vacuum. The solid was then slurried in hot (60-65 °C) ethyl acetate (375ml) for 30min. The solution was maintained for 2h at 25-30 °C and 2h at 0-5°C. The product was collected by filtration. The solid was washed with cold ethyl acetate (62.5mlx2) and dried under reduced plressure at 55-60 °C to give 3-(2-amino-2-oxoethyI)hexanoic acid (190g, 76.8%) as white to off white solid.

ExampIe-2: Preparation of compound (2iS)-3-(2-AminoT2-6xoethyI)hexanoic acid (15)-1-phenylethan-1-amine salt
3-(2-Amino-2-oxoethyl)hexanoic acid (170g, 0.981 mol) was added to a mixture of absolute ethanol (41 ml, 0.24V) and chloroform (1955 ml, 11.5V) and stirred.for 5 min. (Sj-Alpha methylbenzylamine (89.20 g5 0.736 mol) was added drop wise to the above reaction mixture over a period of 30min and stirred for 15 min, maintained the reaction mass to 55-60°C for lh. Slowly cooled the reaction mass to room temperature over a period of 2h and maintained for 30 min, further cooled the reaction mass to 10-15°C and maintained for 30min. The mixture was filtered under nitrogen atmosphere. Wet solid was washed with cold chloroform (85ml, 0.5V) and dried under vacuum at 50-55°C for 12h to give off white solid. The crude solid was then dissolved in absolute ethanol (41 mL, 0.24 V) and chloroform (1955ml, 11.5V) at 55-60°C for 60 min to obtain the clear solution. Slowly cooled the reaction mass to room temperature over a period of 2h and maintained for 30min, further cooled the reaction mass to 10-15°C and maintained for 30min. The mixture was filtered under nitrogen atmosphere. Wet solid was washed with cold chloroform (85ml, 0.5V) and dried under vacuum at 50-55°C gives (2S)-3-(2-Amino-2-oxoethyl)hexanoic acid (lS)-l-phenylethan-l-amine salt (lOOg, 69%) as off white solid.
ExampIe-3: Preparation of (2iS)-3-(2-amino-2-oxoethyl)hexanoic acid
* ■ ■ ■
(2iS)-3-(2-Amino-2-oxoethyl)hexanoic acid (\S)-\-phenylethan-1 -amine salt (90 g, 0.305 mol), was placed into water (270 mL, 3 V). The mixture was given charcoal treatment with 2.85% activated carbon "for lh and filtered through hyflo bed. Washed the bed with water (45mL, 0.5V) then the filtrate passed through the micron paper. Clear filtrate was acidified to pH 1-2 at room temperature with concentrated hydrochloric acid. The mixture was stirred at.25-30°C for 30 min followed by stirring at I0-15°C for 30 min and filtered. The solid was washed with cold water (45ml, 0.5 V) and dried under reduced pressure at room temperature for 2h followed by 40-45°C to give (2£)-3-(2-amino-2-oxoethyl)hexanoic acid (43 g, 82%) as a white solid.
Example-4: Preparation of (i?)-3-((((5)-l-carboxypropyl)amino)methyI)hexanpic acid
To a cold stirred solution of NaOH.(24.Wg, 0.623 mol) in DM water (225 mL) was added (5)-3-(2-amino-2-oxoethyl)hexanoic acid (90 g, 0.519 mol) portion wise at 0-10°C in 3,0-40 min. An

alkaline solution of hypo (mixture -p£35.33 gNaOH dissolved in 35.3 mL DM water and 690.7 g of 5.6% NaOCl) was added dropwise to the reaction mass during 30-40 min at 5-10°C. The reaction mass was warmed to room temperature. The reaction mass was heated to 60-65°C and stirred for 2h at that temperature. It was cooled to 15-20°C, adjusted pH 5-5.5 with cone. HC1, and was stirred at 25-30°C for 2h.(i?)-2-bromobutanoic acid (86.77 g, 0.519 mol) and KOH (58.2 g, 1.04 mol) were added to it at 15-35°C and stirred at 35-40°C for 5h. After cooling the reaction mass/KOH (14.55 g-0.26 mol) was added at 20-35°C. Again the reaction mass was heated and stirred at 35-40°C for 5h. After cooling, (7?)-2-bromobutanoic acid (43.38 g, 0.259 itiol) and KOH (29.1 g, 0:519 mol) were added to the reaction mass at 20-35°C and again stirred at 35-40°C for , 1 Oh. Another lot of (7?)-2-bromobutanoic acid (43.38 g) and KOH (29.1 g) were added after cooling at 20-35°C and the reaction was further continued at 35-40°C for 16h. The reaction mass was cooled to 20°C, adjusted the pH to 3-3.5 with cone. HC1 at 20-30°C and stirred for 2h at room temperature. The precipitated solid was filtered, washed twice with DM water (2 x 270 mL) and sucked to dryness for 30-40 min. The wet solid was made slurry with ethyl acetate (450 mL), filtered, washed with ethyl acetate (2 x 180 mL) and suck dried for 30-40 min at room temperature. The suck dried solid was made slurry in ethyl acetate (1170 mL), heated to 50-55°C for Ih and then cooled to 30-35°C. A solution, of S-phenylethylamine (59.81 g, 0.493 mol) in ethyl acetate (180 mL) was added to the reaction mixture and stirred at 30-35°C for 30 min. The reaction mass was cooled to 25-30°C and stirred for 3h. The solid was filtered, washed with ethyl acetate (2 x 180 mL) and suck dried for 30-40 min. The solid was stirred with ethyl acetate (1350 mL) at 50-55°C for lh, cooled to room temperature/and stirred for 3h. The solid was filtered, washed with ethyl acetate (2 x 180 mL) arid suckedto dryness. To a stirred slurry of the above solid in DM water (360 mL) 20% aqueous NaOH was added dropwise to adjust pH to 10-10.5 at 25-30°C. The reaction mass was washed with DCM(2 x 450 mL) and basic aqueous layer was acidified to pH 3-3.5 with cone. HC1 at room temperature. The reaction mass was stirred at 25-30°C for 2h and the precipitated solid was filtered, washed with DM water (2 xl80 mL) and sucked to dryness. The wet solid was made slurry with EtOAc (450 mL), washed with ethyl acetate (2 x.190 mL), sucked dried and finally dried under vacuum for 12-14h to afford (i?)-3-((((S)-l-carboxypropyI)amino)methyl)hexanoic acid (83 g, 69%) as .white solid.
Example-5: Preparation of Brivaracetam

A stirred mixture of (7?)-3-((((5)-l-carboxyprQpyl)amino)methyl)hexanoic acid (70 g, 0.3 mol) and sulphuric acid (118.77 g, 1.2 mol) in methanol (700 mL) was refluxed.for 20-24 h. After completion, solvents were distilled off completely from reaction mixture under vacuum 45-50°C to get an oil. The residual oil was cooled to 15-20°C, dissolved in toluene (350 mL) arid water (280 mL) and pH initially was adjusted to -5 by using 20% NaOH solution followed by 9.0-9.5 by using 20% Na2C03 at 20-35° C. The layers were separated at 30-35° C and aqueous layer was - re-extracted with toluene (350 mL) at 30-35°C. Combined toluene layeVs was washed with 10% aqueous Na2C03 solution (350 mL) followed by 10% aqueous sodium chloride solution (350 mL). The organic layer was heated with 2-hydroxypyridine (5.76 g, 0.06 mol) at 80-85°C for 6h. After reaction completion, the mixture was cooled to 25-30°C and washed with IN HC1 (2x350 mL), saturated aqueous sodium bicarbonate (2x350 mL) and 10% sodium chloride solution (350 mL) respectively. The residual oil after evaporation of solvent was cooled to 0-5°C and treated slowly with 25% aqueous ammonia solution (420 mL). Gaseous ammonia was purged to the mixture for Ih at 0-5° C and stirring continued further for 20-23 h at 0-5°C. After reaction completion, the reaction mixture was diluted with DCM (560 mL) and stirred for 15-20 min-at 25-30 °C. Separated the layers and aqueous layer was extracted with DCM (560 mL) at room temperature. Combined DCM layers was washed with 30% brine solution (2x140 mL). Organic layer was treated with activated carbon (3.5 g) at room temperature for 15-20 min, filtered through hyflo followed by 0.45// filter paper and washed with DCM (2x140 mL). Combined filtrate was distilled put at atmospheric pressure and residual traces DCM was removed by chasing with 1.5% IPA in cyclohexane (2x140 mL) to get solid residue. The residual solid was dissolved in 1.5% IPA in cyclohexane (420 mL) at 60-65 °C, gradually cooled to 25-30 °C and stirred 3-4 h at 25.-30 °c! Filtered the precipitated solid, washed with 1.5% IPA in cyclohexane mixture (2x105 mL) and dried under vacuum at 40-45 °C for 12-15 h to obtain brivaracetam (38 g, 60%) as white crystalline solid. HPLC Purity: 99.90%, Chiral Purity: 99.98%. Relative particle size distribution: 10th volume percentile particle size D (0.1) is 25.76 jam, the 50th volume percentile particle size D (0.5) is 86.63 jim, and the 90th volume percentile particle size D (0.9) is 219.99 jam!
ExampIe-6: Preparation of (2JR)-2-(2-oxo-4-propylpyrroIidin-l-yI)butanoic acid
A mixture of (^)-3-((((5)-l-carboxypropyI)amino)methyl)hexanoic acid (2 g, 0.008 mol) and 4-dimethylaminopyridine (0.2 lg, 0.001 mol) in toluene was refluxed for 2 h. After completion

(monitored the reaction by TLC) the reaction mass was cooled to room temperature and was - washed with IN aqueous HC1 solution (30 mL). The aqueous layer was extracted with DCM (30 mL). The residue obtained after evaporation of the combined organic layers (toluene and DCM) was dissolved in 10% aqueous NaiCCbsolution and was washed with DCM (30 mL). The aqueous layer was acidified with cone. HC1 to pH 1-2 and was extracted with DCM (2X 30 mL). The organic layer was evaporated under vacuum to obtain the (2i?)-2-(2-oxo-4-propylpyrrolidin-l-yljbutanoic acid (1.65 g) as solid.
Example-7: Preparation of Brivaracetam
To a stirred solution of (27?)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanoic acid (4.8 g, 0.022 mol),
diisopropylethylamine (4.35 g, 0.0335 mol) in THF (60 mL) was added drop wise a solution of
ethyl chloroformate (2.9 g, 0.027 mol) in THF (5mL) at 0-5C. Then the reaction mass was wormed
to room temperature and stirred for 2 h. Reaction mixture was again cooled to 0-5°C and treated
with ammonical-THF solution (50 mL). After stirring at room temperature for 4 h, the solvents
were evaporated under vacuum at 35-40C. The residue was dissolved in methylene dichloride
(100 mL) and IN aqueous HC1 (25mL), stirred for 10 min and separated the layers. The organic
layer was washed with saturated aqueous sodium bicarbonate solution and finally with brine.
Evaporated the organic layer and the residual oil was triturated with diisopropylether to obtain
desired brivaracetam (4.5 g) as semisolid material. '
Example-8: Preparation of Brivaracetam
To a stirred solution of (27?)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanoic acid (1.6 g, 0.0075 mol)
in methanol (16 mL) was added thiony! chloride (1.8 g, 0.015 mol) at 0-5°C. The reaction mass
was wormed to room temperature and stirred for 16 h. Evaporated the solvent under vacuum at
40-45°C and residual oil was dissolved in methylene dichloride (30 mL) at room temperature. The
organic layer was washed with saturated,aqueous sodium bicarbonate solution (2X20 mL), and
brine (20 mL). Evaporated the organic layer under vacuum to furnish cyclic ester as an oil. The
cyclic ester was converted to brivaracetam without any further purification. The oil was treated
with liquor ammonia (25%, 4 g) at 0-5°C for 24 h. The aqueous layer was extracted with methylene
dichloride (2x20 mL). Organic layer was evaporated under vacuum to obtain brivaracetam (1.2 g)
as solid.

We Claim:

1. A process for the preparation of the brivaracetam or pharmaceutically acceptable salt
thereof comprising the steps of:: a) converting (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula-.(II)

NH-
0" OH

(H)
to (i?)-3-(aminomethyl)hexanoic acid of formula (IIA);

NH-
y
(R) V "OH " (HA)
b) reacting 0/?)-3-(aminomethyl)hexanoic acid of formula (IIA) with compound of formula (IIB)

Wherein LG represents suitable leaving group selected from halogen, tosylate, mesylate to obtain~(7?)-3-((((iSf)-l-carboxpropyl)amino)methyl)hexanoic acid of formula (III); .
^COOH
,xNH
(S)|
• * - ' .' O- OH
c) converting (^)-3K(((5)-l-carboxyprp.pyI)amino)methyl)hexanoic acid of formula (III) to . compound of formula (IIIA);;
.COOR!
/\.vNH
O^OR2 (IIIA)
wherein Rj and R2 independently selected from C i-Cecdkyl d) converting compound of formula (IIIA) to compound of formula (IIIB);

N
D»o
0R2

O
. / (1MB)
e) converting compound of formula (IIIB) to brivaracetam of formula (IA) or pharmaceutical^ acceptable salt thereof; and
f) optionally, purifying the brivaracetam of formula (IA) by using purification method to obtain pure brivaracetam or pharmaceutical^ salt thereof, wherein purification method is not purification by chiral chromatography.
2. The process as claimed in claim 1, wherein compound of formula II is prepared by the steps comprising of;
a) converting 3-propylglutaric acid of formula (IV)
,COOH -COOH
(IV)
to 4-propyldihydro-2//-pyran-2,6(3//)-dione of formula (V); '
o ..
. (V) "
b) converting the 4-propyldihydro-2i/-pyran-236(3//)-dione of formula (V) to 3-(2-amino-2-
oxoethyl)hexanoic acid of formula (VI);
^ o
NH2

c) treating the 3-(2Tamino-2-oxoethyl)hexanoic acid of formula (VI) with a suitable resolving
*■ . -
agent to. obtain compound of formula (VII);
O. OH 'Resolving group (VII)
o

d) converting the compound of formula (VII) to (S)-3-(2-amino-2-oxoethyl)hexanoic acid
compound of formula (II). 3. The process as claimed in claim. 1, wherein brivaracetam or pharmaceutically acceptable,
salt thereof is prepared by the process comprising the steps of:
a) converting (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (II) to (i?)-3-(am.inomethyl)hexanoic acid of formula (IIA) using suitable base, reagent in the presence of solvent; " ■■ " .
b) reacting (i?)-3-(aminomethyl)hexanoic acid of formula (IIA) with compound of formula (IIB) using suitable base in the presence of solvent to obtain- (7?)-3-((((S)-l-" carboxpropyl)amino)methyl)hexanoic acid of formula (III); .
c) converting (^?)-3-((((5)-l-carb6xypropyl)amino)methyI)hexanoic acid of formula (III) to compound of formula (IIIA) using suitable acid in the presence of one or more ester forming reagents;
d) converting compound of formula (IIIA) to compound of formula (IIIB) by using suitable catalyst;
e) converting compound of formula (IIIB) to brivaracetam of formula (IA) or pharma¬ceutically acceptable salt thereof by using suitable ammonia source; and
f) optionally,'purifying the brivaracetam of formula (IA) by using purification method to obtain pure brivaracetam or pharmaceutically acceptable salt thereof, wherein purification method is not purification by chiral chromatography.
4. The process as claimed in claim 1, wherein brivaracetam or pharmaceutically acceptable salt thereof is prepared by the process comprising the steps of:
a) converting (S)-3-(2-amino-2-oxoethyI)hexanoic acid of formula (II) to (tf)-3-(aminomethyl)hexanoic acid of formula (IIA) using suitable base, reagent in the presence of solvent; , ' ~
b) reacting (i?)-3-(aminomethyl)hexanoic acid of formula (IIA) with (7?)-2-bromobutyric acid of formula (IIB5) using suitable base in the presence of solvent to obtain (i?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III);
c) converting (7?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) to methyl .(^-S-^^-l-methoxy-l-oxobutan^-yOamino) methyl)hexanoate. of formula (IIIA') using suitable acid in the presence of one or more ester forming reagents;

d) converting methyl (7?)-3-((((5)-l-methoxy-l-oxobutan-2-yI)amino)methyl)hexanoate of formula (IIIA') to methyl (5)72-((7?)»2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB') using suitable catalyst in the presence of solvent;
e) converting methyl (5)-2-((i?)-2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB') to brivaracetam of formula (IA) or pharmaceutieally acceptable salt thereof by using suitable ammonia source; and
f) optionally, purifying the brivaracetam of formula (IA) by using purification method to obtain pure brivaracetam or pharmaceutieally acceptable salt thereof, wherein purification method is not purification by chiral chromatography.
5. The process as claimed in claim 1, wherein brivaracetam or pharmaceutieally acceptable
r ■ . •
salt thereof is prepared by the process comprising the steps of:
a) converting (7?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) to compound of formula (IIIA) using suitable acid in the presence of one or more ester forming reagents;
b) converting compound of formula (IIIA) to compound of formula (IIIB) by using suitable catalyst in the presence of solvent; .
c) converting compound of formula (IIIB) to brivaracetam of formula (IA), or pharmaceutieally acceptable salt thereof by using suitable ammonia source; and
d) optionally, purifying the brivaracetam of formula (IA) by using purification method to obtain pure brivaracetam or pharmaceutieally acceptable salt thereof, wherein purification method is not purification by chiral chromatography.
6. The process as claimed in claim 1, wherein brivaracetam or pharmaceutieally acceptable
salt thereof is prepared by the process comprising the steps of: .
a) converting (7?)-3-((((5')-l-carboxypropyl)amino)methyl)hexanoic acid of formula (III) to methyl (i?)-3-((((iS)-l-methoxy-l-oxobutan-2-yl)amino)methyl)hexanbate of .formula (IIIA?) using suitable acid in the presence of one or more ester forming reagents;
b) converting methyl (i?)-3-((((5)-l-methoxy-l-oxobutan-2-yl)amino)methyl)hexanoate of formula (IIIA') to methyl (5)-2-((i?)-2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB5) by using suitable catalyst in the presence of solvent; ;

!lc) converting methyl (iS)-2-((i?)-2-oxo-4-propylpyrrolidin-l-yl)butanoate of formula (IIIB')
to brivaracetam of formula (IA) or pharmaceutically acceptable salt thereof by using
suitable ammonia source; and d) optionally, purifying the brivaracetam of formula (IA) by using purification method to
obtain pure brivaracetam or pharmaceutically acceptable salt thereof, wherein purification
method is not purification by chiral chromatography.
7. The process as claimed in claim 3 to 6, wherein suitable solvent, one or more ester forming reagents is selected from group comprising of water, alcohol, ether, halogenated hydrocarbons, hydrocarbons, ketone; and suitable base is selected from inorganic or organic bases.
8. The process as claimed in claim 3 to 6, wherein reagent is selected from group comprising of halogen source selected sodium hypochlorite, sodium hypobromite, chlorine, bromine and suitable acid is selected from group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulphuric acid, phosphoric acid, nitric acid.
9. The process as claimed in claim 3 to 6, wherein suitable catalyst is selected from group comprising 4-(dimethylamino)pyridine, 2-hydroxy pyridine and ammonia source is selected from ammonia solution, ammonia gas.