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-[(47?)-2-oxo-4-propyltetrahydro-1//-pyrrol-1-yl] butanamide having structure of Formula (I),
■1ST r°
NH2
O
(!)
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 amination step using (S)-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:

*M^O
x J^0
NH-
O
V

HCT ^o °

PhMe, NaBH4, H20 AcOH-
NH2

O
NH-

O

O NH

HCOONH4 Pd/C "
HoO


N ,^ . + •• N
NH-
O

(I)
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: " •


W^O
O

H

+ H

o

OH
O NH V_
o : HCI, H2O HO^\Q

NH2
o

NH2 •HCI

NH-

Pd/C, H2

N

O NH-

+ N '

O NH-

O

O

O

' (")

~)

Scheme-II
The above method of Scheme-II further involves separation of two diastereomers using chiral chromatography.
U.S. Patent No. 8j957,226 discloses process for preparation of brivaracetam as shown in following Scheme-Ill:


Chiral HPLC
»~
OON;

Raney Ni MeOH

Br
OMe
cxo-^-

N

O.

O O

Aq. NH3

N

O

O NH-

Chiral HPLC

- ^o
NH-
0

(I)
v.
Scheme-Ill
U.S. Patent No. 8,331,621 discloses process for preparation of (S)-2-[4-propyI-2-oxopyrrolidin-l yl]butyramide which is shown in following Scheme-lV:


O

Br

O

H2N OMe + -HCI

O

OMe

O^ J3Me


OMe

V

V^O
OMe
O

(S)-2-[4-propyl-2-oxopyrrolidin-1-yl]butyrarnide

Scheirie-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
MgBr +

O

o

Cul
TMSCI
dry Et20

TMSI |
CH2CI2'

O SOCI2

Chiral HPLC

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 process for the preparation of intermediate compound and its use in preparation of brivaracetam. The process comprising the steps of:
a) converting 3-propylglutaric acid of formula (II) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III);
b) treating 3-(2-arriino-2-bxoethyl)hexanoic acid of formula (III) obtained in step (a) with suitable resolving agent to obtain compound of formula (IV);
c) converting the compound of formula (IV) obtained in step (b) to (S)-3-(2-amino-2-
, oxoethyl)hexandic acid of formula (V); and
d) converting (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) obtained in step (c) to
brivaracetam of formula (I) or pharmaceutical^ acceptable salt thereof.
In another aspect, the present invention provides process for the preparation of intermediate compound and its use in preparation ,of brivaracetam, as shown in Scheme-VI. The process comprising the steps of:

a) converting 3-propyIgIutaric-acid of formula. (II) to 4-propyIdihydro-2//-pyran-2,6(3//)-dione of formula (IIA); .
b) converting 4-propyldihydro-27/-pyran-2,6(3//)-dione of.formula (IIA) obtained in step (a) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III);
c) treating 3-(2-^mino-2-oxoethyl)hexanoic acid of formula (III) obtained in step (b) with suitable resolving agent to obtain compound of formula (IV);
d) converting the compound of formula (IV) obtained in step (c) to (5)-3-(2-amino-2-oxoethy))hexanoic acid of formula (V); and
e) converting (5)-3-(2-amino-2-oxoethyI)hexanoic acid of formula (V) obtain in step (d) to brivaracetam of formula (I) or pharmaceutically acceptable salt thereof
In another aspect, the present invention provides process for preparation of intermediate compound of formula (j§|) or salts thereof and its use.in preparation of brivaracetam, as shown in Scheme-VII. The process comprising the steps of:
a) treating the 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) with suitable resolving agent to obtain compound of formula (IV);
b) converting the compound of formula (IV) obtained in step (a) to (S)-3-(2-amino-2-oxoethyI)hexanoic acid of formula (V);
V *
c) converting (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) obtained in step (b) to
brivaracetam of formula (I) .or pharmaceutically acceptable salt thereof
In another aspect the present invention provides a process for the preparation of the brivaracetam or pharmaceutically acceptable salt thereof, as shown in Scheme-VIIL The process comprising the steps of:
a) treating 3-propylglutaric acid of formula (II) with suitable reagent tq obtain 4-propyldihydroT2iy-pyran-2,6(3//)-dione of formula (IIA);
b) converting 4-propyldihydro-2#-pyran-2,6(3#)-dione of formula (IIA) obtained in step (a) to 3-(2-amino-2-6xoethyl)hexanoic acid of formula (III);
c) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) obtained in step (b) with suitable resolving agent to obtain .compound, of formula (IV);

d) converting the compound of formula (IV) obtained in step (c) to compound (S)-3-(2-amino-2-oxoethyI)hexanoic acid of formula (V);
e) converting (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) obtain in step (d) to (7?)-3-(aminomethyl)hexanoic acid of formula (VI);
f) reacting (i?)-3-(aminomethyl)hexanoic acid of formula (VI) obtained in step (e) with compound of formula (VII) , to obtain (7?)-3-((((5)-l-
carboxypropyl)amino)methyl)hexanoic acid of formula (VIII);
(.■••■
g) converting (i?)-3-((((S)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (VIII)
obtained in step "(f) to compound of formula (IX); h) converting compound of formula (IX) obtained in step (g) to compound of formula (X); i) converting compound of formula (X) 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 pharmaceutical^ acceptable
salt thereof, wherein purification method is not purification by chiral chromatography.
In another aspect the present invention provides a process for the recovery of 3-propylglutaric acid > and (i?)-(naphth-l-yl)ethan-l-amine from the mother liquors during the preparation of (S)-3-(2r amino-2-oxoethyl)hexanoic acid.
DETAIL DESCRIPTION OF THE INVENTION
One aspect of the presentinvention provides process for the'preparation of intermediate compound of formula (V) and its use in preparation of brivaracetam. The process comprising the steps of:
a) converting 3-propylglutaric acidof formula (II) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III);
b) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) obtained in step (a) with suitable resolving agent to obtain compound of formula (IV); ■ /
c) converting the compound of formula (IV) obtained in step (b) to (iS)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V); and
d) converting (S)-3-(2-amino-2-oxoethyl)hexanoic acid" of formula (V) obtain in step (c) to brivaracetam of formula (I) or pharmaceutical ly acceptable salt thereof.

In step a) of the aforementioned process, conversion of 3-propylglutaric acid of formula (II) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) proceed through an intermediate compound 4-propyldihydro-2//-pyran-2,6(3//)-dione 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).
Step a) of the aforementioned process conversion of compound of formula (II) to comipoiind of formula (IIA) is carried out in a suitable reagent selected from the group comprising of acetic anhydride, acetyl chloride or the like, preferably acetic anhydride.
Step a) of the aforementioned process conversion of compound of formula (IIA) to compound of formula (III) is carried ouf by using suitable ammonia source selected from ammonia, aqueous ammonia or the like.
Step b) of the aforementioned process is carried out by using suitable resolving agent selected from the group comprising of either (R) or (S) of the enantiomer of l-(l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine, A^-benzyl phenylethylamine, 1-phenylethylamine or the like.
Step c) of the aforementioned process may be carried out by using suitable base selected from the
group comprising of aqueous sodium hydroxide, sodium hydroxide, potassium hydroxide or the
like. •.'-■'
In another aspect, the present invention provides process for the preparation of intermediate compound and its use in preparation of brivaracetam, as shown in Scheme-VL The process comprising the steps of:
a) converting 3-propylglutaric acid of formula XII) to 4-propyldihydro-2#-pyran-2,6(3//)-diorie'of formula (IIA); : y
b) converting 4-propyldihydro-2//-/pyran-2,6(3//)-dione of formula (IIA) obtained in step (a) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III);
c) treating 3-(2-amino-2-pxoethyl)hexanoic acid of formula (III) obtained in step (b) with suitable resolving agent to obtain, compound of formula (IV);
d) converting the compound of formula (IV) obtained in step (c) to (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V); and

e) converting (6)-3-(2-amino-2-oxoethyI)hexanoic acid of formula (V) obtained in step (d) to brivaracetam of formula (I) or pharmaceutical ly acceptable salt thereof.


r

.COOH
(I")

(MA)

O^ OH

(III)

CroH 'Res°lvin9
NH-
group

0-
NK

(IV)

(V)

(I)

O

Scheme-VI
wherein resolving group is selected from either (R) or (S) of the enantiomer of 1-(1-
naphthyl)ethylamine, 1 -(2-Naphthyl)ethyIamine, TV-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 the group comprising of acetic anhydride, acetyl chloride or the like, preferably acetic anhydri.de.
Step b) of.the aforementioned process is carried out by using suitable ammonia source selected from ammonia, aqueous amrnonia 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 l-(l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine, jV-benzyl phenylethylamine, 1-phenylethylamine or the like.
Step d) of the aforementioned process is carried out by using suitable base selected from the group
■ "N
comprising of aqueous sodium hydroxide, sodium hydroxide, potassium hydroxide or the like.

In another aspect, the present invention provides process for preparation of intermediate compound
of formula (H) or salts thereof and its use in preparation of brivaracetam, as shown in Scheme-VII.
. -> ■
The process comprising the step of:
a) treating the compound of formula (III) with suitable resolving agent to obtain compound of formula (IV); - ,. '- " < '. •
b) converting the compound of formula (IV) obtained in step a) to compound of formula (V);
c) converting compound-of formula (V) obtained in step (b) to brivaracetam of formula (I) or pharmaceutically acceptable salt thereof




o
NH2—- ftsT^ ^NH2 - .^^N^MH^^ _,. _ ^N^O
0^"OH O^^OH 'Resolving ^k \^x^NH2
group MH „
(III) (IV) (V) • m O ■
0)

Scheme-VII
wherein resolving group is selected from the group comprising of either (7?) or (5) of the enantiomer of l-(l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine, Af-benzyl phenylethylamine,
r
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 by using suitable resolving agent selected from the group, comprising of either,(R) or (S) of the enantiomer of l-(l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine, TV-benzyl phenylethylamine, 1-phenylethylamine or the like.
Step b) of the aforementioned process is carried out by using suitable base selected from the group comprising of aqueous sodium hydroxide, sodium hydroxide, potassium hydroxide or the like.
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) treating 3-propyIgIutaric acid of formula "(II) with suitable reagent to obtain 4-
propy!dihydro-2//-pyran-2,6(3//)-dione of formula (HA); b.) converting 4-propyldihydro-2/Apyran-2?6(3/^)-dione of formula (IIA) obtained in step (a)
to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III);
c) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) obtained in step (b) with suitable resolving agent to obtain compound of formula (IV);
d) converting the compound of formula (IV) obtained in step (c) to compound (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V);
e) converting (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) obtained in step (d) to (7?)-3-(aminomethyl)hexanoic acid of formula (VI);
f) reacting (i?)-3-(aminqmethyl)hexanoic acid of formula (VI) obtained in step (e) with compound of formula (VII) to obtain (i?)-3-((((S)-l-carboxypropyl)amino)methyl)hexanoic acid of formula (VIII);
g) converting (7?)-3-((((iS)-l-carbpxypropyl)amino)methyl)hexanoic acid of formula (VIII) obtained in step (f) to compound of formula (IX);.
h) converting compound of formula (IX) obtained in step (g) to compound of formula (X); / i) converting compound of formula (X) obtained in step (h) to brivaracetam of formula (IA)
or pharmaceutically acceptable salt thereof; and j) optionally, purifying the brivaracetam of formula (IA) obtain in step (i) by using purification method to obtain brivaracetam of formula (I) or pharmaceuticaliy-acceptable salt thereof, wherein purification method is not purification by chiral chromatography.v


- r^o —:

.COOH
(I")

O
(HA)

O OH 'Resolving group (IV)
- Oo
COOH
O
(I)
NH-

Scheme-VIII
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 (7?) or (iS) of the enantiomer of l-('l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine,_ Af-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, preferably acetic anhydride.
Step b) of the. aforementioned process is carried but by using suitable ammonia source selected
' ■ , '■•-'•■
from 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. (S) of the enantiomer of l-(l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine, TV-benzyl phenylethylamine, 1-phenylethylamine or the like, in presence of a suitable solvent or mixture of solvents.

Step d) of the aforementioned process is carried out by using.suitable base selected from the group comprising of aqueous sodium hydroxide, sodium hydroxide, potassium hydroxide or the like.
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.
Step f) of the aforementioned process is carried out by using suitable base selected from the group comprising ofhydrides, 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^JV-diisopropylethylamine, TV-
■».'■' ■ " ■ -
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 ajcohol 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 ter/-butyl 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 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, propanol, 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) o'fthe 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.
The product obtained at this stage may be purified further to improve chemical purity and/or chiral
purity. >
In another aspect, present invention provides process for preparation of brivaracetam wherein (S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) used as an intermediate compound.
In another aspect the present invention provides a process for the recovery of 3-propVlglutaric acid and (7?)^(naphth-l-yl)ethan-l-amine from the mother Ijquors during the preparation of (5)-3-(2-amino-2-oxoethyl)hexanoic acid.
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.
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 nitrites, 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, n-propanol, isopfopanol, w-butanol and the like. Ketones are selected from.the group comprising of acetone, methyl ethylketone, 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, methyl iterf-butyl ether (MTBE), diisopropyl ether, cyclopentyl methyl 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 (he 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 suchas chloroform, ethanol, acetone, toluene, Zso-propyl alcohol, methanol, acetonitrile, ethyl acetate and combination thereof or the like. .
As used herein, the suitable leaving group includes chloro, bro.mo, iodo and the like; mesyl, tosyl, nosyl and the like.
As used herein, the pharmaceutically acceptable salt includes acid addition salts formed with inorganic acids or with organic acids. The inorganic acids may be selected from hydrochloric acid, hydrobromic 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, ethanesulfonic acid, benzenesulfonic acid, p-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 belowmentioned 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:
Example-1; Preparation of 3-(2-aminb-2-oxoethyI)hexanoicacid
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-propylglutaric anhydride was dissolved in methyl ter/-butyl ether (250ml) 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 for2h followed by stirring at 0-5 °C for2h 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 pressure at 55-60 °C to give 3-(2-amino-2-oxoethyl)hexanoic acid (190g, 76.8%) as white to off white solid.
ExampIe-2: Preparation of compound (2S)-3-(2-Amino-2-oxoethyI)hexanoic acid (15)-!-. phenyIethan-1-amine salt
3-(2-Amino-2-oxoethyI)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. (S)-A\pha methylbenzylamine (89.20 g, 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, 11S5V) 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-T5°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 (25)-3-(2-Amino-2-oxoethyl)hexahoic acid (lS)-l-phenylethan-l-amine salt (lOOg, 69%) as off white solid.
ExampIe-3: Preparation of (2*S)-3-(2-amino-2-oxoethyl)hexanoic acid
(25)-3-(2-Amino-2-oxoethyl)hex:anoic acid (15)-l-phenylethan-l-amine salt (90 g, 0.305 mol), was placed into water (270 mL, 3V). 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 fijtrate 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 10-15°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 (25)-3-(2-amino-2-oxoethyl)hexanoic acid (43 g, 82%) as'a .white solid.
ExampIe-4: Preparation of (J?)-3-((((5)-l-carboxypropyl)amino)methyl)hexanoic acid
To a cold stirred solution bfNaOH (24.94 g, 0.623 mol) in DM water (225mL) was added (5)-3-(2-amino-2-oxoethyl)hexanoic acid (90 g, 0.519 mol) portion wise at 0-10°C in 30-40 min. An alkaline solution of hypo (mixture of 35.33 g NaOH 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. HCI, 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 mol) 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 I Oh. Another lot of (i?)-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. HCI at 20-30°Cand 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 lh and then cooled to 30-35°C. A solution of S-phenylethy(amine (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 3.0-40 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) and sucked to 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 xl 80 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 12-14 h to afford (R)-3-((((S)-\-carboxypropyl)amino)methyl)hexanoic acid (83 g, 69%) as white solid.
Example-5: Preparation of Brivaracetam
A stirred mixture of (7?)-3-((((5)-l-carboxypropyI)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) and water (280 mL) and pH initially was adjusted to -5 by using 20% NaOH solution followed by 9.0-9.5 by using 20% Na2CC>3 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 layers 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-hydroxy pyridine (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 lh at 0-5° C and stirring continued further for 20-23 h at0-5°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/i filter paper and washed with DCM (2x140 mL). Combined filtrate was distilled out 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
i ■ ■
volume percentile particle size D (0.4 ) is 25.76 ^im, the 50th volume percentile particle size D (0.5)
is 86.63 |im, and the 90th volume percentile particle size D (0.9) is 219.99 ^m.
Example-6: Preparation of (2S)-3-(2-Amino-2-oxoethyl)hexanoic acid (12?)-1-naphthylethan-1-amine salt
i?-(+)-l-(l-Naphthyl)ethylamine (49.35g5 0.28mol) was added to the mixture of (2S)-3-(2-amino-2-oxoethyI)hexanoic acid (50g5 0.28mol) in acetone (400mL, 8V) at 25-30°C. The mixture was stirred at 25-30° C for 30 min and then at 55-60° C for 30 min. The reaction mass was slowly cooled to 25-30° C over a period of 2 h and stirred for 2 h. The solid was isolated by filtration and washed the wet cake with acetone (50 mL) to get off white solid. The solid was made slurry with acetone (150 mL, 3V) at 55-60°C for 30min and then slowly cooled to 25-30° C over a period of 2h. The mixture was stirred at 25-30°C for 2h and filtered, washed with acetone (50mL, IV) to afford (2S)-3-(2-Amino-2-oxoethyI)hexanoic acid (17?)-l-naphthylethan-l-amine salt as white to off white solid. Yield: 32.0g, 64%.
Example-7: Preparation of (2iS)-3-(2-Amino-2-oxoethyl)hexanoic acid
(2S)-3-(2-Amino-2-oxoethyl)hexanoic acid (liJ)-l-naphthylethan-l-amine salt (30g, 0.087mol) was taken in a mixture of water (90mL, 3V) and toluene (150mL, 5V). The mixture was heated to 35-40°C to get clear solution and adjusted thepH to 11-12 using 20%> aqueous sodium hydroxide solution. The. reaction mass was stirred for 30 min and layers were separated. Aqueous layer washed with toluene (90mL, 3V) and separated the layers. Aqueous layer was charcoalized with activated carbon (5%) and filtered through hyflo bed. Filtrate was,passed through micron paper and pH was adjusted to 1-2 using cone, hydrochloric acid at 25-30°C. The slurry was stirred at 25-30°C for 30 min and 10-15°C for 2h. Filtered the solid and washed with water (30 mL, IV), dried at 25-30°C under vacuum for 2h followed by 45-50°C to get (2S)-3-(2-Amino-2-oxoethyl)hexanoic acid as white solid. Yield: 12.5g, 83%.
ExampIe-8: Preparation of (7?>naphth-l-ylethan-l-ammonium (5)-3-(2-amino-2-
. * ■*■
oxoethyl)hexanoate salt:

To a stirred slurry of race/mc-3-(2-amino-2-6xoethyl)hexanoic acid (20 g, 0.1155 mol) in ethyl .acetate (170 mL) and ethanpl (30 mL) was added (7?>(naphth-l-yl)ethan-l-amine (14.83 g, 0.086 mol) slowly at 25-30°C in 15 min. After stirring for 15 min at room temperature, the reaction mass was heated to reflux (75-80°C) and reflux continued for Ih. It was slowly cooled to room temperature during 2 h and stirred for 12 h,at room temperature. Filtered the solid and washed with ethyl acetate (20 mL). The solid was sucked to dryness and the wet solid was heated with ethyl acetate (147 mL) and ethanol (3 mL) at 75-80°C and stirred for 45 min. It was slowly cooled to room temperature in about 2 h, stirred for 2 h. The precipitated solid was filtered, washed with ethyl acetate (20 mL), sucked dried for 1 h at room temperature. The wet solid was heated with ethylacetate (147 mL) and ethanol (3 mL) at 75-80°C and stirred for 45 min. It was slowly cooled to room temperature in about 2 h, stirred for 2 h. Filtered the solid and washed with ethyl acetate (20 mL) and sucked to dryness to furnish the desired chiral (^-naphth-l-ylethari-1 -ammonium (iS)-3-(2-amino-2-oxoethyl)hexanoate salt (12 g, wet) as white solid. The wet solid was directly taken to the next step without any further drying.
ExampIe-9: Preparation of (S)-3-(2-amino-2-oxoethyl)hexanoicacid:
To a stirred suspension of sucked dried solid (7?)-naphth-l-ylethan-l -ammonium (iS)-3-(2-amino-2-dxoethyl)hexanoa:te salt (12 g) in water (42 mL) and toluene (60 mL), 20% aqueous NaOH solution was added to adjust pH~ 12-12.5 at 30-35°C and stirred for 30 min. Separated the layers and the aqueous layer was washed with toluene (60 mL) at 30-35°C. The aqueous layer was acidified with cone. HCl up to pH~l-2 at 25-30°C and stirred for 30 min. The slurry was further cooled to 10-15°C and stirred for 2h at that temperature. The precipitated solid was filtered, washed with cold water (2x5 mL), sucked dried and finally dried at 45-50°C for 10 h to furnish desired (iS)-3-(2-amino-2-6xoethyl)hexanoic acid (5.4 g, 54%) as white crystalline solid. Chiral purity; 99.9%
Example-10: Preparation of Y^"naphth-l-ylethan-l-ammonium (iS)-3-(2-amino-2-
• . .*..... r ..
oxoethyl)hexanoate salt:
To a stirred slurry of race/m'c-3-(2-amino-2-oxoethyl)hexanoic acid (50 g, 0.288 mol) in ethyl acetate (450 mL) and methanol (50 mL) was added /7?,)-(naphth-l-yl)ethan-l -amine (37.07 g, 0.216 mol) slowly at 35-40°C in 20-30 min. After stirring for 15 min at that temperature, the

reaction mass was heated to 70-75°C and stirred for lh. It was slowly cooled to room temperature during 2 h and stirred for 12 h at room temperature. Filtered the solid and washed with ethyl acetate (50 mL). The solid was sucked to dryness and the wet solid was heated with ethyl acetate (367.5 mL) and methanol (7,5 mL) at 70-75°C and stirred for 45 min. It was slowly cooled to room temperature in about 2 h, stirred for 2 h. The precipitated solid was filtered, washed with ethyl acetate (50 mL), sucked dried for, 1 h at room temperature. The wet solid was heated with ethylacetate (367.5 mL) and methanol (7.5 mL) at 70-75°C and stirred for 1 min. It was slowly cooled to room temperature in about 2 h, stirred for 2 h. Filtered the solid and washed with ethyl acetate (50 mL) and sucked to dryness to furnish the desired chiral (7?)-naphth-l-ylethan-l-ammonium (S)-3-(2-amino-2-oxoethyl)hexanoate salt (30 g, wet) as white solid. The wet solid was directly taken to the next step without any further drying.
Example-ll: Preparation of (5*)-3-(2-amino-2-oxoethyl)hexanoic acid:
To a stirred suspension of sucked dried solid/^-naphth-l-ylethan-l-ammonium (5)-3-(2-amino-2-oxoethyl)hexanoate salt in water (105 mL) and toluene (150 mL), 20% aqueous NaOH solution was added to adjust pH~ 12-12.5 at 30-35°C and stirred for 30 min. Separated the layers and the aqueous layer was washed with toluene (150 mL) at 30-35°C. The aqueous layer was acidified with cone. HC1 up to pH~l-2 at 25-30°C and stirred for 30 min. The slurry was further cooled to 10-15°C and stirred for 2h at that temperature. The precipitated solid was filtered, washed with cold water (2x 12.5 mL), sucked dried and finally dried at 45-50°C for 10 h to furnish desired (5)-3-(2-amino-2-oxoethyl)hexanoic acid (13.5 g, 54%) as white crystalline solid. Chiral purity: 99.96%. . / .
Example-llA: Recovery of 3-prdpylglutaric acid and (/?)-(naphth-l-yl)ethan-l-amine from, the mother liquors during the preparation of (iS)-3-(2-amino-2-oxoethyl)hexanoic acid using ethyl acetate/methanol solvent:
Ethyl acetate and methanol mother liquor (obtained from Example 10; 400 mL) were combined and evaporated under vacuum. The residue was stirred with basic toluene layer (300 mL) and aqueous acidic mother liquor (120 mL) at room temperature for 30 min and aqueous NaOH solution was added to the RM to adjust pH-12-12.5. It was further stirred for 30 min at 35-40°C, filtered through hyflo and the hyflo bed was washed with toluene (50 mL). The layers were

separated from the filtrate and the aqueous layer was washed with toluene at 35-40°C. The combined toluene layer was taken for (7?)-(naphth-l-yl)ethan-l-amine-recovery and the aqueous layer was taken to the 3-propylgIutaric acid recovery.
Recovery of (Z?)-(naphth-l-yl)ethan-l-amine: Toluene layer (obtained above) was evaporated under vacuum to furnish (i?)-(naphth-l-yl)ethan-l-amine as oil. DCM (100 mL) and DM water (100 mL) were added to the residue and pH adjusted to 0.5 to 1 using cone. HC1. Stirred the mass for 1 h at RT,.filtered the solid and washed with DCM (50 mL). Filtrate was taken and layer separated. Aqueous layer was mixed with the above solid and pH was again adjusted to 12-12.5 using aq. NaOH solution at 25-40°C. It was extracted with toluene (2x100 mL) at 35-40°C and the combined toluene layer was evaporated at 50-55°C under vacuum to get (7?)-(naphth-l-yl)ethan-1-amine as an oil. Yield 32g, 86%.
Example-llB: Recovery of 3-propyIglutaric acid: To the aqueous layer (obtained in Example 11 A), NaOH (20g) was added and heated to.reflux for 12 h. After completion of the reaction, the mass was cooled to room temperature and acidified to pH~l -2 with cone. H2SO4. The product was extracted twice with toluene (2 x 250 mL) at 35-40°C. Evaporated the toluene layer under vacuum to obtain 3-propyIglutaric acid as an oil which solidifies on keeping at room temperature. Yield 30g,82%.
Example-12: Preparation of (K)-naphth-l-yIethan-l-ammonium (5)-3-(2-amino-2-oxoethyl)hexanoate salt:
To a stirred slurry of race/mc-3-(2-aminq-2-oxoethyl)hexanoic acid (20 g, 0.1155 mol) in toluene (170 mL) and /w-propanol (30 mL) was added (7?)-(naphth-l-yl)ethan-l-amine (14.83 g, 0.086 mol) slowly at 35-40°C in 20-30 min. After stirring for 15 min at that temperature, the reaction mass was heated to 70-75°C and stirred for lh. It was slowly cooled to room temperature during 2 h and stirred for 2 h at room temperature. The reaction mass was again heated to 70-75°C and stirred for lh. It. was slowly cooled to room temperature during 2 h and stirred for 12 h at room temperature. Filtered the solid and washed with 15% IPA in toluene (20 mL). The solid was sucked to dryness and the wet solid was heated with toluene (135, mL) and IPA (15 mL) at 70-75°C and . stirred for 1 h. It was slowly cooled to room temperature in about 2 h, stirred for 2 h. The precipitated solid was filtered, washed with 10% IPA in toluene (20 mL), sucked dried for 1 h at

room temperature. The wet solid was again heated with toluene (142.5 mL) and IPA (7.5 mL) at 75-80°C and stirred for 45 min. It was slowly cooled to room temperature in about 2 h, stirred for 2 h. Filtered the solid and washed with 5% IPA in toluene (20 mL) and sucked to dryness to furnish the desired chiral fi?)-naphth-l-ylethan-l-ammonium (S)-3-(2-amino-2-oxoethyl)hexanoate salt (10 g, wet) as white solid. The wet solid was directly taken to the next step without any further drying.
Example-13: Synthesis of (5)-3-(2-amino-2-oxpethyl)hexanoic acid
To a stirred suspension of sucked dried solid (7?j-naphth-l-ylethan-l -ammonium (S)-3-(2-amino-2-oxoethyl)hexanoate salt in water (35 mL) and toluene (50 mL), 20% aqueous NaOH solution was added to adjust pH~12-12.5 at 30-35°C and stirred for 30 min. Separated the layers and the aqueous layer was washed with toluene (50 mL) at 30-35°C. The aqueous layer was acidified with cone. HC1 upto pH~l-2 at 25-30°C and stirred for 30 min. The slurry was further cooled to 10-15°C and stirred for 2 h at that temperature. The precipitated solid was filtered, washed with cold water (2x5 mL), sucked dried and finally dried at 45-50°C for 10 h to furnish desired (S)-3-(2-aminoT2-oxoethyl)hexanoic acid (4.5 g, 45%) as white crystalline solid.

We Claim:

1. A process for the preparation of (5)-3-(2-amino-2-oxoethyl)hexanoic acid intermediate compound of formula (V) and its use in preparation of brivaracetam or pharmaceutically acceptable salt thereof comprising the steps of:
a).' converting 3-propylglutaric acid of formula (II)
.COOH
.COOH
(M) . to.3-(2-amino-2-oxoethy])hexanoic acid of formula (III);


J

b) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) with suitable resolving agent to obtain compound of formula (IV);

CTT>H "Resolving
- , group
(IV) c) converting the compound of formula (IV) to (*S)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V); and

' •■'■" (V) —
d) converting compound of formula (V) to brivaracetam or pharmaceutically acceptable salt
thereof.

2. The process as claimed in claim 1, wherein (S)-3-(2-amino-2-oxoethyl)hexanoic acid
intermediate compound of formula (V) or salts thereof and its use in preparation of
brivaracetam is prepared by the steps comprising of:
a) converting 3-propyIglutaric acid of formula (II) to 4-propyldihydro-2#-pyran-2,6(3//)-dione of formula (IIA) using suitable reagent;
b) converting 4-propyIdihydro-2//-pyran-2,6(3//)-dione of formula (IIA) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) by using suitable ammonia source in the presence of suitable solvent;
c) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) with suitable resolving agent in the presence of suitable solvent to obtain compound of formula (IV);
d) converting the compound of formula (IV) to (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (y) using suitable base in the presence of suitable solvent; and
e) converting (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) to brivaracetam or pharmaceutical^ acceptable salt thereof;
3. The.process as claimed in claim 1, wherein (S)-3-(2-amino-2-oxoethyl)hexanoic acid
intermediate compound of formula (V) or salts thereof and its use in preparation of
brivaracetam is prepared by the steps comprising of:
a) treating theJ3^(2-amino-2-oxoethyl)hexanoic acid of formula (III) with suitable resolving agent in the presence of suitable solvent to obtain compound of formula (IV);
b) converting the compound of formula (IV) to (5)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) using suitable base in the presence of suitable solvent; and
c) converting compound of formula (V) obtained in step (b) to brivaracetam or pharmaceutically acceptable salt thereof,

4. The process as claimed in claim 2, wherein suitable reagent is selected from the group comprising of acetic anhydride, acetyl chloride and ammonia source is selected from ammonia gas, aqueous ammonia or ammonia solution in any organic solvent.
5. The process as claimed in claim 1 to 3, wherein resolving agent is selected from the group comprising of either (7?) or (S) of the enantiomer of l-(l-naphthyl)ethylamine, l-(2-naphthyl)ethylamine, Af-benzyl phenylethylamine and 1-phenylethylamine;
6. The process as claimed in claim 2 arid 3, wherein solvent is selected from the group comprising of alcohols, ethers, halogenated hydrocarbons, aliphatic or aromatic

hydrocarbons, ketones, nitriles, nitriles, esters, amides, dialkylsulfoxides, water or
mixtures thereof. -
7. The process as claimed in claim 2 and 3, wherein base is selected from the group comprising of inorganic or organic base such as alkali or alkaline earth metal hydrides, hydroxides, ■-• carbonates, bicarbonates or triethylamine, tributylamine, -N-methylmorphoiine, ^A^diisopropylethylamine, A^-methylpyrroIidine, pyridine or mixtures thereof. - " ' 8. A process for the preparation of (5)-3-(2-amino-2-oxoethyl)hexanoic acid intermediate compound of formula (V) and its use in preparation of brivaracetam or pharmaceutically acceptable salt thereof comprising the steps of:
a) converting 3-propylglutaric acid of formula (II) to 4-propyldihydro-2//-pyran-2,6(3//)-
diohe of formula (IIA) using acetic anhyride;
b) converting 4-propyldihydro-2/7-pyran-2,6(3#)-dione of formula (IIA) to 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) by using aqu. ammonia in the presence of methyl tert-butyl ether;
c) treating 3-(2-amino-2-oxoethyl)hexanoic acid of formula (III) with R-(-)-(Naphthyl)ethylamine in the presence of acetone to obtain compound .of formula (IV);
d) converting the compound of formula (IV) to (S)-3-(2-amino-2-pxoethyl)hexanoic acid of formula (V) using base; and
e) converting (iS)-3-(2-amino-2-oxoethyl)hexanoic acid of formula (V) to brivaracetam or pharmaceutically acceptable salt thereof
9. The^use of (5)-3-(2-amino-2-oxoethyl)hexanoic acid compound of formula (V) as an
intermediate for the preparation of brivaracetam or pharmaceutically acceptable salt
thereof.