The present invention relates to a novel compound of Formula I and pharmaceutical acceptable salts thereof. The present invention further provides process for preparation of compound of Formula I that can be used for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-li7-pyrrol-l-yl] butanamide (brivaracetam) of Formula II


O Formula II

BACKGROUND OF THE INVENTION
Brivaracetam (BRIVIACT) chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-l//-pyrrol-l-yl] butanamide is used in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy and is represented as compound of Formula II below:
"t>°
'* NH2
Formula II
US patent 6,784,197 discloses a process of preparation of brivaracetam of Formula-II by hydrogenizing 2, 5-dihydro derivative of Formula B in presence of aqueous solution of ammonium formate and 10% Pd/C in water as represented in scheme-1. The two isomers i.e. Formula II and III were obtained by separating through preparative HPLC on chiral phase.

Scheme-1:


O
NH,
- 'O=o
N
Formula A
Formula B
1 NH, Formula II
N- NH2
a
Formula III
US 7,629,474 discloses preparation of brivaracetam of Formula II by reacting (2S)-2-aminobutyramide free base 5-hydroxy-4-n-propyl-furan-2-one of Formula A in isopropyl alcohol followed by hydrogenation in presence of palladium carbon (5%) in isopropyl alcohol together with hydrogen and acetic acid which on recrystallization resulted into diastereomeric mixture of brivaracetam.
US 8,338,621 discloses an alternate process for the preparation of brivaracetam wherein the process involves reaction of methyl-4-amino-3-propyl butyrate of Formula D with optically pure (S)-2-bromo butyric methyl ester of Formula C in acetonitrile. The resulting compound of Formula E is treated with 2-hydroxypyrridine in toluene to give methyl (2S)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanoate of Formula F which on hydrolysis gives corresponding hydroxyl compound, (2S)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanoic acid of Formula G. The compound so obtained is then treated with ethyl chloroformate and liquid ammonia to give diastereomeric mixture of brivaracetam as represented in scheme-2 below.
Scheme-2:

Br
n HCIH2N
w\ +
O Formula C

O
]
Formula D

X
Formula E

^o
b-o
^>o
N
OH
NH2
I o
Mixture of Formula II and III Formula G

N Formula F

Similarly, WO 2016/191435 discloses another process for the preparation of brivaracetam as represented in the scheme-3 below. Scheme 3:



SOCl2/ZnCl2 / C1
NH2 KOH

HCI
O
K2C03

NH,

Formula H

Formula I

Formula J

Formula-II

Although there are several processes known in the art, however there is always a need to develop a new process for the preparation of brivaracetam by employing novel intermediates and economically favourable steps which are reproducible at large scale production. The present invention focusses on the development of a process which is easy to scale up and is cost effective as well as provides highly pure product in a better yield.
OBJECT OF THE INVENTION
The main object of the present invention is to develop a novel compound of Formula I which can be used in the synthesis of brivaracetam.

Another object of the present invention is to develop a novel process for the preparation of brivaracetam wherein said process involves use of novel intermediate of Formula I.
Another object of the present invention is to develop a cost effective process for the preparation of brivaracetam, (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-li7-pyrrol-l-yl] butanamide, with high purity and yield.
Another object of the present invention is to isolate brivaracetam with diastereomeric purity of 97% and above.
SUMMARY OF THE INVENTION
The present invention relates to a novel compound of Formula I and process of preparation thereof, wherein said compound of Formula I can be used for the preparation of brivaracetam.
Accordingly, in main aspect, the present invention provides a novel compound of Formula I and pharmaceutical acceptable salts thereof;

Formula I.

Formula I
wherein said process comprising the steps of:
In second aspect, the present invention provides a process for preparation of compound of Formula I,

a) preparing alkyl 3-(dimethoxymethyl)hexanoate of Formula V by reacting alkyl 3-(nitromethyl)hexanoate of Formula IV with base in an organic solvent,


0°


Formula IV Formula V
wherein R is an alkyl group;
b) hydrolysing compound of Formula V in presence of a base to get 3-
(dimethoxymethyl)hexanoic acid of Formula VI,
I 0 °- ^

HO
Formula VI and
c) condensing compound of Formula VI with (2S)-2-amino butanamide of Formula
VIII to give N-((S)-1-amino-1-oxobutan-2-yl)-3-(dimethoxymethyl)hexanamide of
Formula I;
NH2
7 ,NH2

0 Formula VIII

.

In one another aspect, the present invention provides a process of preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide (brivaracetam) of Formula II,
" ,NH2 O
6

Formula II
wherein said process comprising the steps of:
a) cyclizing the compound of Formula I in presence of camphorsulphonic acid
followed by reduction in presence of catalyst and hydrogen source to get
diastereomeric mixture of (2S)-2-[2-oxo-4-propyltetrahydro-1H-pyrrol-1-
yl]butanamide of Formula VII,

; and
b) separating diastereomeric mixture of Formula VII to get highly pure brivaracetam of Formula II.
In another aspect, the present invention relates to a process of preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide (brivaracetam) of Formula II,
0*0
0 Formula II
wherein said process comprising the steps of:
a) separating diastereomeric mixture of (2S)-2-[2-oxo-4-propyltetrahydro-1#-pyrrol-1-yl]butanamide of Formula VII by passing through column chromatography in a solvent system to get a desired isomer of Formula II (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl) (brivaracetam) and an undesired isomer of Formula III (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl),
7

XN^0
\^YNH2
0
Formula VII

O O
Formula II Formula III and
b) optionally, epimerizing the undesired isomer of Formula III in presence of base and an organic solvent.
DETAILED DESCRIPTION
Definitions:
The term “alkyl” used in context of the present invention refers to C1-C6 straight or
branched chain alkyl group.
The term “pharmaceutical acceptable salts” used in the context of the present invention refers to any acid salts such as phosphate, tartrate, sulphate, nitrate, diphosphate, hydrochloride, hydrobromide, hydroiodide, clavulanate, isothionate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannate , tosylate, valerate, methanesulfonate, ethanesulfonate, pivalate, benzenesulfonate, p-toluensulfonate, 2-ethane disulfonate, edisylate and naphthalenesulfonate.
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
8

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
In one embodiment, the present invention provides a novel compound of Formula I and pharmaceutical acceptable salts thereof;

Formula I

In another embodiment, the present invention provides a process for preparation of compound of Formula I,
r ° T
H2N. O Formula I
wherein said process comprising the steps of:
a) preparing alkyl 3-(dimethoxymethyl)hexanoate of Formula V by reacting alkyl
3-(nitromethyl)hexanoate of Formula IV with base in an organic solvent,
9


o°


Formula IV Formula V
wherein R is an alkyl group;
b) hydrolysing compound of Formula V in presence of a base to get 3-
(dimethoxymethyl)hexanoic acid of Formula VI,
I 0 °^ ^

HO
Formula VI ; and
c) condensing compound of Formula VI with (2S)-2-amino butanamide of Formula
VIII to give N-((S)-1-amino-1-oxobutan-2-yl)-3-(dimethoxymethyl)hexanamide of
Formula I;
NH2
NH9

0 Formula VIII

.

In another embodiment, the base used in the preparation of alkyl 3-(dimethoxymethyl)hexanoate of Formula V is selected from organic or inorganic base such as ammonia, triethyl amine, diisopropyl ethyl amine, dimethyl amino pyridine, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium bicarbonate, potassium tert-butoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, cesium carbonate, and the like.
10

Preferably the base used for synthesis of compound of Formula V is selected from the group comprising of sodium methoxide or potassium methoxide.
In another preferred embodiment, the base used for hydrolysis of compound of Formula V is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, primary amines, secondary amine and tertiary amines. Preferably the base used for hydrolysis of ester in step b) is selected from sodium hydroxide, potassium hydroxide, and lithium hydroxide.
In one more preferred embodiment, the base used for condensation of (2S)-2-amino butanamide of Formula VIII with compound of Formula VI is selected from diisopropyl ethyl amine, triethyl amine, pyridine, dimethyl amino pyridine and the like.
In another embodiment, the solvent used to perform above said process is selected from the group comprising of alcohols, ketones, esters, halogenated solvents, ethers, sulfoxides, amides and pyrrolidones.
In a preferred embodiment, the solvent used for synthesis of compound of Formula V is selected from alcohols such as methanol, ethanol, butanol, tert-butanol, isopropanol, n-propanol isoamyl alcohol and the like.
In another preferred embodiment, the solvent used in the step of hydrolysis of compound of Formula V is selected from alcohols such as methanol, ethanol, butanol, tert-butanol, isopropanol, n-propanol isoamyl alcohol and mixture thereof.
In one another preferred embodiment, the condensation reaction of 3-(dimethoxymethyl)hexanoic acid of Formula VI with (2S)-2-amino butanamide of Formula VIII to give N-((S)-1-amino-1-oxobutan-2-yl)-3-(dimethoxymethyl) hexanamide of Formula I is carried out in presence of solvents selected from the group comprising of halogenated solvents such as dichloromethane, chlorobenzene,
11

1, 2-dichloroethane, chloroform; ethereal solvents such as tetrahydrofuran, methyl tetrahydrofuran, butyl ether; amides such as dimethyl formamide; esters such as ethyl acetate, butyl acetate; carbonates such as dimethyl carbonates; and mixture thereof.
In one another embodiment, the condensation reaction of 3-
(dimethoxymethyl)hexanoic acid of Formula VI with (2S)-2-amino butanamide of Formula VIII in step c) above is carried out in presence of condensation reagent such as HOBt, CDI, HATU, HCTU, DCC, BOP, PyBOP, SOCl2, Pivaloyl chloride and the like.
In one another embodiment, the present invention provides a novel compound of Formula I, wherein said compound acts as an intermediate and is used for the preparation of Brivaracetam.
In one another embodiment, the present invention provides a process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide (brivaracetam) of Formula II,
O Formula II
wherein said process comprising the steps of:
a) cyclizing compound of Formula I in presence of camphorsulphonic acid followed by reduction in presence of catalyst and hydrogen source to get diastereomeric mixture of (2S)-2-[2-oxo-4-propyltetrahydro-1//-pyrrol-1-yl]butanamide of Formula VII,
12


N °
O lula VII ; and
b) separating diastereomeric mixture of Formula VII to get highly pure brivaracetam of Formula II.
In one of the preferred embodiment, the reduction reaction is carried out in presence of catalyst such as palladium on carbon, raney nickel, platinum; and the hydrogen source such as hydrogen gas or ammonium formate, sodium formate, potassium formate, lithium formate, triethyl ammonium formate and the like. Most preferably, the reduction reaction is carried out in presence of palladium on carbon in presence of hydrogen source such as ammonium formate.
In one more preferred embodiment, the brivaracetam obtained by the process of the present invention is highly pure with purity of 97% and above. In more preferred embodiment, the purity is 98.5% and above and most preferably, the purity is 99.5% and above.
Further, the compound of Formula VII so obtained in step a) is a diastereomeric mixture of two isomers at position C-4.
In another embodiment, the present invention provides a process of preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1//-pyrrol-1-yl]butanamide (brivaracetam) of Formula II,
13

O Formula II
wherein said process comprising the steps of:
a) preparing alkyl 3-(dimethoxymethyl)hexanoate of Formula V by reacting alkyl
3-(nitromethyl)hexanoate of Formula IV with base in an organic solvent,


I


Formula IV Formula V
wherein R is an alkyl group;
b) hydrolysing compound of Formula V in presence of base to get 3-
(dimethoxymethyl)hexanoic acid of Formula VI,
I 0° °

HO
Formula VI
c) preparing N-((S)-1 -amino-1 -oxobutan-2-yl)-3 -(dimethoxymethyl)hexanamide of Formula I by condensing compound of Formula VI with (2S)-2-amino butanamide of Formula VIII,
NH2
H5Nk J'....J< >\ /\ \/\/NH2
0
Formula I Formula VIII.
14

d) cyclizing compound of Formula I in presence of camphorsulphonic acid followed by reduction in presence of catalyst and hydrogen source to get diastereomeric mixture of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide of Formula VII,

; and
e) separating diastereomeric mixture of Formula VII to get highly pure brivaracetam of Formula II.
In another embodiment, the present invention relates to a process for the preparation
of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide
(brivaracetam) of Formula II,
0*0
o
Formula II
wherein said process comprising the steps of:
a) separating diastereomeric mixture of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide of Formula VII by passing through column chromatography in a solvent system to get a desired isomer of Formula II (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide) (brivaracetam) and an undesired isomer of Formula III (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]butanamide),
15

9*0
0 Formula III. and
b) optionally, epimerizing the undesired isomer of Formula III in presence of base and organic solvent.
Further, the technique used for separating diastereomers of Formula VII to obtain desired isomer i.e. brivaracetam is column chromatography using silica gel.
In other embodiment, the solvent system used for separating disastereomeric mixture of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide of Formula VII comprises of one or more organic solvents selected from the group comprising of dichloromethane, chloroform, hexane, ethyl acetate, toluene, acetone, methyl isobutyl ketone, ethyl methyl ketone, diethyl ketone, tert-butanol, toluene or mixture thereof.
In another embodiment, the base used for epimerization of undesired isomer of Formula III is selected from inorganic base. Preferably the base is selected from the group comprising of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium bicarbonate, potassium tert butoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, cesium carbonate, and the like.
In another embodiment, the solvent that can be used for epimerization of undesired isomer of Formula III is selected from group comprising of methanol, ethanol, butanol, tert-butanol, isopropanol, isoamyl alcohol, propanol, water, tetrahydrofuran, dixoane and the like.
16

Compared with other processes for making brivaracetam, the stereoselective method for the synthesis of brivaracetam of the present invention has the following benefits:
i. All the raw materials used in the process are readily available and are
inexpensive and hence making the process economically viable.
ii. The purification and isolation of the brivaracetam, requires a simple column
chromatographic process using inexpensive solvents.
iii. The purity of the product, brivaracetam, is very high which is preferably
above 99.5%.
Another embodiment of the present invention provides the brivaracetam that can be prepared by the process as disclosed in scheme 4:
NH2HC1
: NH2
O
Formula VIII'

NH,
HO O
Formula IX Formula VIII
♦ k. J Formula IXc
N H

O Formula X

Formula VII

H ^O
^

NH,
N mi.

N

NH,

Formula IXa Formula IXb

O
Formula II

O
Formula III
Undesired Isomer

17

In another embodiment, the brivaracetam obtained by the process of the present invention is used as antiepileptic drug and for treating partial onset seizures.
Further, the technique used for separating diastereomers of Formula VII to obtain desired isomer i.e. brivaracetam is column chromatography using silica gel.
In other embodiment, the solvent system used for separating diastereomeric mixture of (2S)-2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide of Formula VII comprises of one or more organic solvents selected from the group comprising of dichloromethane, chloroform, hexane, ethyl acetate, toluene, acetone, methyl isobutyl ketone, ethyl methyl ketone, diethyl ketone, tert-butanol, tolune or mixture thereof.
In one another embodiment, the brivaracetam prepared as per the process of the present invention is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm.
In a preferred embodiment, the brivaracetam prepared as per the process of the present invention is characterized by particle size distribution wherein, d90 is 2.0 µm to 150µm.
In further embodiment, the present invention provides a pharmaceutical composition comprising brivaracetam and at least one pharmaceutical acceptable excipients, wherein said brivaracetam is prepared as per the process of the present invention.
In furthermore embodiment, the present invention provides a process of preparation of brivaracetam that can be isolated in a crystalline form such as Form A or Form B or any other novel crystalline forms.
18

The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
EXAMPLES
EXAMPLE 1: Preparation of ethyl-3-(nitromethyl)hexanoate of Formula IV
(R=ethyl)
To 37.69g of butaraldehyde, 5.54g of dimethyl amino pyridine and 60.0 g of monoethyl malonate to 600ml of DMF and stirred for 20 h at room temperature. After completion of reaction, quenched the reaction mass with saturated solution of sodium bicarbonate and extracted the compound in toluene. Washed the organic layer with 1N HCl and distilled the organic layer to get crude compound. Added 50.6 g of nitromethane and 34.9g of tetramethyl guanidine to the crude compound and stirred the reaction mass for 18 h at room temperature. Added toluene and water and extracted the compound in toluene layer. Distilled the organic layer and purified the compound so obtained by column chromatography using ethyl acetate: hexane to get desired compound as colorless oil with 60.2% yield.
EXAMPLE 2: Preparation of ethyl 3-(dimethoxymethyl)hexanoate of Formula V (R=Et)
Cooled 90 ml of methanol to -10oC and added 19.4g of sulphuric acid. Added separately prepared mixture of 90 ml of methanol, 18g of ethyl-3-(nitromethyl)hexanoate and 30% w/w solution of sodium methoxide (17.91g) at -20oC. Stirred the reaction mass at room temperature for one hour. Cooled the reaction mass so obtained to -10oC and added 30% w/w of sodium methoxide in methanol (50.55g). Adjusted the pH to neutral pH with acetic acid. Distilled out the methanol from the reaction mass followed by addition of toluene. Filtered the reaction mass via celite bed and distilled off the toluene to get crude compound. Purified the crude compound through column chromatography using ethyl acetate: hexane get desired compound as light yellow liquid with 81.8% yield.
19

EXAMPLE 3: Preparation of 3-(dimethoxymethyl)hexanoic acid of Formula VI
Cooled a mixture of 10g of ethyl 3-(dimethoxymethyl)hexanoate and 50 ml of methanol to 10oC. Added the aqueous solution of sodium hydroxide (5g in 20 ml of water) to above mixture. Heated to 30-35oC and stirred for 2h. Distilled out the methanol and added water and acidified to pH 4 with hydrochloric acid. Extracted the compound with DCM and washed the organic layer with water. Distilled out the solvent to get crude material as colorless liquid with 91.3%.
EXAMPLE 4: Preparation of N-((S)-1-amino-1-oxobutan-2-yl)-3-
(dimethoxymethyl)hexanamide of Formula I
Cooled a mixture of 7.0 g of 3-(dimethoxymethyl)hexanoic acid and 100 ml of DCM to 0oC. Added N-(3-Dimethylamino propyl)-N’-ethyl carbodiimide (EDC:HCl) (7.76g), HOBt (6.20g) and DIPEA (11.88g), (2S)-2-amino butanamide (3.75g) and stirred for 16 h at room temperature. Quenched the reaction mass with water and extracted the compound in DCM. Concentrated the organic layer and purified the crude material by column chromatography using dichloromethane: methanol to get desired compound with 91.3% yield.
EXAMPLE 5: Preparation of (2S)-2-(2-oxo-4-propylpyrrolidin-1-
yl)butanamide of Formula VII
Added camphorsulphonic acid (0.169g) to a mixture of 2.0g of N-((S)-1-amino-1-oxobutan-2-yl)-3-(dimethoxymethyl) hexanamide and 40 ml of toluene and heated the reaction mass to reflux. Stirred the reaction mass for 2h at same temperature and cooled to room temperature and extracted the compound in ethyl acetate. Washed the organic layer with saturated solution of sodium bicarbonate and water. Distilled out the solvent to get crude material as colorless liquid (1.2g). Added 10% w/w of palladium on carbon (0.1g) to a mixture of above said colorless liquid (1.0g), ammonium formate (1.08 g) and water (10ml) and heated the mixture to 50oC for 5 hours. Filtered the reaction mass through hyflow bed. Extracted the
20

filtrate with DCM and concentrated the DCM layer to get off white solid with 90% yield having 1:1 mixture of diastereomers.
EXAMPLE 6: Separation of diastereomers to get brivaracetam of Formula II
Charged the mixture of diastereomers obtained from Example 5 to column chromatography in silica gel by using solvent system, dichloromethane: acetone. Pure fractions were collected and concentrated to get pure brivaracetam (yield: 35%) with HPLC purity of 99.7%.
EXAMPLE 7: Epimerization of undesired isomer of Formula III
0.5 g of undesired isomer (having diastereomeric ratio of 17:83) and 5 ml of IPA was mixed with sodium tert-butoxide and stirred at room temperature for 18 hrs. Distilled off the IPA and extracted the compound with dichloromethane. Washed the organic layer with water and concentrated the organic layer under vacuum to get crude material containing diastereomeric ratio of 47:53. Yield: 0.45g (90%).
The crude material thus obtained was purified through column chromatography as per Example 6 and the desired fractions were collected and concentrated to get Brivaracetam.
EXAMPLE 8: Preparation of brivaracetam
Charged triethylamine (28.44 g) and 2S-2-aminobutanamide hydrochloride (22 g) of Formula VIII’ to a solution of 5-hydroxy-4-propylfuran-2(5H)-one (20.0 g) of Formula IX in toluene. Stirred for 1 hour at room temperature. Added 10% aq. NaOH (20 mL) and NaBH4 (4.0 g) and stirred for 1 hour. Added acetic acid (20 mL) and heated for 2 hours. Separated the organic layer and concentrated to get light brown color liquid of (S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-yl)butanamide of Formula X with 80 % yield.
Charged 10% w/w Palladium on carbon (3.0 g) to a mixture of compound of Formula X (23.0 g), ammonium formate (27.5 g) and water (250 mL) at room temperature. Heated the reaction mass to 50-60º C for 10 hours. Filtered the reaction
21

mass and extracted the filtrate with DCM. Distilled out the DCM to get off white solid crude of Formula VI as mixture of two diastereomers with 90 % yield. Compound of Formula VI is then treated through column chromatography in accordance to example 6 to get desired compound, Brivaracetam and undesired isomer of Formula III.
Example 9: Preparation of (2S)-2-aminobutanamide of Formula VIII
Charged (2S)-2 amino butanamide hydrochloride 100 g in DCM (10V). Cooled to 0°C and purged with ammonia gas for 6 hrs. Increased the temperature to RT. Stirred the reaction mass at RT for 10-12 hrs. Filtered out the suspended solid, distilled and degased dichloromethane from filtrate to yield (2S)-2-amino butanamide as off white solid 68.0 g.
Example 10: Preparation of 5-hydroxy-4-propylfuran-2(5H)-one of Formula IX
To 3V of n-heptane was added the mixture of valeraldehyde 50 g (0.5813 moles), glyoxalic acid (0.5813 moles) and morpholine (0.5813 moles) and was stirred at 50°C-60°C. Allowed the reaction mass to cool to RT. The compound was extracted using DCM (10V) and washed with aqueous HCl and water. Solvent was distilled out to get 5-hydroxy-4-propylfuran-2(5H)-one 63.5g as brown colour liquid.
Example 11: Preparation of (S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide of Formula X
5-hydroxy-4-propylfuran-2(5H)-one 50.0 g (0.352 moles) was stirred with 2(S)-amino butyramide (0.359 moles) in toluene (15V) at 20°C-25°C. After 4hrs, the reaction mass was cooled to 0-5°C and slowly charged aqueous solution of sodium borohydride (0.229 moles) in 1 hour. Increased the temperature to RT. Stirred for 1-2 hours at RT. Charged acetic acid (1.1V), heated to 50°C for 4 hrs followed by cooling to RT. Separated the layers and washed the organic layer with brine solution. Distilled out toluene and degased to yield (S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide 64.0g as yellow to orange oil.
22

Example 12: Preparation of diastereomeric mixture of Formula VII
(S)-2-(2-oxo-4-propyl-2,5-dihydro-lH-pyrrol-l-yl)butanamide 10.0 g (0.04761 moles) was stirred with ammonium formate (0.0952 moles) in presence of 10% Pd/C (10% w/w) and DM water (5V) at 50-55°C for 6 hours. Pd/C was removed by filtration and product was extracted using DCM (10V). Washed the organic layer with DM water and distilled out dichloromethane to yield (2S)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanamide 9.0 g as Off white solid.
Example 13: Separation of diastereomers to get desired isomer, brivaracetam of Formula II
Diastereomeric mixture as obtained from example 12 is separated by column chromatography on silica gel using acetone: dichloromethane [2:8 to 3:7] as mobile phase. Pure fractions were collected, distilled and degased to yield brivaracetam Material so obtained was dissolved in IPE (4V) at 50-70°C and then allowed to cool to RT. Filtered out the material and dried under vacuum to yield pure brivaracetam of Formula II 2.7 g
EXAMPLE 14: Epimerization of undesired isomer of Formula III
0.5 g of undesired isomer (having diastereomeric ratio of 17:83) and 5 ml of IP A was mixed with sodium tert-butoxide and stirred at room temperature for 18 hrs. Distilled off the IPA and extracted the compound with dichloromethane. Washed the organic layer with water and concentrated the organic layer under vacuum to get crude material containing diastereomeric ratio of 47:53. Yield: 0.45g (90%).
The crude material thus obtained was purified through column chromatography as per Example 13 and the desired fractions were collected and concentrated to get Brivaracetam.

WE CLAIM
A novel compound of Formula I and pharmaceutical acceptable salts thereof,
f ° °Y°"
O H
Formula I
2. A process for the preparation of compound of Formula I,


H,N

Formula I
wherein said process comprising the steps of:
a) preparing alkyl 3-(dimethoxymethyl)hexanoate of Formula V by reacting alkyl
3-(nitromethyl)hexanoate of Formula IV with a base in an organic solvent,


O °- ^


Formula IV Formula V
wherein R is an alkyl group;
b) hydrolysing compound of Formula V in presence of a base to get 3-
(dimethoxymethyl)hexanoic acid of Formula VI,
HO
Formula VI
0 ^ ^
and

c) condensing compound of Formula VI with (2S)-2-amino butanamide of Formula
VIII to give N-((S)-1-amino-l-oxobutan-2-yl)-3-(dimethoxymethyl)hexanamide of
Formula I;
NH2 ^A^NH2
0 Formula VIII
3. The process as claimed in claim 2, wherein said base used in step a) is selected from the group comprising of triethyl amine, diisopropyl ethyl amine, dimethyl amino pyridine, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium ethoxide, potassium methoxide, potassium bicarbonate, potassium tert-butoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, and cesium carbonate; and wherein said organic solvent used in step a) is selected from methanol, ethanol, butanol, tert-butanol, isopropanol, n-propanol isoamyl alcohol, and mixture thereof.
4. The process as claimed in claim 2, wherein said base used in step b) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, primary amines, secondary amine and tertiary amines; and wherein said hydrolysis in step b) is carried out in presence of solvent is selected from methanol, ethanol, butanol, tert-butanol, isopropanol, n-propanol isoamyl alcohol and mixture thereof.
5. The process as claimed in claim 2, wherein said condensation in step c) is carried out in presence of base selected from diisopropyl ethyl amine, triethyl amine, pyridine, and dimethyl amino pyridine; and in presence of solvent selected from the group comprising of dichloromethane, chlorobenzene, 1, 2-dichloroethane, chloroform, tetrahydrofuran, methyl tetrahydrofuran, butyl ether, dimethyl formamide, ethyl acetate, butyl acetate, dimethyl carbonates, and mixture thereof.

6. A process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-li7-pyrrol-l-yl]butanamide (brivaracetam) of Formula II,
N
NH2
O Formula II
wherein said process comprising the steps of:
a) cyclizing compound of Formula I in presence of camphorsulphonic acid followed by reduction in presence of catalyst and hydrogen source to get diastereomeric mixture of (2S)-2-[2-oxo-4-propyltetrahydro-li7-pyrrol-l-yl]butanamide of Formula VII,

Formula I ,„_.»„ ^ . and
b) separating diastereomeric mixture of Formula VII to get highly pure brivaracetam of Formula II.
7. The process as claimed in claim 6, wherein said catalyst is selected from palladium on carbon, raney nickel, and platinum; and said hydrogen source is selected from hydrogen gas, ammonium formate, sodium formate, potassium formate, lithium formate, and triethyl ammonium formate.
8. The process as claimed in claim 6, wherein said process of separating diastereomeric mixture of (2S)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanamide of Formula VII is carried out by passing compound of Formula VII through column

chromatography in a solvent system to get a desired isomer of Formula II (brivaracetam) and an undesired isomer of Formula III ((2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1 -yljbutanamide),

N' ° NH2
0 Formula III. and
optionally, epimerizing the undesired isomer of Formula III in presence of base and organic solvent.
9. The process as claimed in claim 8, wherein said solvent system comprises of one
or more organic solvents selected from the group comprising of dichloromethane,
chloroform, hexane, ethyl acetate, toluene, tert butanol, acetone, methyl isobutyl
ketone, ethyl methyl ketone, diethyl ketone or mixture thereof.
10. A process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-li7-
pyrrol-l-yl]butanamide (brivaracetam) of Formula II,
0*0
NH2
0 Formula II .
wherein said process comprising the steps of:
a) separating diastereomeric mixture of (2S)-2-(2-oxo-4-propylpyrrolidin-l-yl)butanamide of Formula VII by passing through column chromatography in a solvent system to get a desired isomer of Formula II (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yljbutanamide) (brivaracetam) and an undesired isomer of Formula III (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-l-yljbutanamide),

N

0 NH2

O

Formula III

; and

b) optionally, epimerizing the undesired isomer of Formula III in presence of base and organic solvent.