FIELD OF THE INVENTION
The present invention relates to Novel intermediates of Brivaracetam and their preparation.
The present invention further relates to cost-effective, industrially feasible process for the preparation of Brivaracetam intermediate.
BACKGROUND OF THE INVENTION
Brivaracetam chemical analog of Levetiracetam developed by UCB, Inc. Brivaracetam is approved by FDA in 2016. Brivaracetam is marketed by UCB INC under the brand name BRIVIACT. Brivaracetam is chemically described as (2S)-2-((4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-1-yl] butanamide. Its structural formula is
N U
o The molecular formula of Brivaracetam is C11H20N2O2 and its molecular weight is 212.29.
Brivaracetam is firs disclosed in US 6,784,197 B2, this patent further discloses the process for the preparation of Brivaracetam which is given below:
V- NH2 NaBH4, (""V NH4COOH
)=\ ,^VNH2 Me0H N ° IO%Pd/C
HO-\^0 \ 5 Stage-I \>yNH2 Sta6e-"
O \ 4-n-propyl-hydroxy S-2-amino (5)-2-(2-oxo-4-propyl-2W-pyrrol- '-. t ^"~. furanone butyramide |(5tf)-yl)butanamide j \ )—O 0
Brivaracetam and its isomer
The enantiomeric purity of Brivaracetam prepared according to the above process suffers with low yield, isomeric impurities. Hence, the process above describes is not feasible at

Process for the preparation of 4-n-propyl-5-hydroxy furanone, which is the starting material of Brivaracetam is disclosed in J. Org. Chem., 1981, 46 (24), pp 4889-4894. The process depicted below:
ii r^o V\n
0\ A I I .HCl Dioxan/water /=^^OH -H20 + NH^J _ - OH%>^0
Glyoxylic acid 4-n-propyl-5-hydroxy
hydrate furanone
According to the J. Org. Chem., 1981, 46 (24), pp 4889-4894 the above reaction was performed for around 24 hrs, which is highly unfeasible at bulk level or industrial level.
The present inventors have developed novel intermediates of Brivaracetam and process for their preparation which results in greater efficiency of Brivaracetam than the prior art processes with higher product purity and isomeric purity.
The present inventors further developed an improved process for the preparation of 4-n-propyl-5-hydroxy furanone which involves the reaction time less than 8 hrs by using. aromatic hydrocarbon solvents.
OBJECT OF THE INVENTION
The main object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of Brivaracetam using novel intermediates as well as known intermediates using an improved process which results into higher yields with high purity without formation of undesired impurities such as chiral or diastereomeric impurities.
SUMMARY OF THE INVENTION
' Accordingly, the present invention provides compound of Formula I or its salts, which is used as an intermediate in the preparation of Brivaracetam..

Formula I In a preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I
Formula I or its salts, which comprises reacting compound of Formula II
Formula II or its salts, with (R)-l-phenylethylamine in the presence of reducing agent and in a solvent to give compound of Formula I.
In another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula I
Formula I or its salts, which comprises a) reacting compound of Formula III
Formula III with a reducing agent in a solvent to give compound of Formula II

HO-^Q^O
Formula II b) reacting compound of Formula II
V
HO \)°
Formula II or its salts, with (R)-l-phenylethylamine in the presence of reducing agent and in a solvent to give compound of Formula I.
In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula (III)
Formula III or its salts, which comprises reacting compound of Formula IV
O 0<=i^OH .H20 Formula IV or its hydrate with compound of Formula V
-"""■—""^CHO Formula V in the presence of morpholine or morpholine hydrochloride to give compound of Formula III, wherein the reaction is carried out in aromatic hydrocarbon solvent.
In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula (III)

Formula III or its salts, which comprises reacting compound of Formula IV
O °^OH .H20
Formula IV or its hydrate with compound of Formula V
Formula V in the presence of morpholine or morpholine hydrochloride to give compound of Formula III, wherein the reaction is carried out in aromatic hydrocarbon solvent and preferably reaction is carried out at the temperature of 95-100°C .
In yet another preferred aspect, the present invention provides an improved process for the preparation of Brivaracetam
o
or its salts, which comprises
a) reacting compound of Formula IV
O °^0H .H20
Formula IV or its hydrate with compound of Formula V
Formula V to give compound of Formula III

■ Formula III
b) reacting compound of Formula III with a reducing agent in a solvent to give compound of
Formula II
HO"\) °
Formula II
c) reacting compound of Formula II or its salts, with (R)-l-phenylethylamine in the presence
of reducing agent and in a solvent to give compound of Formula I
Formula I
d) converting compound of Formula I to Brivaracetam.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of compound of Formula I or its salts and its use in the preparation of Brivaracetam.
b-° cr
Formula I Accordingly, the present invention provides an improved process for the preparation of compound of Formula I by reacting compound of Formula II with (R)-l-phenylethylamine in the presence of reducing agent in a solvent.
T nFFTTF PHP W M. AT 1 R '/ C\ 1 i 1 f) 1 £ T P." C\~£

Reducing agent as used in the present invention is selected from borohydrides such as sodium borohydride, potassium borohydride, Sodium cyanoborohydride, Lithium borohydride and Lithium triethylborohydride.
Solvent as used in the present invention is selected from water, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate or formic acid, acetic acid and their mixtures thereof.
Aromatic hydrocarbon solvents as used in the present invention is selected from benzene, toluene and xylene.
In a preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula I
N U
Formula I which comprises reacting compound of Formula II
H°""S) °
Formula II or its salts, with (R)-l-phenylethylamine in the presence of sodium borohydride in toluene or

In another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula I
a"-
Formula I or its salts, which comprises
a) reducing compound of Formula III
HO O °
Formula III using Pd/C in ethyl acetate to give compound of Formula II
- ^
HO \) °
Formula II
b) reacting compound of Formula II
HO-^Q-^O
Formula II or its salts, with (R)-l-phenylethylamine in the presence of sodium borohydride in toluene or mixture of toluene and water to give compound of Formula I.
f In yet another preferred embodiment, the present invention provides an improved
^ process for the preparation of compound of Formula (III)

Formula III or its salts, which comprises reacting compound of Formula IV
O °^^OH -H20
Formula IV or its hydrate with compound of Formula V
Formula V in the presence of morpholine or morpholine hydrochloride to give compound of Formula III, wherein the reaction is carried out in toluene at 95-100°C.
In yet another preferred embodiment, the present invention provides process for the purification of Brivaracetam which comprises purifying crude Brivaracetam using solvent or mixture of solvents selected from aliphatic hydrocarbons, aromatic hydrocarbons, water and alcohols.
The prior art process for the preparation of compound of Formula III involves the use of 1,4-dioxane which is expensive comparatively to toluene which is used in the current invention.
According to the present invention, the compound of Formula I which is advanced intermediate in the preparation of Brivaracetam is further converted to Brivaracetam.
The conversion of compound of Formula I to Brivaracetam may be carried out by debenzylation of compound of Formula I using various debenzylating reagents such as Pd( 0H)2 in ammonium acetate or any metal catalyst such as Mg, Ca, K, Rh etc.,
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and
should not be construed to limit the scope of the invention.
TENT OFFICE CHEMIM'AI 7. S:7 Q"2^ 2 01 8 16!0T~""'.

Examples:
Example 1: Preparation of compound of Formula III:
Formula III 100 gms of Glyoxylic acid monohydrate in 500 ml of toluene was charged to 158 gms of Morpholine hydrochloride at 25-35°C, reaction mass was stirred, 98.5ml of n-Valeraldehyde was added dropwise to the reaction over the period of 20-30 mints, reaction mass was stirred, temperature of the reaction mass was raised to 95-100°C, maintained for 8hrs, reaction mass was cooled, solvent was distilled, crude obtained. The obtained crude dissolved into the mixture of DM water and hexane (500+500ml), reaction mass was stirred, layers were separated, aq layer was extracted with MTBE, MTBE layer was washed with 500ml of 5%NaHCC>3 solution followed by washed with 500ml of 20% sodium chloride solution, organic layer was dried with sodium sulphate, solvent was distilled under vacum to obtain highly pure compound of Formula III. Yield range: 100-130 gms.
Example 2: Preparation of compound of Formula I:
. Formula I 9.3gms of (R)-(+)-a-Methylbenzylamine in 100ml of toluene was added to RB at 25-30°C, reaction mass stirred for 10 minutes and cooled to 10-15°C. lOgms of compound of Formula II was added to the reaction mass at 10-15°C, temperature was raised to 30°C and maintained for 2hrs at same temperature, 4N NaOH (1.8gms of NaOH dissolved in 17.2ml of water) solution was added to the reaction mass. NaBr^ solution (1.7gms of NaBFLi dissolved in 17.0ml of water), reaction mass was maintained for lhr at 25-30°C. 10ml of acetic acid was added slowly, reaction temperature was raised to 50-55°C and maintained for lhr.

reaction mass was stirred for lOmints and separated, aq layer extracted with toluene, followed by washing with .20% NaCl solution (20gm of NaCl in 100ml of water), organic layer was dried over sodium sulphate, solvent was distilled under vacuum. Yield range: 7-8 gms.