DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PROCESS FOR PREPARATION OF BRIVARACETAM INTERMEDIATES AND USE THEREOF

We, Stereokem Pvt. Ltd.,
a company incorporated under the companies act, 1956 having address at
Plot No. 36/A, IDA Uppal, Hyderabad-500039, Telangana,
INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a process for preparation of antiepileptic agent intermediates.

The present invention particularly relates to a process for preparation of Brivaracetam intermediates.

The present invention relates to a process for preparation of Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compounds.

BACKGROUND OF THE INVENTION
Brivaracetam is an antiepileptic drug for the treatment of partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. Brivaracetam is approved by USFDA in May 2016.

Brivaracetam is a racetam derivative with anticonvulsant properties and is 4-n-propyl analog of Levetiracetam. Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl] butanamide. Its empirical Formula is C11H20N2O2 and the molecular weight is 212.29. The structural Formula is:

Brivaracetam was first disclosed in US 6,911,461 B2 and the process for the preparation of Brivaracetam disclosed in this patent is as shown below:


US 8,338,621 B2 discloses a process for preparing Brivaracetam intermediate compounds is as shown below:

wherein X1 is —CONR4R5, —COOH, —COOR3 or —CN
X2 is —CONR4R5, —COOH, —COOR3 or —CN.
Howerer, the patent does not provide the process for the preparation Brivaracetam intermediates of the present invention.

Drugs of the Future, 35(3), 165-172, 2010 (UCB S.A) discloses a process for preparing Brivaracetam intermediate compound is as shown below:

WO2016075082 discloses a process for preparing Brivaracetam intermediate compound is as shown below:

As can be seen from the above, none of the prior art discloses the process for the preparation of compound of Formula (IIA) using pTSA or process for the preparation of compound Formula (IIB) using 2- bromo butanoic acid as of the present invention. In view of the importance, there is a need for developing a relatively simple, commercially feasible process for preparation of Brivaracetam intermediates which involves use of inexpensive, environmental friendly reagents which are easily available or prepared from commercially available sources easily.

The present invention is to provide a simple, economical and commercially feasible process for the synthesis of Brivaracetam intermediates with a commercially acceptable yield and high purity.

It is therefore an object of the present inventors have invented a process for preparation of Brivaracetam is of yield and high purity comprising the process for preparation of intermediates.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for preparation of Brivaracetam intermediates.

In another objective of the present invention is to provide a process for the preparation of Brivaracetam intermediates, which is commercially feasible / industrially scalable.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis of Brivaracetam intermediates with a commercially acceptable yield and high purity.

In another preferred objective of the present invention is to provide the process for reparation of Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compounds.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of compound of Formula (II)

Formula (II)
wherein R is hydrogen, or ;
or its salts, which comprises converting compound of Formula (III)

Formula (III)
to give compounds of Formula (II) or its salts.

In another embodiment, the present invention provides a process for the preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, which comprises cyclizing compound of Formula (III)

Formula (III)
or its salts using an acid in a suitable solvent to give compound of Formula (IIA) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (III)

Formula (III)
or its salts, which comprises converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine group and subsequent hydrolysis of the amide to produce compound of Formula (III) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IVA)

Formula (IVA)
or its salts, which comprises converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA) or its salts along with compound of Formula (IVB).

Formula (IVB)

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, which comprises:
a) converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine group and subsequent hydrolysis of the amide to produce compound of Formula (III)

Formula (III)
or its salts, and
b) converting compound of Formula (III) or its salts; using an acid in a suitable solvent to give compound of Formula (IIA) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide to produce compound of Formula (III)

Formula (III)
or its salts, and
c) converting compound of Formula (III) or its salts; using an acid in a suitable solvent to give compound of Formula (IIA) or its salts.

In another embodiment, the present invention provides a process for the preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:
a) reacting compound of Formula (III)

Formula (III)
with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI),

Formula (VI)

b) converting compound of Formula (VI) in presence of suitable solvent to give compound of Formula (IIB).

In another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
or its salts, which comprises reacting compound of Formula (III)

Formula (III)
with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
or its salts which comprises:
a) converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts, and
b) reacting compound of Formula (III) with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
or its salts which comprises:
a) converting compounds of Formula (V)

Formula (V)
using a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts, and
c) reacting compound of formula (III) or its salts with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
using a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts,
c) reacting compound of formula (III) or its salts with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI), and
d) converting compound of Formula (VI) in presence of suitable solvent to give
compound of Formula (IIB).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
using a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts in-situ by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts, followed by reacting with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI), and
c) converting compound of Formula (VI) in presence of suitable solvent to give
compound of Formula (IIB).

In yet another embodiment, the present invention provides Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compound of Formula (II)

Formula (II)
wherein R is hydrogen, or ; or its salts.

In yet another proffered embodiment, the present invention provides Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compound of Formula (IIA) or Formula (IIB) or Formula (VI).

DETAILED DESCRIPTION OF THE INVENTION
The group R as used herein and not limited to hydrogen, R is hydrogen, or .

Alkyl haloformate as used herein, where in alky group is a straight or branched, substituted or unsubstituted selected from C1-C4 alky; and the halo group selected from chloro, bromo, fluoro or iodo.

The reagent as used herein such as 2-halobutanoic acid, wherein the halo group selected from chloro, bromo, fluoro or iodo.

Accordingly, the present invention provides a process for the preparation of compound of Formula (II)

Formula (II)
wherein R is hydrogen, or ;
or its salts, which comprises converting compound of Formula (III)

Formula (III)
to give compounds of Formula (II) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, which comprises cyclizing compound of Formula (III)

Formula (III)
or its salts using an acid such as pTSA in a suitable solvent to give compound of Formula (IIA) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (III)

Formula (III)
or its salts, which comprises converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis to produce compound of Formula (III) or its salts.
In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IVA)

Formula (IVA)
or its salts, which comprises converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA) or its salts along with compound of Formula (IVB).

Formula (IVB)

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, which comprises:
a) converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis to produce compound of Formula (IV)

Formula (III)
or its salts, and
b) converting compound of Formula (III) or its salts; using an acid such as pTSA in a suitable solvent to give compound of Formula (IIA) or its salts.

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis to produce compound of Formula (III)

Formula (III)
or its salts, and
c) converting compound of Formula (III) or its salts; using an acid such as pTSA in a suitable solvent to give compound of Formula (IIA) or its salts.

In another embodiment, the present invention provides a process for the preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:
a) reacting compound of Formula (III)

Formula (III)
with 2-bromobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI),

Formula (VI)
b) converting compound of Formula (VI) in presence of suitable solvent to give compound of Formula (IIB).

In another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
or its salts, which comprises reacting compound of Formula (III)

Formula (III)
with 2-bromobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
or its salts which comprises:
a) converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis to produce compound of Formula (III)

Formula (III)
or its salts, and
b) reacting compound of Formula (III) with 2-bromobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).

In yet another embodiment, the present invention provides a process for the preparation of compound of Formula (VI)

Formula (VI)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis to produce compound of Formula (III)

Formula (III)
or its salts, and
c) reacting compound of Formula (III) or its salts with 2-bromobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).
In yet another embodiment, the present invention provides a process for preparation of Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compound of Formula (II)

Formula (II)
wherein R is hydrogen, or ; or its salts.

In yet another proffered embodiment, the present invention provides a process preparation of Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compound of Formula (IIA) or Formula (IIB) or Formula (VI).

Cyclization reaction of a compound of Formula (III) to compound of Formula (IIA) is carried out using an acid in presence of a suitable solvent.

The intermediates formed in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain compound of Formula (I) or its intermediates. The above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.

The compound of Formula (IIB) is prepared from compound of Formula (III) via compound of Formula (VI) which the process may or may not in-situ.

Any of the reagents as used herein can be used catalytically or stoichiometrically. Preferably, the reagents are used in an amount from 1 to 10 equivalents.

The reactions in any of the steps of the present invention are carried out in the absence or presence of a solvent. The volumes of the solvents as used herein as taken appropriately based on the quantities of the reactants and reagents.

Any of the reactions as referred herein may be carried out at a temperature in the range 0 °C to 120 °C, preferably at reflux temperature of the solvent used therein.

In yet another embodiment, solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

In yet another preferred embodiment, base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; alkyl metals such as n-butyl lithium or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

In yet another embodiment, converting compound of Formula (IVA) to produce compound of Formula (III), wherein the reaction involves converting carboxylic acid to an amine group via Curtius rearrangement and subsequent hydrolysis of the amide group to produce compound of Formula (III) or its salts.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

Acid used in the cyclization or in any of the reaction as used herein is selected from group of comprising of inorganic acid, organic acid, lewis acid or mixture thereof such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, phosphoric acid (P2O5), poly phosphoric acid, camphorsulfonic acid, formic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, citric acid and oxalic acid, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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.

EXAMPLES
Example 1: Preparation of (3R)-3-[2-oxo-2-[[(1R)-1-phenylethyl]amino] ethylhexanoic acid (IVA)
To a stirred solution of (R)-(+)-phenylethylamine (78 g,0.640 mol) and 4-dimethylaminopyridine (0.30 g, 0.0024 mol) in toluene (800 ml) was added a solution of 3-propyl glutaric acid anhydride (100 g, 0.640 mol) in toluene (100 ml) at -10°C to -15°C over a period of 45-60 min. Stirring was continued for another 1.5 to 2 hrs at the same temperature. The mixture was then extracted with 10% aqueous NaOH solution (500 ml) and the aqueous phase was washed with toluene (1 x 250 ml). The separated aqueous phase pH was adjusted to 2 to 2.5 with hydrochloric acid and extracted with toluene (lx 800 ml) at 70-80°C. The separated toluene layer was washed with 10% sodium chloride solution (700ml) at the same temperature and allowed to crystallize the material. Filtered the solid 120 g (67%) and its optical purity 99.5 % by HPLC.

The toluene mother liquor was distilled off to 3 vol and 32.4 g acetylchloride was added. The mixture was heated to 78-82°C and stirred for 5-6 hrs. Then the reaction mixture was cooled to 50-60°C and water (300 ml) was added to separate the phases. Toluene layer was added to the NaOH solution (12.5 g in 125 mL of water) and the mixture was heated to 78-82°C for 8-10 hrs. Cooled the reaction mixture to 25-30°C and the pH was adjusted to 1-3 with HCl. Further toluene (350 ml) was added to the mixture and the phases were separated at 80°C. The organic phase was cooled to 25-30°C and filtered the solid. Re-crystallized from toluene to give the pure product which optical purity was 99.5%.

Example 2: Preparation of (3R)-3-(((S)-1-carboxypropylamino)methyl)hexanoic acid (VI)
Step A: Ethyl chloroformate (40 g, 0.368 mole) was added to a mixture of (3R)-3-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethylhexanoic acid (100 g, 0.360 mole) and triethylamine (38 g, 0.376 mole) in toluene at -10° to -20°C over a period of 40 min. The mixture was stirred for 1 hour at the same temperature followed by addition of solution of sodiumazide (28g, 0.430 mole in water). The mixture was stirred for 1 hour at -10° to -20°C and quenched over ice water. Separated the toluene layer immediately and was added slowly to a refluxing mixture of toluene and conc. hydrochloric acid (100 ml). Stirring was continued for another 3 hrs. Cooled the mixture to 80°C and separated the organic layer and aq.layer. The aq. layer was refluxed for another 24 hours and cool to 25-30°C. Adjust the PH to 12 with 50% sodium hydroxide solution then extracted with toluene (1000 ml). The aq. solution was directly used for the next step (The aq. solution contains 33-35 gm of (R)-3-(Aminomethyl)hexanoic acid III).

Step B: To the aq. solution of (R)-3-(Aminomethyl)hexanoic acid (33-35 gm) was added (R)-2-Bromo butyric acid (40 g) at 10-15°C and the mixture was stirred for 1 hour at the same temperature. The reaction mixture temperature was slowly raised to 25-30°C and maintained for 18-20 hrs. The reaction mixture was cooled to 10-15°C and PH was adjusted to 2 with conc. hydrochloric acid. The precipitated solid was filtered and washed with water followed by re-crystallization from acetone to get 32 gm (38%) of off white solid (R)-3-(((S)-1-carboxypropylamino)methyl)hexanoic acid with an optical purity of 99.5 %.

Example 3: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid (IIB)
(3R)-3-(((S)-1-carboxypropylamino)methyl)hexanoic acid (100 g) in acetonitrile (3000 ml) was refluxed for 30 hrs. Activated carbon (10 gm) was added, stirred for 15 min and filtered through hyflow bed. Acetonitrile was distilled off completely under vacuum and added diisoproyl ether (500 ml), filtered the solid 75 gm (72%) of off white solid of (R)-2-[(S)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid with an optical purity of 99.72 %.

Example 4: Preparation of (R)-4-Propylpyrrolidin-2-one (IIA)
To a solution of (R)-3-(Aminomethyl)hexanoic acid (30 gm) in toluene (300 ml) was added p-toluene sulphonic acid (1 g) and the mixture was heated to reflux temperature to remove the water by azeotrope distillation for 3-4 hours . Reaction was checked by TLC. After completion of the reaction, the temperature of the reaction mixture was slowly cooled to 25-30°C and washed the toluene layer with 5% sodium bicarbonate solution (150 ml) followed by water (100 ml). Toluene was removed under reduced pressure at 70°C to get (R)-4-Propylpyrrolidin-2-one (IIA) as a pale yellow color liquid 20 g (76%) with an optical purity >99%.
Example-5: Prepartion of (2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidiniyl] butanamide (I)
To a cooled mixture of (R)-2-((S)-2-oxo-4-propylpyrrolidin-1-yl)butanoic acid (100 g, 0.469 mole) and with triethylamine (61.6 g, 0.610 mole) in dichloromethane (1000 ml) was added ethyl chloroformate (66 g, 0.609 mole) at -5° to -10°C. The mixture was stirred for 1 hour at the same temperature. Filter the salts at - 5° to -10°C and washed with dichloromethane (100 ml). Transferred the filtrate in to another dry flask and added ammonium bicarbonate slowly over a period of 3-4 hous at -5° to -10°C. After completion of the reaction water (500 ml) was added to the reaction mixture and separated the organic layer. Washed the organic layer with brine solution (200 ml) and distilled off the solvent completely under vacuum. To the crude product diisopropyl ether (400 ml) was added and filter the solid 75 g (67%) of a white solid of (2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidiniyl]butanamide with an optical purity of 99.8 %. ,CLAIMS:We Claim:

1. A process for the preparation of compound of Formula (II)

Formula (II)
wherein “R” is hydrogen, or ;
or its salts, which comprises converting compound of Formula (III)

Formula (III)
to give compounds of Formula (II) or its salts.

2. The process as claimed in claim 1, wherein the process for preparation of compound of Formula (IIA)

Formula (IIA)
or its salts comprises cyclizing compound of Formula (III)

Formula (III)
or its salts using an acid in a suitable solvent to give compound of Formula (IIA) or its salts.

3. The process as claimed in claim 1, wherein the process for preparation of compound of Formula (III)

Formula (III)
or its salts comprises converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine group and subsequent hydrolysis of the amide to produce compound of Formula (III) or its salts.

4. The process as claimed in claim 3, wherein the process for preparation of compound of Formula (IVA)

Formula (IVA)
or its salts which comprises converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA) or its salts along with compound of Formula (IVB).

Formula (IVB)

5. The process as claimed in claim 2, wherein the process for preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, comprises:
a) converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine group and subsequent hydrolysis of the amide to produce compound of Formula (III)

Formula (III)
or its salts, and
b) converting compound of Formula (III) or its salts; using an acid in a suitable solvent to give compound of Formula (IIA) or its salts.

6. The process as claimed in claim 2, wherein the process for preparation of compound of Formula (IIA)

Formula (IIA)
or its salts, comprises:
a) converting compounds of Formula (V)

Formula (V)
in presence of a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic
acid to an amine and subsequent hydrolysis of the amide to produce compound of Formula (III)

Formula (III)
or its salts, and
c) converting compound of Formula (III) or its salts; using an acid in a suitable
solvent to give compound of Formula (IIA) or its salts.

7. The process as claimed in claim 1, wherein the process for preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:

a) reacting compound of Formula (III)

Formula (III)
with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI),

Formula (VI)
b) converting compound of Formula (VI) in presence of suitable solvent to give
compound of Formula (IIB).

8. The process as claimed in claim 7, wherein the process for preparation of compound of Formula (VI)

Formula (VI)
or its salts, which comprises:
a) converting compound of Formula (IVA)

Formula (IVA)
or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts, and
b) reacting compound of Formula (III) with 2-halobutanoic acid in presence of a
base and suitable solvent to produce of compound of Formula (VI).

9. The process as claimed in claim 7, wherein the process for preparation of compound of Formula (VI)

Formula (VI)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
using a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts, and
c) reacting compound of formula (III) or its salts with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI).

10. The process as claimed in claim 7, wherein the process for the preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
using a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts,
c) reacting compound of Formula (III) or its salts with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI), and
d) converting compound of Formula (VI) in presence of suitable solvent to give
compound of Formula (IIB).

11. A process for the preparation of compound of Formula (IIB)

Formula (IIB)
or its salts, which comprises:
a) converting compounds of Formula (V)

Formula (V)
using a base to give compound of Formula (IVA)

Formula (IVA)
or its salts,
b) converting compound of Formula (IVA) or its salts in-situ by converting the carboxylic acid to an amine and subsequent hydrolysis of the amide in presence of an acid to produce compound of Formula (III)

Formula (III)
or its salts, followed by reacting with 2-halobutanoic acid in presence of a base and suitable solvent to produce of compound of Formula (VI), and
c) converting compound of Formula (VI) in presence of suitable solvent to give
compound of Formula (IIB).

12. The process for the preparation of Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compound of Formula (II)

Formula (II)
wherein “R” is hydrogen, or or its salts as claimed in claim 1.

13. The process for preparation of Brivaracetam compound of Formula (I)

Formula (I)
or its salts comprising the process for preparation of intermediate compound of Formula (IIA) or Formula (IIB) or Formula (VI) as clamed in any of the claims 1-11.

14. The solvent used in any of the preceding claims 1-11 is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

15. The base used in claims 4-11 is selected from inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; alkyl metals such as n-butyl lithium or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

16. Acid used in any of the preceding claims 1-11 is selected from inorganic acid, organic acid, lewis acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, sulfuric acid, phosphoric acid (P2O5), poly phosphoric acid, camphorsulfonic acid, formic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, citric acid and oxalic acid, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.

Dated this Eighteenth (18th) day of January, 2020

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Dr. S. Padmaja
Agent for the Applicant
IN/PA/883