DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of brivaracetam (I).

The present invention also relates to novel intermediate of formula (VIII);

wherein, R can be selected from alkyl alkoxy, alkyl aryloxy, alkyl thio alkoxy, alkyl sulfone or alkyl substituted amine, X can be selected from any suitable leaving group;
Intermediate of formula (X);

wherein, R is as defined above;
Intermediate of formula (V);

and intermediate of formula (VI)

wherein, R is as defined above
BACKGROUND OF THE INVENTION
“Brivaracetam” [357336-20-0] is marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide and is represented by following general Formula (I),

Process for preparation of brivaracetam of formula (I) is known from US 6,784,197 assigned to UCB Pharma. The reported process to prepare brivaracetam can be summarized as follows:

US Patent No. 7,629,474, US 8,957,226, US 8,338,621 and “Kenda et. al” J. Med. Chem. 2004, 47, 530-549 also discloses process for preparation of brivaracetam.
WO 2016191435 A1 discloses scalable synthesis of enantiomerically pure brivaracetam. This application basically focus on process for preparation of (R)-4-propyldihydrofuran-2(3H)-one an intermediate through decarboxylation of (4R)-ethyl 4-isobutyl-2-oxotetrahydrofuran-3-carboxylate.

Org. Process Res. Dev. 2016, 20 (9), pg. 1566–1575 discloses a bio-catalytic synthesis for Brivaracetam wherein enzymatic resolution is attempted to prepare 4-n-propyl intermediate.
WO 2017076737 A1 discloses synthesis of brivaracetam by integrated continuous flow process.
WO 2018042393 A1 discloses synthesis of enantiomerically pure brivaracetam.
Majority of reported process are tedious and requires chiral resolution at the end of the process which results in to a loss of yield. Moreover, said process involved expensive intermediates. In view of the above, it is therefore required to develop an efficient and economical process for the preparation of brivaracetam.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for preparation of brivaracetam of formula (I); wherein intermediate of formula (VIII) is converted to brivaracetam.

[R can be selected from alkyl alkoxy, alkyl, alkyl aryloxy, thio alkoxy, thioether or alkyl substituted amine, X can be selected from any leaving group such as Cl, F, Br or I.
Another object of the present invention is to provide a process for preparation of brivaracetam wherein intermediate of formula (VIII) is reacted with (S)-2-aminobutanamide of formula (IX) to obtain an intermediate of formula (X) which is further converted to brivaracetam of formula (I)

Yet another object of the invention is to provide novel intermediate of formula (VIII)

[Wherein R is as defined above]
Yet, another object of the present invention is to provide use of intermediate of formula (VIII) in preparation of brivaracetam.
Yet another object of the invention is to provide intermediate of formula (X)

[Wherein R is as defined above]
Yet another object of the invention is to provide use of intermediate of formula (X) in preparation of brivaracetam.
Yet another object of the invention is to provide intermediate of formula (V) and its use in preparation of brivaracetam

[Wherein R is as defined above]
Yet another object of the invention is to provide intermediate of formula (VI) and its use in preparation of brivaracetam

[Wherein R is as defined above]
Primarily the object of present invention is to provide an enantioselective and economically viable process for preparation of brivaracetam, involving novel intermediates wherein preparation of all novel intermediates and their conversion to brivaracetam is simple and efficient.
SUMMARY OF THE INVENTION
In an aspect the present invention provides a process for preparation of brivaracetam (I)

comprising a step of converting intermediate of formula (VIII)

to brivaracetam of formula (I); wherein R and X are as defined above.
In another aspect, the present invention provides a process to prepare brivaracetam comprising steps of reacting compound of formula (VIII) with compound of formula (IX) to get intermediate of formula (X)

Further, converting intermediate of formula (X) to brivaracetam.
In yet another aspect the present invention provides a process comprising step of converting intermediate of formula (X) to brivaracetam (I)

In yet another aspect the present invention provides novel intermediates of formula (VIII)

Intermediate of formula (X)

Intermediate of formula (V)

and intermediate of formula (VI)

In yet another aspect the present invention provides use of intermediate of formula (VIII), (X), (V) and (VI) in preparation of brivaracetam (I).
In yet another aspect the present invention provides a process to prepare brivaracetam comprising steps of converting compound of formula (V) to intermediate of formula (VI) which is further converted to furan intermediate of formula (VII):

Further, preparing intermediate of formula (VIII) from furan of formula (VII); reacting (VIII) with (S)-amino butanamide (IX) to get an intermediate of formula (X)

cyclizing intermediate of formula (X) to get brivaracetam (I).

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of present invention is to provide process for preparation of brivaracetam (I); the process also comprises novel intermediate useful in the preparation of brivaracetam. The complete process of present invention can be represented by following scheme.
Scheme:

In an embodiment the present invention provides a process for preparation of intermediate of formula (V) which is used in preparing brivaracetam.
Preparation of intermediate of formula (V) comprises two steps, step I comprises reacting malonic acid (II) with 2-methoxyethan-1-ol; OR 2-(methylthio)ethan-1-ol or similar compounds to obtain substituted malonate of formula (III). The reaction can be carried out in presence of any suitable organic solvent at heating or reflux temperature of the solvent. Alternatively the process of step I can also be carried out in presence of acid chloride such as thionyl chloride and base. This is represented as step I in above scheme.
In Step II of the process the malonate of formula (III) [exemplarily Bis(2-methoxyethyl)malonate] is reacted with (R)-2-(chloromethyl) oxiran (IV) to provide intermediate of formula (V). The reaction is carried out in presence of base and solvent. Preferably a strong base such as sodium methoxide can be used for process of Step II. The reaction can be carried out at a temperature in the range of room temperature to the reflux temperature of solvent. The solvent can be selected from any suitable organic solvent such as nitriles, alkanols, ketonic solvents, ether, chlorinated solvents, hydrocarbons or like thereof. The product of step II i.e. intermediate of formula (V) by extraction and distillation.
In another embodiment the present invention provides a process to prepare intermediate of formula VI; this comprises reacting intermediate of formula (V) with Grignard reagent like ethyl magnesium bromide and a suitable catalyst if required, as represented in step III of above scheme. The process of step III can be carried out in presence of any suitable solvent under cooling or room temperature; the product i.e. intermediate of formula VI can be isolated by extraction and distillation of the solvents.
In yet another embodiment the present invention provides a process to prepare furan intermediate of formula (VII), this process comprises reacting (VI) with metal halide like cuprous chloride, lithium chloride, sodium chloride or like. The reaction is preferably carried out under heating in presence of solvent. The product i.e. intermediate of formula (VII) is isolated by extraction and distillation of the solvents. This is represented by step IV in above scheme.
In yet another embodiment the present invention provides a process to prepare intermediate of formula (VIII), this is represented as step (V) in above scheme. the process of step (V) includes reacting intermediate of formula (VII) in presence of with 2-methoxyethan-1-ol or any reagent similar to 2-methoxyethan-1-ol for example 2-(methylthio)ethan-1-ol. The reaction is carried out in presence of organic acid and halo acid. The product i.e. intermediate of formula (VIII) can be isolated by extraction followed by distilling off the reaction mixture.
In another embodiment the present invention provides process to prepare intermediate of formula (X). This is represented as step (VI) in above scheme. The process of step VI comprises reacting intermediate of formula (VIII) with S-amino butanamide of formula (IX) to provide intermediate of formula (X). The reaction can be carried out in presence of a solvent and base. Additionally phase transfer catalyst such as tetrabutyl ammonium bromide can be used for the purpose of this reaction. The base can be selected from any suitable inorganic or organic base preferably inorganic base like alkali or alkali metal carbonate can be used. The solvent can be selected from any suitable organic solvent like alkanol, ketone, ether, nitrile, alkanes or cycloalkanes. If desired intermediate of formula (X) can be isolated alternatively it can be directly taken for further reaction without isolation.
In another embodiment the present invention provides process for cyclization of intermediate of formula (X) as represented in step VII, the cyclization process can be carried out in presence of any suitable solvent by heating the reaction mixture preferably heating to reflux. If desired catalyst for cyclisation such as acetic acid, para toluene sulfonic acid, 2-hydroxypyridine or any other similar reagent can be used. The solvents for this reaction can be selected from any suitable organic solvent such as ethyl acetate, isopropyl acetate, acetonitrile or any such solvent. Once the reaction is complete the product i.e. brivaracetam can be isolated by extraction and distillation of the solvent. Brivaracetam thus prepared can be washed with any solvent such as diethyl ether, diisopropyl ether or methyl tertiary butyl ether.
Following are the examples to further explain the invention with experimental conditions.

Examples:
Example 1:
Preparation of 2-methoxyethyl (R) -3-(bromomethyl) hexanoate:
A solution of (R)–dihydro-4-propylfuran-2-(3H)-one (10g) in acetic acid (20ml) was added to HBr in acetic acid (25ml) at room temperature and stirred. The reaction mixture was heated to 50-85°C and stirred. The reaction mixture was cooled to room temperature and toluene (60ml) was added to it, followed by addition of water (10ml) this reaction mixture was stirred for 15 minutes. Layers were separated, aqueous layer was extracted with toluene (50ml) and combined oraganic layer was washed with water. The reaction mass thus obtained was partially distilled and then cooled to room temperature, to this 1ml of dimethylformamide and 20 ml of thionyl chloride was added, stirred for 10 minutes distilled off completely. Reaction mass obtained after distillation was cooled to room temperature and to this 100ml of toluene, 15 ml of 2-methoxyethane-1-ol was added. The reaction mixture was stirred for 30 minutes at room temperature and to this 50ml of water was added. Layers were separated, the organic layer was distilled off completely to yield title compound.

Example 2:
Preparation of brivaracetam:
5 g of 2-methoxyethyl (R) -3-(bromomethyl) hexanoate as prepared in example 1, (S)-2-mainobutanamide (2.86g), tetrabutylammonium bromide (0.1g), sodium carbonate (3.8g) and acetonitrile (50ml), were charged into a round bottom flask at room temperature and stirred for 30-40 minutes at reflux temperature. Reaction mixture was cooled to 5-10 °C, filtered and the solid thus obtained was washed with acetonitrile. Filtrate was concentrated and to this 15 ml of isopropyl acetate and 1g of acetic acid was added, temperature of reaction mixture was raised to 65-70°C and reaction mixture was stirred at the same for 60-80 minutes. Reaction mixture was cooled to room temperature, filtered and solid was washed with isopropyl acetate. Layers were separated and organic layer was distilled off completely to give residue which was washed with methyl tertiary butyl ether to obtain title compound i.e. brivaracetam. ,CLAIMS:We Claim:

1. A process for preparation of brivaracetam of formula (I)

comprising a step of converting intermediate of formula (VIII)

to brivaracetam of formula (I), wherein R is selected from alkyl alkoxy, alkyl aryloxy, thioether or alkyl substituted amine; X is selected from any leaving group such as Cl, Br, F or I.

2. The process for preparation of brivaracetam of formula (I) as claimed in claim 1, which comprises steps of:

a) reacting compound of formula (VIII) with (S)-2-aminobutanamide of formula (IX) to obtain an intermediate of formula (X)

b) converting intermediate of formula (X) as obtained in to brivaracetam of formula (I).
wherein, R and X are as defined above.

3. The process as claimed in claim 2, comprises reacting compound of formula (VIII) with (S)-2-aminobutanamide of formula (IX) in presence of solvent and base, wherein base is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; solvent is selected from alkanol, ketone or nitrile such as acetonitrile.

4. The process as claimed in claim 2, comprises cyclisation of compound of formula (X) to obtain brivaracetam of formula (I) in presence of catalyst such as acetic acid, para toluene sulfonic acid and 2-hydroxy pyridine.

5. The process for preparation of brivaracetam of formula (I) as claimed in claim 1, which comprises steps of:

a) converting compound of formula (V) to intermediate of formula (VI)

wherein R is as defined above.
b) converting compound of formula (VI) in to intermediate of formula (VII)

c) further converting compound of formula (VII) to brivaracetam of formula (I).

6. The process as claimed in claim 1, wherein R may be selected from lower alkyl alkoxy, thioethers and dialkyl amine groups.

7. The process as claimed in claim 1, wherein X may be selected form Cl, Br, F or I.

8. A compound of formula (V), (VI), (VIII) and (X) as intermediate for preparation of brivaracetam of formula (I)

wherein, R and X are as defined above.