DESC:TITLE OF THE INVENTION
Process for the preparation of Levetiracetam.

FIELD OF THE INVENTION
The present invention relates to process for the preparation of Levetiracetam having the structural formula (I).

The present invention also relates to process for the preparation of (S)-2-amino-butyric acid methyl ester compound of Formula (V).

BACK GROUND OF THE INVENTION
Levetiracetam is disclosed in US 4943639, assigned to UCB. It is indicated for the treatment of partial onset of seizures.

The process for preparation of Levetiracetam of formula (I) is disclosed in GB 2225322 A, US 6107492 and US 6124473.

CN publication 101550100 discloses the process for the preparation of Levetiracetam wherein the key intermediate SABAM of compound of Formula (V) is prepared by dehalogenation of compound of Formula (IV) using hydrogen as hydrogen source in the presence of a metal catalyst. The process is disclosed in the scheme given below:

Process disclosed in these patent references results in lower yield and purity.

Therefore, it would be desirable to have a process for the preparation of Levetiracetam of formula (I) which gives higher yield and purity.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides process for the preparation of Levetiracetam of compound of formula (I)

which comprises:
a) reaction of L-threonine of Formula (II)

with thionyl chloride in methanol to give methyl ester compound of Formula (III);

b) chlorination of compound of Formula (III) in thionyl chloride to give compound of Formula (IV);

c) dehalogenation of compound of Formula (IV) in the presence of ammonium formate in methanol in the presence of palladium to give compound of Formula (V);

d) ammonolysis of compound of Formula (V) using methonolic ammonia in methanol in the presence of ammonia gas to give compound of Formula (VI);

e) hydrochloride salt formation of compound of Formula (VI) using methanolic HCl in methanol to give compound of Formula (VII) and

f) reaction of compound of Formula (VII) with 4-chlorobutyryl chloride of Formula (VIII)

in the presence of KOH powder and TBAB to give Levetiracetam.

In another aspect, the present invention provides a process for the preparation of (S)-2-amino-butyric acid methyl ester compound of Formula (V),

a key intermediate used in the preparation of Levetiracetam which comprises:
a) dehalogenation of compound of Formula (IV)

in the presence of ammonium formate in methanol in the presence of palladium to give compound of Formula (V).

In another aspect, the present invention provides process for the preparation of Levetiracetam of formula (I) which results in higher yield.

In another aspect, the present invention provides process for the preparation of Levetiracetam of formula (I); which is simple, convenient, economical and environmental friendly.

DETAILED DESCRIPTION
Accordingly, the present invention relates to an improved process for the preparation of Levetiracetam of formula (I).

Scheme -I illustrates the process for preparation of Levetiracetam of formula (I).

In step-1, reaction of L-threonine of Formula (II) using thionyl chloride in methanol to give (2S, 3R) -2-amino-3-hydroxy-butyric acid methyl ester hydrochloride compound of Formula (III).

In step-2, chlorination of compound of Formula (III) using thionyl chloride to give (2S, 3R) -2-amino-3-chloro-butyric acid methyl ester hydrochloride of Formula (IV).

In step-3, dehalogenation of compound of Formula (IV) using ammonium formate in methanol in the presence of palladium to give (S)-2-amino-butyric acid methyl ester of compound of Formula (V).

In step-4, ammonolysis of compound of Formula (V) using methonolic ammonia in methanol in the presence of ammonia gas to give (S) -2-amino-butyramide of compound of Formula (VI).

In step-5, hydrochloride salt formation of compound of Formula (VI) using methanolic HCl in methanol to give (S)-2-amino-butyramide of compound of Formula (VII).

In step-6, reaction of compound of Formula (VII) with 4-chlorobutyrylchloride of compound of Formula (VIII) in the presence of KOH powder and TBAB to give Levetiracetam.

EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example: Process for the preparation of Levetiracetam.
Stage-1: Synthesis of (2S, 3R) -2-amino-3-hydroxy-butyric acid methyl ester hydrochloride compound of Formula (III):
L-Threonine (400 g) was suspended in 4.2 L of methanol, reaction mixture was stirred thoroughly at 0-5 °C. To the resulting reaction mixture was added 0.8L of thionyl chloride dropwise over the period of 2 h. The resulting reaction mixture was heated to the elevated temperature of 40 ºC for 12h. After consumption of L-Threonine, the reaction mixture was dried under reduced pressure at 50-55 °C to obtain 560 g of a viscous product (98.4 % yield). The purity of the product >99.5% by HNMR assay.

Stage-2: Synthesis of (2S, 3R)-2-amino-3-chloro-butyric acid methyl ester hydrochloride compound of Formula (IV):
100 g of (2S, 3R) -2-amino-3-hydroxy-butyric acid methyl ester hydrochloride was dissolved in 2L of methylene chloride at 0-5 °C followed by the addition of thionyl chloride 0.15 L and N,N-dimethylformamide 4.6mL. The resulting homogenous reaction mixture was heated to reflux for 24 h. After consumption of starting material, volatiles were removed and residual sticky mass was recrystallized using acetonitrile to afford white solid 45g (40.59% yield). HNMR show extra peaks, used as such for next step.

Stage-3: Synthesis of (S) -2-amino-butyric acid methyl ester hydrochloride compound of Formula (V)
1.5 g of ammonium formate was added to 5 g of (2S, 3R) -2-amino-3-chloro-butyric acid methyl ester hydrochloride in 250 mL of methanol followed by addition of palladium on activated charcoal. The resulting reaction mixture was refluxed for 12 h, after consumption of starting material, reaction mixture was filtered to remove the catalyst, volatiles were removed under reduced pressure and dried to give the product as off white solid 3.8g (93% yield), used as such for next step.

Stage-4: Synthesis of (S)-2-amino-butyramide compound of Formula (VI)
5 g of (S)-2-amino-butyric acid methyl ester hydrochloride was dissolved in methanol 50mL, reaction mixture was cooled to 0 ºC followed by addition of methanolic ammonia 100mL, stirred the reaction mixture for 0.5 h at 0 ºC. The reaction mixture was filtered, filtrate was distilled up to 1/3 volume and transferred to autoclave vessel. Autoclave was purged three times with ammonia, filled with 3kg of ammonia gas and the stirred the reaction mixture at 35 ºC for 8h. Carefully ventilate the ammonia gas and volatiles were evaporated under reduced pressure to give off white solid.

Stage-5: Synthesis of (S) -2-amino-butyramide hydrochloride compound of Formula (VII)
The solid obtained in step-4 was dissolved in methanol 25mL cooled to 0oC followed by addition of methanolic HCl (PH=1), stirred for 8h at room temperature. Volatiles were evaporated under reduced pressure. Obtained cured suspended in ethyl acetate and filtered to afford 3.2g of product as white solid (71.1% yield), HPLC purity awaited

Stage-6: Synthesis of Levetiracetam compound of Formula (I)
3 g of (S)-2-aminobutyramide hydrochloride was slowly added to the mixture of potassium hydroxide 7g, TBAB 0.35g in dichloromethane 35mL for 2.5 h and stirred the resulting mixture at –5 to -10 ºC. Pre-cooled mixture of 4-chlorobutyl chloride 4g in dichloromethane 3mL and stirring was continued for 3h at same temperature. After complete consumption of starting material, reaction mixture was filtered to remove undissolved salts, washed with dichloromethane (2x10mL) and volatiles were removed under reduced pressure to give the crude product. Crude was recrystallized from ethylacetate 10mL to afford white solid 3.1g (84% yield).

ADVANTAGES OF THE PRESENT INVENTION
1. It is a simple and cost effective process.
2. The process results in higher yield using cheaper raw materials. ,CLAIMS:1. A process for the preparation of Levetiracetam of compound of formula (I)

which comprises:
b) reaction of L-threonine of Formula (II)

with thionyl chloride in methanol to give methyl ester compound of Formula (III);

b) chlorination of compound of Formula (III) in thionyl chloride to give compound of Formula (IV);

c) dehalogenation of compound of Formula (IV) in the presence of ammonium formate to give compound of Formula (V);

d) ammonolysis of compound of Formula (V) using methonolic ammonia in methanol in the presence of ammonia gas to give compound of Formula (VI);

e) hydrochloride salt formation of compound of Formula (VI) using methanolic HCl in methanol to give compound of Formula (VII) and

f) reaction of compound of Formula (VII) with 4-chlorobutyryl chloride of Formula (VIII)

in the presence of KOH powder and TBAB to give Levetiracetam.

2. A process for the preparation of (S)-2-amino-butyric acid methyl ester compound of Formula (V),

which comprises:
a) dehalogenation of compound of Formula (IV)

in the presence of ammonium formate in methanol in the presence of palladium to give compound of Formula (V).