F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PROCESS FOR PREPARING LEVETIRACETAM
2. Applicant(s)

(a) NAME : RUBAMIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Synergy House, Subhanpura, Vadodara 390 023, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

Field of invention
The present invention relates to a new process for preparing (S)-(-) - a-ethyl-2-oxo-l-pyrrolidine acetamide represented by the following formula (I)

The compound is called Levetiracetam, and is known to be useful as an agent for the treatment or prevention of epilepsy and other neurological disorders.
Background of invention
British Pat. No. 1,309,692 teaches the synthesis of (S)-(-) - a—ethyl-2-oxo-l -pyrrolidine acetamide of formula ( I ) The prior art methods for synthesis of Compound (I) could be summarised as follows:
US 4696943 (Gobert et al.) describes the method either by reacting (S)-(-) - a--ethyl-2-oxo-1-pyrrolidineacetic acid successively with an alkyl chloro formate and with ammonia or by condensation followed by cyclization of 2-amino butanamide with 4-chlorobutyryl chloride. This process requires starting reactant with correct stereochemical configuration, the yields are often poor in the resolution.
GB 2225322 (Cossement E. et al.) claims (S)-(-) - a--ethyl-2-oxo-l-pyrrolidine acetamide preparation by hydrogenolysis of (S)- a-[2-(methylthio)ethyl]-2-oxo-l-pyrrolidineacetamide in the presence of a desulfurising reagent. In this process the desulfurizing agents are not environment friendly.
US 6107492 (Futagawa et al.) describes the method by optical resolution of racemic a- ethyl-2-oxo-l-pyrrolidineacetamide by means of preparative high performance liquid chromatography or continuous simulated moving bed chromatographic system using silicagel supported amylose tris (3,5-dimethylphenyl carbamate) as a packing material.
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US 6124473 (Cavoy et al.) claims an industrial scale enatiomeric resolution of racemic mixture of a-ethyl-2-oxo-l-pyrrohdineacetamide by simulated moving bed chromatography, using at least three columns filled with chiral stationary phase.
EP 1477478 (Surtees et al.) describes a process for preparing a-ethyl-2-oxo-l-pyrrolidineacetamide from lactam substituted 2-butenoic acid derivatives based on similar methodologies adopted by Boaz et al in US patent 6686477 which involves preparation of enantiomerically pure lactum substituted propanoic acid derivatives by asymmetric hydrogenation of lactam substituted 2- propenoic acid derivatives. The dis advantage of the process is the reaction time necessary to obtain the conversion is very long and hence not attractive.
WO 03/014080 (Ates et al.) claims an improved process for (S)-(-) - a—ethyl-2-oxo-l-pyrrolidineacetamide from (S)-(+)-2-aminobutyric acid by alkylation of its methyl ester with ethyl -4-bromobutyrate,cyclization and amidation. Here again expensive optical active reactant is required.
WO 2004/069796 (Dolityzky) describes a process for preparing (S)-(-)-a-ethyl-2-oxo-l-pyrrolidineacetamide from (S)-(+)-2-amino butynamide hydrochloride with 4-chlorobutyryl chloride in Acetonitrile or methyl tert butyl ether in the presence of a strong base. Here also expensive optical active reactant is required.
WO 2004/076416 (Surroca et al.) describes a method which comprises of preparation of aminomethyl derivatives of racemic a-ethyl-2-oxo-l-pyrrolidineacetamide, resolution followed by deaminomethylation of sufficiently pure enatiomeric intermediate to make (S)-(-)-a-ethyl-2-oxo-l -pyrrohdineacetamide. The loss during resolution makes this process unattractive
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Object of the Invention

It is an object of the invention to provide a new, short, cost effective process for the preparation of (S)-(-)-a-ethyl-2-oxo-l-pyrrolidineacetamide, also known as Levetiracetam, in high yields.
In our copending application No. IP264/2005 there is disclosed a process
for the preparation of (S)-(-)-a-ethyl-2-oxo-l-pyrrolidineacetamide of Formula (I) in
which the step of resolution is omitted. The process of the copending application
comprises:
i) condensation of (S)-2-amino butanol of Formula (Il)and 4-halobutryl chloride, where
halo group can be chloro, bromo or iodo in solvents to form a-ethyl-2-oxo pyrrolidine
ethanol of Formula (III)

ii) oxidation of (S)-a-ethyl-2-oxo pyrrolidine ethanol to yield (S)-a-ethyl-2-oxo pyrrolidine acetic acid having the formula (IV)

(IV)
iii) esterification of (S)-a-ethyl-2-oxo pyrrolidine acetic acid (IV) with an alcohol to provide alkyl ester of Formula (V) wherein, R is 1-4 Carbon atom.
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(V)
iv) ammonolysis of alkyl esters of formula (V) with ammonia to provide (S)-(-)- a-ethyl-2-oxo-l-pyrrolidine acetamide of formula (I).
Summary of invention
The present invention relates to a process for the preparation of (S)-(-)-a—ethyl-2-oxo-1 -pyrrolidineacetamide of Formula (I), comprising the steps of:

i) resolution of racemic 2-amino butynamide with L-(+)-tartaric acid either in
alcoholic solvents like methanol, isopropanol , ethanol or in water or mixture of water-alcohol.
ii) direct conversion of (S)-(+)-2-amino butynamide tartarate salt ( VI) and 4-halobutryl chloride in presence of inorganic or organic base in suitable solvent and drying agents yielded the desired (S)-(-)-a—ethyl -2-oxo-l-pyrrolidineacetamide (I).
The advantage of this route is that it allows synthesis of (S)-(-)-a ethyl-2-oxo-1-pyrrolidineacetamide (I) in one step from ( VI) and does not require prior isolation of the intermediate (S)-(+)-2-amino butynamide. Hydrochloride
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salt, which is a common practice after resolution before its conversion to (I). This therefore cuts short the synthesis by one step.
iii) If desired , (S)-(+)-2-aminlo butynamide tartarate salt ( VI can also be converted to (S)-(+)-2-amino butynamide hydrochloride salt, by reacting with an inorganic or organic base in a suitable solvent followed by reaction with HC1 gas in an appropriate solvent. (S)-(+)-2-amino butynamide hydrochloride thus formed, can be converted to Levetiracetam of formula (I) based on number of examples as described in prior art..
Detailed description of the invention
The (S)-(+)-2-amino butynamide tartarate salt, used in this invention is obtained from the racemic (±)- 2- amino butynamide by chemical resolution with (L)-(+)- tartaric acid. The amount of (L)-(+)- tartaric acid used could vary from 0.25 molar amount to 1 molar amount. The isolation of the tartarate salt formed by successive crystallizations either in alcoholic solvents like methanol, isopropanol , ethanol or in water or mixture of water and alcohol. The crystallization can be effected at temperature between 25°C to 60°C, but preferably between 40 °C to 50°C.
The preparation of (S)-(-)-a-ethyl-2-oxo-l-pyrrolidineacetamide of Formula (I),

comprising reaction of (S)-(+)-2-amino butynamide tartarate salt and 4-chlorobutyryl chloride in presence of inorganic base selected from potassium carbonate or hydroxide, sodium carbonate or hydroxide, ammonia or the Organic base selected from triethyl amine, DMAP, DABCO and the like. The reaction can be carried out in the presence of tetraalkyl ammonium halide (RAN+X), R can be CI to C4 carbon atom and or Benzyl
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trialkyl ammonium halides, where alkyl group could be Carbon 1 to 4 atom.The suitable solvent used is aprotic solvent selected from chlorinated solvents, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane e; others like Acetonitrile, Dimethyl formamide (DMF), Methyl t-butyl ether and Tetrahydrofuran. In addition, solvent can be chosen from aromatic hydrocarbon solvent, like toluene, xylene, mixed xylenes and like. The drying agents are selected from Sodium sulphate, Magnesium sulphate and molecular sieve. The temperature of the reaction is between 0 to 40°C, preferably between 0 to 5°C.
A process for preparation of (S)-(+)-2-amino butynamide hydrochloride salt, which is an intermediate for Levetiracetam, is prepared from (S)-(+)-2-amino butynamide tartarate salt in presence of inorganic base selected from potassium carbonate or hydroxide, sodium carbonate or hydroxide, ammonia gas, and the Organic base is selected from triethyl amine, DMAP, and the like. The suitable solvent is selected from methanol, isopropanol , ethanol or in water or mixture of water-alcohol. The hydrochloride salt is prepared by passing HCl gas directly , or using a preformed solution of HCl gas in alcoholic solvent like Isopropanol, Methanol, Ethanol, propanol etc to the solution of (S)-(+)-2-amino butynamide in the chosen solvent. The temperature during the reaction is maintained between 0-40°C, preferably between 20-3 0°C.
Examples
1) Preparation of tartarate salt of (S)-amino butynamide
102 gm racemic (±) 2- amino butynamide is suspended in 1400 ml of methanol in a 3-liters of round bottom flask. To this suspension is added gradually 150 gm of L(+) tartaric acid under stirring at 25° C. The mixture is then heated to reflux. After 30 minutes refluxing, salt is precipitated. It is then cooled to 40-50°C , filtered to get 83 g of (S)-(+)-amino butynamide tartarate salt.
Yield: 83 g, Appearance: white solid , [a]25D + 28° (C= 1, water).
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2) Preparation of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide (I)
33.8 g of anhydrous Na2S04 is added to suspension of 50 g of (S)-amino butynamide tartarate salt in 1 liter of Acetonitrile. The mixture is cooled to 0-5° C , 82 g of potassium carbonate is added to it. A solution of (30.7 g) of 4-chloro butyryl chloride in 90 ml acetonitrle is added dropwise at 0°C with vigorous stirring. After the addition , the reaction mixture is allowed to return to 25° C. After 5 hours' cool the reaction mixture, 38.8 g powdered potassium hydroxide is added at 0-5°C . the reaction mixture was stirred for further 10 hrs, filtered and filtrate evaporated under reduce pressure. The residue (28 g, 90% pure ) is dissolved in 130 ml of Acetone and heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 22.6 g of (S)-alpha-ethyl-2-oxo-1 -pyrrolidineacetamide.
Melting point: 115-117°C ; [a]25D -88° (C=l, acetone), Yield : 67%
3) Preparation of (S)-(+)- 2-amino butynamide hydrochloride
150 g (S)-amino butynamide tartarate salt is added in 750 ml of Methanol. The mixture is cooled to 20-30° C. Ammonia gas is passed in to the solution keeping the temperature 20-30° C till the pH of reaction mass becomes 9-10. The reaction mixture was stirred for 30 minutes and filtered. Methanol is removed, 50 ml of isopropanol was added and the reaction mixture was acidified to pH 2 by adding mixture of hydrochloric acid gas in Isopropanol maintaining the temperature between 20-30°C. The solid filtered, and dried to obtain 58 g of (S)-(+)-2-amino butynamide hydrochloride.
[a]25D 26.5° (C=l, methanol), Yield : 70 %
Dated this 1st day of April 2005

Ashwini Sandu
Of S.Majumdar&Co. Applicant's Agent
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