FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - An improved process for the preparation of Levetiracetam
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of Invention
Present invention relates to an improved process for preparation of Levetiracetam
of formula (I).

Background of the invention
Levetiracetam (I) is a 2-oxo-l-pyrrolidine derivative which is chemically known as (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide, having molecular formula C8H14N2O2 and molecular weight 170.21. The current pharmaceutical product containing this drug is being sold by UCB using the tradename Keppra® in the form of tablets and solution.
Levetiracetam (I) is useful in the treatment of epilepsy, hypertonia, motion sickness and hyperkinesia. Levetiracetam acts as N-Type calcium Channel (Ca (v) 2.2) Blockers.
Levetiracetam(I) is first disclosed in US Patent No. 4,696,943 which also discusses its process for preparation wherein Levetiracetam is prepared by condensation of (S)-2-aminobutanamide with 4-halobutyryl halide. However, this patent remains silent about purity and yield of final product. Moreover, it has been observed by present inventors that Levetiracetam as prepared by this process always contains more than 0.1% impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid.
Another process for the preparation of Levetiracetam (I) is disclosed in GB 2,225,322 wherein Levetiracetam (I) is prepared by hydrogenolysis of (S) -α-
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ethyl-[2-(methylthio) ethyl] -2-oxo-l-pyrrolidineacetamide by means of a desulphurizing agent such as Raney Nickel or NaBH4/NiCl2.6H2O. This process is difficult to control at an industrial scale and also requires specifically designed reactor equipment and extraordinary handling precautions.
US Patent No. 6,858,740 which discloses process for preparation of Levetiracetam (I) by asymmetric hydrogenation in the presence of rhodium or ruthenium catalysts. A disadvantage of this process is that racemisation may occur during ammonolysis. Moreover, this process is less preferred with respect to economical value because of the use of costly reagent such as rhodium.
US Application No. 20040259933 which discloses a process wherein Levetiracetam (I) is prepared by reaction of (S)-2-aminobutanamide hydrochloride with 4-halobutyryl halide in solvents like acetonitrile, methyl tertiary butyl ether. The major drawback of this process is use of acetonitrile which has higher boiling range and methyl tertiary butyl ether which is highly prone to catch fire.
In summary, prior art suffers with many disadvantages such as mentioned hereinabove. Therefore, to overcome these disadvantages the present inventors have directed their research work toward developing a process which is avoid the drawbacks associated with prior art processes.
Summary of the invention
It is therefore an object of the present invention is to provide an improved process for the preparation of Levetiracetam (I).
Another object of the present invention is to provide an improved process for the preparation of Levetiracetam (I) which is operationally simple, easy to handle and applicable at an industrial scale.
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Another object of the present invention is to provide an improved process for preparation of Levetiracetam (I) with greater yield and purity.
Another object of the present invention is to provide an improved process for preparation of Levetiracetam (I) having impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid less than 0.1%.
Another object of the present invention is to provide Levetiracetam (I) having impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid less than 0.1 % .
Another object of the present invention is to provide Levetiracetam (I) having impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid less than 0.05 % .
Further object of the present invention is to provide an improved process for preparation of Levetiracetam (I) comprising steps of:
(i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated hydrocarbon, base and in the absence of phase transfer catalyst to obtain crude Levetiracetam ,

(ii) purifying crude Levetiracetam obtained in step (i) in a mixture of ester solvent and an acid to obtain Levetiracetam (I) ,

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Wherein, X represents halogen
Detailed description of the invention
Accordingly, present invention provides a process for preparation of Levetiracetam (I) comprising steps of:
(i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to
obtain crude Levetiracetam ,

(ii) purifying crude levetiracetam obtained in step (i) in a mixture of ester solvent
and an acid to obtain Levetiracetam (I),

Wherein, X represents halogen
In embodiment, present invention provides a process for preparation of Levetiracetam (I) comprising steps of:
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(i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to
obtain crude Levetiracetam ,

(ii) purifying crude Levetiracetam obtained in step (i) in a mixture of ester solvent and an acid to obtain the Levetiracetam (I) having impurity of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid less than 0.1 % ,

Wherein, X represents halogen
In another embodiment, present invention provides a process for preparation of Levetiracetam (I) comprising steps of:

(ii) isolating the compound of formula (V),
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(i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to obtain the compound of formula (V),


(iii) cyclizing the compound of formula (V) obtained from step (ii) in chlorinated
solvent , base and in the absence of phase transfer catalyst to obtain crude
Levetiracetam.
(iv) purifying crude Levetiracetam obtained in step (iii) in a mixture of ester
solvent and an acid to obtain Levetiracetam (I),

Wherein, X represents halogen
In another embodiment, present invention provides a process for preparation of Levetiracetam (I) comprising steps of:
(ii) isolating the compound of formula (V),
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(i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to obtain the compound of formula (V),



(iii) cyclizing the compound of formula (V) obtained from step (ii) in chlorinated
solvent, base and in the absence of phase transfer catalyst to obtain crude
Levetiracetam.
(iv) purifying crude Levetiracetam obtained in step (iii) in a mixture of ester
solvent and an acid to obtain Levetiracetam (I) having impurity of (S)-alpha-ethyl-
2-oxo-1-pyrrolidineacetic acid less than 0.1 %,

Wherein, X represents halogen
For the purpose of this specification, the meaning of the term "treating" as used hereinabove includes suspending, dissolving, washing, mixing and crystallizing or recrystallizing in any of the suitable solvent.
For the purpose of this specification, the meaning of the term "chlorinated solvent" as used hereinabove includes methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like or mixture thereof.
For the purpose of this specification, the meaning of the term "ester solvent" as used hereinabove includes ethyl acetate, butyl acetate, propyl acetate and the like or mixture thereof.
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For the purpose of this specification, the meaning of the term "base" as used hereinabove includes inorganic bases such as alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides. However, potassium hydroxide is most preferable base.
For the purpose of this specification, the meaning of the term "an acid" as used hereinabove includes organic acid such as acetic acid, formic acid, maleic acid, citric acid, succinic acid and the like or mixture thereof.
For the purpose of this specification, the meaning of the term "purifying" as used hereinabove includes any method known to a person skilled in the art such as purification from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.
For the purpose of this specification, the meaning of the term "Levetiracetam (I)" is Levetiracetam having purity of at least 99 %.
All compounds are isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake, crystallization and drying or by evaporation of solvent.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
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Example 1
Preparation of Levetiracetam
Anhydrous sodium sulphate (142gm) was added to a suspension of S (+)-2-amino butyramide hydrochloride (100g) in methylene dichloride (1000ml) at room temperature. The mixture was cooled to 0°C followed by addition of ground potassium hydroxide (170gm) to the reaction mixture. A solution of 4-chlorobutyryl chloride (132gm) in methylene dichloride (100 ml) was added drop wise at same temperature to reaction mixture. After stirring reaction mixture at 0°C for two hours, ground potassium hydroxide (36gm) was added to the mixture. After four hours further ground potassium hydroxide (36gm) was added to reaction mixture and stirring was continued for one hour at 0°C. The reaction mixture was then filtered over hyflo and the filtrate was evaporated under reduced pressure. The residue was purified in a mixture of hot ethyl acetate (600 ml), glacial acetic acid (5ml) and 5% activated carbon to give Levetiracetam (91gm). Purity ~ 99.5 % (by HPLC)
Content of impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid ~ 0.05 % (by HPLC)
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We claim:
1. A process for preparation of Levetiracetam (I) comprising steps of: (i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to obtain crude Levetiracetam ,

(ii) purifying crude levetiracetam obtained in step (i) in a mixture of ester solvent
and an acid to obtain Levetiracetam (I),

Wherein, X represents halogen
2. A process for preparation of Levetiracetam (I) comprising steps of:
(i) treating the compound of formula (II) with the compound of formula (III) or its
salt in chlorinated solvent, base and in the absence of phase transfer catalyst to
obtain crude Levetiracetam ,

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(ii) purifying crude Levetiracetam obtained in step (i) in a mixture of ester solvent and an acid to obtain the Levetiracetam (I) having impurity of (S)-alpha-ethyl-2-oxo-1-Dvrrolidineacetic acid less than 0.1 % .

Wherein, X represents halogen
(ii) isolating the compound of formula (V),

3. A process for preparation of Levetiracetam (I) comprising steps of: (i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to obtain the compound of formula (V),

(iii) cyclizing the compound of formula (V) obtained from step (ii) in chlorinated
solvent , base and in the absence of phase transfer catalyst to obtain crude
Levetiracetam.
(iv) purifying crude Levetiracetam obtained in step (iii) in a mixture of ester
solvent and an acid to obtain Levetiracetam (I),
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Wherein, X represents halogen

(ii) isolating the compound of formula (V),

4. A process for preparation of Levetiracetam (I) comprising steps of: (i) treating the compound of formula (II) with the compound of formula (III) or its salt in chlorinated solvent, base and in the absence of phase transfer catalyst to obtain the compound of formula (V),
(iii) cyclizing the compound of formula (V) obtained from step (ii) in chlorinated
solvent, base and in the absence of phase transfer catalyst to obtain crude
Levetiracetam.
(iv) purifying crude Levetiracetam obtained in step (iii) in a mixture of ester
solvent and an acid to obtain Levetiracetam (I) having impurity of (S)-alpha-ethyl-
2-oxo-l-pyrrolidineacetic acid less than 0.1 %,
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Wherein, X represents halogen
5. The process according to claim 1, 2 ,3 and 4, wherein the chlorinated solvent used is selected from the group consisting of methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof.
6. The process according to claim 1,2,3 and 4, wherein the ester solvent used is selected from the group consisting of ethyl acetate, butyl acetate, propyl acetate or mixture thereof.
7. The process according to claim 1, 2, 3 and 4, wherein the base used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonate, alkali or alkaline earth metal hydrides.
8. The process according to claim 1, 2, 3 and 4, wherein an acid used is selected from the group consisting of organic acids such as acetic acid, formic acid, maleic acid, citric acid, succinic acid or mixture thereof.
9. Levetiracetam having impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic
acid less than 0.1 % .
10. Levetiracetam having impurity of (S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid less than 0.05 % .
11. Levetiracetam having purity of at least 99%.
Dated this 4th day of September 2006

Sonali Bhokarikar
Of S. Majumdar & Co. (Applicant Agent)

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Abstract
Present invention relates to an improved process for preparation of Levetiracetam of formula (I).

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