Field of invention
An improved process for the preparation of pure levetiracetam, with good yield and purity is provided.
Background
Chemically, levetiracetam is (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and is known from US patent No 4,943,639 assigned to UCB societe of Belgium. Levetiracetam can be used for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system.
US patent 4,943,639 discloses the recrystallization of crude levetiracetam from ethylacetate, which is prepared by reacting (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with alkylhaloformate, wherein (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid was obtained by the chemical resolution of racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid. US 6,107,492 and US 6,124,473 focus on the preparation of levetiracetam by optical resolution of the racemic mixture of alpha-ethyl-2-oxo-1-pyrrolidineacetamide through simulated mobile bed chromatography or preparative high performance liquid chromatography. WO 01/64637 discloses the purification of levetiracetam by recrystallization with acetone for reducing the metal catalyst as well as the other enantiomer in the final product. Levetiracetam, in turn was obtained by asymmetric hydrogenation of (Z) or (E)-2-(2-oxotetrahydro-1H-1-pyrrolyl)-2-butenamide, using a chiral catalyst.
Summary
There is provided an improved process (1) for preparation of pure levetiracetam comprising:
a) contacting crude levetiracetam with an organic solvent,
b) removing undissolved material, and
c) isolating pure levetiracetam from the resulting solution.
Alternatively, there is also provided another process (2) for preparation of pure levetiracetam comprising,
a) contacting crude levetiracetam with a first organic solvent,
b) adding a less polar second organic solvent to the above mixture and
c) isolating pure levetiracetam from the resulting mixture.
This process may also have an additional step in which undissolved material is removed before adding the less polar organic solvent.
The undesired R enantiomer of levetiracetam has relatively lower solubility and can be removed or minimized by these processes.
Detailed description
The crude levetiracetam may be obtained by any of the synthetic routes described in the prior art including those described in US 4,943,639, WO 01/64637 and GB 2225322.The term "crude levetiracetam" includes levetiracetam having optical purity of not less than 90%. The crude levetiracetam, obtained as a solution directly from a reaction in which levetiracetam is formed, may be used as such in the process.
The tenn "contacting" includes dissolving, slurrying, stirring or a combination thereof. Isolation may be accomplished by concentration, cooling, filteration, centrifugation or a combination thereof.
The organic solvents used in step (a) of both the processes may be the same and include ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone ; nitriles such as acetonitrile; hydrocarbons such as toluene; chlorinated hydrocarbons such as methylenechloride and ethylene dichloride; ethers such as diethylether and diisopropylether and cyclic ethers such as dioxane, tetrahydrofuran and mixtures thereof.
Examples of less polar organic solvents include esters such as ethylacetate, isobutylacetate and isopropylacetate; hydrocarbons such as hexane, cyclohexane.
toluene and heptane; lower alkyl ethers such as diethylether, diisopropylether and mixtures thereof.
The undissolved material (predominantly R enantiomer) may be removed by processes including filtration, centrifugation or decantation.
In process (1), after removing the undissolved material, pure levetiracetam may be isolated, for example, by cooling the resulting solution.The solution may also be concentrated before cooling to obtain pure levetiracetam in some particular embodiments.
In process (2), the crude levetiracetam may be dissolved in the first organic solvent or may be suspended to get a slurry in some particular embodiments. The mixture of crude levetiracetam and first organic solvent may also be heated to get a solution.
The mixture of crude levetiracetam and first organic solvent may be concentrated before adding the less polar second organic solvent, for example by about 90 to 95% in some particular embodiments.
The volume of less polar second organic solvent may be 0.5 times to 5 times the volume of first organic solvent in some particular embodiments.
Pure levetiracetam may be isolated by optionally cooling the resulting mixture to about 0°C to 25°C, filtration or centrifugation followed by drying.
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the
scope of the present invention. Several variants of this examples would be evident to persons ordinarily skilled in the art.
Example-1
Crude levetiracetam (123g, optical purity ~ 96.00%) was mixed with acetone (2800ml) and stirred at ambient temperature for 60 minutes. The undissolved material was then filtered through hyflo bed and washed with acetone (200ml). Filtrate was combined with washing and concentrated under vacuum at 35 to 40°C to about 240ml of the volume. Ethylacetate (480ml) was then charged into the resulting slurry and stirred for 20 minutes at ambient temperature. It was then filtered and washed with ethylacetate (100ml). The product was dried under vacuum at 40 to 45°C till loss on drying was less than 0.5%. Yield: 108g
Chromatographic purity = 99.99% Optical purity = 99.95%
Exannple-2
Crude levetiracetam (l00 optical purity ~ 98.48%) was mixed with acetone (2300ml) and stirred at ambient temperature for 60 minutes. The undissolved material was then filtered through hyflo bed and washed with acetone (160ml). Filtrate was combined with washing and concentrated under vacuum at 35 to 40°C to about 200ml. Ethylacetate (200ml) was then charged into the resulting slurry and stirred for 20 minutes at ambient temperature. It was then filtered and washed with ethylacetate (400ml). The filtrate contained 16.48% of undesired enantiomer. The product was dried under vacuum at 40 to 45°C till loss on drying was less than 0.5%. Yield: 87g
Chromatographic purity = 99.99% Optical purity = 99.95%

WE CLAIM:
1. A process (1) for preparation of pure levetiracetam comprising:
a) contacting crude levetiracetam with an organic solvent,
b) removing undissolved material, and
c) isolating pure levetiracetam from the resulting solution.
2. A process (2) for preparation of pure levetiracetam comprising:
a) contacting crude levetiracetam with a first organic solvent,
b) adding a less polar second organic solvent to the above mixture and
c) isolating pure levetiracetam from the resulting mixture.

3. The process according to claim 2, wherein undissolved material is removed before addition of less polar second organic solvent
4. The process according to claim 1 or 2, wherein crude levetiracetam is obtained as a solution directly from a reaction in which levetiracetam is formed.
5. The process according to claim 1 or 2, wherein optical purity of crude levetiracetam is not less than 90%.
6. The process according to claim 1 or 2, wherein the organic solvent of step (a) is selected from the group consisting of ketones, nitriles, hydrocarbons,ethers,
chlorinated hydrocarbons and cyclic ethers or mixtures thereof.
7. The process according to claim 6, wherein the ketone is selected from the
group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone and
mixtures thereof.
8. The process according to claim 6, wherein chlorinated hydrocarbon is selected from the group consisting of methylene chloride, ethylenedichloride and mixtures thereof.
9. The process according to claim 6, wherein cyclic ether is selected from the group consisting of dioxane, tetrahydrofuran and mixtures thereof.
10 .The process according to claim 1 or 2, wherein the mixture of organic solvent
and crude levetiracetam in step (a) is stirred at ambient temperature. 11.The process according to claim 1, wherein pure levetiracetam is isolated by
cooling the resulting solution. 12.The process according to claim 1, wherein pure levetiracetam is isolated by
concentrating the resulting solution. 13.The process according to claim 12, wherein concentrated mixture is further
cooled to obtain pure levetiracetam.
14. The process according to claim 2, wherein less polar organic solvent is selected from the group consisting of esters, hydrocarbons, ethers and mixtures thereof.
15. The process according to claim 14, wherein ester is selected from the group consisting of ethylacetate, isobutylacetate and isopropylacetate or mixtures thereof.
16.The process according to claim 14, wherein hydrocarbon is selected from the group consisting of hexane, cydohexane, toluene, heptane, octane and mixtures thereof.
17.The process according to claim 14, wherein ether is selected from the group consisting of diethylether, diisopropylether and mixtures thereof.
18.The process according to claim 2, wherein the crude levetiracetam is dissolved
in the first organic solvent. 19.The process according to claim 18, wherein the crude levetiracetam is
dissolved in first organic solvent by heating. 20.The process according to claim 2, wherein the mixture of crude levetiracetam
and first organic solvent is concentrated before adding the less polar second
organic solvent. 21. The process according to claim 20, wherein 90 to 95% of first organic solvent
is recovered. 22.The process according to claim 2, wherein the volume of less polar second
organic solvent is 0.5 times to 5 times the volume of first organic solvent. 23.The process according to claim 2, wherein pure levetiracetam is isolated by
cooling the resulting mixture.