The present invention is directed to a process for preparation of (S)-2-aminobutanamide of Formula I. In addition, the present invention also provides a process for preparation of levetiracetam of Formula II.
(FORMULA REMOVED)

Levetiracetam is an antiepileptic drug indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. Levetiracetam is a single enantiomer and the chemical name for levetiracetam is (S)-a-ethyl-2-oxo-1-pyrrolidineacetamide.
Several literature reports and patents provide methods for preparation of (S)-2-aminobutanamide and levetiracetam. British Pat. No. 1,309,692 describes the compound a-ethyl-2-oxo-1-pyrrolidineacetamide (melting point 112°C.) and states that the compounds of this type can be used for therapeutic purposes, for example for the treatment of motion sickness, hyperkinesia, hypertonia and epilepsy.
US patent 4,969,943 discloses the levorotatory isomer of a-ethyl-2-oxo-1-pyrrolidineacetamide, which has the absolute S configuration. The '943 Patent further provides two methods for preparing levetiracetam either by reacting (S)-a-ethyl-2-oxopyrrolidineacetic acid successively with alkylhaloformate and with ammonia or by cyclizing an (S)-2-aminobutanamide. The latter process, which involves cyclizing an (S)-2-aminobutanamide to get levetiracetam
US Patent Publication Nos. 2004/192757 and 2004/0092576 describe a process for preparation of levetiracetam from corresponding unsaturated 2-oxo-1-pyrrolidine derivative by asymmetric hydrogenation using a chiral catalyst.
PCT patent application No. 04/069796 provides a process for preparing levetiracetam from (S)-2-aminobutanamide without using a catalyst.
US Patent Application No. 2004/204476 discloses a method of preparing levetiracetam by ammonolysis. US Patent No. 6,124,473 and US Patent Application No. 2004/204476 disclose the methods of separating optical isomers of levetiracetam by chromatographic techniques.
Journal of American Chemical Society, 74, 1580,1952 discloses a process for the preparation of 2-aminobutyramide comprising passing ammonia gas to ethyl-a-bromobutyrate at 0°C and keeping it at -5°C for 10 days for completion of reaction.
Journal of American Chemical Society, 77, 1522, 1955 describes the preparation of amino acid amides comprising contacting corresponding freebase with ammonia at 0°C and keeping for three days.
The present inventors have found that the methods reported in the prior-art require low temperature maintaining for considerable number of days which leads to formation of large quantity of byproducts and impurities including dimeric impurity. These impurities further interfere with the subsequent reactions. In addition, during cyclization step while isolating levetiracetam, the product gets racemized due to the alkaline condition of the reaction mixture.
While working on the problem, the present inventors have found that the (S)-2-aminobutanamide can be prepared by an ammonolysis of (S)-2-aminobutyric acid ester, wherein the process is simple and can be carried out at room temperature. The inventors have found that the use of ammonium salts along with ammonia gas helps in reducing the reaction time and also retards the impurity formation. The present inventors also found that while isolating levetiracetam from the reaction mixture by maintaining the pH towards neutrality, undesired racemization of the
final product can be avoided. The process also enables the production of crude levetiracetam having a high chemical purity.
A first aspect of the present invention provides a process for the preparation of (S)-2-aminobutanamide of Formula I
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents C1-C5alkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia in the presence of an ammonium salt and an organic solvent,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mass
thereof.
(S)-2-aminobutanoic acid ester of Formula III is dissolved in an organic solvent and ammonia gas is passed through the reaction mixture at a low temperature. It is followed by the addition of an ammonium salt. Then the temperature is raised and maintained between 10° to 60°C until the completion of the reaction. Then the reaction mixture is filtered, washed and recrystallized from suitable solvent to get pure (S)-2-aminobutanamide of Formula I.
The ammonium salt is selected from a group comprising of ammonium sulfate, ammonium chloride, ammonium formate, ammonium acetate, ammonium propionate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium
bicarbonate, ammonium chlorate, ammonium bromide, ammonium iodide and ammonium fluoride.
A second aspect of the present invention provides a process for the preparation of (S)-a-ethyl-2-oxo-1-pyrrolidineacetamide of Formula II
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting (S)-2-aminobutanamide of Formula I
(FORMULA REMOVED)

with 4-chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide,
b) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the presence of an alkali
c) neutralizing the pH of the reaction mixture obtained from step b) and
d) isolating (S)-a-ethyl-2-oxo-1-pyrrolidineacetamide of Formula II from the reaction mass thereof.
(S)-2-aminobutanamide is reacted with 4-chlorobutyryl chloride in the presence of an organic solvent to get (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide. It is further cyclized in the presence of an alkali. The organic solvent and the alkali to be used is known to a skilled artisan through prior-art processes. The reaction mixture is neutralized to a pH of about 7 to 8.5 and the (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide of Formula II is separated from the reaction mixture, filtered, washed and dried under vacuum to get the pure product.
third aspect of the present invention provides a process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents C1-C5alkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia in the presence of an ammonium salt and an organic solvent,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mixture
obtained in step b)
(FORMULA REMOVED)

c) reacting (S)-2-aminobutanamide of Formula I obtained in step c) with 4-
chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-
chlorobutyramide,
d) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the presence of an alkali
e) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II from the reaction mass thereof.
A fourth aspect of the invention provides a process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents C1-C5 alkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia and an organic solvent,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mixture
obtained in step b)
(FORMULA REMOVED)

c) reacting (S)-2-aminobutanamide of Formula I obtained in step c) with 4-
chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-
chlorobutyramide,
d) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the
presence of an alkali
e) neutralizing the pH of the reaction mixture obtained from step b) and
f) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of
Formula II from the reaction mass thereof.
EXAMPLE 2
PREPARATION OF LEVETIRACETAM
Part-A: Preparation of (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide
Acetonitrile (1800 ml) and (S)-2-aminobutyramide (100 g) were mixed at room temperature and stirred under nitrogen atmosphere. Pulverized potassium carbonate (203 g) was added and cooled to -5°C. A solution of 4-chlorobutyryl chloride (138.25 g) in acetonitrile (100 ml) was added slowly at a temperature of-5° to 0°C for about 60 minutes. It was stirred at the same temperature till the reaction was completed. The mixture filtered through celite bed and washed with acetonitrile (200 ml). The combined filtrates were concentrated under vacuum at 40° to 45° C to get the residue which was mixed with toluene (200 ml) and the resultant mass was stirred for 30 minutes at room temperature. Toluene was recovered to maximum extent under vacuum at 40° to 45°C to get the residue.
Part-B: Preparation of Crude Levetiracetam
To the residue of the previous step was charged methylene chloride (2200 ml) at room temperature and stirred for 30 minutes. Anhydrous sodium sulphate (218 g) was added and the mixture was stirred for 15 minutes, cooled to 0° C and a solution of tetrabutylammonium bromide (14.2 g) in methylene chloride (100 ml) was added, followed by the addition of pulverized sodium hydroxide in three lots (42.25 g, 10.6 g and 8.8 g) at -5° to 0°C with stirring until the completion of the reaction. The pH of the resultant mixture was adjusted in the range of 7.5 to 8.0 with acetic acid (31 g) and stirred for 15 minutes. The temperature was raised to 20°C and stirred for 15 minutes at 20° to 25°C, filtered through celite bed and washed with methylene chloride (300 ml), and concentrated under vacuum. The residue obtained was successively charged with toluene and ethyl acetate. The mixture was cooled slowly to 10° to 15° C and stirred for 3 hours, filtered, washed and dried the product under vacuum to obtain title compound.
Yield: 76 g
Purity (HPLC): 99.79%
Chiral Purity: 99.89%
(S)-2-aminobutanoic acid ester of Formula III is dissolved in an organic solvent and ammonia gas is passed through the reaction mixture at a low temperature. It is followed by the addition of an ammonium salt. Then the temperature is raised and maintained between 10° to 60°C until the completion of the reaction. Then the reaction mixture is filtered, washed and recrystallized to get pure (S)-2-aminobutanamide of Formula I. (S)-2-aminobutanamide is then reacted with 4-chlorobutyryl chloride in the presence of an inert solvent to get (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide. It is further cyclized in the presence of an alkali. The reaction mixture is neutralized with an acid and the (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II is separated from the reaction mixture, filtered, washed and dried under vacuum to get the pure product.
A fifth aspect of the invention provides a process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents C1-C5alkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia in the presence of an ammonium salt and an organic solvent,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mixture
obtained in step b)
(FORMULA REMOVED)

c) reacting (S)-2-aminobutanamide of Formula I obtained in step c) with 4-chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide,
d) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the presence of an alkali
e) neutralizing the pH of the reaction mixture obtained from step b) and
f) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II from the reaction mass thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF (S)-2-AMINOBUTANAMIDE
Methyl (S)-2-aminobutyric acid ester (220 g) was dissolved in methanol (1200 ml). The reaction mixture was cooled to -5 to -10°C and ammonia gas was passed for about 4 hours. The temperature was raised to 20°C slowly in about 2-3 hours and ammonium sulphate (120 g) was added at 20°-25°C. The reaction mixture was stirred at 20° to 25°C for 2- 3 days. The reaction mixture was filtered through celite bed and washed with methanol (100 ml). The mother liquor was concentrated to get crude product. It was recrystallized from methanol-ethyl acetate to get pure product.
Yield: 138g
Purity (HPLC): 91.36%
Part-C: Preparation of Pure Levetiracetam
Crude levetiracetam (60 g) was dissolved in acetone (1380 ml). The mixture was filtered and washed with acetone (120 ml). The filtrate was concentrated to about 150 ml of the volume and to it was added ethyl acetate (180 ml). The resultant mixture was stirred for 2 hours at 15°C, filtered and washed with cold ethyl acetate (60 ml) to obtain wet product which was dried under vacuum at 40° to 45°C for 8 hours to get pure levetiracetam.
Yield: 50 g
Purity: above 99.9%
Chiral Purity: 100%

WE CLAIM:
1. A process for the preparation of (S)-2-aminobutanamide of Formula I
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents C1-C5 alkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia in the presence of an ammonium salt,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mass
thereof.
2. A process as claimed in claim 1 wherein step a) is carried out at room temperature.
3. A process as claimed in claim 1 wherein the ammonium salt is selected from a group comprising of ammonium sulfate, ammonium chloride, ammonium formate, ammonium acetate, ammonium propionate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium bromide, ammonium iodide and ammonium fluoride.
4. A process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of
a) reacting (S)-2-aminobutanamide of Formula I
(FORMULA REMOVED)

with 4-chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide,
b) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the
presence of an alkali
c) neutralizing the pH of the reaction mixture obtained from step b)
d) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide of Formula II from the reaction mass thereof.
5. A process according to claim 4 wherein the reaction mass is neutralized to
apH of about 7.0 to 8.5.
6. A process for the preparation of (S)-alpha-ethyl-2-oxo-1 -
pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents d-Csalkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia in the presence of an ammonium salt,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mixture
obtained in step b)
(FORMULA REMOVED)

c) reacting (S)-2-aminobutanamide of Formula I obtained in step c) with 4-
chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-
chlorobutyramide,
d) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the presence of an alkali
e) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II from the reaction mass thereof.
7. A process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents CrC5alkyl, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mixture
obtained in step b)
(FORMULA REMOVED)

c) reacting (S)-2-aminobutanamide of Formula I obtained in step c) with 4-chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide,
d) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the presence of an alkali
e) neutralizing the pH of the reaction mixture obtained from step b) and
f) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II from the reaction mass thereof.
8. A process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of Formula II
(FORMULA REMOVED)

wherein the said process comprises of a) reacting a compound of Formula III
(FORMULA REMOVED)

wherein R represents Ci-CsalkyI, haloalkyl, aryl, arylalkyl or heteroaryl or an acid addition salt thereof, with ammonia in the presence of an ammonium salt and an organic solvent,
b) isolating (S)-2-aminobutanamide of Formula I from the reaction mixture
obtained in step b)
(FORMULA REMOVED)

c) reacting (S)-2-aminobutanamide of Formula I obtained in step c) with 4-
chlorobutyryl chloride to get (S)-N-[1-(aminocarbony)propyl]-4-
chlorobutyramide,
d) cyclizing (S)-N-[1-(aminocarbony)propyl]-4-chlorobutyramide in the
presence of an alkali
e) neutralizing the pH of the reaction mixture obtained from step b) and
f) isolating (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) of
Formula II from the reaction mass thereof.