IMPROVED PROCESS FOR THE PREPARATION OF (αSVα-ETHYL-2-OXO-l-
PYRROLIDINEACETAMIDE
TECHNICAL FIELD OF THE INVENTION
The present invention is directed to improved, industrially viable, cost effective processes for the manufacture of substantially pure form of (aS)-a-Ethyl-2-oxo-l-pyrrolidineacetamide and its intermediates thereof.
BACKGROUND OF THE INVENTION
(aS)-a-Ethyl-2-oxo-l-pyrrolidineacetamide, also known as levetiracetam, having the chemical structure as in Formula I, is an anti-epileptic drug indicated as adjunctive in the treatment of partial onset seizures in adults with epilepsy. The drug is available under the trade name "KEPPRA", in the form of tablets, oral solution and injection.

The preparation of Levetiracetam was first disclosed in U.S. Patent No. 4,943,639 by Gobert et. al. The '639 patent also discloses a process for the preparation of levetiracetam, which is
summarized in scheme 1:

This patent also provides method of preparation of its homologues and pharmaceutical
compositions thereof.

Acharyulu et. al. in US 2005182262, describes a process for the preparation of levetiracetam, which is summarized in scheme 2:

Drawbacks:
• Involves an additional step of esterification followed by isolation of the hydrochloride salt.
Futagawa et. al., in US 6,107,492, discloses a method of resolution of racemic mixture of ct-ethyl-2-oxo-1 -pyrrolidine acetamide through chromatography column packed with optical resolution packing material, that contains silica gel-supported amylase tris(3,5-dimethylphenyl carbamate).
WO 2006/095362 describes a process for the preparation of levetiracetam, which is
summarized in Scheme 3. Scheme 3


Drawbacks:
• Involves additional number of steps.
• Involves an additional purification step using Ion exchange resin.
WO 2006/053441 discloses a process for the preparation of levetiracetam by reacting (S)-ct-ethyl-2-oxo-l-pyrrolidineacetic acid with methane sulfonyl chloride and a stream of ammonia in the presence of triethyl amine.
WO 2006/127300 describes a process for the preparation of levetiracetam by reacting (S)-a-ethyl-2-oxo-l-pyrrolidineacetic acid with di-tertiary butyl dicarbonate and ammonium bicarbonate in the presence of acetonitrile and pyridine.
Although various processes for the preparation of levetiracetam are disclosed in the prior art, they suffer from one or more drawbacks. Hence, there is a continuing need for commercially viable processes for preparing levetiracetam which will synthesize the desired stereo isomers directly.
SUMMARY OF THE INVENTION
The aspect of the present invention is to provide improved processes for the manufacture of levetiracetam and its intermediates thereof.
In one embodiment of the present invention, is provided a process for the manufacture of levetiracetam of Formula I which comprises of;


in the presence of a base, selected from potassium or sodium hydroxide, more preferably, potassium hydroxide, wherein the potassium hydroxide used was freshly milled and passed through 2 mm sieve and added to the reaction mixture in two to three different lots; in the presence of a phase-transfer catalyst.
In another embodiment of the present invention, there is provided a process for manufacture of levetiracetam of Formula I which comprises of:
a) reaction between (S)-2-Aminobutyric acid of Formula IV,

Formula IV with a halogenating agent to give a compound,(2S)-2-aminobutanoyl chloride of Formula 1I-A,

Formula II-A followed by in situ reaction with a source of ammonia to form (S)-2-Aminobutyramide hydrochloride of Formula II,

Formula II
b) reacting (S)-2-Aminobutyranude hydrochloride of Formula II with 4-chlorobutyryl chloride of
Formula III using a base, selected from potassium or sodium carbonate, more preferably
potassium carbonate to give N-[(lS)-l-carbamoylpropyi]-4-chlorobutanamide, a compound of
Formula V ;


c) cyclising the compound formed as in Formula V in the presence of a base selected from potassium hydroxide, wherein the potassium hydroxide used was freshly milled and passed through 2 mm sieve and is added to the reaction mixture in a lot-wise manner and a phase transfer catalyst, wherein the phase transfer catalyst is tetra-n-butylammonium bromide.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1: XRPD pattern of a sample of Levetiracetam (prepared as in example 2) Fig. 2: DSC pattern of a sample of Levetiracetam (prepared as in example 2)
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention, is provided a process for the manufacture of levetiracetam of Formula I which comprises of; reaction between S-aminobutyramide of Formula II or its salt,

Formula II and 4-chlorobutyrylchloride of Formula III,

Formula 111 along with equimolar proportions of sodium sulphate,
in the presence of a base, selected from potassium or sodium hydroxide, more preferably, potassium hydroxide, wherein the potassium hydroxide used was freshly milled passed through 2 mm sieve and added to the reaction mixture in two to three different lots; in the presence of a phase-transfer catalyst.
The sodium sulphate, as used herein is a drying agent. Other drying agents used herein may be selected from magnesium sulphate or molecular sieves.
The base that is useful for facilitating this commercially viable reaction is selected from

potassium hydroxide. It has been studied that the rate of the reaction at industrial scale was affected to a great extent with the nature of potassium hydroxide used. Typically, there is little or no reaction with the usage of potassium hydroxide flakes or pellets available commercially. In the preferred embodiment of the present invention, the potassium hydroxide that was used was freshly milled and passed through 2 mm sieve.
It has also been studied and established that addition of potassium hydroxide in lots unexpectedly leads to significant improvement in yield, with commercially desirable consequences. The term "lot-wise" denotes addition of distinct portions of a reagent to a reaction mixture at definite interval of time. Preferably, the potassium hydroxide is added in two to three lots.
Preferably, sodium sulphate was added into a suspension of S-aminobutyramide or its salt in a suitable solvent. The suspension was then reacted with 4-chlorobutyryl chloride, in the presence of a base, preferably freshly milled potassium hydroxide passed through 2mm sieve along with a phase transfer catalyst. Milled potassium hydroxide is added in 2 to 3 lots. Suitable temperature for conducting the reaction ranges from about -5°C to about 15°C, preferably about -5°C to about 5°C. The reaction mixture was then filtered over a hyflo bed thereafter distilled under vacuum maintaining a temperature below 40°C, The crude levetiracetam was isolated thereafter.
S-aminobutyramide may be used as a free base or a salt. The salts are preferably acid addition salts formed either with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid and oxalic acid, more preferably hydrochloric acid.
In a preferred embodiment of the invention, freshly milled potassium hydroxide passed through 2mm sieve is added in two to three lots, It has been discovered that addition of potassium hydroxide in powdered form has a distinct advantage at industrial scale.
The time variation between the additions of each lot of freshly milled potassium hydroxide may be 2-5 hrs. Suitably, the duration for the addition of 4-chlorobutyryl chloride is long, ranging from about 30 minutes to 2 hours, in order to avoid the exothermicity and to maintain the reaction temperature below about 0°C.
The reaction may be carried out in the presence of a suitable solvent and a phase transfer catalyst.
Suitable solvents which may be used include but are not limited to. ketones such ai

acetone, ethy] methyl ketone, and methyl isobutyl ketone: nitriles such as acetonitrile, propionitrile: halogenated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform: hydrocarbons such as toluene, xylene, n-hexane, n-heptne and cyclohexane; or their combinations with water in various proportions.
Suitable phase transfer catalysts that may be used include, but are not limited to tetra-n-butyl ammonium bromide, tetra-n-butyl ammonium chloride, triethyl benzyl ammonium chloride, tributy! benzyl ammonium chloride, trimethyl benzyl ammonium chloride and crown ethers, more preferably tetra-n-butyl ammonium bromide. The reaction may also be carried out without a phase transfer catalyst.
After completion of the reaction, the unwanted salt that forms in the reaction mixture may be separated immediately by filtration over a hyflo bed.
After filtration, the solvent may be distilled out under vacuum below 40°C. To the crude product may be added a co-solvent. The solid product may be then be recovered from the organic layer, by a complete distillation of the co-solvent at a temperature below 40°C under vacuum .
Suitable co-solvents selected includes but are not limited to ketones such as acetone, 2-butanone, methyl ethyl ketone and methyl isobutyl ketone and the mixtures thereof or their combinations with water in various proportions without limitations.
The compound obtained as above was purified in presence of activated carbon, in a suitable solvent selected from the group comprising of acetone, 2-butanone, methyl ethyl ketone and methyl isobutyl ketone and the mixtures thereof.
The temperature for the purification step ranges from 25°C to the reflux of the solvent
chosen.
The molar yield of levetiracetam produced by the above process is believed to be more than 7Q % with respect to S-aminobutyramide hydrochloride.
The levetiracetam of Formula I produced by the above process is believed to be substantially free from Levetiracetam acid, chemically known as (2S)-2-(2-oxopyrrolidin-l-yl)butanoic acid, of Formula VI
Formula VI and the other isomer (2R)-2-(2-oxopyrrolidin-1 -yl)butanamide of Formula VII


Formula VII and from any particulate matter.
In another embodiment of the present invention, there is provided a process for manufacture of levetiracetam of Formula I which comprises of:
a) reaction between (S)-2-Aminobutyric acid of Formula IV,

Formula IV with a halogenating agent to give a compound, (2S)-2-aminobutanoyl chloride of Formula II-A,

followed by in situ reaction with a source of ammonia to form (S)-2-Aminobutyramide hydrochloride of Formula II,
Formula II
b) reacting (S)-2-Aminobutyramide hydrochloride of Formula II with 4-chlorobutyryl chloride
of Formula III using a base, selected from potassium or sodium carbonate, more preferably
potassium carbonate to give N-[(lS)-l-carbamoylpropyl]-4-chlorobutanamide, a compound of
Formula V;

Formula V
c) cyclising the compound formed as in Formula V in the presence of a base selected from
potassium hydroxide, wherein the potassium hydroxide is preferably freshly milled and added to the reaction mixture in a lot-wise manner in presence of a phase transfer catalyst, wherein the catalyst is tetra-n-butylammonium bromide.
The halogenating agent used herein to form the compound of Formula II-A is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride more preferably, thionyl chloride.
Suitable solvents which may be used include but are not limited to methanol, ethanol, iso-propanol, n-propanol, butanol and the mixtures thereof in various proportions; more preferably methanol. Non-limiting examples of the source of ammonia include gaseous ammonia, ammonium chloride and ammonium acetate.
The reaction of the step a) may be carried out at a temperature of from about 25°C to about 60°C, more preferably from about 25°C to about 50°C.
Preferably, the addition of the chlorinating agent is carried out slowly to control the exothermicity of the reaction and to maintain the temperature of the reaction medium low, preferably, from 25°C to 40°C. An increase in temperature may cause formation of side products and process-related impurities.
Suitable phase transfer catalysts that may be used include, but are not limited to tetra-n-butyl ammonium bromide, tetra-n-butyl ammonium chloride, triethyl benzyl ammonium chloride, tributyl benzyl ammonium chloride, trimethyl benzyl ammonium chloride and crown ethers, more preferably tetra-n-butyl ammonium bromide.
Levetiracetam, prepared as in the present invention and as described in Example 2 hereafter, has the characteristic XRPD peak values as shown in Table I below. The X-ray powder diffractogram is depicted in Figure I.



The DSC data for levetiracetam, prepared as in the present invention and as described in
Example 2 is depicted in Figure II.
ADVANTAGES OF THE INVENTION
The advantages of this invention are:
« Addition of commercial grade potassium hydroxide (in flakes or pellet form) caused little or no reaction to proceed at industrial scale, but with the usage of freshly milled potassium hydroxide passed through 2mm sieve has significant improvement in the rate of the reaction with significant commercially desirable consequences
• Addition of sodium sulphate as a drying agent leads to significant improvement in yield.
• Addition of potassium hydroxide in lots also unexpectedly leads to improvement in yield.
The following non-limiting examples illustrate the invention.
EXAMPLES
Method 1:
Example I: Preparation o/(2S)-2-(2-oxopyrrolidine-l-yl)butanamide (Tech)
S-aminobutyramide hydrochloride (200 gm) and dichloromethane (2400 ml) were charged into a clean dry 4 neck round bottom flask. To this was added sodium sulphate (245.0 g) at 25-30°C. The

reactants were cooled to -3°C, followed by the addition of freshly milled potassium hydroxide passed through 2mm sieve (243 g, 1st lot) at -3 to 0°C, over a period of 15-30 minutes. To this was added tetra-butyl ammonium bromide solution (23.5 g) at 0-5°C over a period of 30 minutes to 1 hr. To this was added 4-chlorobutyryl chloride solution (223,8 g dissolved in 300 ml of dichloromethane). The contents were stirred at -3 to 0°C for 5 hrs, followed by addition of freshly milled potassium hydroxide passed through 2mm sieve (81.0 g, 2nd lot) at -3 to 0°C. The contents were stirred at -3 to 0°C for 5 hrs, followed by addition of freshly milled potassium hydroxide passed through 2mm sieve (81.0 g, 3nd lot) at -3 to 0°C. The contents were stirred at 0 to 2°C for 2 hrs, after the completion of the reaction the contents were filtered over hyflow bed and the residue was washed with dichloromethane. The solvent was completely distilled under vacuum, under 40°C. To the residue was charged acetone (100 ml) and the solvent was co-distilled completely under vacuum at a temperature below 40°C.
To the crude was added acetone (1000 ml) and heated to reflux for 15 minutes to get a clear solution. To this was added activated carbon (10 g) and molecular sieves (65 g), refluxed for 15 minutes. The contents were filtered under hot condition, washed with hot acetone (100 ml). The contents were cooled to -5°C for 2 hrs. Product separated was filtered and washed with 100 ml chilled acetone. The obtained solid was dried at about 50-55°C under vacuum for about 8-10 hours to afford the title compound. Dry Weight: 180.0 g; Yield: 73.3% Example 2: Preparation of Levetiracetam (Formula I)
To the compound formed as in Example 1 above (150 g) ethyl acetate (900 ml) was charged and the contents were heated to reflux for 15 minutes. A clear solution was obtained. The above contents were filtered under hot condition and washed with hot ethyl acetate (75 ml). The contents were cooled to 0DC; temperature was maintained for 2 hours. The precipitated solid was filtered and washed with chilled ethyl acetate. The product was dried at 50-55°C to obtain a constant weight. Dry Weight: 141.9 g; Yield: 94.6 %; HPLC Purity: 99.08 %
Method 2:
Example 3: Preparation of(S)-2-Aminobutyramide.hydrochloride (Formula II)
To (2S)-2-Aminobutyric acid hydrochloride (400 g) was added 3 L of methanol. Thionyl chloride was added into the above solution over a period of 60-90 min. at a temperature of 25-40°C.

The contents were then stirred at a temperature of 40-45°C for 4 hrs. After successful completion of the reaction, the contents were cooled to 25°C, solvent was distilled out under vacuum below 40°C. To the residue obtained was charged methanolic ammonia and stirred at 25°C for 30 min. The solid was filtered and washed with methanol (3X200 ml). The filtrate was transferred into an autoclave and ammonia pressure was applied for 32 hrs maintaining a temperature of 40-45°C. After the completion of the reaction the contents were cooled and the ammonia pressure was released, the reaction mass was filtered, washed with methanol (200 ml). The methanol was distilled completely under vacuum below 40°C. Into this was added methanolic HC1 (1600 ml) at 25-30°C and stirred for 30 min. The methanol was distilled completely under vacuum below 40°C. The residue was charged with acetone (600 ml), cooled to 8-10°C for 1 hr. The product was filtered and washed with chilled acetone (100 ml). The product was dried at 50-55°C to get a constant weight. Dry Weight: 351.6 g; Yield: 87.9 %
Example 4: Preparation ofN-[(lS)-l-carbamoylpropylI-4-chlorobutanamide (Formula V)
Acetonitrile (160 ml) was taken in a reaction vessel followed by powdered potassium carbonate (200 g). Into this was added (S)-2-Aminobutyramide hydrochloride (80 g). The contents were stirred at room temperature for 1 hour, followed by cooling the reaction mixture to -2°C. A solution of 4-Chlorobutyryl chloride (lOOg) in acetonitrile(400ml) was added over a period of 4-5 hours maintaining the same temperature. The temperature of the contents were raised to 25-30°C and stirred for 3 hrs. The reaction mass was filtered and and washed with acetonitrile. The solvent was distilled off completely under vacuum at a temperature below 45°C. To the residue was charged diisopropyl ether (1800 ml) and stirred for 1 hr at 25-30°C under an inert atmosphere of nitrogen gas. The product was filtered and washed with diisopropyl ether and dried at 50-55°C to get a constant weight. Dry Weight: 87 g; Yield: 72.9 %
Example 5; Preparation of(2S)-2-(2-oxopyrrotidine-l-yl)butanamide (Tech)
To dichloromethane (1275 ml) was added the compound formed as in Example 4 above followed by tetra-butyl ammonium bromide. The contents were cooled to 0°C under nitrogen followed by the addition of freshly milled potassium hydroxide passed through 2mm sieve (27.6 g, lsl lot) over a period of 30 min. maintaining a temperature from 0-2°C. The reaction mixture was stirred at the same temperature for 1 hour, followed by the addition of remaining 1.3 g of freshly milled potassium

hydroxide passed through 2mm sieve (2nd lot) for another 30 minutes. The temperatures of the contents were raised to 25-30°C and maintained so for 3 hrs. After the completion of the reaction, the contents were filtered, washed with methylene chloride. The filtrate was dried over sodium sulphate, distilled under vacuum at a temperature below 40°C. The residue was charged ethyl acetate (35 ml) followed by distillation under vacuum. Ethyl acetate (595 ml) was charged into the residue and heated to reflux until clear solution was obtained. Dried molecular sieves (25.5 g) were added to it followed by activated carbon (4.25 g) at reflux temperature. It was filtered hot and then washed with ethyl acetate. The filtrate was cooled to 0-5°C for 1 hour. The product got precipitated, which was filtered, washed with ethyl acetate. The product was dried at 50-55°C. Dry weight: 57 g; Yield: 81.35 %
Example 6: Preparation ofLevetiracetam (PHARMA)
Acetone (1430 ml.) having Moisture Content < 0.3% was taken in the reaction vessel. To this was added Levetiracetam (Tech) (55g). The contents were stirred till dissolution, the solution filtered and wash with acetone (70 ml.)- Charge the filtrate again into flask and distill acetone atmospherically at temperature below 55°C. Apply vacuum to remove traces of acetone by maintaining temperature below 50° C. Cool the contents to 25-30°C add ethyl acetate (360 ml.)- Heat the contents to reflux temperature for dissolution. Slowly cool to 25-30°C and cool the solution to 0-2°C, maintain foT 2 hrs at 0-2"C, filter the product and wash the product with chilled ethyl acetate (60 ml.). Dry the product in oven at 50-55°C, till constant weight. Dry Weight: 53.5 g; Yield: 97.2% HPLC purity 99.8%
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of
the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims,

We Claim:
1. An improved process for manufacture of levetiracetam of the formula I wherein the HPLC purity greater than 99.8 % ,
Formula I and substantially free from Levetiracetam acid, chemically known as (2S)-2-(2-oxopyrrolidin-1-y!) butanoic acid, of Formula VI, content not more than 0.1 %

Formula VI
which comprises of:
(a) charging (S)-2-Aminobutyramide hydrochloride in dichloromethane,
(b) addition of anhydrous sodium sulphate ,
(c) cooling the contents,
(d) addition of first lot of freshly milled potassium hydroxide passed through 2mm sieve under cold condition {1.215 w/w),
(e) addition of phase transfer catalyst, under cold condition,
(f) addition of 4-chlorobutyrylchloride, dissolved in dichloromethane imder cold condition
(g) stirring of the reaction mixture under cold conditions,
(h) addition of the second lot of fi-eshly milled potassium hydroxide passed through
2mm sieve under cold condition (0,405 w/w), (i) stirring of the reaction mixture under cold conditions, (j) addition of the third lot of freshly milled potassium hydroxide passed through
2mm sieve under cold condition (0.405 w/w)

(k) stirring of the reaction mixture under cold condition, followed by filtration over hyflo
bed to remove any undissolved particulate matter,
(1) distilling the solvent under vacuum
(m) addition of a co-solvent,
(n) distillation of the co-solvent,
(o) repetition of the process of Stage 1 (m),
(p) treating the resultant solution with activated cabon and dried molecular sieves,
(q) refluxing the solution followed by cooling,
(r) fl Itration of the product.
2. The process of Claim I, wherein the cold conditions maintained throughout the reaction is -5°C to 15°C, more preferably -5X to 5°C.
3. The process as in Claim 1, wherein the potassium hydroxide to be added should be freshly milled and passed through 2mm sieve.
4. An improved process for the preparation of LevetiracetamofFormulal, comprising of: a) reaction between (S)-2-Aminobutyric acid of Formula W,

Formula IV with thionyl chloride to give a compound, (2S)-2-aminobutanoyl chloride of Formula II-A,

Formula 11-A followed by in situ reaction with a source of ammonia to form {S)-2-Aminobutyramide hydrochloride of Formula II,


Formula II b) reacting (S)-2-Aminobutyramide hydrochloride of Formula II with 4-chlorobutyryl chloride of Formula III using potassium carbonate to give N-[(lS)-l-carbamoylpropyl]-4-chlorobutanamide, a compound of Formula V ;

Formula V c) cyclising the compound formed as in Formula V in the presence of a base selected from potassium hydroxide, wherein the potassium hydroxide is preferably freshly milled and passed through 2mm sieve and added to the reaction mixture in a lot-wise manner, in presence of phase transfer catalyst, wherein the phase fransfer catalyst is tetra-n-butylammonium bromide.
5. The process of Claim 4, wherein the sources of ammonia as used in Stage (a) is chosen from gaseous ammonia, ammonium chloride and ammonium acetate.
6. Levetiracetam, as prepared in Claims 1-9 as above, is having HPLC purity more than 99.8 % with all the other impurities less than 0.1 %.
7. Levetiracetam of formula I
Formula -I Prepared in accordance with claim 1 have 26 values at approximately 10.14, 14.90, 18.56, 20.54, 22.20, 23.37, 23.86, 26.85, 28.93, 30.03, 30.57, 31.07, 32.05, 34.76, 36.36.