An improved process for the manufacturing of Levetiracetam Field of the Invention
The present invention relates to the process for the preparation of Levetiracetam of formula (I).
Background of the Invention
The present invention relates to a cost-effective method of preparing Levetiracetam (I) ((S)-2-(2-oxopyrrolidin-1 -yl) butanamide).
Preparation of levetiracetam using (S)-2-aminobutanamide hydrochloride (II) described in the example of US7531673, US4943639 and US4837223.
US7531673 describes a method of preparation of Levetiracetam (I) in two separate steps:
Stepl: Preparation of (S)-2 -aminobutanamide hydrochloride (IV) Reacting (S)-2-aminobutyric acid hydrochloride (II) with thionyl chloride in methanol to form (S)-methy!-2-aminobutanoate hydrochloride (III) followed by the introduction of ammonia gas and isopropanol hydrochloride to yield (S)-2-aminobutanamide hydrochloride (IV) which is isolated as a hydrochloride salt. Step-2: Preparation of Levetiracetam (I)
The isolated intermediate 2-aminobutanamide hydrochloride (IV) is reacted with 4-chlorobutyryl chloride in presence of a Phase transfer catalyst and potassium hydroxide in dichloromethane solvent. After the completion of the reaction, the reaction mass is adjusted to pH 7 - 7.5 with acetic acid to get pure Levetiracetam (I). The process is illustrated by scheme 1

As the process disclosed in Scheme-1, the preparation process comprises two separate
steps.
In the above-mentioned process, the isolation of the compound of formula (IV)
involves adjustment of pH with HC1 to get amide hydrochloride (IV) which in turn
reacts with 4-Chloro butyryl chloride to get pure Levetiracetam (I), and the preparation
method of the patent is a three-step process, each step requires additional solvents and
tedious procedures to get a pure form of Levetiracetam (1). Thus, this process leads to
an increase in production cost and a long manufacturing cycle with a low yield.
CN109134341 teaches the method for the preparation of Levetiracetam comprises the following three steps:
Step 1: Esterification reaction: L-2-aminobutyric acid (IIA) as a starting material,
esterification with thionyl chloride and methanol to obtain (S)-2-aminobutyric acid methyl
ester hydrochloride (III);
Step 2: Ammonolysis reaction: (S)-2-Aminobutyric acid methyl ester hydrochloride (III)
is subjected to an amidation reaction to produce (S)-2-aminobutanamide hydrochloride
(IV).

Step 3: Acylation and ring closure reaction: (S)-2-Aminobutanamide hydrochloride(IV) is reacting with 4-chlorobutyryl chloride in the presence of potassium hydroxide and phase transfer catalyst-tetrabutylammonium bromide and anhydrous sodium sulfate in dichloromethane solvent to form an intermediate in-situ - (S)-N-[l(aminocarbonyl) propyl]-4-bromobutyrainide(IIIA), which in-tum undergoes ring closure reaction to form Levetiracetam (I). The process is illustrated in the following scheme -2
Schi-nie-2
It is clear from the above described prior art processes are involved in the isolation of
intermediates. Thus, the processes lead to a higher process cycle time.
Therefore, they are not effective commercial methods for industrial-scale preparation
of Levetiracetam (I).
Therefore, there is a need for an improved process to prepare Levetiracetam (I), which
could be a commercially viable method.

Objects of (he Invention
It is an object of the present invention is to provide a cost-effective method for
preparing a compound of formula (I) (Levetiracetam) on a large scale.
Another purpose of the present invention is to provide an efficient, industrially feasible
method of preparing the compound of formula (I)
A further purpose of the present invention is to provide a process for the manufacture
of a highly pure compound of formula (I).
Another purpose of the present invention is to provide a method to prepare a compound
of formula (I) from (S)-2-amino butanoic acid (IIA).
Yet another purpose of the present invention is to provide a single stream process,
without the isolation of intermediates, for the production of Levetiracetam (I).
Summary of the Invention
The present invention provides an alternate simple, single-stream synthetic method for the large-scale manufacture of Levetiracetam (I) as represented by scheme-3. Scheme-3

Detailed Description of the Invention
In the present invention, the synthetic process for the manufacture of Levetiracetam (1) comprising of:
a) reacting of (S)-2-Amino butyric acid (IIA)
with aliphatic alcohol in presence of thionyl chloride to form a corresponding ester intermediate (Ill)(in-situ),
b) the resulting intermediate (III), without isolation, reacting with ammonia in an alcoholic solvent to form a corresponding amide intermediate (IV)(in-situ),
c) Further, the amide intermediate (IVA), without isolation, reacts with a compound, 4-halo butyrylhalide, of formula (V),
in the presence of an inorganic base to form Levetiracetam (1)

In one aspect of the invention is the usage of an aliphatic alcoholic solvent in step (a), which may be methanol orethanol, preferably Methanol.
Another aspect of the invention is an amidation reaction, the said alcoholic solvent in step (b) is selected from the group consisting of ethanol, methanol, and isopropanol, preferably methanol.
The third aspect of the invention is the inorganic base is used in step (c) is selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, preferably potassium hydroxide.
The fourth aspect of the invention is the 4-halo butyryl halide (V) is selected from the
group consisting of 4-chloro butyryl chloride, 4-Bromo butyryl bromide, and 4-iodo
butyryl iodide, preferably 4-chloro butyryl chloride
In the fifth aspect of the invention, the organic solvent used in step (c) is selected from
a group consisting of toluene, heptanes, dichloromethane(MDC), Dimethylformamide
(DMF), Dimethyl suIfoxide(DMSO), Tetrahydrofuran (THF), and N-Methyl-2-
pyrrolidone (NMP) NMP, preferably dichloromethane(MDC).
Step (a) and (b) of the process of the present invention is preferably conducted at a
temperature of from 30 to 90° C, more preferably from 50 to 70° C, and most
preferably from 30 to 60°C. Advantageously, the reaction temperature is ranging from
55 to 60° C. Step (c) of the process of the present invention is preferably conducted at
a temperature range of 0 to 5° C.
The process according to the invention gives a compound of formula (I) having a high
optical purity.

The process also provides large-scale production of a compound of formula (I) having
a high chemical purity.
The process provides the compound of formula (1) with less than 0.1% ( HPLC )
Examples
Reference is now made to the following example, which together with the above
descriptions; illustrates the invention in a non-limiting fashion.
Experiment-1: Preparation of (2£)-2-(2-oxopyrrolidin-l-yl) butanamide (I) To a mixture of (S)-2-aminobutyric acid (IIA) (200 g, 1.93 mol) and methanol (1000.0 ml), Thionyl Chloride (249.6 g, 2.09 mol) is added at below 10°C and maintained for 5 hrs at 50 to 55°C. After the completion of the reaction (HPLC Monitoring), methanol is distilled completely under reduced pressure at 50°C. To the residue, methanol (50 ml) is added and stirred for 30 minutes, and placed in an autoclave. The reaction mass is pressurized with dry ammonia gas (50-55 PS I) for 24 hrs at 40 - 45°C. After completion of the reaction, the reaction mass is filtered through a celite bed. The filtrate is concentrated completely under reduced pressure and the obtained residue was suspended in dichloromethane (1750.0 ml). The suspension is cooled to 0 to -5°C and tetrabutylammonium bromide is added (25 g, 0.07 mol) and stirred for 10-15 in in at 0 to - 5°C. Then Potassium hydroxide powder (426 g, 7.59 mol), and 4-chlorobutyryl chloride (260 g, 1.84 mol) solution in dichloromethane (260 ml) is added to the reaction mass in Lot wise in 2 hrs and stirred for 3-4 hrs at 0 to -5°C. After the completion of the reaction (HPLC Monitoring), Con.HC1 (SO ml) is added slowly and undissolved salts are collected by filtration and washed the salts with dichloromethane (2 X 150 ml). The clear filtrate was collected, washed with brine solution dried on anhydrous sodium sulfate, filtered the salts, and the filtrate concentrated under reduced pressure. To the residue, Acetone (20 ml) is added and heated ted to 50 to 60°C, then cooled to 0-5°C and maintain for 2 hrs at 0-5°C. The resulted crystal is filtered and dried.
Yield: 220g (1.1 w/w); HPLC Purity 99.5%
Experiment-2: Preparation of (25)-2-(2-oxopyrrolidin-l-yl) butanamide (1)
To a mixture of (S)-2-aminobutyric acid (IIA) (200 g, 1.93 mol) and methanol (1400.0 ml), Thionyl Chloride (250.0g, 2.10 mol) is added at below I0°C and maintained for 5 hrs at 50 to 55°C. After the completion of the reaction (HPLC Monitoring), methanol is distilled completely under reduced pressure at 50°C. To the residue, methanol (50 ml) is

added and stirred for 30 minutes, and placed in an autoclave. The reaction mass is pressurized with dry ammonia gas (50-55 PSI) for 24 hrs at 40-45°C. After completion of the reaction, the reaction mass is filtered through a celite bed. The filtrate is concentrated completely under reduced pressure and the obtained residue was suspended in dichloromethane (1700.0 ml). The suspension is cooled to 0 to -5°C and tetrabutylammonium bromide is added (25 g, 0.07 mol) and stirred for 10-15 min at 0 to
- 5°C. Then Potassium hydroxide powder (416 g, 7.41 mol), and 4-chlorobutyryl
chloride (275 g, 1.95 mol) solution in dichloromethane (275 ml) is added to the reaction
mass in Lot wise in 2 hrs and stirred for 3-4 hrs at 0 to -5°C. After the completion of
the reaction (HPLC Monitoring), Con.HO (80 ml) is added slowly and undissolved salts
are collected by Filtration and washed the salts with dichloromethane (500 ml). The clear
filtrate is collected, washed with brine solution, dried on anhydrous sodium sulfate,
filtered the salts, and the filtrate concentrated under reduced pressure. To the residue,
Acetone (275 ml) is added and heated ted to 50 to 60°C, then cooled to 0-5°C and
maintain for 2 hrs at 0-5°C. The resulted crystal is filtered and dried.
Yield: 188g( 0.94w/w);, HPLC Purity 99.66%
Experiment-3: Preparation of (25)-2-(2-oxopyrrolidin-l-yl) butanamide (I)
To a mixture of (S)-2-aminobutyric acid (I1A) (200 g, 1.93 mol) and methanol (1400.0 ml), Thionyl Chloride (250.0g, 2.10 mol) is added at below 10°C and maintained for 5 hrs at 50 to 55°C. After the completion of the reaction (HPLC Monitoring), methanol is distilled completely under reduced pressure at 50°C. To the residue, methanol (50 ml) is added and stirred for 30 minutes, and placed in an autoclave. The reaction mass is pressurized with dry ammonia gas (50-55 PSI) for 24 hrs at 40 - 45°C. After completion of the reaction, the reaction mass is filtered through a celite bed. The filtrate is concentrated completely under reduced pressure and the obtained residue was suspended in dichloromethane (1700.0 ml). The suspension is cooled to 0 to -5°C and tetrabutylammonium bromide is added (25 g,0.07 mol) and stirred for 10-15 min at 0 to
- 5°C. Then Potassium hydroxide powder (426 g, 7.59 mol), and 4-chlorobutyryl
chloride (275 g, 1.95 mol) solution in dichloromethane (275 ml) is added to the reaction
mass in Lot wise in 2 hrs and stirred for 3-4 hrs at 0 to -5°C. After the completion of
the reaction (HPLC Monitoring), Con.HCl (80 ml) is addedslowly and undissolved salts
are collected by filtration and washed the salts with dichloromethane (200 ml). The clear

filtrate was collected, washed with brine solution, dried on anhydrous sodium sulfate, filtered the salts, and the filtrate concentrated under reduced pressure. To the residue, Acetone (275 ml) is added and heated ted to 50 to 60°C, then cooled to 0-5°C and maintain for 2 hrs at 0-5°C. The resulted crystal is filtered and dried.
Yield: 2)0g (1.05w/w);, HPLC Purity 99.58%
Experiment-4: Preparation of (25>2-(2-oxopyrrolidin-l-yl) butanamide (I)
To a mixture of (S)-2-aminobutyric acid (HA) (200 g, 1.93 mol) and methanol (1400.0 ml), Thionyl Chloride (250.Og, 2.10 mol) is added at below I0°C and maintained for 5 hrs at 50 to 55°C. After the completion of the reaction (HPLC Monitoring), methanol is distilled completely under reduced pressure at 50°C. To the residue, methanol (50 ml) is added and stirred for 30 minutes, and placed in an autoclave. The reaction mass is pressurized with dry ammonia gas (50-55 PS1) for 24 hrs at 40 - 45°C. After completion of the reaction, the reaction mass is filtered through a celite bed. The filtrate is concentrated completely under reduced pressure and the obtained residue was suspended in dichloromethane (1700.0 ml). The suspension is cooled to 0 to -5°C and tetrabutylammonium bromide is added (25 g, 0.07 mol) and stirred for 10-15 min at 0 to - 5°C. Then Potassium hydroxide powder (426 g, 7.59 mol), and 4-chlorobutyryl chloride (260 g, 1.84 mol) solution in dichloromethane (275 ml) is added to the reaction mass in Lot wise in 2 hrs and stirred for 3-4 hrs at 0 to -5°C. After the completion of the reaction (HPLC Monitoring), Con.HCl (80 ml) is added slowly and undissolved salts are collected by filtration and washed the salts with dichloromethane (500 ml). The clear filtrate was collected, washed with brine solution, dried on anhydrous sodium sulfate, filtered the salts, and the filtrate concentrated under reduced pressure. To the residue, Acetone (275 ml) is added and heated ted to 50 to 60°C, then cooled to 0-5°C and maintain for 2 hrs at 0-5°C. The resulted crystal is filtered and dried.
Yield: 203 g(1.015w/w); HPLC Purity 9S.70

Experiment-5: Preparation of (25)-2-(2-oxopyrrolidin-l-yl) butanamide (I)
To a mixture of (S)-2-aminobutyric acid (11A) (200 g, 1.93 mol) and methanol (1400.0 ml), Thionyl Chloride (275.Og, 2.31 mol) is added at below I0°C and maintained for 5 hrs at 50 to 55°C. After the completion of the reaction (HPLC Monitoring), methanol is distilled completely under reduced pressure at 50°C. To the residue, methanol (50 ml) is added and stirred for 30 minutes, and placed in an autoclave. The reaction mass is pressurized with dry ammonia gas (50-55 PSI) for 24 hrs at 40 - 45°C. After completion of the reaction, the reaction mass is filtered through a celite bed. The filtrate is concentrated completely under reduced pressure and the obtained residue was suspended in dichloromethane (1700.0 ml). The suspension is cooled to 0 to -5°C and tetrabutylammonium bromide is added (25 g, 0.07 mol) and stirred for 10-15 min at 0 to
- 5°C. Then Potassium hydroxide powder (426 g, 7.59 mol), and 4-chlorobutyryl
chloride (260 g, 1.84 mol) solution in dichloromethane (260 ml) is added to the reaction
mass in Lot wise in 2 hrs and stirred for 3-4 hrs at 0 to -5°C. After the completion of
the reaction (HPLC Monitoring), Con.HCI (SO ml) is added slowly and undissolved salts
are collected by filtration and washed the salts with dichloromethane (500 ml). The clear
filtrate was collected, washed with brine solution, dried on anhydrous sodium sulfate,
filtered the salts, and the filtrate concentrated under reduced pressure. To the residue,
Acetone (275 ml) is added and heated ted to 50 to 60°C, then cooled to 0-5°C and
maintain for 2 hrs at 0-5°C. The resulted crystal is filtered and dried.
Yield: 193 (0.965w/w); HPLC Purity 99.53%
Experiment-6: Preparation of (2S)-2-(2-oxopyrrolidin-l-yl) butanamide (I)
To a mixture of (S)-2-aminobutyric acid (IIA) (400 g, 3.87 mol) and methanol (2800.0 ml), Thionyl Chloride (550.Og, 4.62 mol) is added at below 10°C and maintained for 5 hrs at 50 to 55°C. After the completion of the reaction (HPLC Monitoring), methanol is distilled completely under reduced pressure at 50°C. To the residue, methanol (50 ml) is added and stirred for 30 minutes, and placed in an autoclave. The reaction mass is pressurized with dry ammonia gas (50-55 PSI) for 24 hrs at 40 - 45°C. After completion of the reaction, the reaction mass is filtered through a celite bed. The filtrate is concentrated completely under reduced pressure and the obtained residue was suspended in dichloromethane (3400.0 ml). The suspension was cooled to 0 to -5°C and tetrabutylammonium bromide is added (50 g, 0.15 mol) and stirred for 10-15 min at 0 to
- 5°C. Then Potassium hydroxide powder (852 g, 15.18 mol), and 4-chlorobutyryl

chloride (520 g, 3.68 mol) solution in dichloromethane (520 ml) is added to the reaction mass in Lot wise in 2 hrs and stirred for 3-4 hrs at 0 to -5°C. After the completion of the reaction (HPLC Monitoring), Con.HCl (160 ml) is added slowly and undissolved salts are collected by filtration and washed the salts with dichloromethane (1000 ml). The clear filtrate was collected, washed with brine solution, dried on anhydrous sodium sulfate, filtered the salts, and the filtrate concentrated under reduced pressure. To the residue, Acetone (550 ml) is added and heated ted to 50 to 60°C, then cooled to 0-5°C and maintain for 2 hrs at 0-5°C. The resulted crystal is filtered and dried.
Yield: 420g ( l.05w/w), HPLC Purity 99.68%

We claim,
1. An improved process for the preparation of (2S)-2-(2-oxopyrrolidin-l-
yl)butanamide (Levetiracetam I) comprises:
a) reacting (S)-2-Amino butyric acid (HA) with alcohol in presence of thionyl chloride to form a corresponding ester intermediate (III),
b) resulting intermediate (III), without isolation, reacting with ammonia in an alcoholic solvent to form a corresponding amide intermediate (IVA), and
c) further, the amide intermediate (IVA), without isolation, reacts with a
compound of formula (V), 4-halo butyryl halide, in the presence of an
inorganic base in an organic solvent to form Levetiracetam (I)
2. The process as claimed in claim 1, wherein the alcohol in step (a) is methanol and ethanol, preferably Methanol.
3. The process as claimed in claim 1, wherein the alcoholic solvent in step (b) is selected from the group consisting of ethanol, methanol, and isopropanol, preferably methanol.
4. The process as claimed in claim 1, wherein the inorganic base is selected from the group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, and sodium carbonate, preferably potassium hydroxide.
5. The process as claimed in claim 1, wherein the 4-halo butyryl halide is selected from the group consisting of 4-chloro butyryl chloride, 4-Bromo butyryl bromide, and 4-iodo butyryl iodide, preferably 4-chloro butyryl chloride.
6. The process as claimed in claim-1 wherein, the solvent is selected from a group consisting of toluene, heptanes, ethanol, dichloromethane(MDC), Dimethytformamide(DMF), Dimethyl sulfoxide(DMSO), tetrahydrofuran (THF), and N-Methyl-2-pyrrolidone(NMP), preferably dichloromethane(M DC).
7. The process of the claim as claimed in claim-1, wherein the reaction temperature in Steps (a) and (b) is conducted at a temperature of from 30 to 90° C, preferably from 40 to 60° C, and step (c) of the process is preferably conducted at a temperature range of 0 to 5° C.