WO2008077035A2

WO2008077035A2 - Processes for the preparation of levetiracetam

Info

Publication number: WO2008077035A2
Application number: PCT/US2007/087924
Authority: WO
Inventors: Srinivas Reddy Gade; Srinivas Reddy Mallepalli; Venkateshwarlu Muvva; Ravindhranath Tagore Amirisetty; Narasimha Murthy Harikeerthi; Vijaya Anand Ramasamy; Rakeshwar Bandichhor; Ravi Kumar Mylavarapu; Ramachandra Janardana Sarma Kopparapu; Kushal Surajmal Manudhane; Srinivasula Reddy Maddula
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2006-12-18
Filing date: 2007-12-18
Publication date: 2008-06-26
Also published as: WO2008077035A3

Abstract

A process for preparing levetiracetarn of the Formula (I) via a reaction between S-arnlnobutyramide or its salt: and 4-chlqrobutyrylchloride: which process comprses forming a reaction mixture that includes, the S-aminσbutyrarriide or its salt, the 4-chlorobutyrylchloride, and potassium hydroxide, wherein the potassium hydroxide is added to said reaction mixture in a lot-wise manner...

Description

PROCESSES FOR THE PREPARATION OF LEVETIRACETAM

TECHNICAL FIELD This application encompasses processes for preparing levetiracetam and intermediates thereof.

INTRODUCTION

Levetiracetam is chemically known as (-)-(S)-α-ethyl-2-oxo-1 -pyrrolidine acetamide. It is represented by the Formula I:

Formula I

Levetiracetam is an antiepileptic drug useful for the treatment of epilepsy and is available in the market under the brand name "KEPPRA" in the form of tablet, oral solution and injection.

Gobert et. al. in U.S. Patent No. 4,943,639 disclose levetiracetam, its homologues and pharmaceutical composition thereof. The '639 patent also discloses a process for the preparation of levetiracetam, which is summarized in scheme 1 :

Scheme 1 : Process for preparing levetiracetam per USP 4,943,639

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

Scheme 2: Process for preparing levetiracetam as per US 2005182262

Futagawa et al., in US 6,107,492, disclose a method of resolution of racemic mixture of alpha-ethyl-2-oxo-1-pyrrolidineacetamide through chromatography column packed with optical resolution packing material, that contains silica gel-supported amylose tris (3,5-dimethylphenyl carbamate).

WO 2006/095362 describes a process for the preparation of levetiracetam, which is summarized in scheme 3:

Scheme 3: Process for preparing levetiracetam per WO '362

WO 2006/053441 discloses a process for the preparation of levetiracetam by reacting (S)-alpha-ethyl-2-oxo-1-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)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with ditertiary butyl dicarbonate and ammonium bicarbonate in the presence of acetonitrile and pyridine.

Although various processes for preparation of levetiracetam are disclosed in the art, they may suffer from one or more drawbacks. Hence, there is a continuing need for a commercially viable process for preparing levetiracetam. SUMMARY

In one embodiment, there is provided a process for preparing levetiracetam:

(I) via a reaction between S-aminobutyramide or its salt:

and 4-chlorobutyrylchloride:

which process includes forming a reaction mixture from the S-aminobutyramide or its salt, the 4-chlorobutyrylchloride, and potassium hydroxide, wherein the potassium hydroxide is added to the reaction mixture in a lot-wise manner. Various variants are provided.

In another embodiment, there is provided a process for making levetiracetam that includes: a) reacting a compound of the Formula III:

(III) with an oxidizing agent in the presence of a base and a phase transfer catalyst to provide the compound of the Formula II:

(H) b) reacting the compound of the Formula Il with a chlorinating agent to obtain an intermediate acid chloride of the formula (H-A):

(H-A) c) reacting the compound of the formula (N-A) with a source of ammonia to obtain levetiracetam. Various variants are provided.

Also provided is a process for making levetiracetam that includes: a) reacting D-(+)-2-amino butanol:

with dihydro-furan-2-one:

to obtain (S)-α-ethyl-2-oxopyrrolidine ethanol of the Formula

b) converting the (S)-α-ethyl-2-oxopyrrolidine ethanol to the levetiracetam. Various variants are provided.

DETAILED DESCRIPTION As set forth above, the reaction between S-aminobutyramide or its salt and 4-er4tombutyrylehlor4de^fflay^be^ used for roakiag levetiracetaiTL The potassium hydroxide is a base that is useful for facilitating this commercially viable reaction. It has been surprisingly discovered that addition of potassium hydroxide in a lot-wise manner unexpectedly leads to significant improvement in yield, with attendant commercially desirable consequences. The term "lot-wise" denotes addition of distinct portions of a reagent to a reaction mixture. Preferably, the potassium hydroxide is added in three or more lots.

S-aminobutyramide or its salt is reacted with 4-chlorobutyryl chloride and KOH in the presence of a suitable solvent and a phase transfer catalyst. Potassium hydroxide is added in 3 or more lots. The pH is adjusted either before the filtration or after the filtration of the reaction mixture. The resulting crude levetiracetam is then crystallized from a solvent. Suitable temperatures for conducting the reaction range from about -20⁰C to about 5 ⁰C₁ or from about - 1O⁰C to about 15 ⁰C. In a preferred embodiment, KOH is added in more than three lots. It has been surprisingly discovered that addition of KOH in a single lot causes degradation/decomposition of the compound of Formula V and reduction in the yield. The lot-wise addition of KOH leads to reduction of the degradation/decomposition and higher yields.

Preferably, the addition of 4-chlorobutyrylchloride is also carried out in a lot- wise manner. Preferably, 4-chlorobutyrylchloride is added in two or more lots. Each lot of 4-chlorobutyrylchloride is added drop wise either after addition of a lot of potassium hydroxide or simultaneously with a lot of potassium hydroxide. The time variation between each lot of KOH may be from 20 minutes or more to 3 hours or more. Suitably, the addition of 4-chlorobutyryl chloride is carried out slowly range from about 10 minutes to 1 hour, or more to maintain the reaction temperature below about 5 ⁰C. The time intervals between each addition of potassium hydroxide and the compound 4-chlorobutyryl chloride frequently range from about 10 minutes to about 60 minutes.

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 noLJimited to: ketones such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; nitriles such as acetonitrile, and propionitrile; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, 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 (TBAB), tetra-n-butyl ammonium chloride (TBCI), and crown ethers. The reaction may also be carried out without a phase transfer catalyst.

S-aminobutyramide may be used as a free base or a salt. The salts are preferably acid addition salts formed 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, preferably hydrochloric acid.

After completion of the reaction, the unwanted salt that forms in the reaction mixture may be separated immediately, or it may be separated after adjusting the pH to enhance the purity of the product. The pH of the reaction can be adjusted to range of from about 6 to about 8 using a suitable external acid. Suitable external acids that may be used include but not limited to aqueous acids such as acetic acid, hydrochloric acid, and aqueous sulfuric acid.

Suitable temperatures for adjusting the pH range from about 0⁰C to about 35⁰C.

After completion, the reaction mixture may be extracted into an organic layer. The solid product may then be recovered from the organic layer, for example by using precipitation with a precipitating solvent. Crystallization or precipitation of solid product may involve providing a solution of crude levetiracetam in a suitable solvent or mixture of solvents and then recovering the solid from the solution.

Suitable organic solvents for crystallization include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, 2-butanone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, isopropyl acetate, and tertiary-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; and mixtures thereof or their combinations with water in various proportions without limitation. Suitable temperatures for conducting the reaction range from about 25°C to about 50⁰C, or from about 20⁰C to about 40°C, or the reflux temperature of the solvent used.

The molar yield of levetiracetam produced by the above process is believed to be more than 75% or more than 85% with respect to S-aminobutyramide hydrochloride.

The levetiracetam of Formula I produced by the above process is believed to be free from impurities, including process, structural, and isomeric impurities. Typically, the levetiracetam is of high purity with respect to chiral purity and chemical purity, more than about 99.5 wt %. Correspondingly, the level of total impurities may be less than about 0.5 wt %, or about 0.1 wt %, as determined by high performance liquid chromatography (HPLC).

Levetiracetam obtained by the process described herein is believed to have less than 0.1% of one or more of the following structural related impurities: 2- Amino butric acid, S-aminobutyramide hydrochloride, chloramide of Formula A and (-)-(S)-alpha-ethyl-2-oxo-1 -pyrrolidine acetic acid of Formula II.

Formula A

Also provided is a process for making levetiracetam by a) reacting the compound of the Formula III:

(II) b) reacting the compound of the Formula Il with a chlorinating agent to obtain an intermediate acid chloride of the formula (H-A):

(H-A)

c) reacting the compound of the formula (M-A) with a source of ammonia. The process for the preparation of levetiracetam of Formula I is summarized in the scheme 4.

Scheme-4: Process for preparing levetiracetam.

The step a) involves oxidation of the alcohol of the formula (III) with an oxidizing agent to provide the carboxylic acid of the formula (II). Non-limiting examples of oxidizing agents include potassium permanganate, osmium oxide, hydrogen peroxide, benzoyl peroxide, ruthenium oxide (RuC^) and chimissorb 944 catalyst coated with per acetic acid. The oxidation is carried on in the presence of a base. Suitable bases that may be used include but are not limited to: organic bases such as triethylamine, and ethyl di-isopropylamine; and inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate. The oxidation is carried out in the presence of a phase transfer catalyst.

Suitable phase transfer catalysts thaLmay he used innlnrie hut are not limited tn TBAB, TBCI and crown ethers.

Suitable solvents which can be used include but are not limited to water; chlorinated solvents such as dichloromethane, dichloroethane, and chloroform; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), and

N,N-dimethylacetamide (DMA); and mixtures thereof in various proportions. Step b) involves treating the carboxylic acid of the Formula Il with a chlorinating reagent to form an acid chloride (H-A). The preferred chlorinating agent is thionyl chloride.

The acid chloride intermediate of the formula (N-A) is then treated with a source of ammonia to produce levetiracetam. Non-limiting examples of the source of ammonia include gaseous ammonia, ammonium chloride and ammonium acetate.

The reactions of step b) and c) may be carried out at a temperature of from about -20⁰C to about 5⁰C.

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 less than about -20°C to less than about -

10⁰C. An increase in temperature may cause formation of side products and process-related impurities.

Suitable solvents, which may be used, include but are not limited to chlorinated solvents such as dichloromethane, dichloroethane, and chloroform; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; or mixtures thereof. Also provided is a process for preparing the compound of Formula III by reacting D-(+)-2-amino butanol of the Formula Vl:

Formula Vl with the dihydro-furan-2-one of the Formula IV:

Formula IV to provide (S)-α-ethyl-2-oxopyrrolidine ethanol of the Formula III, which may be then converted to levetiracetam. The process for the preparation of the intermediate III is summarized in the scheme 5:

(Vl) (IV) (III)

Scheme-5: Process for preparing Formula III

In one variant, the compound of the Formula Vl is reacted with the compound of Formula IV in presence of monocarboxylic acid and inert gas. Mocarboxylic acids that may be used include, but are not limited to, acetic acid, formic acid, propionic acid, and butanoic acid. Suitable temperatures for preparing

Formula III range from about 150 to about 250⁰C. Inert gas such as nitrogen and/or argon gases used in range from about 2 kg/cm² to about 35 kg/cm² to conduct the reaction. Suitable time for the completion of the reaction range from about 2 hours to about 10 hours.

The condensation of Formula Vl with Formula IV may be carried out in the presence of microwave irradiation. Preferably, the frequency of microwave irradiation ranges from about 2000 to about 2450 MHz. The microwave radiation may be introduced into the reaction mixture by methods known in the art. Preferably, the levetiracetam produced by the processes described herein has residual solvent content may be less than about 10 wt %, or less than about 2 wt %, or less than about 1 wt %, about 0.5 wt %, or about 0.1 wt %, as determined by gas chromatography (GC). More preferably, the levetiracetam produced by the processes described herein is substantially free from residual solvents. Levetiracetam may be milled to get the required particle size. Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities. In a variant, levetiracetam obtained by the processes described herein has a particle size Dg₀ less than about 500 microns, or about 300 microns, or about 200 microns; D₅₀ less than about 300 microns, or about 100 microns; Dio less than about 100 microns, or about 50 microns.

The Dio, D₅O and Dg₀ values are useful ways for indicating a particle size distribution. Dgo refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D₅o and Dio refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining D10, D50 and D90 include laser diffraction, such as using laser light scattering equipment from Malvern Instruments Ltd. of Malvern, Worcestershire.

In another embodiment, also provided is a pharmaceutical composition that includes a therapeutically effective amount of levetiracetam and at least one pharmaceutically acceptable excipient. Preferably, levetiracetam used in the composition is substantially free from impurities.

Levetiracetam obtained by the processes described herein may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin, may be used. The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous, sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable carriers include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

The following non-limiting examples illustrate the invention. EXAMPLE - 1

EXAMPLE1 : PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1-PYRROLIDINE ACETAMIDE (FORMULA I) S-aminobutyramide hydrochloride (25 g) and dichloromethane (300 ml) were^harged into a clean dry4 neck round bottom flask and stirred at about

10⁰C for about 10 minutes. Tetra-n-butyl ammonium bromide (1 1.6 g) was added and stirred at a temperature of about -1O⁰C for about 10 minutes. Potassium hydroxide (20.2 g) was added at a temperature of about -10⁰C and stirred for 15 minutes followed by addition of mixture of 4-chloro butyrlchloride (12.7 g) and dichloromethane (25 ml) was added slowly at a temperature of about -6°C over a period of about 45 minutes. The resultant reaction mixture was stirred for about 45 minutes. Potassium hydroxide (20.2 g) was added at a temperature of about - 1O⁰C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (7.6 g) and dichloromethane (25 ml) slowly over a period of about 30 minutes and stirred for about 45 minutes. A lot of potassium hydroxide (10.1 g) was added at a temperature of about -10⁰C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (7.6 g of) dissolved in dichloromethane (25 ml) slowly over about 30 minutes. The resultant reaction mixture was stirred at a temperature of about -2°C for about 5 hours. Potassium hydroxide (5.05 g) was added followed by stirring for about 2 hours. The separated unwanted solid was filtered and the solid was washed with dichloromethane (50 ml). pH of the filtrate was adjusted to about 7 by addition of acetic acid (0.8 ml). The organic layer was dried over anhydrous sodium sulphate. The obtained clear organic layer was distilled off completely at about 35°C under vacuum. Ethyl acetate (25 X 2 ml) was added to the residue and distilled completely under vacuum to remove the traces dichloromethane, yielding the title compound as a solid residue.

To the obtained residue ethyl acetate (10 ml) was added at a temperature of about 25°C to about 30⁰C and cooled to about 0°C followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with precooled ethyl acetate (10 ml). The obtained solid was dried at about 40⁰C under vacuum for about 3 hours to afford 27 g of pure title compound. Purity by HPLC: 99.94%. Purity by chiral HPLC: 99.7%.

EXAMPLE 2: PREPARATION OF (S)-α-ETHYL-2-OXO-1-PYRROLIDINE

ETHANOL (FORMULA III)

D-2-amino butanol (50 g) and γ-butyrolactone (62 g) were charged into a clean and dry autoclave containing acetic acid (3.6 g). The reaction mixture was maintained under about 20 kg/cm² to about 25 kg/cm² nitrogen pressure at a temperature of about 220⁰C to about 23O⁰C for about 15 to about 20 hours. The resultant reaction mixture was cooled to a temperature of about 25⁰C to about 35°C to afford the 109.2 g of title compound as a residue. Purity by HPLC: 91.79%

EXAMPLE 3: PREPARATION OF (S)-α-ETHYL-2-OXO PYRROLIDINE ACETIC ACID (FORMULA II)

Potassium hydroxide (10 g) was dissolved into water (180 ml) and cooled to a temperature of about 1 O⁰C. Tetra-n-butyl ammonium bromide (2 g) and (S)- α-ethyl-2-oxo pyrrolidine ethanol (10 g) in methylene chloride (18 ml) were charged followed by stirring for about 10 minutes. Potassium permanganate (15 g) was charged followed by stirring at a temperature of about 30⁰C for about 8 hours. The resultant reaction mixture was filtered through a celite bed and the celite was washed with water (100 ml) followed by separation of organic and aqueous layers. The separated aqueous layer was charged into a clean and dry round bottom flask followed by cooling to about 0°C. pH of the reaction solution was adjusted to about 3 by the addition of hydrochloric acid (2 ml) followed by stirring for about 5 minutes. To the resultant reaction mixture sodium phosphate (25 g) was added followed by stirring for about 10 minutes. Toluene (150 ml) was added into the reaction solution and about 50% of the solvent was distilled off. The resultant reaction solution was extracted with dichloromethane (5*50 ml) followed by separation of organic and aqueous layers. The organic layer was dried over anhydrous sodium sulphate (10 g). Organic layer was distilled completely at a temperature of about 30⁰C under vacuum to obtain the title compound as a residue.

To the residue toluene (10 ml) was added and stirred at 0°C for about 30 minutes. The separated solid was filtered and the solid was washed with toluene (5 ml). The obtained solid was dried at a temperature of about 60⁰C under vacuum for about 1 hour to afford the pure 5 3 fj πf title compound.

Purity by HPLC: 97%.

EXAMPLE 4: PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE (FORMULA I)

(-)-(S)-α-ethyl-2-oxo-1 -pyrrolidine acetic acid (5 g) of Formula Il and dichloromethane (50 ml) were charged into a clean and dry round bottom flask and stirred for about 20 minutes. The resultant reaction solution was cooled to about -25°C followed by dropwise addition of a mixture of thionyl chloride (4.5 ml) and dichloromethane (10 ml) slowly over a period of about 10 minutes. The resultant reaction mixture was stirred at a temperature of about -15°C for about 90 minutes. After completion of the reaction thionyl chloride was expelled by purging with nitrogen gas at about -10⁰C for about 90 minutes. Dry ammonia gas was passed slowly into the mixture at about -10⁰C for about 3 hours. The separated solid was filtered and the solid was washed with dichloromethane (50 ml). The resultant filtrate was distilled completely under vacuum to afford the title compound as a residue.

To the crude obtained, ethyl acetate (10 ml) was charged followed by stirring at a temperature of about 30⁰C for about 15 minutes. The separated solid was filtered and the solid was dried at about 6O⁰C under vacuum for about 3 hours to afford 4 g of the title compound. Yield: 80.46% Purity by HPLC: 98.09%. Purity by chiral HPLC: 99.73%. EXAMPLE-5: PREPARATION OF(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ETHANOL (FORMULA III)

D-2-amino butanol (0.515 g) and γ-butyrolactone (0.5 g) were charged into a clean and dry TFM liner vessel. The vessel was placed in microwave oven and irradiated radiation for 1 hour at a temperature of about 200⁰C to give -1-g-of title compound.

Purity: 81.69% by HPLC at 16.56 retention time (RT)

4-hydroxy-N-1-hydroxymethyl-propyl)butyramide intermediate: 8.81% at 6.122 Impurity: 5.71% at 14.32 RT

EXAMPLE-6: PREPARATION OF (S)-α-ETHYL-2-OXO-1-PYRROLIDINE ETHANOL (FORMULA III)

Continuous microwave reactor consisting of tetrafluoro mtoxil vessels (TFM liner) (chemical resistant) a in 500 ml chamber, fiber glass reinforced PEEK safety shield (pressure resistant), TFM bottom sealing with double O-ring, back pressure valve system, tubular microwave reactor, mechanical stirrer, cooling chamber, system having dosing diagram, pumps and chiller, programmable speed controller. The frequency of microwave is 2450 MHz. γ-butyrolactone (500 g) and D-2-amino butanol (517 g) were charged into a cleaned bottle at a temperature of about 27°C. The reaction mixture was pumped with flow rate 6 ml/minute into the sealed TFM liner chamber. The reaction mass was subjected to irradiation of microwaves at a temperature of about 200⁰C for 60 minutes and the resultant reaction mass was collected to afford 975 g of crude of title compound.

Conversion of final compound: 81.69%. 4-hydroxy-N-1-hydroxymethyl-propyl)butyramide intermediate: 8.81 %

EXAMPLE-7: PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE AS PER US 4,943,639

Sodium sulfate (25 g) was added to a suspension of (S)-2-amino- butanamide hydrochloride (20 g) in dichloromethane (175 ml) at a temperature of about 25 to about 35°C. The reaction mixture was cooled to about O⁰C to about - 1O⁰C followed by the addition of potassium hydroxide (33.1 g) and tetra butylammonium bromide (2.3 g). A solution of 4-chlorobutyrylchloride (22.3 g) in dichloromethane (30 ml) was added to the reaction mixture over a period of 1 hour and stirred for about 2 hours. Potassium hydroxide (8.3 g) was added to the reaction mixture and stirred for about 5 hours 30 minutes. The reaction mixture was filtered and washed with dichloromethane (50 ml). The filtrate was concentrated completely followed by the addition of toluene and then distilled off the solvent completely. Ethylacetate (110 ml) was added to the reaction crude and heating given to a temperature of about 75 to about 80⁰C and stirred for about 20 minutes. Filtered the suspension and washed the solid with ethylacetate (10 ml). The obtained filtrate was distilled completely followed by ethylacetate (80 ml) was added and then stirred for about 15 minutes. The reaction suspension was cooled to about 0°C to about 5°C and stirred for about 1 hour 45 minutes. Acetone (10 ml) was added to the reaction mixture and stirred for about 1 hour 40 minutes. The sususpension was filtered and dried the solid at a temperature of about 60⁰C for about 3 hours 30 minutes to afford 8.5 g of title compound. Purity: 96.7% by HPLC; Yield: 34.61% 16.1% of (S)-2-amino-butanamide hydrochloride, 65% of 4-chlorobutyrylchloride and 7.2% of intermediate of Formula A were not converted to title compound.

EXAMPLE-8: PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE (FORMULA I) S-aminobutyramide hydrochloride (60 g) and dichloromethane (720 ml) were charged into a clean dry round bottom flask and stirred at a temperature of about -10°C for about 10 minutes. Tetra-butyl ammonium bromide (27.8 g) was added and stirred at -10°C for about 10 minutes. Potassium hydroxide (48.5 g) was added at about -10°C and stirred for about 15 minutes followed by addition of mixture of 4-chloro butyrlchloride (30.5 g) and dichloromethane (60 ml) was added slowly at a temperature of about -6⁰C over a period of about 45 minutes. The resultant reaction mixture was stirred for about 45 minutes. Potassium hydroxide (48.5 g) was added at about -10°C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (18.4 g) and dichloromethane (60 ml) slowly over about 30 minutes and stirred for about 45 minutes. A lot of potassium hydroxide (24.2 g) was added at a temperature of about -1O⁰C and stirred for about 15 minutes followed by the addition of 4-chlorobutyrl chloride (18.4 g of) dissolved in dichloromethane (60 ml) over a period of about 30 minutes. The restιltantH^r€aεtionHmxture^/vas stirred at a temperature of about -2°C for about 5 hours. Potassium hydroxide (12.1 g) was added followed by stirring for about 2 hours. pH of the reaction mixture was adjusted to about 7 to about 7.5 by addition of acetic acid (45 ml). The unwanted solid was filtered and the solid was washed with dichloromethane (120 ml). The organic layer was dried over anhydrous sodium sulphate (60 g). The obtained clear organic layer was distilled off completely at about 35°C under vacuum. Ethyl acetate (60 X 2 ml) was added to the residue and distilled completely under vacuum to remove the traces dichloromethane, yielding the title compound as a solid residue. To the obtained residue ethyl acetate (120 ml) was added at a temperature of about 25⁰C to about 30⁰C and stirred for about 30 minutes. The reaction mixture was cooled to a temperature of about O⁰C followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with precooled ethyl acetate (24 ml). The obtained solid was dried at about 40°C under vacuum for about 3 hours to afford 70.5 g of pure title compound. Yield: 95.68% Purity by HPLC: 99.15%. Purity by chiral HPLC: 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.

Claims

We claim:

1. A process for preparing levetiracetam of the Formula I:

(I) via a reaction between S-aminobutyramide or its salt:

and 4-chlorobutyrylchloride:

which process comprises forming a reaction mixture that includes the S- aminobutyramide or its salt, the 4-chlorobutyrylchloride, and potassium hydroxide, wherein the potassium hydroxide is added to said reaction mixture in a lot-wise manner.

2. The process of claim 1 , wherein said reaction mixture is formed by adding the S-aminobutyramide or its salt, the 4-chlorobutyrylchloride, and potassium hydroxide to a suitable reaction vessel.

3. The process of claim 1 , wherein the potassium hydroxide is added in three or more lots.

4. The process of claim 3, wherein the potassium hydroxide is added in more than three lots.

5. The process of claim 1 , wherein the 4-chlorobutyrylchloride is added in a lot-wise manner.

6. The process of claim 4, wherein the 4-chlorobutyrylchloride is added in two or more lots.

7. The process of claim 1 , wherein the reaction mixture is formed by adding a ^al^of S-aminobutyramide,

8. The process of claim 7, wherein said salt is a hydrochloride.

9. A process for making levetiracetam, said process comprising: a) reacting the compound of the Formula III:

(H) b) reacting the compound of the Formula Il with a chlorinating agent to obtain an intermediate acid chloride of the formula (M-A):

(H-A)

c) reacting said compound of the formula (M-A) with a source of ammonia to provide said leviteracetam.

10. The process of claim 9, wherein said source of ammonia is ammonia, ammonium chloride or ammonium acetate.

11. The process of claim 9, wherein said chlorinating agent is thionyl chloride.

12. The process of claim 9, wherein the^xidizing agent is potassium permanganate, osmium oxide, hydrogen peroxide, benzoyl peroxide or ruthenium oxide.

13. A process for making levetiracetam, said process comprising: a) reacting D-(+)-2-amino butanol:

with dihydro-furan-2-one:

to obtain (S)-α-ethyl-2-oxopyrrolidine ethanol of the Formula

(III) b) converting the (S)-α-ethyl-2-oxopyrrolidine ethanol to the levetiracetam.

14. The process of claim 13, wherein the reacting step a) is carried out in the presence of microwave radiation.

15. The process of claim 14, wherein the frequency of the microwave radiation ranges from about 2000 MHz to about 2450 MHz.

16. The process of claim 13, wherein the reacting step a) is carried out in the presence of a monocarboxylic acid.

17. The process of claim 16, wherein said monocarboxylic acid is acetic acid.

18. The process of claim 13, wherein the reacting step a) is carried out in an inert gas atmosphere.

19. The process of claim 18, wherein the inert gas is nitrogen and/or argon.

20. The process according to claim 18, wherein the amount of the inert gas in the reaction mixture ranges from about 3 kg/cm² to about 35 kg/cm².