Description:DESCRIPTION

A CONTINUOUS PROCESS FOR PRODUCTION OF LEVETIRACETAM

FIELD OF INVENTION
The present invention relates to a continuous process for production of Levetiracetam.

BACKGROUND OF INVENTION
Levetiracetam (V), which is a known anticonvulsant and used in the field of treating epilepsy is often made by treating (S)-2-aminobutyramide (I) or its hydrochloride salt (II) with 4-chlorobutyryl chloride (III), also referred to as CBC (See Scheme 1). The growing demand (said to be ~6% annually) for Levetiracetam needs to be met by efficient manufacturing in terms of low cost and quick turnaround time to enable its ready availability. Though the literature is replete with this synthesis through batch processing, a continuous process for conversion of I or II into Levetiracetam appears not known. The present disclosure aims at providing a continuous process for the synthesis of Levetiracetam from I or II.

I II
Scheme-1
V

Several literature references have disclosed preparation of Levetiracetam by batch processes for the conversion of the salt compound II by reaction with 4-chlorobutyryl chloride (CBC) as depicted in Scheme 1 into Levetiracetam using potassium hydroxide powder suspended in a solvent such as dichloromethane, at temperatures less than 10oC. Variations of this process have been disclosed in the following references and are summarized below. The reaction mass (as represented in Scheme 1) additionally contains tetrabutylammonium bromide (TBAB) as a catalyst. Patent publication, WO2008077035, discloses the addition of KOH in the reaction mixture in several lots with the total reaction time including addition times exceeding 10 h. The Journal publication- Indian Journal of Chemistry, Section B: Organic Chemistry including Medicinal Chemistry, 53(B), 1218-1221; 2014 and patent publications CN110698379, CN104860863, CN109134341 and IN2009CH00267 disclose similar batch processes. Patent publication CN105063120 discloses a batch process using chloroform as the solvent in place of dichloromethane. Patent publication CN102260721 discloses a process wherein tetrahydrofuran (THF) is used as the solvent in place of dichloromethane, no catalyst is used and where the total reaction time exceeded 8h. Patent publications, WO2004069796 and WO2006103696 disclose the use of acetonitrile as the solvent for the conversion of 2-aminobutyramide into Levetiracetam. The patent publication, CN106432032 discloses the inclusion of polyethylene glycol instead of tetrabutylammonium chloride as catalyst in the reaction mass. Patent publication, IN227709 discloses a process wherein no phase transfer catalyst is used in a solvent such as acetonitrile and methyl tert-butyl ether and the base used was sodium hydroxide in place of potassium hydroxide.
Patent publication, CN102675181 discloses a two-step batch process where, in the first step water is used as the solvent for the reaction of 4-chlorobutyryl chloride (CBC) with 2-aminobutyramide to form an N-acylated product and in the second step potassium hydroxide is used for the cyclization of the N-acylated product to form Levetiracetam.
Patent publications, CN101624362 and CN1583721 disclose the preparation of Levetiracetam from compound 1, instead of the salt, II by batch process using KOH suspended in dichloromethane.
Patent publication, CN101550100 discloses the use of various butylamine hydro halide salts as catalysts in presence of various bases such as sodium carbonate instead of KOH for effecting the transformation of 2-aminobutyramide.HCl salt into Levetiracetam.
Patent publication, IN-2009-CHE-00267, discloses use of freshly milled potassium hydroxide and passed through 2 mm sieve for enhanced reaction rate.
All the batch processes mentioned above suffer from one or the other drawbacks of reaction times longer than 8 h, use of expensive catalysts and low productivity. The inventors of the present invention have addressed these drawbacks and have come up with a new process that is capable of continuous operation and production, thus providing an effective solution to the ever-increasing demand for Levetiracetam.
SUMMARY OF THE INVENTION

An integrated continuous process for Levetiracetam comprises steps a-i, wherein,
the step a) comprises continuously reacting compound I or II in organic solvent-A with 4-chlorobutyryl chloride (CBC) in reactor-A in presence of a mild organic base in the organic solvent-A to form a reaction mixture-I at a temperature ranging from -5 to 10°C.
the step b) comprises continuously reacting the mixture-I with a fine KOH suspension in the organic solvent-A in reactor-B to form a reaction mixture-II at a temperature ranging from -10 to 0°C,
the step c) continuously filtering the reaction mixture-II through a filter
the step d) comprises continuously collecting filtrate in a collection vessel
the step e) comprises continuously adjusting pH of the filtrate in the collection vessel at a temperature ranging from 0 to 10°C to obtain pH-adjusted mixture-III
the step f) comprises continuously pumping the mixture-III to a continuous evaporator
the step g) comprises continuously evaporating the solvent from the pH-adjusted filtrate to form a crude product IV,
the step h) comprises continuously dissolving the crude product IV in a solvent-B and continuously crystallizing to form semi-crude Levetiracetam V, and
the step i) comprises recrystallizing the semi-crude Levetiracetam, V to obtain Levetiracetam, V of purity >99.5%.
The reactor-A, reactor-B and reactor-C are single reactors or a series of multiple reactors.
The reactor-A, reactor-B or reactor-C is selected from a group consisting of continuous stirred tank reactors (CSTRs), Tubular flow reactors (TRs) and a combination thereof.
The mild base is selected from a group consisting of triethylamine, tripropylamine, tributylamine, tri-isopropyl amine, pyridine, and a combination thereof.
Solvent-A is selected from dichloromethane (DCM), dichloroethane, tetrachloroethane, toluene and a combination thereof.
Solvent-B is selected from a group consisting of ethyl acetate, propyl acetate, butyl acetate, amyl acetate and a combination thereof.
Fine KOH suspension is prepared by using a homogenizer in dry dichloromethane.
Particle size of the fine KOH suspension is in the range of 5 to 20 microns.
Residence time in reactor A ranges from 45 min to 75 min.
The residence time in reactor B ranges from 45 min to 75 min.
The obtained chiral purity of Levetiracetam is at least 99.2%.

DETAILED DESCRIPTION OF THE INVENTION
Definitions
Batch reactor: Vessel used for chemical reaction that has no feed or effluent streams. The reactor is well stirred and usually run either isothermally or adiabatically. The main design variable is how much time the reactants are allowed to remain in the reactor to achieve the desired level of conversion.
Integrated continuous process: It is a continuous process wherein there is continuous input of starting materials and reagents and continuous output of the product or product mixture in the process. An Integrated continuous process integrates one or more continuous process steps to make the desired product.
Continuous stirred tank reactor (CSTR): Sometimes called a continuous-flow stirred-tank reactor, with continuous input and output of material. The outlet concentration is assumed to be the same as the concentration at any point in the reactor.
Tubular reactor: It consists of a long pipe or tube. Optionally mixing elements are provided in the tube to cause interphase mixing and turbulence. The tubular reactors are also jacketed to provide heat transfer ability to/from an external fluid to maintain the process side fluid in the desired temperature range for the reaction. The reacting mixture moves down the tube resulting in a change in concentration down the length of the reactor.
Conversion: Fraction or percentage that describes the extent of a chemical reaction. Conversion is calculated by dividing the number of moles of a reactant that reacted by the initial moles of reactant. Conversion is always based on limiting reactant.
Yield: Expressed as a percentage, it is the ratio of moles of a desired product to moles of a limiting reactant used.
SABAM: This abbreviation refers to (S)-2-aminobutyramide or interchangeably (2S)-2-aminobutyramide. The compound is referred to as I.
SABAM.HCl: This abbreviation refers to the HCl salt of SABAM. The compound is referred to as II, in the disclosure.
DCM: Dichloromethane or methylene chloride solvent
LVT: An abbreviation to indicate Levetiracetam, V
Optically Active: The expression, ‘optically active’ refers to the optically active (R) or (S) isomers of chiral compounds in this disclosure.
Optical purity: It is interchangeably used to mean ‘chiral purity’.
Residence time: Average time the molecules of the reaction mixture remain in the reactor combinations. Typically, during the residence time, the reaction occurs to form the product/s.
Yield: Expressed as a percentage, it is the ratio of moles of a desired product to moles of a limiting reactant used.
Productivity: In this disclosure, productivity means the ability to make a product at a high quality and quick speed.
Chiral purity: In this disclosure, ‘chiral purity’ refers to the purity of Levetiracetam in terms of the content of the (S) isomer.

The present invention discloses an integrated continuous process for Levetiracetam, from starting materials I or II.

I II
The present invention discloses an integrated continuous process for Levetiracetam comprising steps a, b, c, d, e, f, g, h, I and j wherein the
the step a) comprises continuously reacting compound I or II in organic solvent-A with 4-chlorobutyryl chloride (CBC) in reactor-A in presence of a mild organic base in the organic solvent-A to form a reaction mixture-I at a temperature ranging from -5 to 10°C.
the step b) comprises continuously reacting the mixture-I with a fine KOH suspension in the organic solvent-A in reactor-B to form a reaction mixture-II at a temperature ranging from -10 to 0°C,
the step c) continuously filtering the reaction mixture-II through a filter
the step d) comprises continuously collecting filtrate in a collection vessel
the step e) comprises continuously adjusting pH of the filtrate in the collection vessel at a temperature ranging from 0 to 10°C to obtain pH-adjusted mixture-III
the step f) comprises continuously pumping the mixture-III to a continuous evaporator
the step g) comprises continuously evaporating the solvent from the pH-adjusted filtrate to form a crude product IV,
the step h) comprises continuously dissolving the crude product IV in a solvent-B and continuously crystallizing to form semi-crude Levetiracetam V, and
the step i) comprises recrystallizing the semi-crude Levetiracetam, V to obtain Levetiracetam, V of purity >99.5%.
The reactor-A, the reactor-B and the reactor-C are single reactors or a series of multiple reactors.
The reactor-A, the reactor-B or the reactor-C is selected from a group consisting of continuous stirred tank reactors (CSTRs), Tubular flow reactors (TRs) and a combination thereof.
The mild base is selected from a group consisting of triethylamine, tripropylamine, tributylamine, tri(isopropyl amine), pyridine and a combination thereof. Preferably, the mild base is triethylamine.
The organic solvent-A is selected from dichloromethane, dichloroethane, tetrachloroethane, tetrahydrofuran, toluene and a combination thereof. Preferably, the solvent-A is dichloromethane.
The solvent-B is selected from a group consisting of ethyl acetate, propyl acetate, butyl acetate, amyl acetate and a combination thereof. Preferably the solvent-B is ethyl acetate.
The fine KOH suspension is prepared by using a homogenizer in dry organic solvent-A preferably dichloromethane and the suspension is kept at 0 to -10°C. On comminution, the particle size of KOH obtained is in the range 10 to 25 microns
Molar ratio of SABAM (I)to triethylamine is taken typically in the range 1:3.0, preferably, in the range 1:2.0 or more preferably in the range 1:1.5
Molar ratio of SABAM (I) to CBC taken is typically in the range 1:3, preferably, in the range 1:2.0 or more preferably in the range 1:1.5
Molar ratio of SABAM to KOH is typically in the range 1:8, preferably, in the range 1:6 or more preferably in the range 1:4.

Scheme 2

I CBC

As shown in scheme 2, the new synthesis of Levetiracetam, V involves the reaction of 1 with 4-chlorobutyl chloride (CBC) at a temperature of -10°C to 0°C, in dichloromethane (DCM) solvent and in the presence of a mild base such as triethylamine leading to the formation of a mixture-I containing an uncyclized diamide intermediate, which is not isolated. It is important to note that any adventitious moisture at this stage can lead to impurities. This uncyclized diamide intermediate mixture-I is then reacted with KOH solid at -10 to -5°C to form a new mixture-II which contains the cyclized product Levetiracetam, which is then isolated and purified as given below.

General Procedure for carrying out the acylation and cyclisation starting from 1

An integrated continuous process for Levetiracetam comprises the following sub-steps, a to i.
the step a) comprises continuously reacting compound I or II in organic solvent-A, DCM with 4-chlorobutyryl chloride (CBC) in reactor-A in presence of a mild organic base, triethylamine (TEA) in the organic solvent-A, DCM to form a reaction mixture-I at a temperature ranging from -5 to 10°C. Mixture-I contains uncyclized amide intermediate (Scheme 2) which is soluble in DCM at > 10°C and less soluble at lower temperatures. Interestingly, it forms a flowable slurry at -10 to 0°C and makes it amenable for pumping conditions.
the step b) comprises continuously reacting the mixture-I with a fine KOH suspension in the organic solvent-A in reactor-B to form a reaction mixture-II at a temperature ranging from -10 to 0°C. In this step, the continuous slurry stream (mixture-I), containing the uncyclized amide intermediate was simultaneously pumped to the reactor-B, where another stream containing homogenized powdered KOH in dry DCM maintained at 0 to -10°C in a vessel having anhydrous sodium sulphate and TBAB catalyst was pumped in. Such a reaction condition amounts to significant intensification of the cyclization of the uncyclized amide intermediate which takes 15-30 mins for >99% conversion.
the step c) continuously filtering the reaction mixture-II through a filter to remove KCl formed
the step d) comprises continuously collecting filtrate in a collection vessel
Steps e) to i) given immediately below are related to product isolation and purification. They are further described in detail in the section on “Product Isolation and purification”
the step e) comprises continuously adjusting pH of the filtrate in the collection vessel by using an acid selected from a group consisting of acetic acid, HCl and H2SO4. Preferably, acetic acid is used for the neutralization at a temperature ranging from 0 to 10°C to obtain pH-adjusted filtrate mixture-III
the step f) comprises continuously pumping the mixture-III to a continuous evaporator.
the step g) comprises continuously evaporating the solvent from the pH-adjusted filtrate to form a crude product IV,
the step h) comprises continuously dissolving the crude product IV in a solvent-B, ethyl acetate and continuously crystallizing to form semi-crude Levetiracetam V, and
the step i) comprises recrystallizing the semi-crude Levetiracetam, V to obtain Levetiracetam, V of purity >99.5%. In this step, the semi-crude Levetiracetam V, was taken for dissolution and continuous crystallization in ethyl acetate to get product Levetiracetam in good optical purity and yield.
All these operations are done in continuous mode of operations. The relative amounts of the reactants are as given in Table 1. Flow of both uncyclized reaction mass and KOH should be simultaneous and the either the flow rate should be similar or the flow rate of uncyclized mass should be higher than that of KOH to ensure that the reaction goes to completion and time required for cyclization is short. Care should be taken in these steps to not allow the temperature to raise above -5°C to ensure that the extent of racemization of LVT is negligible to achieve required optical purity.
The residence time in reactor A for the step (a) ranges from 45 min to 75 min
The residence time in reactor B for the step (b) to form the reaction mixture-II ranges from 45 min to 75 min
Key features of the intensified process of the present invention include the following:
a) A good mixing of the reaction mixture is enabled by choosing the starting material SABAM (I) instead of SABAM.HCl (II) for reaction with CBC
b) Use of triethylamine (TEA) to form the intermediate mixture-I, results in an easily pumpable slurry for the subsequent step
c) Use of the combination of TEA and KOH rather than only KOH ensured good mixing essential for continuous flow process
d) Using homogenized KOH of fine particle size leads to superior mass transfer and lower reaction times.
Product Isolation and Purification
Product isolation and purification may be performed under batch, semi-batch or continuous manner.
Once the reaction is complete, filtration of the reaction mass is done under chilled condition (-5 to-10°C). DCM is used for washing the cake. The filtrate obtained is neutralized using glacial acetic acid in a separate reactor-C under chilled condition (-5 to-10°C). When a pH of 6-7 is achieved, the addition of acetic acid is stopped, and the resulting filtrate is referred to as Mixture III. Anhydrous Sodium sulphate is added to the neutralized filtrate. Mixture III is stirred and then filtered to remove solids. The filtrate which is passed through sodium sulphate is heated to 30°C under vacuum to evaporate DCM. When there is no further DCM being condensed, an oily mass is extracted with ethyl acetate. Ethyl acetate is then stripped off under vacuum at 30°C. The crude is then heated with ethyl acetate to 80°C under reflux. The solution is gradually cooled from 80°C to -5°C and optionally held at this low temperature for some dwell time . The mass is then filtered under vacuum to obtain pure levetiracetam. Ethyl acetate is used to wash the Levetiracetam. The crystals are optionally stirred at this temperature for an hour to complete the growth of crystals, which are then filtered, dried and packed as final product.

Batch Process (covered in comparative examples C.E.1 to C.E. 4- see Table 2)
Levetiracetam is reported to be currently made in batch process starting from L-2-Amino-butyramide (I) and 4-chlorobutyryl chloride in presence of powdered KOH, phase transfer catalyst, tetrabutylammonium bromide (TBAB) and anhydrous sodium sulphate in dry DCM solvent. The reaction is done at low temperatures (-15 to -20°C) with multiple portion-wise slow additions of 4-chlorobutyryl chloride and KOH. The reaction mixture becomes a very thick slurry during the end of the reaction and becomes very difficult to stir. This is due to high percentages of solids in the reaction due to presence of SABAM (I), and insoluble anhydrous sodium sulphate, and powdered KOH. Hence, 20 volumes of dry DCM were used to keep the reaction mixture stirrable. The reaction also generates potassium chloride which increases the solids composition and makes it a thick slurry towards the end of the reaction. The reaction in batch takes close to 12 -14 hrs from start till completion of reaction. The reaction mixture was further neutralized with mild acids to pH neutral and then solids were filtered using filter aids (Hyflo or Celite beds). The filtrate was evaporated to get crude Levetiracetam which was further purified using solvents to get highly pure product with >99.5% purity. The relative amounts of the reactants used are as given in Table 2.

Chiral Purity Determination
Chiral purity was analysed by Chiral HPLC. Enantiomeric separation of Levetiracetam was achieved by Chiralpak AD column (250mm 4.6mm; 10μm particle size), using a mixture of hexane and ethanol (4:1) as a mobile phase, at a flow rate of 1mL/min. Samples were prepared by dissolution of 10mg/ml in ethanol. UV spectrophotometry was used for detection at 210 nm. Under optimized conditions, the (R)- and (S)-enantiomers were highly resolved. Linearity of the quantification of the (R)- and (S)-enantiomers was established, and the limits of detection and quantification were established. The robustness and repeatability of the method were demonstrated, and the precision and accuracy of the assay were shown to be high.
Examples and Comparative Examples
Table 1: Continuous process Acylation and Cyclisation to form Levetiracetam- Examples 1 to 3.
Example No Reactants Qty Rxn Parameters Final Yield (molar yield) Final Purity Comments
1
SABAM
KOH
CBC
TEA
Na2SO4
TBAB
DCM 10 g
31g
15g
12g
3g
1g
250mL Continuous Process
Run time: 2.5h
T: -2 to-10°C 10.8g (=64.8%) 99.4%

Chiral purity-99.90% In Experiment (expt) 1, the LVT synthesis is split into two reactions.
1. Formation of reaction mass containing uncyclized amide (referred to as Uncyclized reaction mass)
2. Cyclization.
Uncyclized reaction mass was generated in one reactor and KOH slurry is generated in another by homogenizing in DCM. Cyclization is carried out by pumping uncyclized reaction mass and KOH slurry simultaneously into second reactor. This reduces rxn time to < 3h.
2
SABAM
KOH
CBC
TEA
Na2SO4
TBAB
DCM 15g
54g
23g
18g
4g
1.5g
520mL Continuous Process
Run time: 2.5h
T:-2 to-10°C 15.5g (62.0%) 99.1%

Chiral purity-97.17% Expt 2 was similar to Expt 1 except KOH slurry addition was faster which led to exothermicity and T>0°C. Cyclization temperature should not exceed 0°C throughout the rxn.
3
SABAM
KOH
CBC
TEA
Na2SO4
TBAB
DCM 15g
43g
23g
18.2g
4g
1.5g
586mL Continuous Process
Run time: 2.5h
T:-2 to-10°C 13g (52.0%) 99.2%

Chiral purity-99.94% In expts 1 & 3 the uncyclized rxn mass after CBC addition was allowed to achieve a T of 15-20°C leading to easy pumping. This rise in temperature does not lead to racemization.

The chiral purity of Levetiracetam at values greater than 99.2% can easily be obtained by the continuous process of the invention as evidenced in the Table 1.

Table 2: Comparative Examples C.E.1 to C.E.4 - Batch process
Example No. Reactants Qty Rxn Parameters Final Yield Final Purity Comments
C. E. 1
SABAM.HCl
KOH
CBC
Na2SO4
TBAB
DCM 15g (0.109 moles)
36g
16.8g
3.45g
1.5g
225mL Batch Process
Rxn time: 10hrs
T: -2 to -10°C 12.7g (68.4% yield) 96.2% In C.E 1,2 &3 it was seen that if the starting material is SABAM.HCl or SABAM+ NH4Cl it was difficult to stir due to the solids present. Stirring of reaction mass with SABAM as starting material was comparatively easier as shown in C.E.2.
Therefore, SABAM was chosen as starting material for further expts.
C. E. 2
SABAM
KOH
CBC
Na2SO4
TBAB
DCM 16.6g
53.6g
25.2g
3.81g
1.6g
250mL Batch Process
Rxn time: 10hrs
T: -2 to -10°C 15.3g (55.4% yield) 99.2%
C. E. 3
SABAM+NH4Cl
KOH
CBC
Na2SO4
TBAB
DCM 31g
109g
47g
31
3.1
372mL Batch Process
Rxn time: 12hrs
T: -2 to -10°C 31g (60% yield)
99.34%
C. E. 4
SABAM
KOH
CBC
TEA
Na2SO4
TBAB
DCM 40g
116g
60g
51g
6g
4g
1L Batch Process
Rxn time: 6.5hrs
T: -2 to -10°C 46.9g (70.4% Yield)
99.4% In C.E. 2 & 4, it was observed that yield and Rxn time significantly improved due to better mixing with combination of TEA and KOH rather than only KOH.

Advantages of the present Invention include
• Effective Mass transfer & control on exothermicity.
• Almost Complete conversion of uncyclized intermediate into LVT rapidly by simultaneous pumping of slurries.
• Overall Reaction time reduced from 11-12h for batch to < 3 hrs for the continuous process of the present invention and thus increasing the productivity for making LVT
• Reduced Quantity of KOH usage from 5-6 molar Equivalents to 4-4.5 molar Equivalents.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.”
, Claims:We Claim:
1. An integrated continuous process for Levetiracetam comprising steps a-i, wherein,
the step a) comprises continuously reacting compound I or II in organic solvent-A with 4-chlorobutyryl chloride (CBC) in reactor-A in presence of a mild organic base in the organic solvent-A to form a reaction mixture-I at a temperature ranging from -5 to 10°C.
the step b) comprises continuously reacting the mixture-I with a fine KOH suspension in the organic solvent-A in reactor-B to form a reaction mixture-II at a temperature ranging from -10 to 0°C,
the step c) continuously filtering the reaction mixture-II through a filter
the step d) comprises continuously collecting filtrate in a collection vessel
the step e) comprises continuously adjusting pH of the filtrate in the collection vessel at a temperature ranging from 0 to 10°C to obtain pH-adjusted mixture-III
the step f) comprises continuously pumping the mixture-III to a continuous evaporator
the step g) comprises continuously evaporating the solvent from the pH-adjusted filtrate to form a crude product IV,
the step h) comprises continuously dissolving the crude product IV in a solvent-B and continuously crystallizing to form semi-crude Levetiracetam V, and
the step i) comprises recrystallizing the semi-crude Levetiracetam, V to obtain Levetiracetam, V of purity >99.5%.
2. The process as claimed in Claim 1, wherein reactor-A, reactor-B and reactor-C are single reactors or a series of multiple reactors.
3. The process as claimed in Claim 2, wherein the reactor-A, reactor-B or reactor-C is selected from a group consisting of continuous stirred tank reactors (CSTRs), Tubular flow reactors (TRs) and a combination thereof.
4. The process as claimed in Claim 1, wherein the mild base is selected from a group consisting of triethylamine, tripropylamine, tributyl amine, tri(isopropyl)amine, pyridine and a combination thereof.
5. The process as claimed in Claim 1, wherein the solvent-A is selected from dichloromethane, dichloroethane, tetrachloroethane, toluene and a combination thereof.
6. The process as claimed in Claim 1, wherein the solvent-B is selected from a group consisting of ethyl acetate, propyl acetate, butyl acetate, amyl acetate and a combination thereof.
7. The process as claimed in Claim 1, wherein the fine KOH suspension is prepared by using a homogenizer in dry dichloromethane.
8. The process as claimed in Claim 1, wherein the particle size of the fine KOH suspension is in the range of 5 to 20 microns.
9. The process as claimed in Claim 1, wherein the residence time in reactor A ranges from 45 min to 75 min.
10. The process as claimed in Claim 1, wherein the residence time in reactor B ranges from 45 min to 75 min.
11. The process as claimed in Claim 1, wherein the chiral purity of Levetiracetam is at least 99.2%.