WO2018042393A1

WO2018042393A1 - Novel process for the preparation of brivaracetam

Info

Publication number: WO2018042393A1
Application number: PCT/IB2017/055295
Authority: WO
Inventors: Pramod Kumar; Srimurugan SANKARESWARAN; Madhavarao MANNAM; Venugopal Reddy GADDAM; Srikanth CHILUUKURU; Bipin Kumar CHAUBEY
Original assignee: Micro Labs Limited
Priority date: 2016-09-05
Filing date: 2017-09-04
Publication date: 2018-03-08

Abstract

The present invention relates to a cost effective, novel and efficient process for the preparation of Brivaracetam which offers industrially viable, highly pure Brivaracetam in high yields and avoiding chiral resolutions by chromatography and enzymatic resolutions.

Description

NOVEL PROCESS FOR THE PREPARATION OF BRIVARACETAM

FIELD OF THE INVENTION

The present invention provides novel process for preparation and purification of Brivaracetam.

BACK GROUND OF THE INVENTION

Brivaracetam is a chemical analog of levetiracetam, marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy.

Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH- pyrrol-l-yl]butanamide and is represented by following general Formula I,

Formula I

Brivaracetam as well as their processes and uses as pharmaceuticals are described in US patents having publication numbers US6784197 B2 & US6911461 B2. The synthetic scheme exemplified in above patents is given in Scheme 1.

Scheme 1

The reported process utilizes preparative HPLC for chiral resolution of isomers. This process used for chiral resolution makes it difficult for bulk manufacturing as well as it affects the overall yield making the process uneconomical.

Apart from the above, US Patents US7122682 B2, US7629474 B2, US8076493 B2, US8338621 B2 and US8957226 B2 also describe processes for preparing Brivaracetam.

The processes for the preparation of Brivaracetam described in the above mentioned patents suffer from many disadvantages which includes difficulty in achieving desired chiral purity, tedious and cumbersome work up procedures, high temperature and longer time reaction, multiple crystallizations or isolation steps, use of excess reagents and solvents, column chromatographic separations & purifications etc. All these disadvantages affect the overall yield as well as the quality of the final product.

Based on the above discussed facts there is a need for an improved process for the preparation of Brivaracetam with high purity and yield which overcome the drawback of prior publications. The present inventors have found an efficient process for the preparation of Brivaracetam which offers the following advantages over the prior publications such as simple scalable procedures suitable for large scale production, high yields, less effluent and substantially pure Brivaracetam.

The present disclosure provides a cost effective, novel and efficient process for the preparation of Brivaracetam which offers industrially viable, highly pure Brivaracetam in high yields and avoiding chiral resolutions by chromatography.

OBJECTS OF THE INVENTION

The main object of the present invention is to provide a novel process for the preparation of Brivaracetam.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of Brivaracetam. According to first aspect of the present invention, provides a novel process for preparing Brivaracetam of Formula (I) comprising:

1) converting enantiomerically pure compound of Formula VII to give enantiomerically pure compound of

Compound VII Compound XI wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR & R is optionally substituted C₁-C₁₂ alkyl, aryl, alkyl aryl or aryl alkyl;

2) treating enantiomerically pure compound of formula XI with (S)-aminobutyramide of formula XII or its salt thereof to give Brivaracetam of Formula I.

(I) wherein X is as defined above

According to second aspect of the present invention, provides a novel process for preparing enantiomerically pure compou I

Compound XI wherein X is each independently selected from halogen, alkyl or aryl sulfonyloxy or OR ; R is optionally substituted Q-Q₂ alkyl, aryl, alkyl aryl or aryl alkyl; involves converting enantiomerically pure compound of Formula VII to give enantiomerically pure compound of Formula XI;

Compound VII Compound XI wherein above process comprises:

1) hydrolyzing compound of formula VII to give enantiomerically pure compound of formula VIII:

Compound VII Compound VIII wherein R as defined above; and

2) converting compound of formula VIII to give enantiomerically pure compound of formula XI:

Compound VIII Compound XI wherein X is halogen; (or)

cyclizing compound of formula VII to give enantiomerically pure compound of formula IX:

Compound VII Compound IX wherein R as defined above;

2) converting the compound of formula IX to give a enantiomerically pure compound of formula X:

Compound IX Compound X

wherein X is halogen;

3) converting compound of formula X to give a enantiomerically pure compound of formula XI:

Compound X Compound XI

wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 ; R 2 as defined above; (or)

1) reacting compound of formula VII with sulfonyl halide derivatives in presence of base and solvent to give enantiomerically pure compound of formula XI:

Compound VII Compound XI

wherein R= Alkyl or aryl groups; Y= Halogen

wherein both X≠ halogen and X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 and R 2 as defined above; (or) 1) reacting compound of formula VII with CY₄ and PPh₃ in presence of solvent to give enantiomerically pure compound of formula XI:

Compound VII Compound XI wherein both X≠ halogen and X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 and R 2 as defined above.

According to a third aspect of the present invention, provides a process for the preparation of enantiomerically pure compound of Formula VII or its salts thereof,

Compound VII

wherein R is optionally substituted C₁-C₁₂ alkyl, aryl, alkyl aryl or aryl alkyl, and process comprises the steps of:

1) reacting valeryl chloride or its acid anhydride with a chiral auxiliary of formula III to obtain a compound of formul

Valeryl chloride Compound IV wherein chiral auxiliary of formula III is

Formula Ma Formula Mb wherein X is— O— ,— S— or— N(d-C₆ alkyl); Y is = O or = S ; and R¹ is Ci-C₆ alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, Ci-C₆ alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1-3 substituents selected from the group consisting of Ci-C₆ alkyl, phenyl and benzyl; Formula Ila is R or S enantiomer and formula lib is D or L configuration; 2) treating chiral compound of formula IV with alkyl 2-haloacetate derivatives compound of formula (i) to obtain a enantiomerically pure compound of formula V:

Compound IV Compound V wherein X is halogen & R is as defined above;

3) converting the compound of formula V to obtain enantiomerically pure compound of formula VII,

Compound V Compound VII wherein R is as defined above; (or)

a) hydrolyzing the compound of formula V to obtain enantiomerically pure compound of formula VI:

Compound V Compound VI wherein R is as defined above;

b) optionally, treating compound of Formula VI with an organic base to obtain salt of compound of Formula VI;

c) converting compound of Formula VI or its salts thereof to obtain a compound of Formula VII

Compound VI Compound VII

2

wherein R is as defined above. According to the fourth aspect of the present invention, provides process for the preparation of compound of formula IX comprising:

1) treating racemic compound of formula B with an resolving agent to obtain a enantiomerically pure compound of Formula C:

C

indicates single or double bond

2) optionally reducing compound of formula C (when is double bond) to obtain a compound of formula IX:

C

IX

indicates double bond

According to the fifth aspect of the present invention, provides process for the preparation of substantially pure crystalline form which comprises the following steps:

1) dissolving Brivaracetam in a solvent or a mixture of solvents,

2) crystallizing Brivaracetam,

3) obtaining substantially pure crystalline form.

In accordance with yet another aspect of the present invention, novel process for the preparation of Brivaracetam overcomes the as above discussed disadvantages associated with the process disclosed in the cited prior arts.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 is the characteristic powder XRD pattern of crystalline Brivaracetam prepared as per present invention.

Figure 2 is the characteristic differential scanning calorimetric thermogram of crystalline Brivaracetam prepared as per present invention.

Figure 3 is the characteristic infrared absorption spectrum of crystalline Brivaracetam prepared as per present invention.

Figure 4 is the characteristic 1H NMR spectrum of Brivaracetam prepared as per present invention. DETAILED DESCRIPTION

Definitions:

The term "about", as used herein, refers to any value which lies within the range defined by a number up to + 10% of the value.

The term "substantially pure" as used herein shall be understood to mean compound formed with little or no content of the impurities. The amount of any impurity of compound resulting from the process of the preparation will be relatively minor, e.g., less than about 0.15 weight percent, or less than about 0.1 weight percent, or less than about 0.05 weight percent, of any impurity of compound i.e. Brivaracetam.

The expression "enantiomerically pure" as used herein when referring to a particular compound means that at least 95%, preferably at least 96%, more preferably at least 97%, most preferably at least 98%, even most preferably at least 99% of the compound having the stereo genie centre in a given configuration (R) or (S).

DESCRIPTION OF THE INVENTION

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms. embodiment of the present invention provides a novel process for preparing

)

Scheme 2

In one embodiment of the present invention provides a novel process for preparing Brivaracetam of Formula (I) comprising:

Compound VII Compound XI wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR & R is optionally substituted C1-C12 alkyl, aryl, alkyl aryl or aryl alkyl;

2) treating enantiomerically pure compound of formula XI with (S)-aminobutyramide of formula XII or its salt thereof to give Brivaracetam of Formula I. C

ompound XI

wherein X is as defined above

The reaction of step 1) involves converting enantiomerically pure compound of Formula VII to give enantiomerically pure compound of Formula XI.

In an embodiment of the present invention, reaction of step 1) involves three pathways such as Pathway 1, Pathway 2 and Pathway 3 for preparation of enantiomerically pure compound of Formula XI from enantiomerically pure compound of Formula VII as shown in Scheme 2 above.

According to Pathway 1, the compound of formula VII undergo hydrolysis to get enantiomerically pure compound of formula VIII using base and solvent.

In an embodiment, the base used is selected from hydroxides, carbonates and bicarbonates of alkali & alkaline earth metals such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate or the like; ammonium hydroxide, ammonium bicarbonate or mixture thereof.

The selectivity of the hydrolysis can be adjusted by controlling the concentration of the base, the reaction circumstances and the solvent, in order to achieve the final result desired in each case.

The compound of formula VIII is further converted to enantiomerically pure compound of formula XI using halogenating agent and solvent.

In an embodiment, the halogenating agent used herein either known in the literature or is selected from the group preferably comprises of SOCl₂, SOBr₂, POCl₃, PCI₅, POBr₃, PBr₅ and oxalylchloride.

In an embodiment, solvent used in Pathway 1 is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.

According to Pathway 2, the compound of formula VII undergo cyclization using cyclizing agent and solvent to give enantiomerically pure compound of formula IX.

In an embodiment, the cyclization agent used is an acid, which can be selected from group of comprising of inorganic acid, organic acid, lewis acid or mixture thereof for example HC1, H₂S0₄, P₂Os, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.

In an embodiment, solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.

The compound of formula IX further converted to enantiomerically pure compound of formula X using acid and solvent.

In an embodiment, acid used is selected from the group comprising of inorganic acids known in the literature preferably such as hydrochloric acid, hydrobromic acid or mixtures thereof.

In an embodiment, solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol and cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; acetic acid; propionic acid; water or mixtures thereof.

The compound of formula X further converted to enantiomerically pure compound of formula XI using halogenating agent and solvent.

In an embodiment, the halogenating agent used is selected from group comprising of which are known in the literature such as SOCl₂, SOBr₂, POCl₃, PC1₅, POBr₃, PBr₅ and oxalylchloride.

In an embodiment, solvents used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol and cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

In an embodiment, optionally silyl halide can also be used for the preparation of compound of formula XI from compound of formula IX, which is selected from trimethyl silyl chloride (TMSC1), trimethyl silyl bromide (TMSBr), trimethyl silyl iodide (TMSI) or mixture thereof.

According to Pathway 3, the compound of formula VII is reacted with sulfonyl halide derivatives in presence of base and solvent to obtain enantiomerically pure compound of formula XI, wherein both X≠ Halogen and X is halogen; alkyl or aryl sulfonyloxy or OR².

In an embodiment, sulfonyl halide used in is represented by the formula R-S0₂Y, wherein Y is halogen and R is an alkyl or aryl groups having 1 to 20 carbon atoms and are not limited to methane sulfonyl chloride, ethane sulfonyl chloride, /?-toluenesulfonyl chloride or benzene sulfonyl chloride.

In an embodiment, solvent used in is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4- dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

In an embodiment, base used in include both organic and inorganic bases. Organic bases include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA (Ν,Ν-diisopropylethylamine), N-methylpiperidine, N-methylmorpholine and like. Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide etc and the like.

Further compound of formula VII can also be converted to compound of formula XI by reacting with CY₄ and PPh₃ in presence of solvent.

In an embodiment, CY₄ reagent used above is selected from the group comprising of

CF₄, CC1₄, CBr₄ or C more preferably CBr₄.

In an embodiment, solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4- dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t- butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N- dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.

The reaction of step 2) involves treating enantiomerically pure compound of formula XI with (S)-aminobutyramide of formula XII or its salt thereof using base and solvent, followed by cyclization in presence of an acid and solvent to give Brivaracetam of Formula I.

In an embodiment, base used herein is selected from the group comprising of both organic and inorganic bases. Organic bases include but not limited to pyridine, DMAP (4- dimethylaminopyridine), triethylamine, DIEA (Ν,Ν-diisopropylethylamine), N- methylpiperidine, DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4- diazabicyclo[2.2.2]octane), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), N-methylmorpholine and the like. Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide; and like.

In an embodiment, acid used for cyclization is selected from group of inorganic acid, organic acid, lewis acid or mixture thereof and is selected from a group comprising HC1, H₂S0₄, P₂0₅, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.

In an embodiment, solvent used for condensation or cyclization is individually selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol and cyclohexanol; esters such as methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.

In the present embodiment, the compound of formula I optionally can also be prepared by carrying out the reaction in the presence of a suitable additive at any step, such as, ionic additive, a phase transfer catalyst or mixture thereof. Thus, addition of an additive makes the reaction effective in terms of both energy and cost.

Ionic additive includes, but not limited to sodium salts such as sodium iodide, sodium sulfate, sodium chloride; potassium salts such as potassium iodide, potassium sulfate, potassium chloride; mixtures thereof.

Phase transfer catalyst includes, but not limited to tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetraethylammonium tetrafluoroborate, triphenylphosphonium chloride, benzyltrimethylammonium chloride and hexadecyltributylphosphonium bromide. According to a another embodiment of the present invention, provides a process for the preparation of enantiomerically pure compound of Formula VII or its salts thereof,

Compound VII wherein R is optionally substituted Q-Cn alkyl, aryl, alkyl aryl or aryl alkyl as per the scheme 2, wherein process comprises the steps of:

1) reacting valeryl chloride or its acid anhydride with a chiral auxiliary of formula III to obtain a compound of formula IV:

V l l hl id Compound IV wherein chiral auxiliary of formul

Formula I la Formula lib

wherein X is— O— ,— S— or— N(Ci-C₆ alkyl); Y is = O or = S ; and R¹ is Ci-C₆ alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, Ci-C₆ alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1-3 substituents selected from the group consisting of Ci-C₆ alkyl, phenyl and benzyl; Formula Ila is R or S enantiomer and formula lib is D or L configuration;

2) treating chiral compound of formula IV with alkyl 2-haloacetate derivatives compound of formula (i) to obtain a enantiomerically pure compound of formula V:

Compound IV Compound V wherein X is halogen & R is as defined above;

3) converting the compound of formula V to obtain enantiomerically pure compound of formula VII or its salts thereof . The starting compounds valeryl chloride or its acid anhydride and chiral auxiliary compounds are commercially available or may be prepared according to methods known in the literature as well as known to those of ordinary skill in the art.

The reaction of step 1) involves reacting valeryl chloride or its acid anhydride with the chiral auxiliary of formula III in presence of solvent and base.

In an embodiment, a particular enantiomer of compound of the present invention is desired, it may be prepared by derivation with a chiral auxiliary, where the resulting mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.

In an embodiment, "chiral auxiliary" as used in the specification is meant a non- racemic functional group that imparts enantio selective reaction at a remote prochiral center of a molecule. Chiral auxiliaries are as used herein further include: 8-phenylmenthol (5- methyl-2-(l -methyl- l-phenyl-ethyl)cyclohexanol, such as described in D. Comins et al. J. Org. Chem., vol. 58, 4656 (1993)), N-substituted bornane-2, 10-sultams (e.g., 10,10- dimethyl-3-thia-4-aza-tricyclo[5.2.1.01.5]decane 3,3-dioxide such as described in W. Oppolzer J. Am. Chem. Soc, 112, 2767 (1990)), preferably, 4-substituted or 4,5-substituted 2-oxazolidinones derived from amino acid derivatives such as phenylglycinol or valinol (e.g., 4-phenyl-2-oxo-oxazolidin-3-yl or 4-isopropyl-2-oxo-oxazolidin-3-yl, respectively, such as described in D. Evans et al. J. Am. Chem. Soc, 109, 6881 (1987) and in D. Evans et al. Tet. Lett., 28, 1123 (1987)) and, most preferably, 4-substituted or 4,5-substituted 2- imidazolidinones derived from compounds such as ephedrine (e.g., 3,4-dimethyl-5-phenyl- 2-oxo-imidazolidin-l-yl, such as described in S. E. Drewes, et al. Chem. Ber., 126, 2663 (1993)).

In an embodiment, the solvent used in step 1) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

In an embodiment, the base used in step 1) is selected from organic base or inorganic base, wherein organic base is selected from trimethylamine, triethylamine, tributylamine, Ν,Ν-dimethylaniline, N,N-dimethylbenzylamine, Ν,Ν-diisopropylethylamine, N-methyl morpholine, piperidine, l,4-diazabicyclo[2.2.2]octane (DABCO), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and inorganic bases selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate or mixtures thereof.

In an embodiment, step 1) may be optionally be carried out in the presence of a suitable catalyst, such as, for example, triethylamine, pyridine, 1-methylmorpholine, 1- methylpiperidine, 1,5-diazabicyclo [4.3.0]non-5-ene, Ν,Ν-dimethylpiperazine, N,N- dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5, 6-tetramethylpyridine (TEMP), and the like.

The reaction of step 2) involves treating chiral compound of Formula IV with alkyl 2-haloacetate compound of formula (i) to obtain a compound of Formula V in presence of solvent and base.

In an embodiment, base used above is an alkali metal alkyl disilazide; and wherein alkali metal alkyl disilazide is at least one compound selected from lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) and potassium bis(trimethylsilyl)amide (KHMDS) or related bases such as lithium tetramethylpiperidide (LiTMP), n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi), tert- Butyllithium (t-BuLi), or lithium diisopropylamide (LDA).

In an embodiment, the solvent used above is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

The reaction of step 3) involves converting compound of formula V to enantiomerically pure compound of formula VII, either directly converting to formula VII in presence of reducing agent or first hydrolysis in presence of base and solvent to give compound of formula VI or its salts thereof, which undergo reduction give compound of formula VII or its salts thereof. In an embodiment, suitable reducing agent that may be used for direct conversion to compound of formula VII includes but not limited to alkali metal hydrides and alkali metal borohydrides, such as lithium aluminium hydride, sodium borohydride, lithium borohydridesodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride, tetrabutyl ammonium borohydride or the like, more preferably sodium borohydride.

In an embodiment, the solvent used for direct conversion to compound of formula VII is selected from group comprising of halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof more preferably THF and water mixture.

In an embodiment, the base used for the hydrolysis step is selected from group comprising but not limited to ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.

In an embodiment, the solvent used in hydrolysis is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol; ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.

In an embodiment, hydrolysis is undergoing optionally in presence and absence of a suitable catalyst, such as peroxides for example hydrogen peroxide.

In an embodiment, reducing agent used for the conversion of compound of formula

VI or its salts thereof to compound of formula VII is selected from group the group comprising of but not limited to borane or its complex such as borane and N,N- diethylaniline complex (DEANB), borane and dimethyl sulfide complex (DMSB), borane and tetrahydrofuran (BTHF) complex, borane and 2-methyltetrahydrofuran complex, borane-pyridine complex; borane-picoline complex; borane-triethylamine complex.

In an embodiment, the solvent used in above stage is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N- dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

The compound for formula VI can also be converted to its salts thereof by reacting it with organic base in presence of solvent. The organic base used herein is selected from the group comprising of but not limited to (S)-phenylethyl amine, cyclohexyl amine, dicyclohexyl amine and the like.

In an embodiment, solvent used for the preparation of salt of formula VI are selected from group comprising aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as toluene and xylene; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, i-butyl alcohol, ethylene glycol, t-butanol; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, Ν,Ν-dimethyl acetamide; sulfoxides such as dimethyl sulfoxide; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, methyl t-butyl ether, 1,4-dioxane; or mixtures thereof. Preferred embodiment solvents are aliphatic hydrocarbons such as hexane or heptane.

According to another embodiment of the present invention, provides process for the preparation of compound of formula IX comprising:

C

indicates single or double bond 2) reducing compound of formula C (when is double bond) to obtain a compound of formula IX:

C

IX

indicates double bond

The starting compound B which is rac-dihydro-4-(prop-l-enyl)furan-2(3H)-one or rac-dihydro-4-propylfuran-2(3H)-one may be prepared according to methods known to those of ordinary skill in the art.

The reaction of step 1) above involves treating racemic compound of formula B with an optically active chiral resolving agent in presence of lewis acid to obtain an enantiomeric salt, followed by cyclization with an acid to obtain an enantiomerically pure compound of formula C.

In an embodiment, resolving agent used is selected from group comprising of but not limited to chiral amines, chiral thiols, chiral alcohols such as phenylethanethiol, 2- phenylcyclohexanethiol, N-Boc-cysteine methyl ester, menthol, borneol, valinol, quinine, (S)-l-phenyl ethyl amine; (S)-l-phenyl butyl amine; l-(l-naphthyl) ethyl amine or l-(4- nitrophenyl)ethyl amine, preferably (S)-l -phenyl ethyl amine.

In an embodiment, lewis acid serves as an electron acceptor, has a typical element, such as boron, aluminum, silicon, or tin, or a transition metal element belonging to the fourth period, such as titanium, iron, nickel, copper, or zinc, as the central element. The lewis acid used herein is selected from group include boron trihalides such as boron trifluoride, boron trichloride, and boron tribromide, aluminum trihalides such as aluminum chloride and aluminum bromide, tin tetrahalides such as tin tetrachloride, tin dihalides such as tin dichloride, titanium tetrahalides such as titanium tetrachloride, titanium trihalides such as titanium trichloride, titanium alkoxides such as titanium isopropoxide, iron dihalides such as iron dichloride, iron trihalides such as iron trichloride, nickel dihalides such as nickel dichloride, and zinc halides such as zinc chloride and zinc bromide, preferably titanium isopropoxide.

In an embodiment, acid used for cyclization is selected from group of inorganic acid, organic acid or mixture thereof and is selected from a group comprising HC1, H₂S0₄, P₂Os, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid or mixture thereof.

In an embodiment, the solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4- dioxane; methyl tertiary-butyl ether; and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

The reaction of step 2) above involves reducing compound of formula C ( is double bond) to compound of formula IX using reducing agent and solvent.

The reduction may be carried out in the presence of hydrogen source and a catalyst such as Pd/C, Rh/C, Pt/C, and the like, preferably Pd/C.

The solvent used for reduction is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4- dioxane; methyl tertiary-butyl ether; and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i- butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as Ν,Ν-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.

Further according to the invention optionally reduction of double bond can be done first followed by resolution.

Further according the present invention the compound or intermediate as mentioned i.e. compound of formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (C) may optionally be isolated either as per the methods known in the art or by the procedure described in this application. Apart from that the reaction mixture comprising the above compounds of formulae may also be further taken forward for the next steps, without isolating.

According to yet another embodiment of the present invention provides process for the preparation of substantially pure crystalline form which comprises the following steps:

1) dissolving Brivaracetam in a solvent or a mixture of solvents,

2) crystallizing Brivaracetam, 3) obtaining substantially pure crystalline form.

The crystallization of Brivaracetam is achieved either by isolating the compound by lowering the reaction mass temperature or removal of the solvent from Brivaracetam solution. Further crystallization can also be achieved by addition of an anti-solvent to a solution of Brivaracetam or vice versa.

The crystallization can be optionally be achieved by adding seed of the target material in the reaction mass.

Preferred solvents for preparing the crystallization mixture are selected from group comprising alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, i-butyl alcohol, ethylene glycol, t-butanol; nitriles such as acetonitrile; amides such as N,N- dimethylformamide, Ν,Ν-dimethyl acetamide; sulfoxides such as dimethyl sulfoxide; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, isopropyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, methyl t-butyl ether, 1,4- dioxane; acetic acid, water or mixtures thereof.

The anti-solvent used herein is selected from group comprising of hydrocarbon solvents such as hexane, heptane and petroleum ether.

Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), atmospheric distillation, vacuum distillation and the like, or any other suitable technique.

The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure.

Example 1: Preparation of (S)-3-pentanoyl-4-phenyloxazolidin-2-one

(S)-4-phenyloxazolidin-2-one (25g), dichloromethane (125 mL) and triethylamine (38 g) were charged into a round bottom flask at room temperature and stirred. To the reaction mixture, DMF (10 mL) and DMAP (5g) were added and stirred. The reaction mass was cooled to 0-5°C and added valeryl chloride (23 g). The reaction mass was stirred followed by addition of water (125 mL). The organic layer was separated, washed with HCl (150 mL), sodium bicarbonate solution (150 mL) and distilled under reduced pressure to obtain a residue. To the residue n-Heptane (250 mL) was added under stirring, cooled the reaction mass to 10-15°C and filtered. The obtained solid was washed with n-heptane (75 mL), suck dried and dried under vacuum to give the title compound as off-white to pale yellow solid. Yield: 33 g (86%) Example-2: Preparation of (R)-dihydro-4-propylfuran-2(3H)-one

(5)-3-pentanoyl-4-phenyloxazolidin-2-one (10 g) and THF (100 mL) was charged at room temperature and cooled to -55 to -60°C. LiHMDS solution (43 mL) was added to above reaction mixture and stirred. Te/t-butyl bromoacetate (9 g) was added to the reaction mass, raised the reaction mass temperature to -20 to -25°C and maintained. Ammonium chloride (70 mL) solution was added at -20 to -25°C, raised the temperature to room temperature and the layers were separated. The organic layer was washed with NaCl solution (50 mL), separated and cooled to 0 to 5°C. A solution of LiOH.H₂0 (25 g) in water (60 mL) was added to above reaction mass and stirred. Sodium sulphite solution (60 mL) was added and warmed the reaction mass to room temperature. The layers were separated and the aqueous layer was washed with toluene (30 mL). The combined aqueous layer was acidified to pH 3- 4 using citric acid solution (30 mL) and toluene (40 mL) was added, stirred and layers were separated. The toluene layer was distilled completely under vacuum at 55-60°C to obtain residue (8 g). Toluene (70 mL) was added to the above residue and cooled the reaction mass to 0-5°C. BDMS complex (12 mL) was added, stirred. The reaction mass temperature was raised to room temperature and stirred. The reaction mass was cooled to 0-5°C, methanol (8 mL) was added and stirred. H₂0₂ (4 mL) was added and stirred. Sodium sulfite solution (40 mL) was added to the reaction mass at 0-5°C, reaction mass was raised to room temperature and separated the layers. The aqueous layer was extracted with toluene (20 mL) and combined toluene layers are washed with NaCl solution (30 mL). TFA (30 mL) was added to the toluene layer and stirred the reaction mass. The obtained reaction mass was completely distilled off at 50-60°C under vacuum to obtain oily residue. Toluene (40 mL) was added and cooled the reaction mass to room temperature. NaHC0₃ solution (40 mL) was added to the reaction mass and the layers were separated. The obtained toluene layer was washed with water, separated, distilled under reduced pressure at 55-60°C to obtain above title compound as oily mass. Yield: 4g (78%)

Example-3: Preparation of (R)-dihydro-4-propylfuran-2(3H)-one Sodium borohydride (15 g) was added to a solution of tert-butyl (3S)-3-[( K)-2-oxo- 4-phenyl-l,3-oxazolidine-3-carbonyl]hexanoate (30 g) in THF/H₂0 mixture (400mL) and obtained reaction mixture was stirred at room temperature. Aqueous NH₄C1 was added to the reaction mass. The reaction mixture was extracted with toluene (50 mL x 2), washed with brine, and concentrated to obtain {R)-tert-buty\ 3-(hydroxymethyl)hexanoate. CH₂C1₂ and p-TsOH was added to above reaction mass and stirred under reflux. The organic layer separated was washed with sodium bicarbonate, water and evaporated under vacuum to provide title compound (yellow oil).

Example-4: Preparation of methyl (/?)-3-(bromomethyl)hexanoate A solution of (R)-dihydro-4-propylfuran-2(3H)-one (10 g) in AcOH (20 mL) was added to HBr in AcOH (25mL) at room temperature and stirred. The reaction mass temperature was raised to 50-55°C and stirred. The obtained reaction mass was cooled to room temperature and toluene (60 mL) was added. Water (10 mL) was added and stirred the biphasic reaction mass. The layers were separated; aqueous layer extracted with toluene (50 mL) and combined the organic layer is washed with water (30 mL), NaCl solution, separated, distilled partially and cooled to room temperature. DMF (1 mL) and thionyl chloride (20 mL) were added to the reaction mass, stirred and distilled off completely. The reaction mass was cooled and treated with toluene (100 mL) and Methanol (15 mL) and stirred. The reaction mass was cooled to 10-15 °C and water (50 mL) was added. The obtained reaction mass was stirred and separated the layers. The obtained organic layer was washed with NaHC0₃ solution, separated and distilled under reduced pressure to afford title compound. Yield: 16 g (92%).

Example-5: Preparation of Brivaracetam from methyl (/?)-3-(bromomethyl)hexanoate

Methyl ( ?)-3-(bromomethyl)hexanoate (10 g), (S)-2-aminobutanamide (7 g), tetrabutylammonium iodide (5 g), sodium carbonate (10 g) and isopropyl acetate (50 mL) were charged into a round bottom flask at room temperature. The suspension was raised to reflux temperature and stirred. The reaction mass was cooled to 15°C, filtered and obtained cake was washed with isopropyl acetate (10 mL). Isopropyl acetate (50 mL) was added to obtained filtrate in a flask and raised the temperature to 60-65 °C. Acetic acid (2 g) was added and stirred. The suspension was cooled to room temperature, filtered and washed the solid with isopropyl acetate (10 mL). Water (20 mL) and sodium bicarbonate is added and the layers are separated. The organic layer was distilled under reduced pressure to give crude product. MTBE (30 mL) and n-heptane (30 mL) was added to the above residue, stirred, filtered and washed with MTBE: n-heptane mixture (5 mL) to obtain the title compound. S.O.R: -59.6; Moisture Content: 0.45%

Example-6: Preparation of (/?)-2-((fert-butoxycarbonyl)methyl)pentyl methanesulfonate

(R)-tert-Butyl 3-(hydroxymethyl)hexanoate (5 g) and DCM (50 mL) was charged into a round bottom flask and stirred for 10 minutes. Triethylamine (7 mL) was added and cooled the reaction mass to 0-5°C. A solution of methanesulfonyl chloride (4 g) in DCM (50 mL) was added and stirred. Water was added, raised the reaction mass temperature to room temperature and separated the layers. The organic layer separated, washed with NaHC0₃ solution and distilled under reduced pressure to give (R)-2-((tert- butoxycarbonyl)methyl)pentyl methanesulfonate (6 g)

Example-7: Preparation of Brivaracetam from (K)-2-((tert- butoxycarbonyl)methyl)pentyl methanesulfonate

(R)-2-((ieri-butoxycarbonyl)methyl)pentyl methanesulfonate (10 g), (S)-2- aminobutanamide (6 g), tetrabutylammonium iodide (4 g), sodium carbonate (8g) and isopropyl acetate (50 mL) were charged into a round bottom flask at room temperature. The suspension was raised to reflux, maintained for few hours and cooled to 15°C. The suspension is filtered and obtained cake was washed with isopropyl acetate (10 mL). Isopropyl acetate (50 mL) was added to the filtrate and raised reaction mixture temperature to 60-65°C. Acetic acid (2 g) was added slowly and stirred. The suspension was cooled to room temperature, filtered and washed the solid with isopropyl acetate (10 mL). Water (20 mL) and sodium bicarbonate was added and the layers are separated. The organic layer was distilled under reduced pressure to give crude product as an oily. MTBE (30 mL) and n- heptane (30 mL) was added to the above residue, stirred for 2-3 h, filtered and washed with MTBE: n-heptane mixture (5 mL) to obtain the title compound. S.O.R: -59.59; Moisture Content: 0.47%

Example-8: Preparation of (R)-tert-butyl 3-(bromomethyl)hexanoate

Triphenylphosphine (10 g) was added to a mixture of (R)-te rt-butyl 3- (hydroxymethyl)hexanoate (5 g) and CBr₄ (12 g) in dichloromethane (100 mL) in a round bottom flask at room temperature and stirred. The solvent was removed under reduced pressure to yield {R)-tert-buty\ 3-(bromomethyl)hexanoate. Yield: 2.5 g (90%) Example-9: Preparation of Brivaracetam from (R)-tert-butyl 3- (bromomethyl)hexanoate

Methyl ( ?)-3-(bromomethyl)hexanoate (10 g), (S)-2-aminobutanamide (6 g), tetrabutylammonium iodide (4 g), sodium carbonate (8.0 g) and isopropyl acetate (50 mL) were charged into a round bottom flask at room temperature. The obtained suspension was heated to reflux, stirred and cooled to 15°C. The suspension is filtered and obtained cake was washed with isopropyl acetate (10 mL). The filtrate is charged into a fresh round bottom flask, isopropyl acetate (50 mL) was added and heated to 60-65 °C. Acetic acid (2 g) was added and stirred. The suspension is cooled to ambient temperature, filtered and washed the solid with isopropyl acetate (10 mL). Water (20 mL) and sodium bicarbonate was added and the layers are separated. The organic layer was distilled under reduced pressure to obtain residue. MTBE (30 mL) and n-heptane (30 mL) was added to the above residue, stirred, filtered and washed with MTBE: n-heptane mixture (5 mL) to afford product as off- white solid. S.O.R: -59.59; Moisture Content: 0.47% Example-10: Preparation of basic salts of (R)-2-((tert- butoxycarbonyl)methyl)pentanoic acid

(H)-2-((ferf-butoxycarbonyl) (R)-2-((fert-butoxycarbonyl)methyl)

methyl) pentanoic acid pentanoic acid cyclohexylamine salt n-Heptane

(R)-2-((fert-butoxycarbonyl)methyl)

pentanoic acid dicyclohexylamine salt

A solution of ( ?)-2-((ieri-butoxycarbonyl)methyl)pentanoic acid (1 g) in n-heptane (10 mL) was charged into a round bottom flask and treated with organic bases (1 eq; (5)- phenylethylamine or cyclohexylamine or dicyclohexylamine) at room temperature and stirred. The solid formed was filtered, washed with n-heptane to afford corresponding crystalline salts of ( ?)-2-((ieri-butoxycarbonyl)methyl)pentanoic acid (80-85%).

Example-11: Process for preparation of Dihydro-4-propylfuran-2(3H)-one Dihydro-4-(prop-l-enyl)furan-2(3H)-one (lOg), methanol (100 mL), 10% Pd/C was charged into a high pressure autoclave and hydrogenated using hydrogen pressure of 1.0-2.0 Kg/cm . After completion of the reaction, the catalyst was filtered, washed and distilled to give title product. Yield: 9.65 (95%) Example-12: Process for preparation of (R)-dihydro-4-propylfuran-2(3H)-one

(R)-Dihydro-4-(prop-l-enyl)furan-2(3H)-one (10 g), methanol (100), 10% Pd/C was charged into a high pressure autoclave and hydrogenated using hydrogen pressure of 1.0-2.0 Kg/cm . The reaction mass was filtered, washed with methanol (10 mL) and distilled to give title product. Yield: 9.65 (95%) Example-13: Process for preparation of (R)-dihydro-4-(prop-l-enyl)furan-2(3H)-one from rac -dihydro-4-(prop-l-enyl)furan-2(3H)-one

Racemic dihydro-4-(prop-l-enyl)furan-2(3H)-one (10 g), (S)-l-benzylmethylamine (10 g); Ti^OPr^ (15.5 g) and THF (20 mL) were charged into a round bottom flask at room temperature and stirred. The reaction mass temperature was raised to 75 °C and stirred. The reaction mixture was cooled to room temperature and aqueous HCl (30 mL; 2M) was added and stirred. The organic layer was separated, extracted with ethyl acetate (3 x 20 mL). The combined organic layers was washed with brine and concentrated to afford residue. The obtained residue was dissolved in MTBE (15 mL) and stirred. The obtained reaction mixture was seeded with pure R-isomer at 5°C and stirred. The obtained solid was filtered (3.2 g) and to the obtained solid, water (25 mL), cone. H₂S0₄ (5 mL), 1,4-dioxane (15 mL) were charged at room temperature and reaction mixture was raised to 80 °C and stirred. After completion of reaction, reaction mixture was cooled to room temperature and water (20 mL) was added. The reaction mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layer washed with brine, filtered and concentrated to yield title product. Yield: 7.9 g (80 %)

Example 14: Process for preparation of (/?)-dihydro-4-propylfuran-2(3H)-one from rac-dihydro-4-propylfuran-2(3H)-one

Racemic dihydro-4-propylfuran-2(3H)-one (10 g), (S)-l-benzylmethylamine (10 g); Ti( Pr)₄ (15.5 g) and THF (20 mL) were charged into a round bottom flask at room temperature and stirred. The reaction mass temperature was raised to 75 °C and stirred. The reaction mixture was cooled to 25-30 °C and aqueous HCl (30 mL; 2M) was added and stirred. The organic layer was separated, extracted with ethyl acetate (3 x 20 mL). The combined organic layers was washed with brine and concentrated to afford crude residue. The obtained residue was dissolved in MTBE (15 mL) and stirred for 10 minutes. The obtained reaction mixture was seeded with pure isomer at 5°C and stirred. The obtained solid was filtered (3.2 g) and to the obtained solid water (25 mL), cone. H₂S0₄ (5 mL), 1,4- dioxane (15 mL) were charged at room temperature and stirred. The reaction mixture was raised 80 °C and stirred for few hours. The reaction mixture was cooled to room temperature and water (20 mL) was added. The reaction mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layer washed with brine, filtered and concentrated to yield title product. Yield: 7.9 g (80%)

Example-15: Process for preparation of crystalline Brivaracetam.

Brivaracetam (lOg) and water (10 mL) are charged into a round bottom flask and stirred for 15 minutes. The obtained reaction mass is subjected to lyophilization to get crystalline Brivaracetam.

Example-16: Process for preparation of crystalline Brivaracetam.

Brivaracetam (lOg), water (7 mL) and methanol or acetonitrile (3 mL) were charged into a round bottom flask and stirred for 15 minutes. The obtained reaction mass is subjected to lyophilization to get crystalline Brivaracetam.

Claims

Claims:

1. A process for the preparation of Brivaracetam of Formula (I) comprising:

1) converting enantiomerically pure compound of Formula VII to obtain enantiomerically pure compound of Formula XI:

Compound VI I Compound XI wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 ; R 2 is optionally substituted Q-Q2 alkyl, aryl, alkyl aryl, aryl alkyl;

2) treating enantiomerically pure compound of formula XI with (S)-aminobutyramide of formula XII or its salt thereof to obtain Brivaracetam of Formula I.

(I)

2

wherein X & R as defined above.

2. A process for the preparation of enantiomerically pure compound of formula (XI) comprising:

1) converting enantiomerically pure compound of Formula VII to obtain enantiomerically pure compound of Fo

Compound VII Compound XI wherein X is each independently selected from halogen; alkyl or aryl suflonyloxy; OR 2 ; R 2 is optionally substituted Q-Q2 alkyl, aryl, alkyl aryl or aryl alkyl.

3. The process according to claim 1 or 2, wherein the conversion of enantiomerically pure compound of Formula VII to enantiomerically pure compound of Formula XI comprises: 1) hydrolyzing compound of formula VII to obtain enantiomerically pure compound of formula VIII:

Compound VI I Compound VIII wherein R is optionally substituted Q-Cn alkyl, aryl, alkyl aryl or aryl alkyl; and

2) converting compound of formula VIII to obtain enantiomerically pure compound of formula XI:

Compound VII I Compound XI

wherein X is halogen.

4. The process according to claim 1 or 2, wherein the conversion of enantiomerically pure compound of Formula VII to enantiomerically pure compound of Formula XI comprises:

1) cyclizing compound of formula VII to give enantiomerically pure compound of formula IX:

Compound VII Compound IX wherein R is optionally substituted C_\-Cn alkyl, aryl, alkyl aryl or aryl alkyl;

Compound IX Compound X

wherein X is halogen;

Compound X Compound XI

wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 ; R 2 as defined above.

5. The process according to claim 1 or 2, wherein the conversion of enantiomerically pure compound of Formula VII to enantiomerically pure compound of Formula XI (both X≠ Halogen) comprises:

1) reacting compound of formula VII with sulfonyl halide in presence of base and solvent to give enantiomerically pure compound of formula XI:

Compound VII Compound XI

wherein R= Alkyl or aryl groups; Y= Halogen

wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR and R is optionally substituted C1-C12 alkyl, aryl, alkyl aryl or aryl alkyl.

6. The process according to claim 1 or 2, wherein the conversion of enantiomerically pure compound of Formula VII to enantiomerically pure compound of Formula XI (both X≠ Halogen) comprises:

1) reacting compound of formula VII with CY₄ and PPh₃ in presence of solvent to give enantiomerically pure compound of formula XI:

Compound VII Compound XI

2

wherein X & R as defined above.

7. A process for the preparation of enantiomerically pure compound of Formula VII or its salts thereof,

Compound VII wherein R is optionally substituted C₁-C₁₂ alkyl, aryl, alkyl aryl or aryl alkyl; comprises the steps of:

Valeryl chloride Compound IV wherein chiral auxiliary of formula III is

Formula Ma Formula Mb wherein X is— O— ,— S— or— N(Ci-C₆ alkyl); Y is = O or = S ; and R¹ is Ci-C₆ alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, Ci-C₆ alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1-3 substituents selected from the group consisting of Ci-C₆ alkyl, phenyl and benzyl; Formula Ila is R or S enantiomer and formula lib is D or L configuration;

2) treating chiral compound of formula IV with alkyl 2-haloacetate derivatives compound of formula formula V:

Compound IV Compound V wherein X is halogen & R is as defined above;

3) converting the compound of formula V to obtain enantiomerically pure compound of formula VII:

Compound V Compound VII

2

wherein R is as defined above.

8. The process according to claim 7, wherein the conversion of enantiomerically pure compound of Formula V to enantiomerically pure compound of Formula VII comprises: a) hydrolyzing the compound of formula V to obtain enantiomerically pure compound of formula VI:

Compound V Compound VI

2

wherein R is optionally substituted Q-Cn alkyl, aryl, alkyl aryl or aryl alkyl;

b) optionally, treating compound of Formula VI with an organic base to obtain compound of Formula VI;

c) converting compound of Formula VI to obtain a compound of Formula VII

Compound VI Compound VII

2

wherein R is as defined above.

9. The process according to claim 7, wherein the conversion of enantiomerically pure compound of Formula V to enantiomerically pure compound of Formula VII comprises: a) converting compound of formula V to obtain enantiomerically pure compound of formula VII:

Compound V Compound VII

2

wherein R is optionally substituted Q-Cn alkyl, aryl, alkyl aryl or aryl alkyl.

10. A process for the preparation of compound of formula IX comprising:

C

indicates single or double bond

C

IX

indicates double bond

11. A process for the preparation of enantiomerically pure compound of formula IX comprising:

1) reducing compound of formula C to obtain a compound of formula IX:

IX

2) treating racemic compound of formula IX with an resolving agent to obtain a enantiomerically pure compound of Formula IX:

IX

12. A process for the preparation of compound of formula IX comprising reducing compound of formula C to obtain a compound of formula IX: C

IX

13. A process for the preparation of substantially pure crystalline form which comprises the following steps:

1) dissolving Brivaracetam in a solvent or a mixture of solvents,

2) crystallizing Brivaracetam,

3) obtaining substantially pure crystalline form.

14. A salt of compound of Formula VI.

15. A process for preparation of salt of compound of formula VI comprising reacting compound of formula VI with organic base.