DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF BRIVARACETAM”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of brivaracetam and salts thereof.
BACKGROUND OF THE INVENTION
The chemical name of BRIVIACT (brivaracetam) is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide, depicted by compound of formula I.
I IA
BRIVIACT® is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients 4 years of age and older with epilepsy. BRIVIACT® is available as 10mg, 25mg, 50mg, 75mg, and 100mg tablets, as 10mg/mL oral solution and as 50mg/5mL single-dose vial injection, for intravenous use. Brivaracetam has two chiral centers (2S, 4R) in the molecule. The methods disclosed in the art involve a non-asymmetric hydrogenation step, that leads to the generation of diastereomeric mixture of brivaracetam, a compound I, which is the desired compound and also formation of a substantial amount of unwanted diastereomer compound of formula IA, which is the (2S,4S)-diastereomer (S,S isomer) of brivaracetam. The individual diastereomers (I and IA) obtained are then separated by multi-column continuous chromatography using chiral stationary phase (Chiralpak) and an eluent system. There is need in the art for an enantioselective process for preparing brivaracetam that is cost effective, scalable and avoids both silica gel column chromatography and chiral chromatographic methods of separation of the diastereoisomers. The process of the present invention provides a novel approach to prepare brivaracetam via stereoselective synthesis and leads to the formation of brivaracetam in high chemical and chiral purity, substantially free of diastereoisomer compound IA. The process of the present invention proceeds via novel compound of formula XII or salt thereof; wherein the compound of formula XII or salt is obtained as a solid in high chiral purity which on further reaction leads to the formation of brivaracetam, a compound of formula I directly in high chiral purity, in a diastereomeric excess of at least 98% and substantially free of diastereomer compound IA without any column or chiral chromatography or recrystallization.
The process of the present invention proceeds via solid intermediate compounds VIII’, VII’, XIIA and XIVA, which can be purified to ensure that the brivaracetam obtained has high chiral purity, and a diastereomeric excess of at least 98% and high chemical purity as against the process known in the art.
SUMMARY OF THE INVENTION
In a first aspect, the invention provides methods of making brivaracetam, a compound of formula I, comprising (a) reducing a compound of formula XII or a salt thereof to obtain a compound of formula XIV or a salt thereof ; and
XII XIV
(b) cyclizing the compound of formula XIV or a salt thereof, to obtain brivaracetam in a diastereomeric excess of at least 98%. According to the invention, such methods may yield brivaracetam, a compound of formula I in high chiral purity, in a diastereomeric excess of at least 98% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 1% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the diastereomeric excess is at least 98.5% and the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.5% w/w of brivaracetam as determined by chiral HPLC. In yet another embodiment, the diastereomeric excess is at least 99% and the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.15% w/w of brivaracetam as determined by chiral HPLC. The invention also provides compositions comprising an isolated compound of formula I, in a diastereomeric excess of at least 98% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 1% w/w of brivaracetam as determined by chiral HPLC.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is a chiral HPLC chromatogram of brivaracetam as obtained in Example 10.
Figure 2 is a chiral HPLC chromatogram of brivaracetam RLD sample as obtained in Example 16
DETAILED DESCRIPTION OF THE INVENTION
The term "C1-C6 alkyl" as used herein refers to an aliphatic-hydrocarbon group which may be straight or branched having C1-C6 carbon atoms in the chain. Branched means that one or lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl groups include but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl. The term "C1-C6 alkylaryl” as used herein refers to an aliphatic-hydrocarbon group which may be straight or branched having C1-C6 carbon atoms in the chain and attached to an aryl group like phenyl, benzyl, naphthyl, tolyl and the like. The term “halogen” refers to iodo, bromo, chloro or fluoro. The term “diastereomeric excess”(de) herein means brivaracetam, a compound of formula I is present in a diastereomeric excess, relative to said at least one additional stereoisomer, i.e. compound of formula IA, which is the 2S,4S diastereomer of brivaracetam.
In one embodiment, the diastereomeric excess of brivaracetam is at least 98% (meaning the ratio of brivaracetam, compound I: 2S,4S diastereoisomer of brivaracetam, compound IA is 99:1) at least 98.5%, at least 99% or at least 99.9%. According to the invention, the method of the present invention yields brivaracetam, a compound of formula I in high chiral purity, in a diastereomeric excess of at least 98%. In some embodiments, the diastereomeric purity is greater than 98.5%. In one embodiment, the present invention provides a process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide (brivaracetam), a compound of formula I, comprising: (a) reducing a compound of formula XII’ or a salt thereof, wherein R is selected from C1-C6 alkyl or C1-C6 alkylaryl, to obtain a compound of formula XIV’ or a salt thereof wherein R is selected from C1-C6 alkyl or C1-C6 alkylaryl; and
XII’ XIV’
(b) cyclizing the compound of formula XIV or a salt thereof wherein R is selected from C1-C6 alkyl or C1-C6 alkylaryl, to obtain brivaracetam in a diastereomeric excess of at least 98%. In one embodiment, the present invention provides a process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide (brivaracetam), a compound of formula I, comprising (a) reducing a compound of formula XII or a salt thereof to obtain a compound of formula XIV or a salt thereof; and (b) cyclizing the compound of formula XIV or a salt thereof, to obtain brivaracetam in a diastereomeric excess of at least 98%.In one embodiment, the present invention provides a process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide (brivaracetam), a compound of formula I, comprising (a) reducing a salt of compound of formula XII to obtain a salt of compound of formula XIV; and (b) cyclizing the salt of compound of formula XIV, to obtain brivaracetam in a diastereomeric excess of at least 98%. In one embodiment the salt of compound of formula XII may be selected from inorganic acid or organic acid. The inorganic acid salt may be selected from the group consisting of hydrochloride, sulfate, hydrobromide, borate and the like. The organic acid salt may be selected from the group consisting of mesylate, tosylate, benzoate, tartrate, mandelate, acetate, formate, dibenzoyl tartrate, diparatoluoyl tartrate and like.
In one embodiment, the present invention provides a process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide (brivaracetam), a compound of formula I, comprising (a) reducing a compound of formula XII A to obtain a compound of formula XIVA; and
XIIA XIVA

(b) cyclizing the compound of formula XIVA, to obtain brivaracetam in a diastereomeric excess of at least 98%.
In one embodiment, the starting compound of formula XII or salt has a chiral purity of at least 99% and the level of unwanted isomer (2S,3S) of compound of formula XII or salt thereof is less than 0.1% w/w of compound of formula XII, as determined by chiral HPLC. In one embodiment, the starting compound of formula XIIA has a chiral purity of at least 99% and the level of unwanted isomer (2S, 3S) of compound of formula XII or salt thereof is less than 0.1% w/w of compound of formula XII, as determined by chiral HPLC. In one embodiment, the reduction in step a of compound of formula XII or salt thereof to obtain compound XIV, may be carried out in the presence of hydrogen or hydrogen transfer reagents using metal catalysts. The reduction of the compound of formula XII or salt thereof to compound of formula XIV or salt thereof may be carried out in the presence of hydrogen or hydrogen transfer reagents using metal catalysts such as platinum, palladium, nickel, rhodium or ruthenium supported on solid supports like calcium carbonate, alumina, barium sulfate, silica or activated charcoal carbon. The hydrogen transfer reagents may be selected from formic acid/triethyl amine, ammonium formate, triethylammonium formate, hydrazinium monoformate, phosphinic acid, phosphinates, phosphorus acid, phosphites, hydrazine, alcohol, hydrides of boron, aluminium and silicon, amines and the like. The reduction may be carried out in a solvent system selected from alcohols, esters, aromatic hydrocarbon, carboxylic acid, ketones, aliphatic ethers, water and mixtures thereof. The alcohol solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and the like. The ester solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like. The aromatic hydrocarbon solvent is selected from the group consisting of toluene, xylene and the like. The carboxylic acid is selected from the group consisting of formic acid, acetic acid, propionic acid and the like. The ketone solvent is selected from the group consisting of acetone and the like. The aliphatic ether solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and like.
In one embodiment, the cyclization in step b of compound of formula XIV or salt thereof to obtain brivaracetam is carried out in presence of a base. The base may be selected form an inorganic or organic base. In one embodiment, the cyclization in step b of compound of formula XIV or salt thereof to obtain brivaracetam is carried out in presence of an acid. The acid may be selected from the group consisting of inorganic acid or organic acid. The inorganic acid may be selected from hydrochloric acid, sulphuric acid and the like. The organic acid may be selected from the group consisting of acetic acid, trifluoroacetic acid, formic acid and the like.
In one embodiment, the cyclization may be carried out in presence of a solvent. The solvent may be selected from the group consisting of Isopropyl acetate, isopropyl alcohol, ethyl acetate, toluene, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, xylene, dimethylformamide, N-methyl pyrrolidone, N,N-dimethylacetamide and the like. In one embodiment, cyclization of the compound of formula XIVA may be carried out in presence of acid. The acid may be selected as discussed supra. In one embodiment, the cyclization of compound of formula XIV or XIVA in presence of an acid may be carried out at a temperature in the range of 20-75°C. In one embodiment, after complete addition of acid the reaction mass may be heated at reflux temperature. The heating may be carried out for a period of 15-40 hours. In one embodiment, the process of the present invention brivaracetam salt may be generated insitu or may be isolated and which on treatment with base or base wash is converted to brivaracetam. In one embodiment, the process of the present invention provides brivaracetam, wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 1% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the present invention provides a composition comprising brivaracetam, a compound of formula I; wherein said compound is synthesized according to a method comprising the steps of: a) reducing a compound of formula XII or a salt thereof to obtain a compound of formula XIV or a salt thereof b) cyclizing the compound of formula XIV or a salt thereof to obtain brivaracetam in a diastereomeric excess of at least 98%. In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 98% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA, is less than 1% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 99% and wherein the level of any of the unwanted enantiomers (2S,4S)-diastereomer of brivaracetam, compound of formula IA, or (2R,4R) enantiomer of brivaracetam or (2R, 4S) enantiomer of brivaracetam is less than 0.5% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 99% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.5% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 99.70% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.15% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 99.90% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.05% w/w of brivaracetam as determined by chiral HPLC. In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 99.90% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.05% w/w of brivaracetam as determined by chiral HPLC and a chemical purity of at least 99.5%. In one embodiment, the present invention provides a process for a composition comprising an isolated compound of formula I, brivaracetam, in a diastereomeric excess of at least 99.70% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 0.15% w/w of brivaracetam as determined by chiral HPLC comprising cyclizing the compound of formula XIV or a salt thereof and isolating the compound of formula I without chiral chromatography or recrystallization. The process of the present invention provides brivaracetam, using novel compound XII or XIIA which has a chiral purity of greater than 99.5% and wherein the other unwanted enantiomers are less than 0.5% leading to brivaracetam in high chiral and chemical purity, by simple chemical steps and does not involve column or chiral chromatographic techniques to achieve the chiral and chemical purity. The process of the present invention is able to high achieve chiral purity wherein the unwanted (2S,4S)-diastereomer of brivaracetam, compound of formula IA is absent and the other enantiomers (2R,4R) and (2R, 4S) of brivaracetam are below 0.10%.
In one embodiment, the present invention provides compound of formula XII, t-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hex-5-enoate, characterized by 1-H NMR 400MHz, DMSO): d 7.27 (s,1H), 6.97 (s,1H), 5.80–5.70 (m,1H), 5.00–4.99 (m,2H), 3.35 (bs,1H), 2.76 (t,1H), 2.47-2.43 (m,1H), 2.25–2.11 (m,4H), 2.05–1.82 (m,2H), 1.40 (m,11H), 0.86 (t,3H).
In one embodiment, the present invention provides compound XII, in a chiral purity of at least 99% and wherein the level of unwanted isomer (2S, 3S) of compound of formula XII is less than 0.1% w/w of compound of formula XII as determined by chiral HPLC. In one embodiment, the compound of formula XII may or may not be isolated and reacted with an acid selected from the group consisting of acetic acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid and the like, to form salt which can be directly used for further reaction.
In one embodiment, the present invention provides t-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hex-5-enoate, tartrate, compound of formula XIIA, characterized by 1-H NMR 1H NMR (400MHz, DMSO): d 7.6 (s,1H), 7.3 (s,1H), 7.3 (bs,2H), 5.79-5.69 (m,1H), 5.06-5.10 (m,2H), 4.1 (s,1H), 3.1 (t,1H), 2.58-2.43 (m,3H), 2.33-2.28 (m,1H), 2.17–2.00 (m,5H), 1.63–1.56 (m,3H), 1.40 (s,9H), 0.87 (t,3H).
In one embodiment, the present invention provides compound XIIA, in a chiral purity of at least 99% and wherein the level of unwanted isomer (2S, 3S) of compound of formula XIIA is less than 0.1% w/w of compound of formula XII as determined by chiral HPLC. In one embodiment, the compound of formula XII can be resolved by using chiral reagents selected from the group consisting of camphorsulfonic acid, bromocamphorsulfonic acid, camphanic acid, camphoric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyl tartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid, ditoluyl tartaric acid, quinic acid, pyroglutamic acid, phenylpropionic acid, naphthyl ethylsuccinamic acid, malic acid, mandelic acid, glutamic acid, or mixtures thereof. Use of a compound XII or salt thereof, in the preparation of brivaracetam, a compound of formula I.
In one embodiment, the present invention provides compound of formula XIVA, tert-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hexanoate, tartrate, characterized by 1H NMR (400MHz, DMSO): d 7.65 (s,1H), 7.3 (s,1H), 7.2 (bs,2H), 4.12 (s,2H), 3.17 (t,1H), 2.59-2.51 (m,2H), 2.37-2.32 (m,1H), 2.16–2.11 (m,1H), 1.98–1.95 (t,1H), 1.64 -1.60 (t,3H), 1.39 (s,9H), 1.32-1.19 (m,4H), 0.89-0.84 (m,6H).
In one embodiment, the present invention provides a process for preparation of the compound of formula XII or a salt thereof by a) converting a compound of formula VI to a compound of formula II, wherein R1 is selected from the group consisting of mesylate, tosylate, nosylate or R1 is halogen selected from the group consisting of Cl, Br, I ; R2 is O- C1-6 alkyl or O-C1-6 alkylaryl by a process comprising (b) reacting the compound of formula VI with mesyl chloride, nosyl chloride, or tosyl chloride to obtain the compound of formula II, wherein R1 is selected from the group consisting of mesylate, tosylate, and nosylate ; R2 is R2 is O- C1-6 alkyl or O-C1-6 alkylaryl; or carbon tetrabromide or N-halosuccinimide and triphenyl phosphine, hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein R1 is halogen selected from the group consisting of Cl, Br, I; R2 is O- C1-6 alkyl or O-C1-6 alkylaryl.
VI II
(c) reacting the compound of formula II, with (S)- 2- aminobutanamide, a compound of formula III or a salt thereof to obtain the compound of formula XII.
III
(d) optionally treating the compound of formula XII with an acid to obtain salt of the compound of formula XII. In one embodiment, the present invention provides a process for preparation of the compound of formula XII or a salt thereof by converting a compound of formula VI to a compound of formula II, wherein R1 is selected from the group consisting of mesylate, tosylate, nosylate or R1 is halogen selected from the group consisting of Cl, Br, I ; R2 is O-C(CH3)3 , by a process comprising (a) reacting the compound of formula VI with mesyl chloride, nosyl chloride, or tosyl chloride to obtain the compound of formula II, wherein R1 is selected from the group consisting of mesylate, tosylate, and nosylate ; R2 is O-C(CH3)3; or carbon tetrabromide or N-halosuccinimide and triphenyl phosphine, hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein R1 is halogen selected from the group consisting of Cl, Br, I; R2 is O-C(CH3)3. (b) reacting the compound of formula II, with (S)- 2- aminobutanamide, a compound of formula III or a salt thereof to obtain the compound of formula XII. (c) optionally treating the compound of formula XII with an acid to obtain salt of the compound of formula XII. In one embodiment, the compound of formula II is obtained by reaction of compound of formula VI with (a) mesyl chloride, nosyl chloride, or tosyl chloride to obtain the compound of formula II, wherein R1 is selected from the group consisting of mesylate, tosylate and nosylate; R2 is O-C(CH3)3; or (b) carbon tetrabromide or N- bromosuccinimide and triphenyl phosphine to obtain the compound of formula II, wherein R1 is Br; R2 is O-C(CH3)3; or (c)hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein R1 is Br; R2 is O-C(CH3)3; or d)N-halo succinimide in acetic acid to obtain the compound of formula II, wherein R1 is halogen; R2 is O-C(CH3)3.
In one embodiment, the present invention provides a process for preparation of the compound of formula XII or a salt thereof by (a) converting a compound of formula VI to a compound of formula II” by a process comprising
VI II”
reacting the compound of formula VI with a brominating agent; (b) reacting the compound of formula II”, with (S)- 2- aminobutanamide, a compound of formula III or a salt thereof to obtain the compound of formula XII; (c) optionally treating the compound of formula XII with an acid to obtain salt of the compound of formula XII.
The brominating agent may be selected from the group consisting of carbon tetrabromide or N-bromosuccinimide, hydrogen bromide or bromine in acetic acid. In one embodiment, the compound of formula II’’ is obtained by reaction of compound of formula VI with carbon tetrabromide and triphenyl phosphine. In one embodiment, the compound of formula II’’ is obtained by reaction of compound of formula VI with N-bromosuccinimide and triphenyl phosphine. The reaction of compound of formula VI with brominating agent, may be carried out by using reagents like triphenylphosphine, polymer bound triphenylphosphine and the like. The reaction of compound of formula II or II” with a compound of formula III may be carried out using a base selected from an organic base or an inorganic base. In one embodiment, the organic base is selected from the group consisting of amines, organolithiums, metal alkaloids, amides, tetraalkylammonium hydroxides, phosphonium hydroxides and the like. In one embodiment, the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines and heterocyclic amine. In one embodiment, the cyclic aliphatic amine is selected from the group consisting of piperidine and piperazine. In one embodiment, the trialkyl amine is selected from the group consisting of triethylamine and diisopropylethylamine (DIPEA). In one embodiment, the heterocyclic amine is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, pyrimidine or 4-(dimethylamino)pyridine (DMAP). In one embodiment, the inorganic base is selected from the group consisting of metal carbonate, metal bicarbonate and metal hydroxide, wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium or magnesium. In one embodiment, the reaction of compound of formula II or II” with a compound of formula III may be carried out using a base selected from alkali metal hydroxide like sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides like calcium hydroxide, alkoxides like sodium methoxide, sodium or potassium tert butoxide, alkali metal carbonate such as sodium carbonate, alkaline earth metal carbonates like calcium carbonates, sodium hydride, lithium bis(trimethylsilyl)amide and the like. In one embodiment, the reaction of compound of formula II with a compound of formula III may be carried out using a base in presence of a phase transfer catalyst. In one embodiment the phase transfer catalyst may be selected from the group consisting of quaternary ammonium salts like tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium fluoride (TBAF), tetrabutyl ammonium hydroxide (TBAH), tetrabutyl ammonium iodide (TBAI), crown ether, phosphonium salts and the like.
In one embodiment, the present invention provides a compound of formula II”, tert-butyl (3R)-3-(bromomethyl)hex-5-enoate, characterized by 1H NMR (400MHz, CDCl3): d 5.79–5.68 (m,1H), 5.15–5.10 (m,2H), 3.55–3.46 (m,2H), 2.38 (d,1H), 2.31 (d,1H), 2.27-2.16 (m,3H), 1.40 (s,9H).
In one embodiment, the compound of formula VI is obtained by reduction of compound of formula VII-A
VII-A VI
wherein, R is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl, benzyl or naphthyl; P is t-butyl. The reduction may be carried out by using reducing agents selected from the group consisting of alkali metal hydrides, alkali metal borohydride such as lithium aluminium hydride, sodium borohydride, VITRIDE®, sodium cyanoborohydride, tetrabutylammonium borohydride, sodium triacetoxyborohydride and the like.
In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A.
Scheme A
In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A, wherein R is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl, benzyl, or naphthyl; P is carboxyl protecting group selected from the group consisting of t-butyl, benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl; substituent X is halogen. In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A, wherein R is phenyl. In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A, wherein R is benzyl.
In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A, wherein the compound IX-A is Evans’ chiral oxazolidin-2-ones. Some of the examples of compound IX-A are as follows,
IX IX’ IX”
In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained by reacting the compound of formula VIII-A with O-protected halo acetate. In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained by reacting the compound of formula VIII-A with O-protected halo acetate in presence of a base.
In one embodiment, the base used is alkali metal alkyl disilazide such as sodium bis (trimethylsilyl)amide (NaHMDS), lithium HMDS, potassium HMDS and the like; lithium tetramethylpiperidide, n-butyl lithium, sec-butyl lithium, t-butyl lithium, lithium diisopropylamide In one embodiment, the present invention provides a process wherein the compound of formula VII-A is obtained by reacting the compound of formula VIII-A with t-butyl bromoacetate. In one embodiment, the present invention provides a process wherein the compound of formula VIII-A is obtained by reacting the compound of formula IX-A with the compound of formula X. In one embodiment, the present invention provides a process wherein the compound of formula VIII-A is obtained by reacting the compound of formula IX-A with the compound of formula X in presence of acid activating compound and base. In one embodiment, the acid activating compound may be selected from the group consisting of thionyl chloride, pivaloyl chloride, POCl3, PCl5, oxalyl chloride, EDC, DCC and the like. In one embodiment, the base may be selected from the group consisting of organic base such as pyridine, DMAP (4-dimethylaminopyridine), triethyl amine, Hunig’s base, N-methylmorpholine, N-methylpiperidine and the like; inorganic base such as alkali metal hydrides like sodium hydride, potassium hydride, lithium hydride; metal carbonates like potassium carbonate, sodium carbonate; bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal alkoxides like sodium ethoxide, sodium methoxide, potassium t-butoxide; n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like. In one embodiment, the compound of formula VIII-A is not isolated and carried forward in situ for further reaction. In one embodiment, any of the compounds of formulae VIII-A, VII-A, VI are isolated by any method known in the art. In one embodiment, any of the compounds of formulae VIII-A, VII-A, VI are not isolated and carried forward in situ for further reaction. In one embodiment, the present invention provides a process wherein the compound of formula VII-A wherein R is benzyl, P is t-butyl, a compound of formula VII is obtained as depicted in scheme I.

Scheme I
In one embodiment, the present invention provides a process, wherein the compound of formula VIIA, wherein R is phenyl, P is t-butyl, a compound of formula VII’ is obtained as depicted in scheme IV
Scheme IV
In one embodiment, any of the compounds of formulae VIII/VIII’, VII/VII’, VI are isolated by any method known in the art. In one embodiment, any of the compounds of formula VIII/VIII’, VII/VII’, VI are not isolated and carried forward in situ for further reaction. In one embodiment, the present invention provides a compound of formula VII-A wherein R is phenyl; P is t-butyl, a compound of formula VII’. In one embodiment, the present invention provides (R)-tert-butyl 3-((S)-4-phenyl-2-oxo oxazolidine-3-carbonyl)hex-5-enoate a compound of formula VII’ in a chiral purity of at least 99% and wherein the level of unwanted S,S diastereomer is less than 0.15% w/w. In one embodiment, the present invention provides a process for the compound of formula VII’ comprising: a) reacting compound of formula IX’ with the compound of formula X in presence of acid activating agent and base to form the compound of formula VIII’; b) reacting the compound of formula VIII’ with t-butyl bromoacetate in presence of base to obtain the compound of formula VII’.
VIII’
The acid activating agent and organic base used is selected from the group as discussed supra. Preferably the acid activating agent is pivaloyl chloride and the organic base is triethyl amine. In one embodiment, compound of formula VII’ obtained by the process of the present invention is purified by using solvent selected from alkanes, ether and the like. The alkane may be selected from the group consisting of hexane, heptane, cyclohexane and the like. The ether may be selected from diisopropyl ether, cyclopentyl methyl ether, methyl tert butyl ether and the like. In one embodiment, compound of formula VII’ obtained by the process of the present invention is purified by using diisopropylether to obtain formula VII’ in a chiral purity of at least 99% and wherein the level of unwanted S,S diastereomer is less than 0.15% w/w.
In one embodiment, the present invention provides a compound of formula VII’,
characterized by 1H NMR (400MHz, CDCl3): d 7.36-7.27 (m,5H), 5.86-5.75 (m,1H), 5.43-5.40 (m,1H), 5.12-5.07 (m,2H), 4.67 (t,1H), 4.36-4.29 (m,1H), 4.26-4.23 (m,1H), 2.71-2.64 (m,1H), 2.46-2.35 (m,2H), 2.23–2.16 (m,1H), 1.29 (s,9H); Mass: M/Z = 360 (M+H).
In one embodiment, the present invention provides substantially pure brivaracetam, the compound of formula I. In one embodiment, the present invention provides the compound of formula I, wherein the content of (2S,4S) compound IA and/or (2R,4S) and/or (2R,4R) isomers of the compound of formula I, is less than 1% w/w with respect to (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide, the compound of formula I, as determined by HPLC. In one embodiment, present invention provides substantially pure brivaracetam, the compound of formula I; with at least 99% w/w, wherein the level of impurity is less than 1%, as determined by HPLC.
In one embodiment the brivaracetam obtained by the process of purification of the present invention has a chiral purity of at least 99.5% and wherein the level of unwanted diastereomer compound 1A is less than 0.15%w/w and other unwanted isomers (2R,4R) & (2R 4S) are not detected. The present invention provides another process for the preparation of brivaracetam, a compound of formula I comprising reducing a compound of formula IV
IV I
The reduction of the compound of formula IV to compound of formula I may be carried out in the presence of hydrogen or hydrogen transfer reagents using metal catalysts as discussed supra. In one embodiment, the reduction of the compound of formula IV to a compound of formula I is carried out in the presence of hydrogen or hydrogen transfer reagents using palladium metal as catalyst using alcohol as a solvent. In one embodiment, the compound of formula IV is obtained by reacting a compound of formula II, wherein R1 is selected from the group consisting of halogen, mesylate, tosylate, and nosylate; R2 is selected from the group consisting of OH, halogen and O-C1-6 alkyl with (S)-2-aminobutanamide, a compound of formula III or salt thereof. In one embodiment, the compound of formula IV is obtained by reacting a compound of formula II, wherein R1 is halogen; R2 is selected from the group consisting of OH, halogen with (S)-2-aminobutanamide, a compound of formula III or salt thereof. The reaction of compound of formula II with a compound of formula III may be carried out using a base selected from an organic base or an inorganic base. In one embodiment, the reaction of compound of formula II with a compound of formula III may be carried out using a base in presence of a phase transfer catalyst.
In one embodiment, the present invention provides a process for the compound of formula IV, comprising; cyclizing the compound of formula XII with an acid.In one embodiment, the compound of formula IV is obtained by reacting a compound of formula V, with (S)-2-aminobutanamide, a compound of formula III or salt thereof with or without isolating the compound formula II.
V III IV
In one embodiment, the compound of formula IV is obtained by reacting the compound of formula V with trimethylsilyl iodide, trimethylsilyl bromide or trimethylsilyl chloride, optionally followed by reaction with thionyl chloride or oxalyl chloride; and then further reacted with the compound of formula III.
Instrumental Settings
Proton NMR spectra were recorded in CDCl3 and DMSO-d6 using NMR instrument- Varian 300 MHZ.
HPLC Methodology (1) HPLC chromatography: Column: Inertsil ODS 3V (Make: GL-Science), (250 x 4.6) mm, 5µ. Mobile Phase A: Buffer: 0.1% of Perchloric acid in water. Mobile Phase B: Acetonitrile: Buffer (90: 10, V/V). Diluent: Water: Acetonitrile (60: 40, V/V). Sample concentration of 7?M was prepared in diluent. Gradient elution was performed with a flow rate of 1.0 mL/min. The retention time of brivaracetam is about 30 minutes under these conditions. Detection wavelength 215 nm.(2) Chiral HPLC chromatography: Column: Chiralpak AD-H (Make: Daicel), (250 x 4.6) mm, 5?. Mobile Phase: n-hexane: isopropyl alcohol: diethylamine (850:150:0.2, V/V/V). Diluent: n-hexane: isopropyl alcohol (80:20, V/V). Sample concentration of 9?M was prepared in diluent. Gradient elution was performed with a flow rate of 1.0 mL/min. The retention time of brivaracetam is about 10 minutes under these conditions. Detection wavelength 215 nm.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example 1: Preparation of (4S)-3-(pent-4-enoyl)-4-phenyl-1,3-oxazolidin-2-one (compound VIII’): 4-Pentenoic acid (compound X), 4-dimethylammoniumpyridine (DMAP) was added to MDC and DMF at about 20oC - 30oC; cooled to 15°C- 20°C. Triethylamine and (S)-(+)-4-Phenyl-2-oxazolidinone (compound IX’) was added to the reaction mass; stirred for about 5-10 minutes, cooled to 0oC -5°C. A solution of pivaloyl chloride in MDC was added to the reaction mass; temperature was raised to about 25oC - 30°C; stirred for about 10-15 hours; quenched in dilute sulfuric acid at about 0oC to 5oC, temperature was raised to about 20oC-30oC and layers were separated. The aqueous layer was extracted with MDC, washed with 5% potassium carbonate solution followed by brine, the organic layer was distilled off completely to obtain oily residue. To this oily mass, cyclohexane was added at about 50oC-55°C; cooled gradually to 20oC-30oC; stirred for 2 hours, filtered, the residue obtained was dried to get compound VIII’ as off-white to pale yellow solid. HPLC Purity more than 98.0%.
Example 2: Preparation of (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate (compound VII’): To a solution of compound VIII’ in THF, 2M sodium hexamethyldisilazane (NaHMDS) was added at -70oC to -80°C over a period of about 1 hour; stirred for 2-3 hours. t-butyl bromoacetate was added in 30-45 minutes; stirred for 1 hour at -70oC to -80°C. After completion of reaction, the temperature was raised to -10oC to -20°C; quenched in saturated ammonium chloride solution; stirred for 10-15 minutes and the layers were separated. Aqueous layer was extracted with ethyl acetate; washed with brine, the organic layer was distilled off and the residue was recrystallized using n-heptane to get compound VII’ as a white to yellow solid with purity about 95.0%; SS Isomer – 1.0%, SOR - [a] 25/D + 99° (C=1.0 in Methanol).
Example 2A: Preparation of compound VII’: Process was same as described in Example 2 where t-butyl bromoacetate was added to the reaction mass in about 30-45 minutes; stirred for 1 hour at about -85oC to about -95°C.White to yellow solid with purity about 99.2%; SS Isomer – 1.0%, SOR - [a] 25/D + 99° (C=1.0 in Methanol).
Example 3: Purification of compound VII’: compound VII’ as obtained in Example 2 was dissolved in Diisopropyl ether by heating at about 65°C to 70°C. The solution was cooled to room temperature, filtered, dried to get pure compound VII’, off white solid, purity: 99.16%; SS isomer – not detected; SOR - [a] 25/D +105° (C=1.0 in Methanol).
Example 4: Preparation of t-butyl(3R)-3-(hydroxymethyl)hex-5-enoate (compound VI): Compound VII’ was added to THF and water; sodium borohydride was added; stirred for 15-20 hours at 20°C-30°C. After completion of the reaction, quenched with acetic acid; extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate; distilled to get pale yellow oil; diisopropyl ether was added to it; the reaction mass was cooled to 10°C-15°C and stirred for about 1hour and filtered and washed with diisopropyl ether. The solvent was distilled off from the filtrate to get compound VI. 1H NMR (400MHz, CDCl3): d 5.79–5.68 (m,1H), 5.15–5.10 (m,2H), 3.55–3.46 (m,2H), 2.38 (d,1H), 2.31 (d,1H), 2.27-2.16 (m,3H), 1.40 (s,9H).
Example 5: Preparation of t-butyl (3R)-3-(bromomethyl)hex-5-enoate (compound II”): Compound VI was dissolved in methylene dichloride; cooled to 10oC-15oC; triphenyl phosphine was added in portions over about 15 minutes under vigorous stirring; then stirred at 25oC-15oC and N-Bromosuccinimide was added in lots; n-heptane was added and stirred. The precipitate was filtered, filtrate was concentrated at 25°C-30°C and n-hepate was added to the obtained residue; cooled to about -10°C to -5°C; stirred, filtered, n-heptane was distilled off to get oily mass. The oily mass was dissolved in n-heptane, washed with acetic acid:methanol:water followed by water, distilled to get compound II”, oil. 1HNMR(400MHz,CDCl3):d5.79-5.68 (m,1H),5.15-5.10(m,2H),3.55-3.46(m,2H),2.38(d,1H),2.31(d,1H),2.27-2.16(m,3H), 1.40 (s,9H).
Example 6: Preparation of t-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hex-5-enoate (compound XII): In a clean and dry assembly, under nitrogen atmosphere, compound II”, (S)-2-aminobutanamide hydrochloride (compound III), tetrabutylammonium iodide, sodium carbonate and isopropyl acetate were charged; heated to reflux for 28 hours; cooled to 15°C, filtered, washed with isopropyl acetate. The filtrate was distilled to obtain compound XII as oily mass.
Example 7: Preparation of t-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hex-5-enoate, tartrate (compound XII-A): In a clean and dry assembly, under nitrogen atmosphere, compound II”, (S)-2-aminobutanamide hydrochloride (compound III), tetrabutylammonium iodide, sodium carbonate and isopropyl acetate were charged, heated to reflux for about 28 hours, cooled to about 15°C, the reaction mass was filtered and washed with isopropyl acetate. The filtrate was distilled under to vacuum to obtain t-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hex-5-enoate (compound XII) as oily mass. The oily mass was dissolved in acetone and added to preheated solution of L- (+) Tartaric acid in methanol at about 50°C-55°C. The reaction mass was cooled to room temperature and filtered, obtained product was dried and further purified using mixture of acetonitrile and methanol at about 50°C-55°C. The reaction mass was cooled to room temperature and stirred. The reaction mass was filtered and obtained compound XII-A was dried. Chemical purity>98.0%, Chiral purity-99.74%, R,R Isomer-0.20%, S,S Isomer 0.06%.
Example 8: Preparation of tert-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hexanoate, tartrate (compound XIVA): Compound XII-A was hydrogenated using 10% Pd/C in methanol:water at about 15oC-20°C at 2Kg/cm2. The reaction mass was stirred for about 1-1.5 hours. After completion of reaction, the catalyst was filtered and filtrate was evaporated to yield white solid. To this solid, added isopropyl acetate and stirred, then filtered and dried to get compound XIVA as white solid.
Example 9: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide (Brivaracetam compound I), Compound XIVA was charged in the mixture of isopropyl acetate and isopropyl alcohol): under nitrogen atmosphere, heated to 60°C-65oC. Acetic acid was added slowly over a period of 30 minutes; stirred for about 36 hours at 80°C-90°C; cooled to 0oC-10oC, filtered; washed with isopropyl acetate; filtrate was distilled to get oily mass. Oily mass was dissolved in ethyl acetate. Ethyl acetate layer was washed with NaCl solution; pH was adjusted to about 7 with sodium bicarbonate, stirred; layers were separated. Organic phase washed with water and distilled to obtain Brivaracetam as a yellow solid with purity 96.0%, Chiral purity 99.45%, compound IA (S,S isomer)-0.05%, R,S isomer-0.07%, R,R isomer- 0.43%.
Example 10: Purification Brivaracetam: Brivaracetam was added in mixture of isopropyl acetate and n-Heptane, stirred for about 10-15minutes at room temperature, heated further at about 55°C-60°C to get clear solution, cooled to 20°C-25°C. The solid was filtered, washed with mixture of isopropyl acetate and n-Heptane and dried to obtain pure Brivaracetam; with chemical purity 99.88%; chiral purity 99.94%; diasteromeric excess (d.e) 99.88; compound IA (S,S isomer) - 0.05%; R,S isomer-not detected; R,R isomer-not detected; SOR - [a]25/D -59.73° (C=1.0 in Methanol). Chiral chromatography data
Peak Names Ret Time Type Width [min] Area mAU*s Height mAU Area % RRT
1. Compound IA
8.17 MM 0.18 11.98 1.1 0.055 0.78
2. Compound I
10.54 MM 0.28 2.30 e4 1375.59 99.944 1.0
Example 11: Purification of Brivaracetam: Brivaracetam was added in n-Heptane and heated to about 55°C-60°C; ethyl acetate added; cooled to 20°C-25°C. The solid was filtered, washed with of ethyl acetate, n-heptane and dried to obtain pure Brivaracetam. Chemicalpurity99.79%; chiralpurity99.89%, compoundIA (S,Sisomer0.06%), R,S isomer -notdetected,R,Risomer-0.05%,SOR-[a]25/D57.15°(C=1.0in Methanol).
Example 12: Preparation (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-1-yl]butanamide (compound IV): Compound XII was added to isopropyl acetate and isopropyl alcohol; heated to about 60°C-65oC. Acetic acid was added; stirred for about 36 hours at about 80°C-90°C, then cooled and filtered and washed with isopropyl acetate. The filtrate was distilled to get oily mass and dissolved in ethyl acetate. The ethyl acetate layer washed with sodium chloride solution; pH was adjusted to about 7-8 with sodium bicarbonate; stirred and layers were separated. The organic phase was washed with water and distilled under vacuum to obtain compound IV as a yellow semisolid.
Example 13: Preparation of Brivaracetam: compound IV was hydrogenated using 10% Pd/C in methanol at about 25°C-30°C; 2Kg/cm2 pressure; stirred for about 1-1.5 hours. Catalyst was filtered and solvent was evaporated to yield Brivaracetam. Chiral purity 98.97%, compound IA (S,S isomer) 0.5%, R,S isomer -0.03%, R,R isomer - 0.5%.
Example 14: Preparation of Brivaracetam: Comp XIV and HOBt were added to toluene; stirred for about 3 hours at 90 °C and conversion was checked by TLC, found unreacted starting material. The reaction mass was then stirred further for 12 hours. After the reaction was complete, saturated sodium carbonate solution was added at room temperature; extracted with ethyl acetate. Organic layers were washed with brine and dried over anhydrous sodium sulfate. The reaction mass was filtered and solvent was evaporated from the filtrate to obtain the crude product. Purification was carried out by silica gel column chromatography using EA/TEA (100/1) to Obtain (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide (Brivaracetam compound I) (40% yield) as a white solid. Chiral purity 96.13%, compound IA (S,S isomer) - not detected, R,S isomer -0.60%, R,R isomer - 3.26%.
Example 15: Purification of Brivaracetam: Crude brivaracetam was added in diisopropyl ether and stirred for about 10-15 minutes and heated at about 50°C-55°C, filtered; filtrate was then cooled to about 0°C-5°C. The solid was filtered and dried to obtain pure Brivaracetam.
Example 16: Brivaracetam RLD sample analysis: Brivaracetam tablet (BRIVIACT) Lot No. 242137 (UCB. Inc. Belgium) expiry date August 2021 was used for analysis. 80 mg API was present in each tablet. The obtained tablet was crushed to powder form and sample was dissolved in diluent (n-hexane: isopropyl alcohol (80:20, V/V)) and filtered through 0.45 ?m filter to obtain the concentration of 1500 ppm of API in the solution and the solution was used for chiral HPLC analysis, detection wavelength 215 nm. Chiral purity: 98.97%; diasteromeric excess (d.e) 97.94%; compound IA (S,S isomer) 1.021%. Chiral chromatography data:
Peak Names Ret Time Type Width [min] Area mAU*s Height mAU Area % RRT
1. Compound IA
7.35 MM 0.17 232.13 22.80 1.021 0.79
2. Compound I
9.29 MM 0.28 2.25 e4 1333.15 98.979 1

,CLAIMS:WE CLAIM
1] A process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide (brivaracetam), a compound of formula I, comprising
(a) reducing a compound of formula XII or a salt thereof to obtain a compound of formula XIV or a salt thereof ; and
I XII XIV
(b) cyclizing the compound of formula XIV or a salt thereof, to obtain brivaracetam in a diastereomeric excess of at least 98%.

2] The process as claimed in claim 1, wherein the reduction in step a, is carried out in the presence of hydrogen or hydrogen transfer reagents using metal catalysts.

3] The process as claimed in claim 1, wherein the cyclization in step b is carried out in presence of an acid.

4] The process as claimed in claim 1, wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA
IA
is less than 1% w/w of brivaracetam as determined by chiral HPLC.

5] The process as claimed in claim1, wherein the compound of formula XII or salt thereof is obtained by
(a) converting a compound of formula VI to a compound of formula II, by a process comprising
VI II
(b) reacting the compound of formula VI with i) mesyl chloride, nosyl chloride, or tosyl chloride to obtain the compound of formula II, wherein R1 is selected from the group consisting of mesylate, tosylate, and nosylate ; R2 is O-C(CH3)3; or ii) carbon tetrabromide or N-halosuccinimide and triphenyl phosphine, hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein R1 is halogen selected from the group consisting of Cl, Br, I; R2 is O-C(CH3)3.
(c) reacting the compound of formula II, with (S)- 2- aminobutanamide, a compound of formula III or a salt thereof to obtain the compound of formula XII.
III
(d) optionally treating the compound of formula XII with an acid to obtain salt of the compound of formula XII.

6]The process as claimed in claim 5, wherein the compound of formula XII is obtained in a chiral purity of at least 99% and wherein the level of unwanted isomer (2S, 3S) of compound of formula XII is less than 0.1% w/w of compound of formula XII as determined by chiral HPLC.

7] The process as claimed in claim 5, wherein the compound of formula VI is obtained by
a) converting compound of formula IX-A to compound of formula VII-A as depicted in scheme below

wherein R is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl, benzyl, or naphthyl; P is carboxyl protecting group selected from the group consisting of P is carboxyl protecting group selected from the group consisting of C1-C6 alkyl, benzhydryl, o-nitrobenzyl, p-nitrobenzyl, benzyl; substituent X is halogen.
b) reduction of compound of formula VII-A
VII-A VI
wherein, R is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl, benzyl, or naphthyl; P is carboxyl protecting group selected from the group consisting of C1-C6 alkyl, benzhydryl, o-nitrobenzyl, p-nitrobenzyl, benzyl.

8] The process as claimed in claim 7 step a, wherein a compound of formula VII’ (VIIA, wherein R is phenyl P is t-butyl) is obtained as depicted in scheme below

9] A composition comprising (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide (brivaracetam), a compound of formula I
I XII XIV
wherein said compound is synthesized according to a method comprising the steps of:
(a) reducing a compound of formula XII or a salt thereof to obtain a compound of formula XIV or a salt thereof
(b) cyclizing the compound of formula XIV or a salt thereof to obtain brivaracetam in a diastereomeric excess of at least 98%.

10] A composition comprising an isolated compound of formula I, (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide (brivaracetam),
I IA
in a diastereomeric excess of at least 98% and wherein the level of (2S,4S)-diastereomer of brivaracetam, compound of formula IA is less than 1% w/w of brivaracetam as determined by chiral HPLC.

Dated this 18th day of December, 2018

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED