WO2019087172A1

WO2019087172A1 - Process for preparation of brivaracetam

Info

Publication number: WO2019087172A1
Application number: PCT/IB2018/059910
Authority: WO
Inventors: Ranjeet Nair; Shekhar Bhaskar Bhirud; Bhavin Prabhudas THANKI; Sanjay Shashikant BHISE; Shrikant Prabhakar KESHAV; Rajendra JAGDHANE; Ganesh Bhaskar CHAUDHARI; Nandkumar Gaikwad; Sandip GADGE
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2017-12-19
Filing date: 2018-12-12
Publication date: 2019-05-09
Anticipated expiration: 2020-06-19

Abstract

The present invention relates to a process for the preparation of brivaracetam and salts thereof. The present invention provides process for the preparation of brivaracetam and salts thereof with high chiral purity. The present invention provides process for the preparation of brivaracetam and salts thereof wherein the amount of other stereoisomers of brivaracetam is low.

Description

"PROCESS FOR PREPARATION OF BRIVARACETAM"

PRIORITY

[0001] This application claims the benefit of Indian Provisional Applications 201721045662 filed on December 19, 2017 and 201821018717 filed on May 18, 2018, entitled "PROCESS FOR PREPARATION OF BRIVARACETAM", the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for the preparation of brivaracetam and salts thereof.

BACKGROUND OF THE INVENTION

[0003] The chemical name of BRIVIACT (brivaracetam) is (2S)-2-[(4R)-2-oxo-4- propyltetrahydro-lH-pyrrol-l-yl]b by compound of formula I.

I

[0004] 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 lOmg, 25mg, 50mg, 75mg, and lOOmg tablets, as lOmg/mL oral solution and as 50mg/5mL single-dose vial injection, for intravenous use.

[0005] 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 brivaraceta

IA [0006] The individual diastereomers (I and IA) obtained are then separated by multi-column continuous chromatography using chiral stationary phase (Chiralpak) and an eluent system.

[0007] 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.

[0008] 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.

[0009] The process of the present invention proceeds via novel compound of formula XII or salt thereof

XII

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.

[0010] The process of the present invention proceeds via solid intermediate compounds VTfl', VTT, XIIA and XIV A, 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

[0011] 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%.

[0012] 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

[0013] 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.

[0014] The present invention provides a process for the preparation of (2S)-2-[(4R)-2-oxo-4- propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam), a compound of formula I, comprising

I

reducing a compound of formula XII or a salt thereof to obtain a compound of formula a salt thereof

XII XIV

BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 is a chiral HPLC chromatogram of brivaracetam as obtained in Example 10.

[0016] Figure 2 is a chiral HPLC chromatogram of brivaracetam RLD sample as obtained in Example 27

[0017] Figure 3 is a characteristic XRPD of brivaracetam as obtained in Example 10

[0018] Figure 4 is characteristic 1H NMR of compound of formula XIIA as obtained in Example

7. DETAILED DESCRD7TION OF THE INVENTION

[0019] The term "Ci-Ce alkyl" as used herein refers to an aliphatic-hydrocarbon group which may be straight or branched having Ci-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.

[0020] The term "C1-C6 alkylaryl" as used herein refers to an aliphatic-hydrocarbon group which may be straight or branched having Ci-C₆ carbon atoms in the chain and attached to an aryl group like phenyl, benzyl, naphthyl, tolyl and the like.

[0021] The term "halogen" refers to iodo, bromo, chloro or fluoro.

[0022] 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

Formula IA

which is the 2S,4S diastereomer of brivaracetam.

[0023] 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%.

[0024] 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%.

[0025] In one embodiment, the present invention provides a process for the preparation of (2S)-2- [(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam), a compound of formula I, comprising

I

reducing a compound of formula ΧΙΓ or a salt thereof, wherein R is selected from Ci-C₆ alkyl or Ci-C₆ alkylaryl, to obtain a compound of formula XIV' or a salt thereof wherein R is selected from Ci-C₆ alkyl or Ci-C₆ al

ΧΙΓ XIV

cyclizing the compound of formula XIV or a salt thereof wherein R is selected from Ci-C₆ alkyl or Ci-C₆ alkylaryl, to obtain brivaracetam in a diastereomeric excess of at least 98%. [0026] In one embodiment, the present invention provides a process for the preparation of (2S)-2- [(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam), a compound of formula I, comprising

I

(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

[0027] In one embodiment, the present invention provides a process for the preparation of (2S)-2- [(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-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%.

[0028] In one embodiment the salt of compound of formula XII may be selected from inorganic acid or organic acid.

[0029] The inorganic acid salt may be selected from the group consisting of hydrochloride, sulfate, hydrobromide, borate and the like.

[0030] The organic acid salt may be selected from the group consisting of mesylate, tosylate, benzoate, tartrate, mandelate, acetate, formate, dibenzoyl tartrate, diparatoluoyl tartrate and the like. [0031] In one embodiment, the present invention provides a process for the preparation of (2S)-2- [(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam), a compound of formula I, comprising

(a) reducing a compound of formula XII A to obtain a compound of formula XTVA; and

XIIA XIVA

(b) cyclizing the compound of formula XIV A, to obtain brivaracetam in a diastereomeric excess of at least 98%.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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. [0038] The alcohol solvent may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and the like.

[0039] The ester solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like.

[0040] The aromatic hydrocarbon solvent is selected from the group consisting of toluene, xylene and the like.

[0041] The carboxylic acid is selected from the group consisting of formic acid, acetic acid, propionic acid and the like.

[0042] The ketone solvent is selected from the group consisting of acetone and the like.

[0043] The aliphatic ether solvent is selected from the group consisting of diethyl ether, tetrahydrofuran and the like.

[0044] 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.

[0045] The base may be selected form an inorganic or organic base.

[0046] 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.

[0047] The acid may be selected from the group consisting of inorganic acid or organic acid

[0048] The inorganic acid may be selected from hydrochloric acid, sulphuric acid and the like.

[0049] The organic acid may be selected from the group consisting of acetic acid, trifluoroacetic acid, formic acid and the like.

[0050] 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, Ν,Ν-dimethylacetamide and the like.

[0051] In one embodiment, cyclization of the compound of formula XTVA may be carried out in presence of acid. The acid may be selected as discussed supra.

[0052] 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.

[0053] 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. [0054] 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.

[0055] In one embodiment, the process of the present invention provides brivaracetam, wherein the level of (2S,4S)-diastereomer of br ound of formula IA

IA

is less than 1% w/w of brivaracetam as determined by chiral HPLC.

[0056] In one embodiment, the present invention provides a composition comprising brivaracetam, a compound of formula I

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

XII XIV

(b) cyclizing the compound of formula XIV or a salt thereof to obtain brivaracetam in a diastereomeric excess of at least 98%.

[0057] In one embodiment, the present invention provides a composition comprising an isolated compound of formula I, brivaracetam,

I

in a diastereomeric excess of at least 98% and 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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. [0062] 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%.

[0063] 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.

[0064] The process of the present invention provides brivaracetam, using novel compound ΧΠ 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%.

[0065] In one embodiment, the present invention provides compound of formula XII, t-butyl (3R)- 3-({[(2S)-l-amino-l-oxobutan-2-yl]amino}methyl)hex-5-enoate

XII.

[0066] In one embodiment, the present invention provides compound XII, characterized by 1 -H NMR 400MHz, DMSO): δ 7.27 (s,lH), 6.97 (s,lH), 5.80-5.70 (m,lH), 5.00-4.99 (m,2H), 3.35 (bs,lH), 2.76 (t,lH), 2.47-2.43 (m,lH), 2.25-2.11 (m,4H), 2.05-1.82 (m,2H), 1.40 (m,l lH), 0.86 (t,3H).

[0067] 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. [0068] 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.

[0069] In one embodiment, the present invention provides t-butyl (3R)-3-({[(2S)-l-amino-l- oxobutan-2-yl]amino}methyl)he -5-enoate, tartrate, compound of formula XIIA,

XIIA

[0070] In one embodiment, the present invention provides compound of formula XIIA, characterized by 1-H NMR 1H NMR (400MHz, DMSO): δ 7.6 (s,lH), 7.3 (s,lH), 7.3 (bs,2H), 5.79-5.69 (m,lH), 5.06-5.10 (m,2H), 4.1 (s,lH), 3.1 (t,lH), 2.58-2.43 (m,3H), 2.33-2.28 (m,lH), 2.17-2.00 (m,5H), 1.63-1.56 (m,3H), 1.40 (s,9H), 0.87 (t,3H).

[0071] 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.

[0072] 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.

[0073] Use of a compound XII or salt thereof, in the preparation of brivaracetam, a compound of formula I.

[0074] 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.

XTVA

[0075] In one embodiment the present invention provides compound of formula XIV A, characterized by 1H NMR (400MHz, DMSO): δ 7.65 (s,lH), 7.3 (s,lH), 7.2 (bs,2H), 4.12 (s,2H), 3.17 (t,lH), 2.59-2.51 (m,2H), 2.37-2.32 (m,lH), 2.16-2.11 (m,lH), 1.98-1.95 (t,lH), 1.64 -1.60 (t,3H), 1.39 (s,9H), 1.32-1.19 (m,4H), 0.89-0.84 (m,6H).

[0076] 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 Ri is selected from the group consisting of mesylate, tosylate, nosylate or Ri is halogen selected from the group consisting of CI, Br, - Ci-6 alkyl or O-Ci-6 alkylaryl by a process comprising

VI II

(b) reacting the compound of formula VI with

i. mesyl chloride, nosyl chloride, or tosyi chloride to obtain the compound of formula II, wherein Ri is selected from the group consisting of mesylate, tosylate, and nosylate ; R₂ is R₂ is O- Ci-6 alkyl or O-Ci-6 alkylaryl, or

ii. carbon tetrabromide or N-halosuccinimide and tnphenyl phosphine, hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein Ri is halogen selected from the group consisting of CI, Br, I; R₂ is O- Ci-6 alkyl or O-Ci-6 alkylaryl.

(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.

Ill (d) optionally treating the compound of formula XII with an acid to obtain salt of the compound of formula XII.

[0077] 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 Ri is selected from the group consisting of mesylate, tosylate, nosylate or Ri is halogen selected from the group consisting of CI, Br, -C(CH3)3 , by a process comprising

VI II

reacting the compound of formula VI with

i. mesyl chloride, nosyl chloride, or tosyi chloride to obtain the compound of formula II, wherein Ri is selected from the group consisting of mesylate, tosylate, and nosylate ; R₂ is O- C(CH₃)₃; or

i. carbon tetrabromide or N-halosuccinimide and triphenyl phosphine, hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein Ri is halogen selected from the group consisting of CI, Br, I; R₂ is 0-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.

Ill

(c) optionally treating the compound of formula XII with an acid to obtain salt of the compound of formula XII.

[0078] In one embodiment, the compound of formula II is obtained by reaction of compound of formula VI with

VI II (a) mesyl chloride, nosyl chloride, or tosyl chloride to obtain the compound of formula II, wherein Ri is selected from the group consisting of mesylate, tosylate and nosylate; R₂ is 0-C(CH3)3 ; or

(b) carbon tetrabromide or N- bromosuccinimide and triphenyl phosphine to obtain the compound of formula II, wherein Ri is Br; R₂ is 0-C(CH3)3 ; or c)hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein Ri is Br; R₂ is 0-C(CH3)3 ; or d)N-halo succinimide in acetic acid to obtain the compound of formula II, wherein Ri is halogen; R₂ is 0-C(CH3)3.

[0079] 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 Π" by a process comprising

VI IF

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.

III

[0080] The brominating agent may be selected from the group consisting of carbon tetrabromide or N-bfomosuccinimide, hydrogen bromide or bromine in acetic acid

[0081] In one embodiment, the compound of formula IT ' is obtained by reaction of compound of formula VI with carbon tetrabromide and triphenyl phosphine

VI II". [0082] In one embodiment, the compound of formula ΙΓ ' is obtained by reaction of compound of formula VI with N-bromosuccinimide and triphenyl phosphine.

[0083] The reaction of compound of formula VI with brominating agent, may be earned out by using reagents like triphenylphosphine, polymer bound triphenylphosphine and the like.

[0084] The reaction of compound of formula II or Π" with a compound of formula ΙΠ may be carried out using a base selected from an organic base or an inorganic base.

[0085] 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.

[0086] In one embodiment, the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines and heterocyclic amine.

[0087] In one embodiment, the cyclic aliphatic amine is selected from the group consisting of piperidine and piperazine.

[0088] In one embodiment, the trialkyl amine is selected from the group consisting of triethylamine and diisopropylethylamine (DIPEA).

[0089] In one embodiment, the heterocyclic amine is selected from the group consisting of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), pyridine, pyrimidine or 4-(dimethylamino)pyridine (DMAP).

[0090] 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.

[0091] In one embodiment, the reaction of compound of formula II or Π" 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.

[0092] 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. [0093] 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.

[0094] In one embodiment, the present invention provides a compound of formula Π", tert-butyl (3R)-3-(bromomethyl)hex-5-enoate

ΙΓ

[0095] In one embodiment, the present invention provides a compound of formula Π" characterized by 1H NMR (400MHz, CDC13): δ 5.79-5.68 (m,lH), 5.15-5.10 (m,2H), 3.55-3.46 (m,2H), 2.38 (d,lH), 2.31 (d,lH), 2.27-2.16 (m,3H), 1.40 (s,9H).

[0096] In one embodiment, the compound of formula VI is obtained by reduction of compound of formula VII-A

VII-A VI

[0097] wherein, R is selected from the group consisting of Ci-C₆ alkyl, Ci-C₆ alkoxy carbonyl, phenyl, benzyl or naphthyl; P is t-butyl.

[0098] 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.

[0099] 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

[0100] 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 Ci-C₆ alkyl, Ci-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.

[0101] 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.

[0102] 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.

[0103] 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"

[0104] 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.

[0105] 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.

[0106] 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 [0107] 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. [0108] 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.

[0109] 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.

[0110] In one embodiment, the acid activating compound may be selected from the group consisting of thionyl chloride, pivaloyl chloride, POCh, PCls, oxalyl chloride, EDC, DCC and the like.

[0111] In one embodiment, the base may be selected from the group consisting of organic base such as pyridine, DMAP (4-dimethylaminopyridine), tri ethyl 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.

[0112] In one embodiment, the compound of formula VIII-A is not isolated and carried forward in situ for further reaction.

[0113] In one embodiment, any of the compounds of formulae VIII-A, VII- A, VI are isolated by any method known in the art. The method, may involve any of the techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, evaporation by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the solution, cooling the solution if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.

[0114] 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. [0115] 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.

IX VIII VII

Scheme I

[0116] 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 VTT is obtained as depicted in scheme IV

Scheme IV

[0117] In one embodiment, any of the compounds of formulae VIII/VIIF, VQ/VII', VI are isolated by any method known in the art.

[0118] In one embodiment, any of the compounds of formula VIII/VIII', VQ/VII', VI are not isolated and carried forward in situ for further reaction.

[0119] 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 VTT

w.

[0120] 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.

[0121] In one embodiment, the present invention provides a process for the compound of formula vir

vir

comprising:

a) reacting compound of formula ΓΧ' with the compound of formula X in presence of acid activating agent and base to form the compound of formula Vffi';

o

NH o

Ph HO

ΓΧ' X

b) reacting the compound of formula VIIF with t-butyl bromoacetate in presence of base to obtain the compound of formula VII'.

VIIF

[0122] The acid activating agent and organic base used is selected from the group as discussed supra.

[0123] Preferably the acid activating agent is pivaloyl chloride and the organic base is triethyl amine.

[0124] In one embodiment, compound of formula VTT obtained by the process of the present invention is purified by using solvent selected from alkanes, ether and the like.

[0125] The alkane may be selected from the group consisting of hexane, heptane, cyclohexane and the like.

[0126] The ether may be selected from diisopropyl ether, cyclopentyl methyl ether, methyl tert butyl ether and the like.

[0127] In one embodiment, compound of formula VTT 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.

[0128] In one embodiment, the present invention provides a compound of formula VTT, (R)-tert- butyl 3((S)-4-phenyl-2-oxo oxazolidine-3-carbonyl)hex-5-enoate.

vir

[0129] In one embodiment, the present invention provides compound of formula VII' characterized by 1H NMR (400MHz, CDCh): δ 7.36-7.27 (m,5H), 5.86-5.75 (m,lH), 5.43-5.40 (m,lH), 5.12-5.07 (m,2H), 4.67 (t,lH), 4.36-4.29 (m,lH), 4.26-4.23 (m,lH), 2.71-2.64 (m,lH), 2.46-2.35 (m,2H), 2.23-2.16 (m,lH), 1.29 (s,9H); Mass: M/Z = 360 (M+H).

[0130] In one embodiment, the present invention provides substantially pure brivaracetam, the compound of formula I

I

[0131] In one embodiment, the present invention provides (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin- l-yl]butanamide, 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-l-yl]butanamide, the compound of formula I, as determined by HPLC.

[0132] In one embodiment, present invention provides substantially pure brivaracetam, the compound of formula I

I

with at least 99% w/w, wherein the level of impurity is less than 1%, as determined by HPLC.

[0133] In one embodiment the present invention provides a process for preparing substantially pure brivaracetam, the compound of formula I, comprising the steps:

a. dissolving brivaracetam in a solvent or mixture thereof; and

b. isolating brivaracetam by precipitation by lowering the reaction temperature, removing the solvent or by addition of antisolvent. [0134] In one embodiment, solvent is selected from the group consisting of an amide, Ci-C₆ ester, Ci-C₆ aliphatic ketone, Ci-C₆ carboxylic acid, Ci-C₆ carboxylic anhydride, Ci-C₆ aliphatic ether, Ci-C₄ haloalkane, C₆-Ci2 aromatic hydrocarbon, Ci-C₆ alcohol or mixtures thereof.

[0135] In one embodiment, the antisolvent is selected from the group consisting of aliphatic hydrocarbon, C₆-Ci2 cyclic hydrocarbon.

[0136] In one embodiment the present invention provides a process for preparing substantially pure brivaracetam, the compound of formula I, comprising the steps:

i. dissolving brivaracetam in a solvent or mixture of solvent wherein solvent is alkane or mixture of alkane with acetate; and

i. isolating brivaracetam by precipitation or by lowering the reaction temperature or removing the solvent or by addition of antisolvent to obtain brivaracetam in a diastereomeric excess of at least 99.5% .

[0137] The alkane may be selected from hexane, cyclohexane, heptane, octane and the like.

[0138] The acetate may be selected from ethyl acetate, isopropyl acetate, butyl acetate and the like.

[0139] 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.

[0140] The present invention provides another process for the preparation of brivaracetam, a compound of formula I c

IV

a) reducing a compound of formula IV to obtain brivaracetam a compound of formula I.

b) 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. [0141] 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.

[0142] In one embodiment, the compound of formula IV is obtained by reacting a compound of formula II, wherein Ri is selected from the group consisting of halogen, mesylate, tosylate, and nosylate; R₂ is selected from the group consisting of OH, halogen and O-Ci-6 alkyl with (S)-2- aminobutanamide, a compound of formula III or salt thereof

II III IV.

[0143] In one embodiment, the compound of formula IV is obtained by reacting a compound of formula II, wherein Ri is halogen; R₂ is selected from the group consisting of OH, halogen with (S)-2-aminobutanamide, a compound of formula III or salt thereof.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] In one embodiment, the compound of formula XIII, wherein Ri is selected from the group consisting of halogen, mesylate, tosylate, and nosylate formed by reaction of compound of formula II with compound of formula III or salt thereof, may or may not be isolated and carried forward in situ for further reaction to form the compound of formula IV.

ΧΙΠ

[0148] In one embodiment, the compound of formula IV is obtained by reacting a compound of formula ΙΓ; with (S)-2-aminobutanamide, a compound of formula III or salt thereof

ΙΓ III IV.

[0149] In one embodiment, the present invention provides a process for the compound of formula IV

IV

comprising:

a) reducing the compound of formula VQ' to obtain the compound of formula VI;

vir VI

b) reacting the compound of formula VI with carbon tetrabromide and triphenyl phosphine to obtain the compound of formula Π";

O CH₃

H₃C

Π"

c) reacting the compound of formula Π" with (S)-2-aminobutanamide or salt thereof, a compound of formula III to obtain the compound of formula XII, which may or may not be isolated; and

III XII

d) cyclizing the compound of formula XII with an acid to obtain the compound of formula IV.

[0150] In one embodiment, the present invention provides a compound of formula Π, wherein Ri is selected from the group consisting of halogen, mesylate, tosylate, and nosylate; R₂ is selected from the group consisting of OH, halogen and O-Ci-6 alkyl by ring opening of compound of formula V with

H₂C^ H₂C^

V II

a)trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride optionally followed by reaction with thionyl chloride or oxalyl chloride; or b)HBr, HC1 or HI optionally in presence of alcohol; or c)thionyl chloride and zinc chloride; or d) niesyl chloride, tosyl chloride, nosyl chloride followed by hydrolysis under basic conditions.

[0151] In one embodiment, the present invention provides a compound of formula II wherein Ri is halogen; R₂ is halogen, b rin o enin of com ound of formula V with

V II

trimethylsilyl iodide, trimethylsilyl bromide or trimethylsilyl chloride optionally followed by reaction with thionyl chloride or oxalyl chloride.

[0152] In one embodiment, the present invention provides a compound of formula ΙΓ

V by ring opening of compound of formula V with trimethylsilyl iodide, followed by reaction with thionyi chloride.

[0153] 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.

[0154] 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 thionyi chloride or oxalyl chloride; and then further reacted with the compound of formula III.

[0155] In one embodiment, the compound of formula IV is obtained by reacting the compound of formula V with HBr, HC1 or HI optionally in presence of alcohol; and then further reacted with the compound of formula III.

[0156] In one embodiment, the compound of formula IV is obtained by reacting the compound of formula V with thionyi chloride and zinc chloride; and then further reacted with the compound of formula III

[0157] In one embodiment, the compound of formula IV is obtained by reacting the compound of formula V with mesyi chloride, tosyl chloride or nosyl chloride followed by hydrolysis under basic conditions; and then further reacted with the compound of formula III.

[0158] In one embodiment, after addition of compound of formula III, a base selected from an organic base or an inorganic base, is added to the reaction mass.

[0159] In embodiment, after addition of compound of formula III, base is added to the reaction mass, optionally in presence of phase transfer catalyst.

[0160] In one embodiment, the present invention provides a compound of formula IV substantially free of other diastereoisomers, without chiral chromatography.

[0161] In one embodiment, the present invention provides enantiomerically pure compound of formula IV. [0162] In one embodiment, the present invention provides enantiomerically pure compound of formula IV containing less than 1% of (2R,4S) and/or (2S,4S) and/or 2R,4R isomers with respect to (2S)-2-[(4R)-4-allyl-2-oxo-4-(prop-2-en-lyl)pyrrolidin-l-yl]butanamide, the compound of formula IV, as determined by HPLC.

[0163] In one embodiment, the compound of formula V is obtained by reduction of the compound of formula VII-A, followed by acid catalyzed cyclization

VII-A V

wherein, R is selected from the group consisting of Ci-C₆ alkyl, Ci-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.

[0164] In one embodiment, the present invention provides a process wherein the compound of formula V is obtained by reduction of the compound of formula VII-A with alkali metal hydrides, alkali metal borohydride such as lithium aluminium hydride, sodium borohydride, VITRIDE^®, sodium cyanoborohydride, tetrabutylammonium borohydride and the like, in a solvent followed by acid catalyzed cyclization.

[0165] In one embodiment, the present invention provides a process wherein the compound of formula V is obtained by reduction of the compound of formula VII-A wherein R is phenyl and P is t-butyl, a compound of formula VTT, with sodium borohydride in a solvent followed by acid catalyzed cyclization.

vir V

[0166] In one embodiment, the solvent may be selected from the group consisting of THF, alcohol, water and mixtures thereof.

[0167] In one embodiment, acid catalyzed cyclization can carried out by using an acid selected from the group of consisting of inorganic acid, organic acid, lewis acid or mixture thereof for example hydrochloric acid, sulfuric acid, phosphorus pentoxide, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, p-toluene sulfonic acid, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.

[0168] In one embodiment, the present invention provides a process wherein the compound of formula V is obtained from the compound of formula VI.

VI V

[0169] In one embodiment, the present invention provides a process wherein the compound of formula V is obtained from the compound of formula VI by acid catalyzed cyclization, which can be selected from the group of consisting of inorganic acid, organic acid, lewis acid or mixture thereof for example hydrochloric acid, sulfuric acid, phosphorus pentoxide, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, p-toluene sulfonic acid, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.

[0170] In one embodiment, the compound of formula VI is not isolated and carried forward for further reaction.

[0171] In one embodiment, the present invention provides a process wherein the compound of formula V is obtained from the compound of formula VII- A.

[0172] In one embodiment, the present invention provides brivaracetam obtained by the processes herein described, having D90 particle size of less than about 250 microns, D50 particle size of less than about 100 microns, D₁₀ particle size of less than about 30 microns.

Instrumental Settings

[0173] Proton NMR spectra were recorded in CDCh and DMSO-de using NMR instrument-

Vanan 300 MHZ.

[0174] 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 7μΜ 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, 5μ. 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 9μΜ 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.

[0175] 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

[0176] Example 1: Preparation of (4S)-3-(pent-4-enoyl)-4-phenyl-l,3-oxazolidin-2-one (compound VIII')

4-Pentenoic acid (compound X), 4-dimethylammoniumpyridine (DMAP) was added to a mixture of methylene dichloride and DMF at about 20°C to about 30°C and the reaction mass was cooled to about 15°C to about 20°C. Triethylamine and (S)-(+)-4-Phenyl-2-oxazolidinone (compound ΓΧ') was added to the reaction mass and the reaction mass was stirred for about 5-10 minutes. The reaction mass was then cooled to about 0°C to about 5°C. A solution of pivaloyl chloride in methylene dichloride was added to the reaction mass. The temperature of reaction mass was then raised to about 25°C to about 30°C and stirred for about 10-15 hours. After completion of reaction, the reaction mass was quenched in dilute sulfuric acid at about 0°C to about 5°C. The temperature of the reaction mass was raised to about 20°C to about 30°C and layers were separated. The aqueous layer was extracted with methylene dichloride. After washing with 5% potassium carbonate solution followed by brine, the organic layer was distilled off completely under reduced pressure to obtain oily residue. To this oily mass, cyclohexane was added at about 50°C to about 55°C and the reaction mass was cooled gradually to about 20°C to about 30°C and stirred for 2 hours, the reaction mass was filtered, the residue obtained was dried to get (4S)-3-(pent-4-enoyl)- 4-phenyl-l,3-oxazolidin-2-one (compound Vffl') as off-white to pale yellow solid. HPLC Purity more than 98.0%.

[0177] Example 2: Preparation of (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VTT)

To a solution of (4S)-3-(pent-4-enoyl)-4-phenyl-l,3-oxazolidin-2-one (compound VTfl') in THF, 2M sodium hexamethyldisilazane (NaHMDS) was added at about -70°C to about -80°C over a period of around 1 hour and the reaction mass was stirred for about 2-3 hours at about -70°C to about -80°C. t-butyl bromoacetate was added to the reaction mass in about 30-45 minutes and the reaction mass was stirred for 1 hour at about -70°C to about -80°C. After completion of reaction, the temperature of reaction mass was raised to about -10°C to about -20°C and quenched in saturated ammonium chloride solution. The obtained mass then stirred for about 10-15 minutes and the layers were separated. The aqueous layer was extracted with ethyl acetate. After washing with brine, the organic layer was distilled off under reduced pressure and the residue was recrystallized using n-heptane to get (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (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).

[0178] Example 2A: Preparation of (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VIF)

Process was same as described in Example 2 where t-butyl bromoacetate was added to the reaction mass in about 30-45 minutes and the reaction mass was stirred for 1 hour at about -85°C 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).

[0179] Example 3: Purification of (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VIP)

(R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate (compound VIP) as obtained in Example 2 was dissolved in Diisopropyl ether by heating at about 65°C to about 70°C. The clear solution was cooled to room temperature, filtered, dried to get pure (R)-tert-butyl 3-((S)- 4-phenyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate, as off white solid with purity: 99.16%; SS isomer - ND; SOR - [a] 25/D +105° (C=1.0 in Methanol).

1H NMR (400MHz, CDCh): δ 7.36-7.27 (m,5H), 5.86-5.75 (m,lH), 5.43-5.40 (m,lH), 5.12-5.07 (m,2H), 4.67 (t,lH), 4.36-4.29 (m,lH), 4.26-4.23 (m,lH), 2.71-2.64 (m,lH), 2.46-2.35 (m,2H), 2.23-2.16 (m,lH), 1.29 (s,9H); Mass: M/Z = 360 (M+H).

[0180] Example 4: Preparation of tert-butyl (3R)-3-(hydroxymethyl)hex-5-enoate (compound VI)

(R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate (compound VIP) was added to mixture of THF and water. Sodium borohydride was added in portions to the reaction mass and the reaction mass was stirred for about 15 to 20 hours at about 20°C to about 30°C. After completion of the reaction, the reaction mass was quenched with acetic acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate and distilled under vacuum to get pale yellow oil. To the obtained oil, diisopropyl ether was added and the reaction mass was cooled to 10°C to about 15°C and stirred for about lhour. The reaction mass was filtered and washed with diisopropyl ether. The solvent was distilled off from the filtrate under reduced pressure to get tert-butyl (3R)-3-(hydroxymethyl)hex-5-enoate (compound VI). 1H NMR (400MHz, CDC13): δ 5.79-5.68 (m,lH), 5.15-5.10 (m,2H), 3.55-3.46 (m,2H), 2.38 (d,lH), 2.31 (d,lH), 2.27-2.16 (m,3H), 1.40 (s,9H).

[0181] Example 5: Preparation of t-butyl (3R)-3-(bromomethyl)hex-5-enoate (compound Π") (R)-tert-butyl (3R)-3-hydroxymethyl)hex-5-enoate (compound VI) was dissolved in methylene di chloride and the reaction mass was cooled to about 10°C to about 15°C. Triphenyl phosphine was added in portions over about 15 minutes under vigorous stirring to the reaction mass. After addition, the reaction mass was stirred at about 25°C to about 15°C and N-Bromosuccinimide was added in lots. After completion of reaction, n-heptane was added to the reaction mass and stirred. The precipitate was filtered, filtrate was concentrated under vacuum at about 25 °C to about 30°C and n-hepate was added to the obtained residue. The reaction mass was cooled to about -10°C to about -5°C and stirred. The reaction mass was filtered, and n-heptane was distilled off to get oily mass. The oily mass was dissolved in n-heptane and washed with mixture of acetic acid: methanol: water followed by water washings and distillation to get t-butyl (3R)-3- (bromomethyl)hex-5-enoate (compound Π") as a colorless oil.

1H NMR (400MHz, CDC13): δ 5.79-5.68 (m,lH), 5.15-5.10 (m,2H), 3.55-3.46 (m,2H), 2.38 (d,lH), 2.31 (d,lH), 2.27-2.16 (m,3H), 1.40 (s,9H).

[0182] 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, t-butyl (3R)-3-(bromomethyl)hex-5- enoate (compound Π"), (S)-2-aminobutanamide hydrochloride (compound III), tetrabutylammonium iodide, sodium carbonate and isopropyl acetate were charged. The reaction mass was heated to reflux for about 28 hours and then 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)-l -amino-l-oxobutan-2-yl]amino}methyl)hex-5-enoate (compound XII) as oily mass.

1H NMR (400MHz, DMSO): δ 7.27 (s,lH), 6.97 (s,lH), 5.80-5.70 (m,lH), 5.00-4.99 (m,2H), 3.35 (bs,lH), 2.76 (t, lH), 2.47-2.43 (m,lH), 2.25-2.11 (m,4H), 2.05-1.82 (m,2H), 1.40 (m,l lH), 0.86 (t,3H); Mass: M/Z = 285 (M+H)

[0183] 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, t-butyl (3R)-3-(bromomethyl)hex-5- enoate (compound Π"), (S)-2-aminobutanamide hydrochloride (compound III), tetrabutylammonium iodide, sodium carbonate and isopropyl acetate were charged. The reaction mass was heated to reflux for about 28 hours and then 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)-l-amino-l-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 to about 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 to about 55°C. The reaction mass was cooled to room temperature and stirred. The reaction mass was filtered and obtained t-butyl (3R)-3-({[(2S)-l-amino-l-oxobutan-2- yl]amino}methyl)hex-5-enoate, tartrate (compound XII-A) was dried. Chemical purity more than 98.0%, Chiral purity - 99.74%, R,R Isomer - 0.20%, S,S Isomer -0.06%.

1H NMR (400MHz, DMSO): δ 7.6 (s,lH), 7.3 (s,lH), 7.3 (bs,2H), 5.79-5.69 (m,lH), 5.06-5.10 (m,2H), 4.1 (s,lH), 3.1 (t,lH), 2.58-2.43 (m,3H), 2.33-2.28 (m,lH), 2.17-2.00 (m,5H), 1.63-1.56 (m,3H), 1.40 (s,9H), 0.87 (t,3H); Mass: M/Z = 285 (M+H), 149 (M-H),

[0184] Example 8: Preparation of tert-butyl (3R)-3 -({[(2S)-1 -amino- 1 -oxobutan-2- yl]amino}methyl)hexanoate, tartrate (compound XIV A)

t-butyl (3R)-3-({[(2S)-l-amino-l-oxobutan-2-yl]amino}methyl)hex-5-enoate, tartrate was hydrogenated using 10% Pd/C in methanol: water at about 15°C to about 20°C at 2Kg/cm². The reaction mass was stirred for about lto 1.5 hours. After completion of reaction, the catalyst was filtered and filtrate was evaporated to yield white solid. To this solids, added isopropyl acetate and reaction mass was stirred. The reaction mass was filtered and vacuum dried to get t-butyl (3R)-3- ({[(2S)-l-amino-l-oxobutan-2-yl]amino}methyl)hexanoate, tartrate (compound XIV A) as white solid.

1H NMR (400MHz, DMSO): δ 7.65 (s,lH), 7.3 (s,lH), 7.2 (bs,2H), 4.12 (s,2H), 3.17 (t,lH), 2.59- 2.51 (m,2H), 2.37-2.32 (m,lH), 2.16-2.11 (m,lH), 1.98-1.95 (t,lH), 1.64 -1.60 (t,3H), 1.39 (s,9H), 1.32-1.19 (m,4H), 0.89-0.84 (m,6H) ; Mass: M/Z = 287 (M+H), 149 (M-H).

[0185] Example 9: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I) In a clean and dry assembly under nitrogen atmosphere, t-butyl (3R)-3 -({[(2S)-1 -amino- 1- oxobutan-2-yl]amino}methyl)hexanoate, tartrate was charged in the mixture of isopropyl acetate and isopropyl alcohol and the reaction mass was heated to about 60°C to about 65°C. Acetic acid was added slowly to the reaction mass over a period of about 30 minutes and the reaction mass was stirred for about 36 hours at about 80°C to about 90°C. The reaction mass was cooled to about 0°C to about 10°C, filtered through celite and the celite was washed with isopropyl acetate. The filtrate was distilled out under vacuum to get oily mass. The oily mass was dissolved in ethyl acetate. The Ethyl acetate layer further washed with Sodium chloride solution. The pH of the Ethyl acetate layer was adjusted to about 7 with sodium bicarbonate, stirred and layers were separated. The organic phase washed with water and distilled under vacuum to obtain (2S)-2-[(4R)-2-oxo-4- propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I) as a yellow solid (4.0g) with purity 96.0% and Chiral purity 99.45%, compound IA (S,S isomer) - 0.05%, R,S isomer -0.07%, R,R isomer - 0.43%.

1H NMR (400MHz, CDC13): δ 6.54 (brs,lH), 5.92 (brs,lH), 5.67-5.92 (m,lH), 5.05-5.10 (m, 2H), 4.47 (dd,lH), 3.49 (dd,lH), 3.15 (dd,lH), 2.55-2.61 (m,lH), 2.38-2.45 (m,lH), 2.13-2.20 (m,3H), 1.87-1.97 (m,lH), 1.64-1.69 (m,lH), 0.88 (t,3H); Mass: M/Z = 211.15 (M+H)

[0186] Example 10: Purification of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I)

2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide was added in mixture of isopropyl acetate and n-Heptane, the reaction mass was stirred for about 10 to 15minutes at room temperature. The reaction mass was heated further at about 55°C to about 60°C to get clear solution. The reaction mass then then cooled to about 20°C to about 25°C. The solid was filtered, washed with mixture of isopropyl acetate and n-Heptane and dried to obtain pure (2S)-2-[(4R)-2-oxo-4- propylpyrrolidin-l-yl]butanamide (Brivaracetam compound I); with chemical purity 99.88% and 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 HLC data

XRPD characterization

[0187] Example 11: Purification_of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I)

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide was added in n-Heptane and the reaction mass was heated to about 55°C to about 60°C and ethyl acetate was added to the reaction mass to obtain clear solution. The reaction mass was then cooled to about 20°C to about 25°C. The solid was filtered, washed with mixture of ethyl acetate and n-heptane and dried to obtain pure (2S)-2- [(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide (Brivaracetam compound I). Chemical Purity: 99.79%; chiral purity 99.89%, compound IA (S,S isomer - 0.06%), R,S isomer - not detected, R,R isomer - 0.05%, SOR - [a]25/D -57.15° (C=1.0 in Methanol).

[0188] Example 12: Preparation (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound TV)

In a clean and dry assembly under nitrogen atmosphere, t-butyl (3R)-3 -({[(2S)-1 -amino- 1 - oxobutan-2-yl]amino}methyl)hex-5-enoate, tartrate was charged in a mixture of isopropyl acetate and isopropyl alcohol and then heated to about 60°C to about 65°C. Acetic acid was added slowly to the reaction mass over a period of about 30 minutes and then stirred for about 36 hours at about 80°C to about 90°C. The reaction mass was cooled to about 0°C to about 10°C, the reaction mass was filtered and washed with isopropyl acetate. The filtrate was distilled out under vacuum to get oily mass and dissolved in ethyl acetate. The ethyl acetate layer further washed with sodium chloride solution. The pH of the ethyl acetate layer was adjusted to about 7-8 with sodium bicarbonate, the reaction mass was stirred and layers were separated. The organic phase was washed with water and distilled under vacuum to obtain (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l- yl]butanamide (compound IV) as a yellow semisolid.

[0189] Example 13: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide (Brivaracetam compound I)

(2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV) was hydrogenated using 10% Pd/C in methanol at about 25°C to about 30°C and 2Kg/cm² pressure. The reaction was stirred for about 1 to 1.5 hours. After completion of the reaction, the catalyst was filtered and solvent was evaporated to yield (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide (Brivaracetam compound I). Chiral purity 98.97%, compound IA (S,S isomer) 0.5%, R,S isomer -0.03%, R,R isomer - 0.5%.

[0190] Example 14: Preparation of (2S)-2-[(4R)-4-allyl-2-oxo-4-(prop-2-en-lyl)pyrrolidin-l- yl]butanamide (compound IV)

In a clean and dry assembly under nitrogen atmosphere, t-butyl (3R)-3 -({[(2S)-1 -amino- 1- oxobutan-2-yl]amino}methyl)hex-5-enoate (compound XII) was charged in about 9 to about 10 volume of isopropyl acetate and then heated to about 60°C to about 65oC. Acetic acid was added slowly to the reaction mass over a period of about 30 minutes and then stirred for about 90 minutes at about 60°C. The reaction mass was cooled to about 25°C to about 30°C, filtered and the wet cake was washed with isopropyl acetate. The pH of the filtrate was adjusted to about 7 with sodium bicarbonate, stirred and layers were separated. The organic phase was distilled under vacuum to obtain 2S)-2-[(4R)-4-allyl-2-oxo-4-(prop-2-en-lyl)pyrrolidin-l-yl]butanamide (compound IV) as a yellow semi solid.

[0191] Example 15: Preparation of (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV)

Trimethyl silyl iodide was added over a period of 1 hour, to a solution of (4R)-4-allyldihydrofuran- 2(3H)-one (compound V) in methylene dichloride at about 0°C to about 5°C. The reaction temperature was then raised to about 20°C to about 30°C and stirred for about 2 to 3 hours. After completion, the reaction was quenched in IN hydrochloric acid and stirred for 1 hour at about 20°C to about 30°C. The layers were separated and organic layer was extracted with 5% sodium thiosulphate solution. The organic layer then washed with sodium chloride solution, dried over sodium sulphate and distilled out under vacuum to obtain oily residue. The oily residue was dissolved in toluene, thionyl chloride was added and stirred for about 2 to 3 hours. After completion of reation, the solvents were distilled off under vacuum to obtain acid chloride. The acid chloride was dissolved in methylene dichloride.

In another assembly, (S)-2-aminobutanamide hydrochloride, sodium sulphate and TBAB was added in methylene dichloride and reactin mass was cooled to about 0°C to about 5°C. Powdered potassium carbonate (20g) was added to the reaction mass. To this reaction mass, acid chloride solution was slowly added and reaction mass was stirred for about 7 to 8 hours. The reaction mass then filtered, washed with dichloromethane and distilled off under reduced pressure to get (2S)-2- [(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV). HPLC purity of about 90% to about 95%.

1H NMR (400MHz, CDC13): δ 6.54 (brs,lH), 5.92 (brs,lH), 5.67-5.92 (m,lH), 5.05-5.10 (m,2H), 4.47 (dd,lH), 3.49 (dd,lH), 3.15 (dd,lH), 2.55-2.61 (m,lH), 2.38-2.45 (m,lH), 2.13-2.20 (m,3H), 1.87-1.97 (m,lH), 1.64-1.69 (m,lH), 0.88 (t,3H)

Mass: M/Z = 211.15 (M+H)

[0192] Example 16: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I)

t-butyl (3R)-3-({[(2S)-l-amino-l-oxobutan-2-yl]amino}methyl)hexanoate and HOBt were added to toluene. The solution was 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 to the reaction mass at room temperature. The reaction mass was extracted with ethyl acetate. The combined 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-l-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%.

[0193] Example 17: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I) (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV) was hydrogenated using 10% Pd/C in methanol at about 25°C to about 30°C at 3Kg/cm² pressure. The reaction mass was stirred for about 5 to 6 hours. After completion of reaction, the catalyst was filtered and solvent was evaporated to yield pale yellow solid. Obtained product was purified by column chromatography on silica gel to obtain (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide (compound I, 0.5 gm) as off white solid.

[0194] Example 18: Purification of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I)

Crude (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide was added in diisopropyl ether and stirred for about 10 to 15 minutes. The reaction mass was heated at about 50 °C to about 55°C to get clear solution. The reaction mass was filtered; filtrate was then cooled to about 0°C to about 5°C. The solid was filtered and dried to obtain pure (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l- yl]butanamide (Brivaracetam compound I). XRPD characterized

[0195] Example 19: Preparation of (4S)-4-benzyl-3-pent-4-enoyl-l,3-oxazolidin-2-one (compound VIII)

4-Pentenoic acid (compound X) was added to a mixture of methylene dichloride and N,N-dimethyl formamide to obtain a reaction mass. Triethylamine was slowly added to the reaction mass at about 20°C to about 30°C and reaction mass was stirred for about 5 to 10 minutes. Dimethylaminopyridine followed by (4S)-benzyl-l ,3-oxazolidin-2-one (compound IX) was added to the reaction mass, at about 20°C to about 30°C. A solution of pivaloyl chloride in methylene dichloride was added to the reaction mass at about 20°C to about 25°C over a period of around 1 hour and the reaction mass was stirred for about 3 hours at about 20°C to about 30°C. After completion of reaction, it was quenched in dilute sulfuric acid at about 0°C to about 5°C and extracted with methylene dichloride. After washing with 5% sodium bicarbonate solution & brine, the organic layer was distilled under vacuum. The crude product was purified on silica gel (n- Hexane/Ethyl acetate; 9.6:0.4) to get (4S)-4-benzyl-3-pent-4-enoyl-l,3-oxazolidin-2-one (compound VIII) as a pale yellow oil.

[0196] Example 20: Preparation of (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VII)

To a solution of (4S)-4-benzyl-3-pent-4-enoyl-l,3-oxazolidin-2-one (compound VIII) in THF, sodium HMDS was added at about -65°C to about -75°C over a period of about 30 minutes and reaction mass was stirred for about 4 hours at about -65°C to -75°C. t-butyl bromoacetate was added to the reaction mass in 30 to 45 minutes at about -65°C to about -75°C and reaction mass was stirred for 1 hour at about -65°C to about -75°C. After completion of reaction, temperature was raised to about - 10°C to about -20°C. The reaction mass was quenched in saturated ammonium chloride solution and extracted with ethyl acetate. After washing with brine, the organic layer was distilled under vacuum and crystallized to get (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VII) as a white solid.

[0197] Example 21: Preparation of t-butyl (3R)-3-(hydroxymethyl)hex-5-enoate (compound VI) Sodium borohydride was added to a solution of (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine- 3-carbonyl)hex-5-enoate (compound VII) in THF/water mixture and stirred for about 15 to 20 hours at about 20°C to about 30°C. After completion, reaction mass was quenched in saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and distilled under vacuum to get tert-butyl (3R)-3- (hydroxymethyl)hex-5-enoate (compound VI) as a pale yellow oil.

[0198] Example 22: Preparation of (4R)-4-allyldihydrofuran-2(3H)-one (compound V)

To a solution of t-butyl (3R)-3-(hydroxymethyl)hex-5-enoate (compound VI) in methylene dichloride, p-toulene sulfonic acid was added and the reaction mass was refluxed for about 3 hours. After completion of reaction, the reaction mass was quenched with brine. The organic layer was distilled under vacuum and the crude oil was obtained; purification was carried by column chromatography on silica gel to get (4R)-4-allyldihydrofuran-2(3H)-one (compound V) as a pale yellow oil.

[0199] Example 23: Preparation of (3R)-3-(iodomethyl)hex-5-enoic acid

Trimethylsilyl iodide was added to a solution of (4R)-4-allyldihydrofuran-2(3H)-one (compound V) in methylene dichloride at about 0°C to about 5°C and stirred for about 2 to 3 hours at about 20°C to about 30°C. After completion of reaction, 1 N hydrochloric acid was added and reaction mass was stirred for about 1 hour at about 20°C to about 30°C. Aqueous layer was extracted with methylene dichloride. The organic layer was washed with brine and distilled under vacuum to obtain (3R)-3-(iodomethyl)hex-5-enoic acid as a pale yellow oil.

[0200] Example 24: Preparation of (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV)

Thionyl chloride was added to a solution of (3R)-3-(iodomethyl)hex-5-enoic acid (compound II'")in toluene and stirred for about 12 hours at about 20°C to about 30°C. After completion of reaction, solvent was distilled out under vacuum at about 35°C to about 40°C to obtain acid chloride. The acid chloride was added drop wise to methylene chloride solution of (S)-2-amino butanamide hydrochloride (compound III), sodium sulphate, tetrabutyl ammonium bromide and powdered potassium hydroxide at about 0°C to about 5°C. The reaction mixture was stirred for about 4 to 5 hours. After completion, reaction mass was filtered. The organic layer was distilled under vacuum to obtain crude product. The crude product obtained was crystallized from ethyl acetate/n-heptane to get (2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV) as pale yellow solid.

[0201] Example 25: Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide (Brivaracetam compound I)

(2S)-2-[(4R)-4-allyl-2-oxopyrrolidin-l-yl]butanamide (compound IV) was hydrogenated using 10% Pd/C in methanol at about 25°C to about 30°C and 3Kg/cm² pressure. The reaction mass was stirred for about 5 to 6 hours. After completion of the reaction, the catalyst was filtered and solvent was evaporated to yield pale yellow solid. It was purified by column chromatography on silica gel to obtain (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl]butanamide (Brivaracetam compound I) as yellow solid.

[0202] Example 26: Preparation of (4R)-4-allyldihydrofuran-2(3H)-one (compound V) Sodium borohydride was added to the solution of Preparation of (R)-t-butyl 3-((S)-4-phenyl-2- oxooxazolidine-3-carbonyl)hex-5-enoate (compound VTT) in THF, water mixture at about 20°C to about 30°C and reaction mass was stirred overnight. After completion of the reaction, the reaction mass was quenched in saturated ammonium chloride solution and layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated under vacuum to get pale yellow oil.

The obtained oil was dissolved in methylene dichloride; p-toulene sulfonic acid was added to the reaction mass and the reaction mass was stirred at about 30°C to about 35°C. After completion of the reaction, the reaction mass was quenched with water. The layers were separated and the organic layer was distilled off under vacuum to get oily residue. The temperature was raised to about 90°C to about 120°C to distill out oily residue under high vacuum to get pure (4R)-4-allyldihydrofuran- 2(3H)-one (compound V) as a pale yellow oil, [a]D17.9= +24°, (c 1.02, CHC13). 1H NMR (400MHz, CDC13): δ 5.76-5.68 (m,lH), 5.12-5.07 (m,2H), 4.40-4.36 (m,lH), 4.00 (dd,lH), 2.67- 2.60 (m,2H), 2.23-2.19 (m,3H).

[0203] Example 27: 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 μπι 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%; diasteromenc excess (d.e) 97.94%; compound IA (S,S isomer) 1.021%. Chiral HPLC data

Claims

1] A process for the preparation of (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam), a compound of formula I comprising

I

XII XIV

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 claiml, 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 Ri is selected from the group consisting of mesylate, tosylate, and nosylate ; R₂ is O- C(CH₃)₃; or

li) carbon tetrabromide or N-halosuccinimide and triphenyi phosphine, hydrogen bromide or bromine in acetic acid to obtain the compound of formula II, wherein Ri is halogen selected from the group consisting of CI, Br, I; R₂ is 0-C(CH3)3.

Ill

(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 reduction of VII- A

VII-A VI

wherein, R is selected from the group consisting of Ci-C₆ alkyl, Ci-C₆ alkoxy carbonyl, phenyl, benzyl, or naphthyl; P is carboxyl protecting group selected from the group consisting of Ci-C₆ alkyl, benzhydryl, o-nitrobenzyl, p-nitrobenzyl, benzyl.

8] The process as claimed in claim 7, wherein the compound of formula VII-A is obtained as depicted in scheme belo

VII-A

wherein R is selected from the group consisting of Ci-C₆ alkyl, Ci-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 Ci-C₆ alkyl, benzhydryl, o- nitrobenzyl, p-nitrobenzyl, benzyl; substituent X is halogen.

9] The process as claimed in claim 8, wherein R is phenyl, benzyl or isopropyl; P is t-butyl; substituent X is halogen.

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

IX' VIII'

11] A composition comprising (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam), a compound of formula I

I

XII XIV

12] A composition comprising an isolated compound of formula I, (2S)-2-[(4R)-2-oxo-4- propyltetrahydro-lH-pyrrol-l-yl] butanamide (brivaracetam),

I

IA

is less than 1% w/w of brivaracetam as determined by chiral HPLC.

A compound represented by formula XII or salt thereof

XII.

13] The compound as claimed in claim 12, wherein the salt of compound of formula XII is tartrate salt, compound XIIA.

XIIA

14] Use of a compound XII or salt thereof, in the preparation of brivaracetam, a compound of formula I. 15] A process for the preparation of brivaracetam, a compound of formula I comprising reducing a compound of formula IV to obtain brivaracetam a compound of formula I

16] The process as claimed in claim 15, wherein the compound of formula IV is obtained by reacting a compound of formula II, wherein Ri is selected from the group consisting of halogen, mesylate, tosylate, and nosylate; R₂ is selected from the group consisting of OH, halogen and O- Ci-C₆ alkyl with (S)- -aminobutanamide, a compound of formula III

II III IV.

17] The process as claimed in claim 15, wherein the compound of formula IV is obtained by reacting a compound of formula V, with (S)-2-aminobutanamide, a compound of formula III

V III IV

18] The process as claimed in claim 16, wherein the compound of formula II is obtained by ring opening of the compound of formula V with

V II

(a) trimethylsilyi iodide, trimethylsilyi bromide optionally followed by reaction with thionyl chloride or oxalyl chloride, or

(b) HBr, HQ or HI optionally in presence of alcohol, or

(c) thionyl chloride and zinc chloride; or

(d) mesyl chloride, tosyl chloride, nosyl chloride followed by hydrolysis under basic conditions.

19] The process as claimed in claim 18, wherein the compound of formula V is obtained by reduction of the compound of formula VII- A, followed by acid catalyzed cyclization

VII-A V

wherein, R is selected from the group consisting of Ci-C₆ alkyl, Ci-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, trimethylsilyi, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2- (trimethylethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4- pyridylmethyl.