WO2019087172A1 - Procédé pour la préparation de brivaracétam - Google Patents

Procédé pour la préparation de brivaracétam Download PDF

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Publication number
WO2019087172A1
WO2019087172A1 PCT/IB2018/059910 IB2018059910W WO2019087172A1 WO 2019087172 A1 WO2019087172 A1 WO 2019087172A1 IB 2018059910 W IB2018059910 W IB 2018059910W WO 2019087172 A1 WO2019087172 A1 WO 2019087172A1
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Prior art keywords
compound
formula
brivaracetam
salt
xii
Prior art date
Application number
PCT/IB2018/059910
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English (en)
Inventor
Ranjeet Nair
Shekhar Bhaskar Bhirud
Bhavin Prabhudas THANKI
Sanjay Shashikant BHISE
Shrikant Prabhakar KESHAV
Rajendra JAGDHANE
Ganesh Bhaskar CHAUDHARI
Nandkumar Gaikwad
Sandip GADGE
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Glenmark Pharmaceuticals Limited
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Priority claimed from IN201721045662A external-priority patent/IN201721045662A/en
Publication of WO2019087172A1 publication Critical patent/WO2019087172A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to a process for the preparation of brivaracetam and salts thereof.
  • BRIVIACT brivaracetam
  • 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.
  • 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
  • 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 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.
  • the invention provides methods of making brivaracetam, a compound of formula I, comprising
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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 27
  • Figure 3 is a characteristic XRPD of brivaracetam as obtained in Example 10.
  • Figure 4 is characteristic 1H NMR of compound of formula XIIA as obtained in Example
  • Ci-Ce alkyl refers to an aliphatic-hydrocarbon group which may be straight or branched having Ci-C 6 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.
  • C1-C6 alkylaryl refers to an aliphatic-hydrocarbon group which may be straight or branched having Ci-C 6 carbon atoms in the chain and attached to an aryl group like phenyl, benzyl, naphthyl, tolyl and the like.
  • halogen refers to iodo, bromo, chloro or fluoro.
  • diastereomeric excess 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
  • 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%.
  • 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%.
  • 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
  • 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
  • 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
  • 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 the like.
  • 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
  • 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.
  • 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.
  • 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.
  • 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 the like.
  • 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.
  • 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.
  • 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, ⁇ , ⁇ -dimethylacetamide and the like.
  • cyclization of the compound of formula XTVA may be carried out in presence of acid.
  • the acid may be selected as discussed supra.
  • 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.
  • brivaracetam salt may be generated insitu or may be isolated and which on treatment with base or base wash is converted to brivaracetam.
  • the process of the present invention provides brivaracetam, wherein the level of (2S,4S)-diastereomer of br ound of formula IA
  • brivaracetam is less than 1% w/w of brivaracetam as determined by chiral HPLC.
  • the present invention provides a composition comprising brivaracetam, a compound of formula I
  • the present invention provides a composition comprising an isolated compound of formula I, brivaracetam,
  • brivaracetam is less than 1% w/w of brivaracetam as determined by chiral HPLC.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • the present invention provides a process for a composition
  • 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 ⁇ 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%.
  • the present invention provides compound of formula XII, t-butyl (3R)- 3-( ⁇ [(2S)-l-amino-l-oxobutan-2-yl]amino ⁇ methyl)hex-5-enoate
  • the present invention provides compound XII, characterized by 1 -H NMR 400MHz, DMSO): ⁇ 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).
  • 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.
  • 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.
  • 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
  • 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,
  • the present invention provides compound of formula XIIA, characterized by 1-H NMR 1H NMR (400MHz, DMSO): ⁇ 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).
  • 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.
  • 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.
  • camphorsulfonic acid bromocamphorsulfonic acid, camphanic acid
  • camphoric acid diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyl tartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid,
  • the present invention provides compound of formula XIVA, tert-butyl (3R)-3-( ⁇ [(2S)- 1 -amino- 1 -oxobutan-2-yl]amino ⁇ methyl)hexanoate, tartrate.
  • the present invention provides compound of formula XIV A, characterized by 1H NMR (400MHz, DMSO): ⁇ 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).
  • the present invention provides a process for preparation of the compound of formula XII or a salt thereof by
  • the present invention provides a process for preparation of the compound of formula XII or a salt thereof by
  • the compound of formula II is obtained by reaction of compound of formula VI with
  • the present invention provides a process for preparation of the compound of formula XII or a salt thereof by
  • the brominating agent may be selected from the group consisting of carbon tetrabromide or N-bfomosuccinimide, hydrogen bromide or bromine in acetic acid
  • the compound of formula IT ' is obtained by reaction of compound of formula VI with carbon tetrabromide and triphenyl phosphine
  • the compound of formula ⁇ ' is obtained by reaction of compound of formula VI with N-bromosuccinimide and triphenyl phosphine.
  • reaction of compound of formula VI with brominating agent may be earned out by using reagents like triphenylphosphine, polymer bound triphenylphosphine and the like.
  • reaction of compound of formula II or ⁇ " with a compound of formula ⁇ may be carried out using a base selected from an organic base or an inorganic base.
  • the organic base is selected from the group consisting of amines, organolithiums, metal alkaloids, amides, tetraalkylammonium hydroxides, phosphonium hydroxides and the like.
  • the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines and heterocyclic amine.
  • the cyclic aliphatic amine is selected from the group consisting of piperidine and piperazine.
  • the trialkyl amine is selected from the group consisting of triethylamine and diisopropylethylamine (DIPEA).
  • 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).
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • DBN l,5-diazabicyclo[4.3.0]non-5-ene
  • DABCO 1,4- diazabicyclo[2.2.2]octane
  • pyridine pyrimidine
  • DMAP 4-(dimethylamino)pyridine
  • 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.
  • the reaction of compound of formula II or ⁇ " 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a compound of formula ⁇ ", tert-butyl (3R)-3-(bromomethyl)hex-5-enoate
  • the present invention provides a compound of formula ⁇ " characterized by 1H NMR (400MHz, CDC13): ⁇ 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).
  • the compound of formula VI is obtained by reduction of compound of formula VII-A
  • R is selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 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.
  • alkali metal borohydride such as lithium aluminium hydride, sodium borohydride, VITRIDE ® , sodium cyanoborohydride, tetrabutylammonium borohydride, sodium triacetoxyborohydride and the like.
  • the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A.
  • 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-C 6 alkyl, Ci-C 6 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
  • the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A, wherein R is phenyl.
  • the present invention provides a process wherein the compound of formula VII-A is obtained as depicted in scheme A, wherein R is benzyl.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • organic base such as pyridine, DMAP (4-dimethylaminopyridine), tri ethyl amine, Hunig's base, N- methylmorpholine, N-methylpiperidine and the like
  • the compound of formula VIII-A is not isolated and carried forward in situ for further reaction.
  • 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.
  • any of the compounds of formulae VIII-A, VII- A, VI are not isolated and carried forward in situ for further reaction.
  • 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.
  • 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
  • any of the compounds of formulae VIII/VIIF, VQ/VII', VI are isolated by any method known in the art.
  • any of the compounds of formula VIII/VIII', VQ/VII', VI are not isolated and carried forward in situ for further reaction.
  • the present invention provides a compound of formula VII-A wherein R is phenyl; P is t-butyl, a compound of formula VTT
  • 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.
  • the present invention provides a process for the compound of formula vir
  • the acid activating agent and organic base used is selected from the group as discussed supra.
  • the acid activating agent is pivaloyl chloride and the organic base is triethyl amine.
  • compound of formula VTT 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.
  • 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.
  • the present invention provides a compound of formula VTT, (R)-tert- butyl 3((S)-4-phenyl-2-oxo oxazolidine-3-carbonyl)hex-5-enoate.
  • the present invention provides substantially pure brivaracetam, the compound of formula I
  • 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.
  • present invention provides substantially pure brivaracetam, the compound of formula I
  • the present invention provides a process for preparing substantially pure brivaracetam, the compound of formula I, comprising the steps:
  • solvent is selected from the group consisting of an amide, Ci-C 6 ester, Ci-C 6 aliphatic ketone, Ci-C 6 carboxylic acid, Ci-C 6 carboxylic anhydride, Ci-C 6 aliphatic ether, Ci-C 4 haloalkane, C 6 -Ci2 aromatic hydrocarbon, Ci-C 6 alcohol or mixtures thereof.
  • the antisolvent is selected from the group consisting of aliphatic hydrocarbon, C 6 -Ci2 cyclic hydrocarbon.
  • the present invention provides a process for preparing substantially pure brivaracetam, the compound of formula I, comprising the steps:
  • brivaracetam 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% .
  • the alkane may be selected from hexane, cyclohexane, heptane, octane and the like.
  • the acetate may be selected from ethyl acetate, isopropyl acetate, butyl acetate and the like.
  • 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 c
  • 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.
  • 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; R 2 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
  • the compound of formula IV is obtained by reacting a compound of formula II, wherein Ri is halogen; R 2 is selected from the group consisting of OH, halogen with (S)-2-aminobutanamide, a compound of formula III or salt thereof.
  • 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.
  • 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.
  • 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.
  • TBAB tetrabutyl ammonium bromide
  • TBAF tetrabutyl ammonium fluoride
  • TBAH tetrabutyl ammonium hydroxide
  • TBAI tetrabutyl ammonium iodide
  • crown ether phosphonium salts and the like.
  • 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.
  • the compound of formula IV is obtained by reacting a compound of formula ⁇ ; with (S)-2-aminobutanamide, a compound of formula III or salt thereof
  • the present invention provides a process for the compound of formula IV
  • the present invention provides a compound of formula ⁇ , wherein Ri is selected from the group consisting of halogen, mesylate, tosylate, and nosylate; R 2 is selected from the group consisting of OH, halogen and O-Ci-6 alkyl by ring opening of compound of formula V with
  • the present invention provides a compound of formula II wherein Ri is halogen; R 2 is halogen, b rin o enin of com ound of formula V with
  • trimethylsilyl iodide trimethylsilyl bromide or trimethylsilyl chloride optionally followed by reaction with thionyl chloride or oxalyl chloride.
  • the present invention provides a compound of formula ⁇
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • a base selected from an organic base or an inorganic base is added to the reaction mass.
  • base is added to the reaction mass, optionally in presence of phase transfer catalyst.
  • the present invention provides a compound of formula IV substantially free of other diastereoisomers, without chiral chromatography.
  • the present invention provides enantiomerically pure compound of formula IV.
  • 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.
  • the compound of formula V is obtained by reduction of the compound of formula VII-A, followed by acid catalyzed cyclization
  • R is selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 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-
  • 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.
  • alkali metal hydrides such as lithium aluminium hydride, sodium borohydride, VITRIDE ®
  • sodium cyanoborohydride sodium cyanoborohydride
  • tetrabutylammonium borohydride and the like
  • 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.
  • the solvent may be selected from the group consisting of THF, alcohol, water and mixtures thereof.
  • 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.
  • 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, hex
  • the present invention provides a process wherein the compound of formula V is obtained from the compound of formula VI.
  • 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.
  • 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 sulf
  • the compound of formula VI is not isolated and carried forward for further reaction.
  • the present invention provides a process wherein the compound of formula V is obtained from the compound of formula VII- A.
  • 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, D 10 particle size of less than about 30 microns.
  • 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.
  • 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.
  • Example 2A Preparation of (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VIF)
  • Example 3 Purification of (R)-tert-butyl 3-((S)-4-phenyl-2-oxooxazolidine-3- carbonyl)hex-5-enoate (compound VIP)
  • Example 5 Preparation of t-butyl (3R)-3-(bromomethyl)hex-5-enoate (compound ⁇ ") (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 ⁇ ”) as a colorless oil.
  • Example 7 Preparation of t-butyl (3R)-3 -( ⁇ [(2S)-1 -amino- 1 -oxobutan-2- yl]amino ⁇ methyl)hex-5-enoate, tartrate (compound XII-A)
  • 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.
  • Example 8 Preparation of tert-butyl (3R)-3 -( ⁇ [(2S)-1 -amino- 1 -oxobutan-2- yl]amino ⁇ methyl)hexanoate, tartrate (compound XIV A)
  • 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.
  • Example 9 Preparation of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-l-yl] butanamide (Brivaracetam compound I)
  • 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.
  • (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).
  • (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/cm 2 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%.
  • 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.
  • 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.
  • 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.
  • 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/cm 2 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.
  • 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.
  • 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.
  • 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.
  • (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/cm 2 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.
  • 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.
  • Example 27 Brivaracetam RLD sample analysis
  • Brivaracetam tablet 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 ⁇ 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

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Abstract

La présente invention porte sur un procédé de préparation de brivaracétam et de sels de celui-ci. La présente invention porte sur un procédé de préparation de brivaracétam et de sels de celui-ci à pureté chirale élevée. La présente invention porte sur un procédé de préparation de brivaracétam et de sels de celui-ci, la quantité d'autres stéréoisomères de brivaracétam étant faible.
PCT/IB2018/059910 2017-12-19 2018-12-12 Procédé pour la préparation de brivaracétam WO2019087172A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN112834674A (zh) * 2020-12-29 2021-05-25 浙江和泽医药科技股份有限公司 一种布立西坦及其异构体的检测方法
CN113281434A (zh) * 2021-05-20 2021-08-20 上海应用技术大学 一种布瓦西坦异构体及其中间体异构体的hplc方法
EP4036244A1 (fr) * 2021-02-01 2022-08-03 Divi's Laboratories Limited Procédé enzymatique pour la préparation d'acide butyrique (2s)-2-[(4r)-2-oxo-4-propyl-pyrrolidin-1-yl] et son procédé de conversion en brivaracétam
US11673862B2 (en) 2015-05-25 2023-06-13 Suzhou Pengxu Pharmatech Co. Ltd. Processes to produce brivaracetam
EP4077278A4 (fr) * 2019-12-20 2023-12-06 Glenmark Life Sciences Limited Procédé de préparation de brivaracétam

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WO2016191435A1 (fr) * 2015-05-25 2016-12-01 Peng Wang Procédés de production du brivaracetam
CN107216276A (zh) * 2017-06-29 2017-09-29 爱斯特（成都）生物制药股份有限公司 一种新的布瓦西坦的合成方法

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Publication number Priority date Publication date Assignee Title
WO2016191435A1 (fr) * 2015-05-25 2016-12-01 Peng Wang Procédés de production du brivaracetam
CN107216276A (zh) * 2017-06-29 2017-09-29 爱斯特（成都）生物制药股份有限公司 一种新的布瓦西坦的合成方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11673862B2 (en) 2015-05-25 2023-06-13 Suzhou Pengxu Pharmatech Co. Ltd. Processes to produce brivaracetam
EP4077278A4 (fr) * 2019-12-20 2023-12-06 Glenmark Life Sciences Limited Procédé de préparation de brivaracétam
CN112834674A (zh) * 2020-12-29 2021-05-25 浙江和泽医药科技股份有限公司 一种布立西坦及其异构体的检测方法
EP4036244A1 (fr) * 2021-02-01 2022-08-03 Divi's Laboratories Limited Procédé enzymatique pour la préparation d'acide butyrique (2s)-2-[(4r)-2-oxo-4-propyl-pyrrolidin-1-yl] et son procédé de conversion en brivaracétam
JP2022117945A (ja) * 2021-02-01 2022-08-12 ディヴィズ・ラボラトリーズ・リミテッド （２ｓ）－２－［（４ｒ）－２－オキソ－４－プロピル－ピロリジン－１－イル］酪酸の調製のための酵素的プロセスおよびそのブリバラセタムへの変換
JP7280984B2 (ja) 2021-02-01 2023-05-24 ディヴィズ・ラボラトリーズ・リミテッド （２ｓ）－２－［（４ｒ）－２－オキソ－４－プロピル－ピロリジン－１－イル］酪酸の調製のための酵素的プロセスおよびそのブリバラセタムへの変換
CN113281434A (zh) * 2021-05-20 2021-08-20 上海应用技术大学 一种布瓦西坦异构体及其中间体异构体的hplc方法
CN113281434B (zh) * 2021-05-20 2023-08-18 上海应用技术大学 一种布瓦西坦异构体及其中间体异构体的hplc方法

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