WO2018042393A1 - Nouveau procédé de préparation de brivaracétam - Google Patents

Nouveau procédé de préparation de brivaracétam Download PDF

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WO2018042393A1
WO2018042393A1 PCT/IB2017/055295 IB2017055295W WO2018042393A1 WO 2018042393 A1 WO2018042393 A1 WO 2018042393A1 IB 2017055295 W IB2017055295 W IB 2017055295W WO 2018042393 A1 WO2018042393 A1 WO 2018042393A1
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compound
formula
alkyl
enantiomerically pure
aryl
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PCT/IB2017/055295
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English (en)
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Pramod Kumar
Srimurugan SANKARESWARAN
Madhavarao MANNAM
Venugopal Reddy GADDAM
Srikanth CHILUUKURU
Bipin Kumar CHAUBEY
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Micro Labs Limited
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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

Definitions

  • the present invention provides novel process for preparation and purification of Brivaracetam.
  • Brivaracetam is a chemical analog of levetiracetam, marketed under the brand name of BRIVIACT for the treatment as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy.
  • Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-lH- pyrrol-l-yl]butanamide and is represented by following general Formula I,
  • the present disclosure provides a cost effective, novel and efficient process for the preparation of Brivaracetam which offers industrially viable, highly pure Brivaracetam in high yields and avoiding chiral resolutions by chromatography.
  • the main object of the present invention is to provide a novel process for the preparation of Brivaracetam.
  • the present invention provides a novel process for the preparation of Brivaracetam.
  • a novel process for preparing Brivaracetam of Formula (I) comprising:
  • Compound VII Compound XI wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR & R is optionally substituted C 1 -C 12 alkyl, aryl, alkyl aryl or aryl alkyl;
  • Compound XI wherein X is each independently selected from halogen, alkyl or aryl sulfonyloxy or OR ; R is optionally substituted Q-Q 2 alkyl, aryl, alkyl aryl or aryl alkyl; involves converting enantiomerically pure compound of Formula VII to give enantiomerically pure compound of Formula XI;
  • X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 ; R 2 as defined above; (or)
  • Compound VII Compound XI wherein both X ⁇ halogen and X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR 2 and R 2 as defined above.
  • a third aspect of the present invention provides a process for the preparation of enantiomerically pure compound of Formula VII or its salts thereof,
  • R is optionally substituted C 1 -C 12 alkyl, aryl, alkyl aryl or aryl alkyl, and process comprises the steps of:
  • Formula Ila is R or S enantiomer and formula lib is D or L configuration; 2) treating chiral compound of formula IV with alkyl 2-haloacetate derivatives compound of formula (i) to obtain a enantiomerically pure compound of formula V:
  • novel process for the preparation of Brivaracetam overcomes the as above discussed disadvantages associated with the process disclosed in the cited prior arts.
  • Figure 1 is the characteristic powder XRD pattern of crystalline Brivaracetam prepared as per present invention.
  • Figure 2 is the characteristic differential scanning calorimetric thermogram of crystalline Brivaracetam prepared as per present invention.
  • Figure 3 is the characteristic infrared absorption spectrum of crystalline Brivaracetam prepared as per present invention.
  • Figure 4 is the characteristic 1H NMR spectrum of Brivaracetam prepared as per present invention. DETAILED DESCRIPTION
  • substantially pure shall be understood to mean compound formed with little or no content of the impurities.
  • the amount of any impurity of compound resulting from the process of the preparation will be relatively minor, e.g., less than about 0.15 weight percent, or less than about 0.1 weight percent, or less than about 0.05 weight percent, of any impurity of compound i.e. Brivaracetam.
  • enantiomerically pure as used herein when referring to a particular compound means that at least 95%, preferably at least 96%, more preferably at least 97%, most preferably at least 98%, even most preferably at least 99% of the compound having the stereo genie centre in a given configuration (R) or (S).
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
  • the described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
  • embodiment of the present invention provides a novel process for preparing
  • Compound VII Compound XI wherein X is each independently selected from halogen; alkyl or aryl sulfonyloxy; OR & R is optionally substituted C1-C12 alkyl, aryl, alkyl aryl or aryl alkyl;
  • step 1) involves converting enantiomerically pure compound of Formula VII to give enantiomerically pure compound of Formula XI.
  • reaction of step 1) involves three pathways such as Pathway 1, Pathway 2 and Pathway 3 for preparation of enantiomerically pure compound of Formula XI from enantiomerically pure compound of Formula VII as shown in Scheme 2 above.
  • the base used is selected from hydroxides, carbonates and bicarbonates of alkali & alkaline earth metals such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate or the like; ammonium hydroxide, ammonium bicarbonate or mixture thereof.
  • the selectivity of the hydrolysis can be adjusted by controlling the concentration of the base, the reaction circumstances and the solvent, in order to achieve the final result desired in each case.
  • the compound of formula VIII is further converted to enantiomerically pure compound of formula XI using halogenating agent and solvent.
  • the halogenating agent used herein either known in the literature or is selected from the group preferably comprises of SOCl 2 , SOBr 2 , POCl 3 , PCI 5 , POBr 3 , PBr 5 and oxalylchloride.
  • solvent used in Pathway 1 is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as
  • the cyclization agent used is an acid, which can be selected from group of comprising of inorganic acid, organic acid, lewis acid or mixture thereof for example HC1, H 2 S0 4 , P 2 Os, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.
  • an acid which can be selected from group of comprising of inorganic acid, organic acid, lewis acid or mixture thereof for example HC1, H 2 S0 4 , P 2 Os, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.
  • solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethyl
  • acid used is selected from the group comprising of inorganic acids known in the literature preferably such as hydrochloric acid, hydrobromic acid or mixtures thereof.
  • solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol and cyclohexanol; nitriles such as acetonitrile; amides such as ⁇ ,
  • the halogenating agent used is selected from group comprising of which are known in the literature such as SOCl 2 , SOBr 2 , POCl 3 , PC1 5 , POBr 3 , PBr 5 and oxalylchloride.
  • solvents used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol and cyclohexanol; nitriles such as acetonitrile; amides such as ⁇
  • optionally silyl halide can also be used for the preparation of compound of formula XI from compound of formula IX, which is selected from trimethyl silyl chloride (TMSC1), trimethyl silyl bromide (TMSBr), trimethyl silyl iodide (TMSI) or mixture thereof.
  • TMSC1 trimethyl silyl chloride
  • TMSBr trimethyl silyl bromide
  • TMSI trimethyl silyl iodide
  • the compound of formula VII is reacted with sulfonyl halide derivatives in presence of base and solvent to obtain enantiomerically pure compound of formula XI, wherein both X ⁇ Halogen and X is halogen; alkyl or aryl sulfonyloxy or OR 2 .
  • sulfonyl halide used in is represented by the formula R-S0 2 Y, wherein Y is halogen and R is an alkyl or aryl groups having 1 to 20 carbon atoms and are not limited to methane sulfonyl chloride, ethane sulfonyl chloride, /?-toluenesulfonyl chloride or benzene sulfonyl chloride.
  • solvent used in is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4- dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and ⁇ , ⁇ -dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.
  • aliphatic hydrocarbons such as hexane, heptane and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene xylene
  • halogenated hydrocarbons such as methylene chloride,
  • base used in include both organic and inorganic bases.
  • Organic bases include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIEA ( ⁇ , ⁇ -diisopropylethylamine), N-methylpiperidine, N-methylmorpholine and like.
  • Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride etc; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate etc; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide etc and the like.
  • CY 4 reagent used above is selected from the group comprising of
  • solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4- dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t- butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -
  • step 2) involves treating enantiomerically pure compound of formula XI with (S)-aminobutyramide of formula XII or its salt thereof using base and solvent, followed by cyclization in presence of an acid and solvent to give Brivaracetam of Formula I.
  • base used herein is selected from the group comprising of both organic and inorganic bases.
  • Organic bases include but not limited to pyridine, DMAP (4- dimethylaminopyridine), triethylamine, DIEA ( ⁇ , ⁇ -diisopropylethylamine), N- methylpiperidine, DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4- diazabicyclo[2.2.2]octane), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), N-methylmorpholine and the like.
  • Inorganic bases include but not limited to alkali metal hydrides like sodium hydride, potassium hydride and lithium hydride; metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate; bicarbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and hydroxides such as, sodium hydroxide, potassium hydroxide and lithium hydroxide; and like.
  • acid used for cyclization is selected from group of inorganic acid, organic acid, lewis acid or mixture thereof and is selected from a group comprising HC1, H 2 S0 4 , P 2 0 5 , camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid, butyric acid, pentanoic acid, isobutyric acid, hexanoic acid or mixture thereof.
  • solvent used for condensation or cyclization is individually selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol and cyclohexanol; esters such as methyl acetate, ethyl,
  • the compound of formula I optionally can also be prepared by carrying out the reaction in the presence of a suitable additive at any step, such as, ionic additive, a phase transfer catalyst or mixture thereof.
  • a suitable additive such as, ionic additive, a phase transfer catalyst or mixture thereof.
  • Ionic additive includes, but not limited to sodium salts such as sodium iodide, sodium sulfate, sodium chloride; potassium salts such as potassium iodide, potassium sulfate, potassium chloride; mixtures thereof.
  • Phase transfer catalyst includes, but not limited to tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetraethylammonium tetrafluoroborate, triphenylphosphonium chloride, benzyltrimethylammonium chloride and hexadecyltributylphosphonium bromide.
  • Formula Ila is R or S enantiomer and formula lib is D or L configuration;
  • valeryl chloride or its acid anhydride and chiral auxiliary compounds are commercially available or may be prepared according to methods known in the literature as well as known to those of ordinary skill in the art.
  • step 1) involves reacting valeryl chloride or its acid anhydride with the chiral auxiliary of formula III in presence of solvent and base.
  • a particular enantiomer of compound of the present invention is desired, it may be prepared by derivation with a chiral auxiliary, where the resulting mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • chiral auxiliary as used in the specification is meant a non- racemic functional group that imparts enantio selective reaction at a remote prochiral center of a molecule.
  • Chiral auxiliaries are as used herein further include: 8-phenylmenthol (5- methyl-2-(l -methyl- l-phenyl-ethyl)cyclohexanol, such as described in D. Comins et al. J. Org. Chem., vol.
  • N-substituted bornane-2 N-substituted bornane-2, 10-sultams (e.g., 10,10- dimethyl-3-thia-4-aza-tricyclo[5.2.1.01.5]decane 3,3-dioxide such as described in W. Oppolzer J. Am. Chem.
  • the solvent used in step 1) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.
  • aliphatic hydrocarbons such as hexane, heptane and
  • the base used in step 1) is selected from organic base or inorganic base, wherein organic base is selected from trimethylamine, triethylamine, tributylamine, ⁇ , ⁇ -dimethylaniline, N,N-dimethylbenzylamine, ⁇ , ⁇ -diisopropylethylamine, N-methyl morpholine, piperidine, l,4-diazabicyclo[2.2.2]octane (DABCO), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and inorganic bases selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate or mixtures thereof.
  • organic base is selected from trimethylamine, triethylamine,
  • step 1) may be optionally be carried out in the presence of a suitable catalyst, such as, for example, triethylamine, pyridine, 1-methylmorpholine, 1- methylpiperidine, 1,5-diazabicyclo [4.3.0]non-5-ene, ⁇ , ⁇ -dimethylpiperazine, N,N- dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5, 6-tetramethylpyridine (TEMP), and the like.
  • a suitable catalyst such as, for example, triethylamine, pyridine, 1-methylmorpholine, 1- methylpiperidine, 1,5-diazabicyclo [4.3.0]non-5-ene, ⁇ , ⁇ -dimethylpiperazine, N,N- dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetra
  • step 2) involves treating chiral compound of Formula IV with alkyl 2-haloacetate compound of formula (i) to obtain a compound of Formula V in presence of solvent and base.
  • base used above is an alkali metal alkyl disilazide; and wherein alkali metal alkyl disilazide is at least one compound selected from lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS) and potassium bis(trimethylsilyl)amide (KHMDS) or related bases such as lithium tetramethylpiperidide (LiTMP), n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi), tert- Butyllithium (t-BuLi), or lithium diisopropylamide (LDA).
  • LiHMDS lithium bis(trimethylsilyl)amide
  • NaHMDS sodium bis(trimethylsilyl)amide
  • KHMDS potassium bis(trimethylsilyl)amide
  • LDA lithium diisopropylamide
  • the solvent used above is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, terahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.
  • aliphatic hydrocarbons such as hexane, heptane and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as
  • step 3 involves converting compound of formula V to enantiomerically pure compound of formula VII, either directly converting to formula VII in presence of reducing agent or first hydrolysis in presence of base and solvent to give compound of formula VI or its salts thereof, which undergo reduction give compound of formula VII or its salts thereof.
  • suitable reducing agent that may be used for direct conversion to compound of formula VII includes but not limited to alkali metal hydrides and alkali metal borohydrides, such as lithium aluminium hydride, sodium borohydride, lithium borohydridesodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride, tetrabutyl ammonium borohydride or the like, more preferably sodium borohydride.
  • alkali metal hydrides and alkali metal borohydrides such as lithium aluminium hydride, sodium borohydride, lithium borohydridesodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride, tetrabutyl ammonium borohydride or the like, more preferably sodium borohydride.
  • the solvent used for direct conversion to compound of formula VII is selected from group comprising of halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and ⁇ , ⁇ -dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof more preferably THF and water mixture.
  • halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane
  • ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxan
  • the base used for the hydrolysis step is selected from group comprising but not limited to ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.
  • the solvent used in hydrolysis is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol; ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl prop
  • hydrolysis is undergoing optionally in presence and absence of a suitable catalyst, such as peroxides for example hydrogen peroxide.
  • a suitable catalyst such as peroxides for example hydrogen peroxide.
  • VI or its salts thereof to compound of formula VII is selected from group the group comprising of but not limited to borane or its complex such as borane and N,N- diethylaniline complex (DEANB), borane and dimethyl sulfide complex (DMSB), borane and tetrahydrofuran (BTHF) complex, borane and 2-methyltetrahydrofuran complex, borane-pyridine complex; borane-picoline complex; borane-triethylamine complex.
  • borane or its complex such as borane and N,N- diethylaniline complex (DEANB), borane and dimethyl sulfide complex (DMSB), borane and tetrahydrofuran (BTHF) complex, borane and 2-methyltetrahydrofuran complex, borane-pyridine complex; borane-picoline complex; borane-triethylamine complex.
  • borane or its complex such as borane and N,
  • the solvent used in above stage is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane and 1,2- dimethoxyethane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethylformamide and N,N- dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.
  • aliphatic hydrocarbons such as hex
  • the compound for formula VI can also be converted to its salts thereof by reacting it with organic base in presence of solvent.
  • organic base used herein is selected from the group comprising of but not limited to (S)-phenylethyl amine, cyclohexyl amine, dicyclohexyl amine and the like.
  • solvent used for the preparation of salt of formula VI are selected from group comprising aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as toluene and xylene; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, i-butyl alcohol, ethylene glycol, t-butanol; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, ⁇ , ⁇ -dimethyl acetamide; sulfoxides such as dimethyl sulfoxide; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroe
  • the starting compound B which is rac-dihydro-4-(prop-l-enyl)furan-2(3H)-one or rac-dihydro-4-propylfuran-2(3H)-one may be prepared according to methods known to those of ordinary skill in the art.
  • step 1) involves treating racemic compound of formula B with an optically active chiral resolving agent in presence of lewis acid to obtain an enantiomeric salt, followed by cyclization with an acid to obtain an enantiomerically pure compound of formula C.
  • resolving agent used is selected from group comprising of but not limited to chiral amines, chiral thiols, chiral alcohols such as phenylethanethiol, 2- phenylcyclohexanethiol, N-Boc-cysteine methyl ester, menthol, borneol, valinol, quinine, (S)-l-phenyl ethyl amine; (S)-l-phenyl butyl amine; l-(l-naphthyl) ethyl amine or l-(4- nitrophenyl)ethyl amine, preferably (S)-l -phenyl ethyl amine.
  • lewis acid serves as an electron acceptor, has a typical element, such as boron, aluminum, silicon, or tin, or a transition metal element belonging to the fourth period, such as titanium, iron, nickel, copper, or zinc, as the central element.
  • a typical element such as boron, aluminum, silicon, or tin
  • a transition metal element belonging to the fourth period such as titanium, iron, nickel, copper, or zinc
  • the lewis acid used herein is selected from group include boron trihalides such as boron trifluoride, boron trichloride, and boron tribromide, aluminum trihalides such as aluminum chloride and aluminum bromide, tin tetrahalides such as tin tetrachloride, tin dihalides such as tin dichloride, titanium tetrahalides such as titanium tetrachloride, titanium trihalides such as titanium trichloride, titanium alkoxides such as titanium isopropoxide, iron dihalides such as iron dichloride, iron trihalides such as iron trichloride, nickel dihalides such as nickel dichloride, and zinc halides such as zinc chloride and zinc bromide, preferably titanium isopropoxide.
  • boron trihalides such as boron trifluoride, boron trichloride, and boron tribromide
  • aluminum trihalides such as aluminum chloride and aluminum bro
  • acid used for cyclization is selected from group of inorganic acid, organic acid or mixture thereof and is selected from a group comprising HC1, H 2 S0 4 , P 2 Os, camphorsulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, pTSA, propionic acid or mixture thereof.
  • the solvent used is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4- dioxane; methyl tertiary-butyl ether; and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide; sulfoxides such as dimethyl sulfoxide or mixtures thereof.
  • aliphatic hydrocarbons such as hexane, heptane and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene xy
  • step 2) above involves reducing compound of formula C ( is double bond) to compound of formula IX using reducing agent and solvent.
  • the reduction may be carried out in the presence of hydrogen source and a catalyst such as Pd/C, Rh/C, Pt/C, and the like, preferably Pd/C.
  • a catalyst such as Pd/C, Rh/C, Pt/C, and the like, preferably Pd/C.
  • the solvent used for reduction is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4- dioxane; methyl tertiary-butyl ether; and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i- butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, cyclohexanol; nitriles such as
  • the compound or intermediate as mentioned i.e. compound of formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (C) may optionally be isolated either as per the methods known in the art or by the procedure described in this application. Apart from that the reaction mixture comprising the above compounds of formulae may also be further taken forward for the next steps, without isolating.
  • the crystallization of Brivaracetam is achieved either by isolating the compound by lowering the reaction mass temperature or removal of the solvent from Brivaracetam solution. Further crystallization can also be achieved by addition of an anti-solvent to a solution of Brivaracetam or vice versa.
  • the crystallization can be optionally be achieved by adding seed of the target material in the reaction mass.
  • Preferred solvents for preparing the crystallization mixture are selected from group comprising alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, i-butyl alcohol, ethylene glycol, t-butanol; nitriles such as acetonitrile; amides such as N,N- dimethylformamide, ⁇ , ⁇ -dimethyl acetamide; sulfoxides such as dimethyl sulfoxide; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, isopropyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofur
  • the anti-solvent used herein is selected from group comprising of hydrocarbon solvents such as hexane, heptane and petroleum ether.
  • Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), atmospheric distillation, vacuum distillation and the like, or any other suitable technique.
  • a rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), atmospheric distillation, vacuum distillation and the like, or any other suitable technique.
  • BDMS complex (12 mL) was added, stirred. The reaction mass temperature was raised to room temperature and stirred. The reaction mass was cooled to 0-5°C, methanol (8 mL) was added and stirred. H 2 0 2 (4 mL) was added and stirred. Sodium sulfite solution (40 mL) was added to the reaction mass at 0-5°C, reaction mass was raised to room temperature and separated the layers. The aqueous layer was extracted with toluene (20 mL) and combined toluene layers are washed with NaCl solution (30 mL). TFA (30 mL) was added to the toluene layer and stirred the reaction mass.
  • Example-3 Preparation of (R)-dihydro-4-propylfuran-2(3H)-one Sodium borohydride (15 g) was added to a solution of tert-butyl (3S)-3-[( K)-2-oxo- 4-phenyl-l,3-oxazolidine-3-carbonyl]hexanoate (30 g) in THF/H 2 0 mixture (400mL) and obtained reaction mixture was stirred at room temperature. Aqueous NH 4 C1 was added to the reaction mass. The reaction mixture was extracted with toluene (50 mL x 2), washed with brine, and concentrated to obtain ⁇ R)-tert-buty ⁇ 3-(hydroxymethyl)hexanoate. CH 2 C1 2 and p-TsOH was added to above reaction mass and stirred under reflux. The organic layer separated was washed with sodium bicarbonate, water and evaporated under vacuum to provide title compound (yellow oil).
  • Example-4 Preparation of methyl (/?)-3-(bromomethyl)hexanoate A solution of (R)-dihydro-4-propylfuran-2(3H)-one (10 g) in AcOH (20 mL) was added to HBr in AcOH (25mL) at room temperature and stirred. The reaction mass temperature was raised to 50-55°C and stirred. The obtained reaction mass was cooled to room temperature and toluene (60 mL) was added. Water (10 mL) was added and stirred the biphasic reaction mass.
  • Triphenylphosphine (10 g) was added to a mixture of (R)-te rt-butyl 3- (hydroxymethyl)hexanoate (5 g) and CBr 4 (12 g) in dichloromethane (100 mL) in a round bottom flask at room temperature and stirred. The solvent was removed under reduced pressure to yield ⁇ R)-tert-buty ⁇ 3-(bromomethyl)hexanoate. Yield: 2.5 g (90%)
  • Example-9 Preparation of Brivaracetam from (R)-tert-butyl 3- (bromomethyl)hexanoate
  • Example-11 Process for preparation of Dihydro-4-propylfuran-2(3H)-one Dihydro-4-(prop-l-enyl)furan-2(3H)-one (lOg), methanol (100 mL), 10% Pd/C was charged into a high pressure autoclave and hydrogenated using hydrogen pressure of 1.0-2.0 Kg/cm . After completion of the reaction, the catalyst was filtered, washed and distilled to give title product. Yield: 9.65 (95%)
  • Example-12 Process for preparation of (R)-dihydro-4-propylfuran-2(3H)-one
  • reaction mixture was seeded with pure R-isomer at 5°C and stirred.
  • the obtained solid was filtered (3.2 g) and to the obtained solid, water (25 mL), cone.
  • H 2 S0 4 (5 mL), 1,4-dioxane (15 mL) were charged at room temperature and reaction mixture was raised to 80 °C and stirred.
  • reaction mixture was cooled to room temperature and water (20 mL) was added.
  • the reaction mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layer washed with brine, filtered and concentrated to yield title product. Yield: 7.9 g (80 %)
  • Example 14 Process for preparation of (/?)-dihydro-4-propylfuran-2(3H)-one from rac-dihydro-4-propylfuran-2(3H)-one
  • the obtained reaction mixture was seeded with pure isomer at 5°C and stirred.
  • the obtained solid was filtered (3.2 g) and to the obtained solid water (25 mL), cone.
  • H 2 S0 4 (5 mL), 1,4- dioxane (15 mL) were charged at room temperature and stirred.
  • the reaction mixture was raised 80 °C and stirred for few hours.
  • the reaction mixture was cooled to room temperature and water (20 mL) was added.
  • the reaction mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layer washed with brine, filtered and concentrated to yield title product. Yield: 7.9 g (80%)
  • Example-15 Process for preparation of crystalline Brivaracetam.
  • Example-16 Process for preparation of crystalline Brivaracetam.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé rentable, innovant et efficace pour la préparation de Brivaracétam qui offre des rendements industriellement viables, hautement purs avec des rendements élevés et évite des résolutions chirales par chromatographie et résolutions enzymatiques.
PCT/IB2017/055295 2016-09-05 2017-09-04 Nouveau procédé de préparation de brivaracétam WO2018042393A1 (fr)

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WO2018220646A1 (fr) * 2017-05-29 2018-12-06 Msn Laboratories Private Limited, R&D Center Procédé amélioré pour la préparation de (2s)-2-[(4r)-2-oxo-4-propyltétrahydro-1h-pyrrol-1-yl]butanamide et de ses intermédiaires
CN109134406A (zh) * 2018-08-02 2019-01-04 丽珠集团新北江制药股份有限公司 一种布瓦西坦中间体及布瓦西坦的合成方法
CN109266630A (zh) * 2018-08-31 2019-01-25 上海弈柯莱生物医药科技有限公司 一种脂肪酶及其在制备布瓦西坦中间体中的应用
CN109942516A (zh) * 2019-03-27 2019-06-28 成都克莱蒙医药科技有限公司 化合物ra在制备布瓦西坦中间体手性丁内酯中的用途
CN110358752A (zh) * 2019-07-05 2019-10-22 浙江工业大学 一种米曲霉脂肪酶及在制备布瓦西坦手性中间体中的应用
IT201800006320A1 (it) * 2018-06-14 2019-12-14 Processo per la sintesi asimmetrica di (r)-4-propildiidrofuran-2(3h)-one
WO2019242780A1 (fr) * 2018-06-19 2019-12-26 上海博氏医药科技有限公司 Composés intermédiaires utilisés pour la préparation de brivaracétam, procédés de préparation de composés intermédiaires, et utilisation
CN110790731A (zh) * 2018-08-01 2020-02-14 北京万全德众医药生物技术有限公司 4取代-γ丁内酯的制备方法
WO2020052545A1 (fr) * 2018-09-12 2020-03-19 上海宣泰医药科技有限公司 Procédé de préparation de brivaracétam et ses intermédiaires
CN111170881A (zh) * 2018-11-09 2020-05-19 上海医药集团股份有限公司 一种布瓦西坦中间体的制备方法
CN111170920A (zh) * 2018-11-12 2020-05-19 浙江京新药业股份有限公司 从布瓦西坦中去除基因毒性警示中间体的方法
CN111333563A (zh) * 2018-12-19 2020-06-26 上海科胜药物研发有限公司 一种布瓦西坦中间体的制备方法
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

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WO2018220646A1 (fr) * 2017-05-29 2018-12-06 Msn Laboratories Private Limited, R&D Center Procédé amélioré pour la préparation de (2s)-2-[(4r)-2-oxo-4-propyltétrahydro-1h-pyrrol-1-yl]butanamide et de ses intermédiaires
IT201800006320A1 (it) * 2018-06-14 2019-12-14 Processo per la sintesi asimmetrica di (r)-4-propildiidrofuran-2(3h)-one
WO2019239341A1 (fr) * 2018-06-14 2019-12-19 Procos S.P.A. Procédé de synthèse asymétrique de (r)-4-propyldihydrofuran-2 (3h)-one
WO2019242780A1 (fr) * 2018-06-19 2019-12-26 上海博氏医药科技有限公司 Composés intermédiaires utilisés pour la préparation de brivaracétam, procédés de préparation de composés intermédiaires, et utilisation
CN110790731A (zh) * 2018-08-01 2020-02-14 北京万全德众医药生物技术有限公司 4取代-γ丁内酯的制备方法
CN109134406A (zh) * 2018-08-02 2019-01-04 丽珠集团新北江制药股份有限公司 一种布瓦西坦中间体及布瓦西坦的合成方法
CN109266630B (zh) * 2018-08-31 2021-02-02 弈柯莱生物科技(上海)股份有限公司 一种脂肪酶及其在制备布瓦西坦中间体中的应用
CN109266630A (zh) * 2018-08-31 2019-01-25 上海弈柯莱生物医药科技有限公司 一种脂肪酶及其在制备布瓦西坦中间体中的应用
CN112739683B (zh) * 2018-09-12 2024-04-16 上海宣泰医药科技股份有限公司 布瓦西坦的制备方法及其中间体
CN112739683A (zh) * 2018-09-12 2021-04-30 上海宣泰医药科技股份有限公司 布瓦西坦的制备方法及其中间体
WO2020052545A1 (fr) * 2018-09-12 2020-03-19 上海宣泰医药科技有限公司 Procédé de préparation de brivaracétam et ses intermédiaires
CN111170881A (zh) * 2018-11-09 2020-05-19 上海医药集团股份有限公司 一种布瓦西坦中间体的制备方法
CN111170881B (zh) * 2018-11-09 2023-08-01 上海医药集团股份有限公司 一种布瓦西坦中间体的制备方法
CN111170920A (zh) * 2018-11-12 2020-05-19 浙江京新药业股份有限公司 从布瓦西坦中去除基因毒性警示中间体的方法
CN111333563A (zh) * 2018-12-19 2020-06-26 上海科胜药物研发有限公司 一种布瓦西坦中间体的制备方法
CN111333563B (zh) * 2018-12-19 2023-11-07 上海科胜药物研发有限公司 一种布瓦西坦中间体的制备方法
US12116342B2 (en) 2018-12-19 2024-10-15 Zhejiang Huahai Pharmaceutical Co., Ltd Method for preparing brivaracetam and intermediate thereof
CN109942516A (zh) * 2019-03-27 2019-06-28 成都克莱蒙医药科技有限公司 化合物ra在制备布瓦西坦中间体手性丁内酯中的用途
CN110358752A (zh) * 2019-07-05 2019-10-22 浙江工业大学 一种米曲霉脂肪酶及在制备布瓦西坦手性中间体中的应用
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

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