WO2011114210A2 - Procédés de préparation de linézolide - Google Patents

Procédés de préparation de linézolide Download PDF

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Publication number
WO2011114210A2
WO2011114210A2 PCT/IB2011/000527 IB2011000527W WO2011114210A2 WO 2011114210 A2 WO2011114210 A2 WO 2011114210A2 IB 2011000527 W IB2011000527 W IB 2011000527W WO 2011114210 A2 WO2011114210 A2 WO 2011114210A2
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Prior art keywords
process according
fluoro
group
oxo
methyl
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PCT/IB2011/000527
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English (en)
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WO2011114210A3 (fr
Inventor
Ashish Kumar Gupta
Shishupal Singh
Atulya Kumar Panda
Sujay Biswas
Dharam Vir
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Jubilant Life Sciences Limited
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Publication of WO2011114210A2 publication Critical patent/WO2011114210A2/fr
Publication of WO2011114210A3 publication Critical patent/WO2011114210A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Definitions

  • the present invention relates to the improved processes for the preparation of linezolid.
  • the present invention is directed to a novel process for the preparation of linezolid, which avoids the use of sodium azide in the reaction.
  • the present invention also includes preparation of linezolid going through a novel intermediate of Formula XIa.
  • the present invention also includes the processes of preparation of linezolid, free of bis-linezolid impurity.
  • the present invention further relates to preparation of linezolid by preparing azide intermediate, and converting it into linezolid in one-pot. It also provides linezolid with high yield and high chemical purity without the use of tedious, complicated purification steps, such as chromatography.
  • Linezolid, (S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide is an antimicrobial agent.
  • Linezolid is an oxazolidinone, having the empirical formula C!6H 20 FN3O 4 and the following structure (I):
  • the present invention seeks to overcome the prior art limitations and provide a cost effective and industrially favorable process for the preparation of linezolid.
  • the invention encompasses a process for preparation of linezolid comprising: (a) condensation of 3,4-difluoronitrobenzene (III) with morpholine (II) to obtain 3-fluoro-4-morpholinyl nitrobenzene (IV); (b) reduction of IV obtained in step 'a' to 3-fluoro-4-morpholinyl aniline (V); (c) protection of amino group of V obtained in step 'b' to generate a carbamate derivative like ethyl carbamate (Via) or benzyl carbamate (VIb); and the like (d) conversion of carbamate Via or VIb as obtained in step 'c' into oxazolidinone derivative, (R)-N-[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol (VIII); (e) further, conversion of the hydroxy group of VIII as obtained in step 'd' into a
  • the present invention provides a process for preparing a linezolid comprising acetylating (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine. ⁇ -TSA salt (XIa) in presence of a base and solvent.
  • the present invention provides a novel intermediate (S)-N- [[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine. 7-TSA salt of formula XIa.
  • present invention provides a novel polymorph Form J of (S)-N-[[3 ⁇ (3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine.
  • ?-TSA salt (XIa) which is characterized by a powder X-Ray diffraction pattern with peaks at about 4.1, 15.6, 20.6, 22.7, 23.4 ⁇ 0.2° 2 ⁇ , as depicted in Figure I.
  • present invention provides a novel polymorph Form J of (S)- N-[[3-(3-fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine.
  • )-TSA salt (XIa) which is characterized by Infrared spectrum having main bands at about 3440, 1746, 1518, 1421, 1224, 1153, 680 and 564 cm “1 , as depicted in Figure II.
  • present invention provides a novel polymorph Form J of (S)- N- [ [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] amine .p-TSA salt (XIa), which is characterized by DSC thermogram as depicted in Figure III and TGA as depicted in Figure IV.
  • reaction occurs in a similar fashion as in the first embodiment till the formation of (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa).
  • reaction comprises (a) treatment of IXa with benzylamine leading to the formation of compound (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methyl] benzylamine (XIII) (b) hydrogenolysis of XIII as obtained in step 'a' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine (XI), i.e. an amine intermediate and (c) acetylation of XI as obtained in step 'b' to provide linezolid (I).
  • reaction occurs in a similar fashion as in the earlier embodiment till the formation of (R)-N-[[3-(3-fluoro-4- morpholinylphenyi)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa).
  • reaction comprises of: (a) conversion of IXa into corresponding (S)-N-[[3-(3- fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]azide (X) and (b) the azide intermediate X obtained in step 'a' is reduced as well as acetylated simultaneously in one pot to form linezolid (I) avoiding the formation of bis linezolid (XII).
  • present invention provides linezolid having a total purity of at least about 98%.
  • the total purity is at least about 99%, more preferably, total purity is at least about 99.8%.
  • linezolid (I) is prepared comprising the steps of:
  • the base may be selected from a group comprising of an organic or inorganic base.
  • Organic base is selected from the group comprising of N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, 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), 4-dimethylaminopyridine (4-DMAP) and mixtures thereof.
  • DBU 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
  • 4-dimethylaminopyridine (4-DMAP) and
  • the inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.
  • the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and the like. More preferably the base is sodium bicarbonate.
  • the solvent as defined herein is selected from the group comprising of alcohols, nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the mixtures thereof.
  • Alcohols are selected . from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like.
  • Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
  • Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Chlorinated solvents are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, Methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like.
  • Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from the group comprising of dimethyl sulfoxide (DMSO), diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
  • Preferred solvent is water; thus making the process more cost effective.
  • the solvent as defined herein is selected from the group comprising of alcohols, esters ⁇ chlorinated solvents, ethers or mixtures thereof.
  • Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Chlorinated solvents are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like.
  • the hydrogenation is carried out in presence of suitable catalyst, but not limited to Raney-Ni/H 2 , Palladium-C/H 2 and the like; c) carboxylation of an amino compound (V) with alkyl chloroformate or alkaryl chloroformate in an organic solvent in presence of base to yield carbamate derivative (VI).
  • suitable catalyst but not limited to Raney-Ni/H 2 , Palladium-C/H 2 and the like
  • R is alkyl or alkaryl group
  • Organic base is selected from the group comprising of N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DBN, DABCO, 4-
  • the inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.
  • the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and the like. More preferably the base is sodium bicarbonate.
  • the solvent as defined herein is selected from the group comprising of nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the mixtures thereof.
  • Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
  • Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Chlorinated solvents are selected from the group comprising of
  • DCM dimethylform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like.
  • Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
  • Preferred solvent is DCM for ethyl carbamate and acetone for benzyl carbamate derivates.
  • the base may be selected from a strong base selected from the group comprising of organometallic or non-nucleophilic hindered base.
  • Metal from organometallic base is selected from Li, Na, K and the like. It may be preferably selected from base containing Li ion e.g. n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropyl amide, lithium bis(trimethylsilyl) amine, lithium t-butoxide or lithium amyloxide.
  • the solvent may be selected from non protic inert polar solvents.
  • the preferable non protic inert polar solvent is selected from a group comprising of tetrahydrofuran (THF), diethylether, dioxan, methyl tertiary butyl ether and the like; e) treatment of methanol derivative (VIII) with suitable reagent to convert the alcoholic group into a leaving group selected from the group comprising of: tosylate, mesylate, nosylate, triflate, besylate, halo and the like.
  • THF tetrahydrofuran
  • VIII methanol derivative
  • reaction except for halo derivative takes place in an organic solvent in presence of a base to yield (R)-N-[[3- (3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]derivative (IXb) having LG as a leaving group.
  • Methanol derivative on treatment with thionyl halide provides halo derivatives.
  • the reaction is carried out with tosyl chloride to yield (R)- N- [ [3 - (3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]/?- toluenesulfonate (IXa).
  • the base may be selected from a group comprising of an organic or inorganic base.
  • Organic base is selected from the group comprising of N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-
  • the inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.
  • the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and the like.
  • the organic solvent as defined herein is selected from the group comprising of nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides or mixtures thereof.
  • Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
  • Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, diisopropyl ether,
  • Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
  • Preferred solvent is selected from group comprising of DCM, chloroform, THF, dioxan or mixture thereof; f) reaction of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]p-toluenesulfonate (IXa) with amine source which may be dissolved in solvent like water or alcohol.
  • Preferred amine source is ammonium hydroxide. Reaction occurs in presence of a solvent to provide an amine intermediate (XIa).
  • XIa is a novel intermediate compound, which helps in providing linezolid in high yield.
  • the solvent as defined herein is selected from the group comprising of alcohols, nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the mixtures thereof.
  • Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol and the like.
  • Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
  • Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like.
  • Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from .
  • Preferred solvent is selected from THF and IPA; g) acetylation of the intermediate amine (XIa) in the form of p-TSA salt, in presence of a base and a solvent provides linezolid (I) in high yields in comparison to the conversion into free amine and further free amine providing linezolid. Moreover, the preparation of intermediate XIa is economically and industrially more viable and is operationally safe.
  • the acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably acetic anhydride.
  • the base may be selected from a group comprising of an organic or inorganic base.
  • Organic base is selected from the group comprising of ⁇ , ⁇ -diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-DMAP and mixtures thereof.
  • the inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.
  • the solvent as defined herein is selected from the group comprising of water, nitriles, ketones, esters, hydrocarbons, chlorinated solvents, ethers, amides, dialkylsulfoxides or mixtures thereof.
  • Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
  • Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Hydrocarbons are selected from toluene, xylene, cyclohexane and the like.
  • Chlorinated solvents are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like.
  • Amides are selected from the group comprising , of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
  • the solvent may be preferably selected from hydrocarbons, halogenated hydrocarbons, C 2-4 acetates, water or mixtures thereof. More preferably the solvent is selected from DCM, ethyl acetate, chloroform, toluene or water and mixture thereof.
  • the present method involves the direct conversion of tosylate derivative (IXa) in to an amine salt (XIa), which is a novel intermediate used for the preparation of linezolid.
  • IXa tosylate derivative
  • XIa amine salt
  • the said process avoids the usage of sodium azide, formation of azide intermediate (X), the use of hydrogen gas, high hydrogen pressure and moreover, reducing the number of the steps of the reaction and making the process cost effective as well as environment friendly.
  • the crude linezolid formed can be obtained with high purity just by recrystallization avoiding cumbersome purification techniques.
  • present invention provides linezolid having a total purity of at least about 98%.
  • the total purity is at least about 99%, more preferably, total purity is at least about 99.8%.
  • the present invention provides a novel intermediate (S)-N- [ [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl]methyl] amine .p-TS A salt of formula XIa.
  • present invention provides a novel polymorph Form J of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine.
  • present invention provides a novel polymorph Form J of (S)- N- [ [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] amine .p-TS A salt (XIa), which is characterized by Infrared spectrum having bands at about 3440, 1746, 1518, 1421 , 1224, 1153, 680 and 564 cm “1 , further characterized by 2970, 1 195, 1175,1058, 801 cm “1 or as depicted in Figure II.
  • present invention provides a novel polymorph Form J of (S)- N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine.
  • >-TSA salt (XIa) which is characterized by DSC thermogram as depicted in Figure III and TGA as depicted in Figure IV.
  • the (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa) is treated with benzylamine to provide S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]benzylamine (XIII), which on hydrogenolysis leads to formation of S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (XI), which is further converted to linezolid (I).
  • the reaction comprises of the following steps: a) reaction of the compound having a leaving group e.g. tosylate derivative (IXa) with benzylamine to yield N-benzyl methyl amine derivative of oxazolidinone compound i.e. (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]benzylamine (XIII);
  • the catalysts may be selected from the group comprising of zinc, nickel, platinum, palladium and the like.
  • the metal catalyst may be provided on an inert support such as carbon, activated carbon or alumina.
  • the reducing agent may be selected from formic acid and salts or acetic acid and salts thereof.
  • the organic solvent is selected from the group comprising of alcohols, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, or the mixtures thereof.
  • Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like.
  • Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, MTBE, diisopropyl ether, THF, dioxane and the like.
  • Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
  • Preferred solvent is selected from methanol, ethanol, toluene, DCM and the like; c) acetylation of the intermediate amine (XI) in presence of a base and a solvent to form linezolid (I).
  • the acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably acetic anhydride.
  • the base may be selected from a group comprising of an organic or inorganic base.
  • Organic base is selected from the group comprising of ⁇ , ⁇ -diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-DMAP and mixtures thereof.
  • the inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline 5 earth metals and the like.
  • the solvent as defined herein is selected from the group comprising of nitriles, ketones, esters, hydrocarbons, chlorinated solvents, ethers, amides, dialkylsulfoxides, or mixtures thereof.
  • Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.
  • Ketones are selected from the group comprising of acetone, methyl ethyl ketone,
  • esters are selected from the group comprising of ethyl acetate, propyl acetate and the like.
  • Hydrocarbons are selected from toluene, Ht- xylene, cyclohexane and the like.
  • Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
  • Ethers are selected from the group comprising of diethyl ether, MTBE, diisopropyl ether,
  • Amides are selected from the group comprising of DMF, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like.
  • Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.
  • Preferred solvent is selected from DCM, ethyl acetate, chloroform or toluene.
  • N-benzyl methyl amine derivative The benefit of preparing the N-benzyl methyl amine derivative is that it avoids the usage of sodium azide. Accordingly, the formation of azide intermediate as well as bis-linezolid (XII) is avoided and linezolid (I) formed can be purified just by recrystallization. Thus, the process provides linezolid in purified form.
  • (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulfonate (IXa) is converted into corresponding (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]azide (X).
  • the azide intermediate X is reduced as well as 30 acetylated simultaneously in one pot to produce linezolid (I) avoiding the formation of bis-linezolid (XII).
  • reaction comprises of the following steps: a) reaction of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]p-toluenesulfonate (IXa) with sodium azide in presence of a solvent to yield an azide intermediate (X);
  • the solvent may be selected from the group of aprotic polar solvents comprising of nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides or the mixtures thereof. Nitriles like acetonitrile etc., ketones like acetone, l-methyl-2- pyrrrolidinone etc., esters like ethyl acetate etc., chlorinated solvents like DCM etc., ethers like THF etc., amides like dimethylformamide (DMF) etc., dialkylsulfoxides like DMSO and the like. Preferred solvents are selected from DMF, l-methyl-2- pyrrrolidinone or DMSO. b) reaction of the azide intermediate (X) with a reducing agent in presence of acetylating agent in a solvent to form linezolid (I) in one pot avoiding the formation of an amine intermediate (XI).
  • aprotic polar solvents
  • the reducing agent may be selected from the group of catalysts comprising of zinc, nickel, platinum, palladium and the like combined with H 2 source.
  • the metal catalyst may be provided on an inert support such as carbon, activated carbon or alumina.
  • the acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably acetic anhydride.
  • the solvent as defined herein is selected from the group comprising of esters, chlorinated solvents, hydrocarbons, ethers, amides, dialkylsulfoxides or mixtures thereof. Esters are selected from the group comprising of ethyl acetate, propyl - acetate and the like.
  • Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.
  • Hydrocarbons are selected from benzene, toluene, cyclohexane and the like.
  • Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like.
  • Amides are selected from the group comprising of DMF, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides .
  • DMSO dimethyl methacrylate
  • Preferred solvents are selected from benzene, toluene, DCM, chloroform, ethyl acetate.
  • the present method involves the conversion of azide intermediate (X) directly to linezolid (I).
  • the amine intermediate (XI) is formed in one pot and further produces converts into linezolid avoiding the formation of bis-linezolid.
  • the crude linezolid formed can be obtained with high purity just by recrystallization avoiding cumbersome purification techniques.
  • N-carboethoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (500 ml).
  • n-butyllithium (245 ml in hexane) was added under nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (53.75 g, in THF (100 ml)) was added.
  • the resulting solution was stirred at -78°C for 2h, further it was warmed to room temperature and stirred for overnight.
  • saturated ammonium chloride (345 ml) was added followed by the addition of water (300 ml).
  • N-carboethoxy-3-fluoro-4-morpholinylaniline (50 g) was dissolved in THF (300 ml).
  • n-butyllithium (122.5 ml in hexane) was added under nitrogen at -78°C over 30 min and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (29.5 g, in THF (50 ml)) was added and stirred at -78°C for 2h. It was warmed to room temperature and stirred overnight.
  • saturated ammonium chloride (173 ml) was added followed by the addition of water (50ml).
  • the reaction mixture was stirred at room temperature for 30 min and further ethyl acetate (400 ml) was added to it, which was stirred for 15 min.
  • Organic layer was separated and aqueous layer was extracted with ethyl acetate.
  • the combined organic layer was washed with water.
  • the organic layer was concentrated under vacuum at 45-50°C, which resulted into an oily mass that was diluted with a mixture (1 : 1) of ethyl acetate and hexanes (750 ml).
  • the suspended solution was warmed to 60°C and further stirred at 55-60°C for 30 min.
  • the resulting clear solution was cooled to room temperature and stirred for 3h.
  • the solid mass was filtered, washed with a mixture (1 : 1) of ethyl acetate and hexanes and suck dried.
  • the suck dried material was suspended in ethyl acetate (380 ml) and heated to 80°C, which was further stirred at 75-80°C for 30 min.
  • hexanes (380 ml) were added at 75-80°C and stirred at the same temperature for 15 min, further cooled to room temperature and stirred for lOh.
  • the solid mass was filtered, washed with a mixture (1 :1) of ethyl acetate and hexanes and dried to obtain the titled compound (30.5 g) with 55% yield.
  • N-carbobenzoxy-3-fluoro-4-morpholinylaniline (50 g) was dissolved in THF (400 ml).
  • n-butyllithium (99.5 ml in hexane) was added under nitrogen at -78°C over 40 min and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (24 g in THF (50 ml)) was added and stirred for 2h.
  • the reaction mixture was warmed to room temperature and stirred for overnight.
  • saturated ammonium chloride (173 ml) was added and stirred for 30 min followed by the addition of water (50 ml).
  • N-carbobenzoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (800 ml).
  • n-butyllithium (208 ml in hexane) was added under nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (52.3 g in THF (100 ml)) was added and stirred for 2h.
  • the reaction mixture was warmed to room temperature and stirred for overnight.
  • saturated ammonium chloride (345 ml) was added followed by the addition of water (50 ml).
  • Example-8 Preparation of (R)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl] 4-methylmethanesulfonate (IX)
  • IP A 180 ml
  • IP A 180 ml
  • the solid mass was filtered and dried under vacuum at 50°C.
  • DCM was added and heated to reflux for 2h. Further, cooled to room temperature and stirred the obtained suspension for lh. The solid mass was filtered, washed with DCM and dried under vacuum at 50-55°C for overnight to obtain the titled compound (45 g) with 72% yield.
  • benzylamine (5 g) was dissolved in methanol (55 ml). To the resulting solution ammonium formate (4.5 g) was added. Further, 10% Pd/C (0.55 g) was added to the resulting mixture. The mixture was heated to 65°C and stirred for 8 h. After completion of reaction it was cooled to room temperature. The solution was filtered and washed with methanol. The filtrate was concentrated under vacuum at 50-55°C to obtain the titled compound as oil.
  • Example-14 Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine
  • Example-15 Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl azide
  • Linezolid (I) (2 g) was dissolved in ethyl acetate (50 ml) and heated to 65°C, further, was stirred at 60-65°C for 15 min. To the clear solution obtained hexanes (8 ml) were added at 50-55°C. The resulting solution was cooled to room temperature and stirred for lh. The solid mass was filtered, washed with a 1 : 1 mixture of ethyl acetate and hexanes (4 ml) and dried to obtain pure linezolid (1.6 g) with 70% yield.
  • Linezolid (I) (10. Og) was dissolved in methanol (100 ml) and heated to 65°C, further, was stirred at 60-65°C for 30 min. The resulting solution was cooled to room temperature and stirred for 2h. The solid mass was filtered, washed with methanol (10 ml) and dried to obtain pure linezolid (8 g) with 80% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé permettant de préparer la linézolide, la linézolide résultante est dépourvue d'impuretés et implique un procédé facile et économique. L'invention concerne en outre la préparation de la linézolide par utilisation d'un intermédiaire azide et d'un procédé concernant ledit intermédiaire.
PCT/IB2011/000527 2010-03-15 2011-03-14 Procédés de préparation de linézolide WO2011114210A2 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102491954A (zh) * 2011-12-06 2012-06-13 江苏正大丰海制药有限公司 利奈唑胺的制备方法
WO2013111048A1 (fr) 2012-01-24 2013-08-01 Jubilant Life Sciences Limited Procédé amélioré de préparation de la forme cristalline stable i du linézolide, pratiquement exempte de solvant résiduel
CN103601704A (zh) * 2013-11-22 2014-02-26 赵军旭 无定形卡巴他赛的制备
WO2014045292A1 (fr) * 2012-09-20 2014-03-27 Symed Labs Limited Procédé amélioré pour la préparation d'un intermédiaire de linézolide
CN104262280A (zh) * 2014-09-22 2015-01-07 山东华生化学股份有限公司 一种利奈唑酮的制备方法
WO2017182853A1 (fr) * 2016-04-21 2017-10-26 Optimus Drugs Pvt Ltd Procédé perfectionné pour la préparation de linézolide
CN110483431A (zh) * 2019-09-04 2019-11-22 桂林南药股份有限公司 利奈唑胺杂质化合物、其制备方法以及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US20060252932A1 (en) 2005-02-24 2006-11-09 Entire Interest Isolated bis-linezolid, preparation thereof, and its use as a reference standard
US20090093631A1 (en) 2007-09-06 2009-04-09 Ben-Zion Dolitzky Processes for the preparation of a linezolid intermediate, linezolid hydroxide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US20060252932A1 (en) 2005-02-24 2006-11-09 Entire Interest Isolated bis-linezolid, preparation thereof, and its use as a reference standard
US7291614B2 (en) 2005-02-24 2007-11-06 Teva Pharmaceutical Industries Ltd. Processes for the preparation of linezolid intermediate
US20090093631A1 (en) 2007-09-06 2009-04-09 Ben-Zion Dolitzky Processes for the preparation of a linezolid intermediate, linezolid hydroxide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRICKER ET AL., J. MED. CHEM., vol. 39, 1996, pages 673 - 679
TETRAHEDRON LETT, vol. 40, no. 26, 1999, pages 4855

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102491954A (zh) * 2011-12-06 2012-06-13 江苏正大丰海制药有限公司 利奈唑胺的制备方法
CN102491954B (zh) * 2011-12-06 2014-04-23 江苏正大丰海制药有限公司 利奈唑胺的制备方法
WO2013111048A1 (fr) 2012-01-24 2013-08-01 Jubilant Life Sciences Limited Procédé amélioré de préparation de la forme cristalline stable i du linézolide, pratiquement exempte de solvant résiduel
US20170066728A1 (en) * 2012-01-24 2017-03-09 Jubilant Life Sciences Limited Process for the preparation of stable crystalline form-i of linezolid, substantially free of residual solvent
WO2014045292A1 (fr) * 2012-09-20 2014-03-27 Symed Labs Limited Procédé amélioré pour la préparation d'un intermédiaire de linézolide
CN103601704A (zh) * 2013-11-22 2014-02-26 赵军旭 无定形卡巴他赛的制备
CN104262280A (zh) * 2014-09-22 2015-01-07 山东华生化学股份有限公司 一种利奈唑酮的制备方法
CN104262280B (zh) * 2014-09-22 2016-07-20 山东华生化学股份有限公司 一种利奈唑酮的制备方法
WO2017182853A1 (fr) * 2016-04-21 2017-10-26 Optimus Drugs Pvt Ltd Procédé perfectionné pour la préparation de linézolide
CN110483431A (zh) * 2019-09-04 2019-11-22 桂林南药股份有限公司 利奈唑胺杂质化合物、其制备方法以及其应用

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