USRE47606E1 - Process for the preparation of linezolid - Google Patents
Process for the preparation of linezolid Download PDFInfo
- Publication number
- USRE47606E1 USRE47606E1 US16/117,126 US201816117126A USRE47606E US RE47606 E1 USRE47606 E1 US RE47606E1 US 201816117126 A US201816117126 A US 201816117126A US RE47606 E USRE47606 E US RE47606E
- Authority
- US
- United States
- Prior art keywords
- formula
- compound
- preparation
- fluoro
- isoindole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title abstract description 39
- 229960003907 linezolid Drugs 0.000 title abstract description 30
- GZPUHNGIERMRFC-ZETCQYMHSA-N 4-[[(2s)-oxiran-2-yl]methyl]isoindole-1,3-dione Chemical compound O=C1NC(=O)C2=C1C=CC=C2C[C@H]1CO1 GZPUHNGIERMRFC-ZETCQYMHSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 16
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 10
- 229910052987 metal hydride Inorganic materials 0.000 claims description 9
- 150000004681 metal hydrides Chemical class 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 2
- RSHAOIXHUHAZPM-UHFFFAOYSA-N magnesium hydride Chemical compound [MgH2] RSHAOIXHUHAZPM-UHFFFAOYSA-N 0.000 claims description 2
- 229910012375 magnesium hydride Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- FKZUTWSVQLXKQE-OAHLLOKOSA-N 2-[[(5s)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]isoindole-1,3-dione Chemical compound FC1=CC(N2C(O[C@@H](CN3C(C4=CC=CC=C4C3=O)=O)C2)=O)=CC=C1N1CCOCC1 FKZUTWSVQLXKQE-OAHLLOKOSA-N 0.000 abstract description 16
- 239000000543 intermediate Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- -1 azide compound Chemical class 0.000 description 19
- DUILGEYLVHGSEE-ZETCQYMHSA-N 2-[[(2s)-oxiran-2-yl]methyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C[C@H]1CO1 DUILGEYLVHGSEE-ZETCQYMHSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000010410 layer Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002002 slurry Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 8
- 0 C.CCCCCN1C(=O)C2=C(C=CC=C2)C1=O.CCCCN1C(=O)C2=C(C=CC=C2)C1=O.CCCN1C(=O)C2=C(C=CC=C2)C1=O.CCCNC(=O)*N.CNC(=O)OC Chemical compound C.CCCCCN1C(=O)C2=C(C=CC=C2)C1=O.CCCCN1C(=O)C2=C(C=CC=C2)C1=O.CCCN1C(=O)C2=C(C=CC=C2)C1=O.CCCNC(=O)*N.CNC(=O)OC 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 6
- KBRVYEPWGIQEOF-SSDOTTSWSA-N 2-[(2s)-3-chloro-2-hydroxypropyl]isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(C[C@@H](CCl)O)C(=O)C2=C1 KBRVYEPWGIQEOF-SSDOTTSWSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 6
- 150000007530 organic bases Chemical group 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- VXIWZOWWQMRVRF-NSHDSACASA-N (5s)-5-(aminomethyl)-3-(3-fluoro-4-morpholin-4-ylphenyl)-1,3-oxazolidin-2-one Chemical compound O=C1O[C@@H](CN)CN1C(C=C1F)=CC=C1N1CCOCC1 VXIWZOWWQMRVRF-NSHDSACASA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OCAJYYFZSMCPCT-LHMWIJMLSA-N C.C.ClC[C@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl.O=C1NC(=O)C2=C1C=CC=C2 Chemical compound C.C.ClC[C@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl.O=C1NC(=O)C2=C1C=CC=C2 OCAJYYFZSMCPCT-LHMWIJMLSA-N 0.000 description 2
- XWUQZAIPMKGACE-MQIYEYLPSA-N C.C.O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl Chemical compound C.C.O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl XWUQZAIPMKGACE-MQIYEYLPSA-N 0.000 description 2
- XSHYPAIAEDURIV-AWEZNQCLSA-N CC(=O)CC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1 Chemical compound CC(=O)CC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1 XSHYPAIAEDURIV-AWEZNQCLSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- IWTBSIYVZHKYHB-UHFFFAOYSA-N (3-fluoro-2-methyl-4-morpholin-4-ylphenyl) carbamate Chemical compound C(N)(OC1=C(C(=C(C=C1)N1CCOCC1)F)C)=O IWTBSIYVZHKYHB-UHFFFAOYSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- FZLSDZZNPXXBBB-KDURUIRLSA-N 5-chloro-N-[3-cyclopropyl-5-[[(3R,5S)-3,5-dimethylpiperazin-1-yl]methyl]phenyl]-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine Chemical compound C[C@H]1CN(Cc2cc(Nc3ncc(Cl)c(n3)-c3c[nH]c4cc(C)ccc34)cc(c2)C2CC2)C[C@@H](C)N1 FZLSDZZNPXXBBB-KDURUIRLSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- MEYNINPRLJMTSB-UHFFFAOYSA-M BrCC1CO1.C.CI.O=C1C2=C(C=CC=C2)C(=O)N1CC1CO1.O=C1C2=C(C=CC=C2)C(=O)N1[K] Chemical compound BrCC1CO1.C.CI.O=C1C2=C(C=CC=C2)C(=O)N1CC1CO1.O=C1C2=C(C=CC=C2)C(=O)N1[K] MEYNINPRLJMTSB-UHFFFAOYSA-M 0.000 description 1
- WTYASPLZJFIRJZ-PKBNRGDKSA-N C.C.CI.ClC[C@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl.O=C1NC(=O)C2=C1C=CC=C2 Chemical compound C.C.CI.ClC[C@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl.O=C1NC(=O)C2=C1C=CC=C2 WTYASPLZJFIRJZ-PKBNRGDKSA-N 0.000 description 1
- QBVFJCBRRVGEDB-YIAWQPRTSA-N C.CI.ClC[C@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl.O=C1NC(=O)C2=C1C=CC=C2 Chemical compound C.CI.ClC[C@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1.O=C1C2=C(C=CC=C2)C(=O)N1C[C@H](O)CCl.O=C1NC(=O)C2=C1C=CC=C2 QBVFJCBRRVGEDB-YIAWQPRTSA-N 0.000 description 1
- CSMMBZJFQVRDCU-OLNHWQRASA-N CC(=O)NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1.CC(=O)OC(C)=O.CS(=O)(=O)OC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1.I.NC1=CC(F)=C(N2CCOCC2)C=C1.NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1.O=C(NC1=CC(F)=C(N2CCOCC2)C=C1)OCC1=CC=CC=C1.O=C1CC(=O)C2=C1C=CC=C2.O=C1O[C@@H](CN2C(=O)C3=CC=CC=C3C2=O)CN1C1=CC(F)=C(N2CCOCC2)C=C1.O=C1O[C@@H](CO)CN1C1=CC(F)=C(N2CCOCC2)C=C1.O=[N+]([O-])C1=CC(F)=C(N2CCOCC2)C=C1.[N-]=[N+]=NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1 Chemical compound CC(=O)NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1.CC(=O)OC(C)=O.CS(=O)(=O)OC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1.I.NC1=CC(F)=C(N2CCOCC2)C=C1.NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1.O=C(NC1=CC(F)=C(N2CCOCC2)C=C1)OCC1=CC=CC=C1.O=C1CC(=O)C2=C1C=CC=C2.O=C1O[C@@H](CN2C(=O)C3=CC=CC=C3C2=O)CN1C1=CC(F)=C(N2CCOCC2)C=C1.O=C1O[C@@H](CO)CN1C1=CC(F)=C(N2CCOCC2)C=C1.O=[N+]([O-])C1=CC(F)=C(N2CCOCC2)C=C1.[N-]=[N+]=NC[C@H]1CN(C2=CC(F)=C(N3CCOCC3)C=C2)C(=O)O1 CSMMBZJFQVRDCU-OLNHWQRASA-N 0.000 description 1
- JWGVDNNVRNQZRQ-QVEQSUBQSA-M CC(=O)NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.ClC[C@H]1CO1.I.NC1=CC=C(N2CCOCC2)C(F)=C1.NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.O=C1C2=C(C=CC=C2)C(=O)[N+]1=[K-].O=C1O[C@@H](CCl)CN1C1=CC=C(N2CCOCC2)C(F)=C1.O=C1O[C@@H](CN2C(=O)C3=CC=CC=C3C2=O)CN1C1=CC=C(N2CCOCC2)C(F)=C1.O[C@@H](CCl)CNC1=CC=C(N2CCOCC2)C(F)=C1 Chemical compound CC(=O)NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.ClC[C@H]1CO1.I.NC1=CC=C(N2CCOCC2)C(F)=C1.NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.O=C1C2=C(C=CC=C2)C(=O)[N+]1=[K-].O=C1O[C@@H](CCl)CN1C1=CC=C(N2CCOCC2)C(F)=C1.O=C1O[C@@H](CN2C(=O)C3=CC=CC=C3C2=O)CN1C1=CC=C(N2CCOCC2)C(F)=C1.O[C@@H](CCl)CNC1=CC=C(N2CCOCC2)C(F)=C1 JWGVDNNVRNQZRQ-QVEQSUBQSA-M 0.000 description 1
- JBCNBGWTLCBKDV-WKAXXBCZSA-N CC(=O)NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.I.NC1=CC=C(N2CCOCC2)C(F)=C1.NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.O=C1C2=CC=CC=C2C(=O)N1C[C@H](O)CNC1=CC=C(N2CCOCC2)C(F)=C1.O=C1C2=CC=CC=C2C(=O)N1C[C@H]1CO1.O=C1O[C@@H](CN2C(=O)C3=CC=CC=C3C2=O)CN1C1=CC=C(N2CCOCC2)C(F)=C1 Chemical compound CC(=O)NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.I.NC1=CC=C(N2CCOCC2)C(F)=C1.NC[C@H]1CN(C2=CC=C(N3CCOCC3)C(F)=C2)C(=O)O1.O=C1C2=CC=CC=C2C(=O)N1C[C@H](O)CNC1=CC=C(N2CCOCC2)C(F)=C1.O=C1C2=CC=CC=C2C(=O)N1C[C@H]1CO1.O=C1O[C@@H](CN2C(=O)C3=CC=CC=C3C2=O)CN1C1=CC=C(N2CCOCC2)C(F)=C1 JBCNBGWTLCBKDV-WKAXXBCZSA-N 0.000 description 1
- DOBCCCCDMABCIV-UHFFFAOYSA-N CC1CN(C)C(=O)O1 Chemical compound CC1CN(C)C(=O)O1 DOBCCCCDMABCIV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- DUILGEYLVHGSEE-SSDOTTSWSA-N O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1 Chemical compound O=C1C2=C(C=CC=C2)C(=O)N1C[C@@H]1CO1 DUILGEYLVHGSEE-SSDOTTSWSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940123573 Protein synthesis inhibitor Drugs 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- YLNSNVGRSIOCEU-ZCFIWIBFSA-N [(2r)-oxiran-2-yl]methyl butanoate Chemical compound CCCC(=O)OC[C@H]1CO1 YLNSNVGRSIOCEU-ZCFIWIBFSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
Classifications
-
- 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
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing(S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide and (S)-glycidylphthalimide intermediates, which are used in the preparation of Linezolid.
- Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA).
- MRSA methicillin-resistant Staphylococcus aureus
- the antibacterial effect of oxazolidinones is by working as protein synthesis inhibitors targeting an early step involving the binding of N-formylmethionyl-t-RNA to the ribosome.
- Linezolid is marketed by Pfizer under the trade name “Zyvox” and it is chemically known as (S)—N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide having the formula (I).
- Linezolid is first disclosed in U.S. Pat. No. 5,688,792 and its process comprises the use of R-glycidylbutyrate which results in the formation of (R)—N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol which in the subsequent stages has to be converted to various intermediary compounds to finally form Linezolid.
- Said process which is depicted in the scheme-I given below, also encompasses an intermediary azide compound, which is difficult to handle at industrial level:
- WO 1999/24393 A1 discloses a process for the preparation of oxazolidinone derivatives, which is depicted in scheme-II given below:
- R oxa is phenyl substituted with one fluoro and one substituted amino group, wherein the substituted amino groups include 4-(benzyloxycarbonyl)-1-piperazinyl, 4-morpholinyl and 4-hydroxyacetylpiperazinyl
- WO' 393 does not disclose any specific examples or suitable conditions for the preparation of Linezolid.
- WO 2005/099353 A2 discloses a process for the preparation of Linezolid, which is depicted in scheme-III given below:
- WO 2006/008754 A1 discloses a process for the preparation of Linezolid, which is depicted in scheme-IV given below
- WO2007116284 discloses a process for preparing Linezolid, which is depicted in the scheme-V below, by reacting a compound of structure (1) with a compound of structure (2) at a temperature range from ambient temperature to about 65° C. to provide a compound of structure (3), which is hydrolyzed and subsequently acylated to give Linezolid:
- U.S. Pat. No. 5,608,110 discloses a process for the preparation of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (I) comprising the reaction of phthalimide with (S)-(+)-epichlorohydrin under reflux in ethyl acetate/hexane under a nitrogen atmosphere to get (S)-1-chloro-3-phthalimido-2-propanol which is cyclized in presence of NaH/THF.
- U.S. Pat. No. 6,875,875 discloses a process for the preparation of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (I) comprising the reaction of phthalimide with (S)-epichlorohydrin in the presence of an alkali metal carbonate, an alkali metal hydrogen carbonate or a quaternary ammonium salt to get (S)-1-chloro-3-phthalimido-2-propanol which is cyclized in the presence of metal alkoxides.
- This process is schematically shown as below:
- the main objective of the present invention is to provide a cost-effective and commercially feasible process for the preparation of Linezolid.
- Another objective of the present invention is to provide a process for the preparation of the (S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide and (S)-glycidyl phthalimide intermediates, which employs less expensive, easily available and eco-friendly reagents.
- R represents hydrogen, C 1 -C 5 alkyl, aryl, aralkyl; with (S)-glycidyl phthalimide of formula (IX)
- the present invention provides an improved process for the preparation of the compound of formula (I) comprising the steps of;
- the present invention provides an improved process for the preparation of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione of formula (IX) comprising the steps of:
- An embodiment of the present invention provides an improved process for the preparation of (S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]A methyl] phthalimide of formula (VI)
- R represents hydrogen, C 1 -C 5 alkyl, aryl, aralkyl; with (S)-glycidyl phthalimide of formula (IX)
- the reaction is carried using an alkali metal iodide and in the presence or absence of a solvent at a temperature in the range of 60 to 120° C. The reaction is carried out for a period of 10 to 14 hours.
- the reaction is carried using a lithium tertiary butoxide used in the range 0.2-0.4 mole equivalents in the presence of a suitable solvent at a temperature in the range of 40 to 100° C.
- the reaction is carried out for a period of 4 to 12 hours.
- the suitable alkali metal iodides are selected from lithium iodide, sodium iodide, potassium iodide and the like;
- the suitable solvent is selected from alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, and the like; ethers, such as 1,4-dioxane, tetrahydrofuran, and the like; and amides such as N,N-dimethylform
- the reaction between the compound of formula (III) with (S)-Glycidyl phthalimide of formula (IX) is carried out in the presence of a suitable alkali metal iodide (or) a metal hydride and a solvent at a suitable temperature to give a compound of formula (VI); this compound is subjected to deprotection with hydrazine hydrae (or) aqueous methyl amine to give (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one, which is subsequently acylated with acetic anhydride or acetyl chloride to give (S)—N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide (Linezolid) of formula I.
- a suitable alkali metal iodide or a metal hydride
- the reaction between the compound of formula (III) with (S)-glycidyl phthalimide of formula (IX) is carried out in the presence of a suitable metal hydride and a solvent at a suitable temperature to give a compound of formula (VI); the reaction is completed within a shorter time span and provides good quantity of yield and high purity
- the alkali metal iodide is selected from lithium iodide, sodium iodide, potassium iodide and the like; the metal hydride is selected from sodium hydride, lithium hydride or magnesium hydride.
- the suitable solvent is selected from alcohols such as methanol, ethanol, isopropyl alcohol, and the like or mixture thereof; ketones, such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone, and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform, and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents, such as toluene, xylene, cyclohexane, and the like; ethers, such as 1,4-dioxane, tetrahydrofuran, and the like; and amides such as N,N-dimethylformamide, N,N-dimethyl acetamide and the like or dimethyl sulfoxide or mixture of solvents thereof; ketones, such as methyl isobutyl ketone
- the present invention further involves a conversion of the compound of formula (VI) to Linezolid of formula (I), which involves the conversion of the phthalimide compound of formula (VI) to an amine, followed by acylation to yield Linezolid using conventional methods known in the prior art.
- the acylation is carried out in the presence of acetic anhydride or acetyl chloride.
- the reaction is performed at or below boiling temperature of the solvent, preferably between 10° C. and boiling temperature of the solvent and even more preferably at the boiling temperature of the solvent.
- the time required for completion of the reaction depends on factors such as the solvent used and the applied temperature.
- the present invention relates to an improved process for the preparation of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione of formula IX comprising the steps of:
- Linezolid produced according to the present invention may be in amorphous form or in crystalline forms I or II.
- the compound of formula (I) or Linezolid has a HPLC purity of not less than 99%.
- the reaction mixture was cooled to ambient temperature, ethyl acetate (50 ml) was added, and the resultant slurry was stirred for 30 min at a temperature of 25-30° C. The solid was filtered off. The resultant crude solid was added to ethyl acetate (250 ml) at a temperature of 25-30° C. and heated to 70-75° C. The slurry was stirred for 15-20 min, cooled to 25-30° C. and stirred for 30 min.
- reaction mass was cooled to below 20° C., quenched with 25 ml methanol to decompose the excess sodium hydride.
- the solvent was distilled off and methanol was added (125 ml).
- the resulting slurry was stirred for 30 min at 25 30° C. and filtered.
- the obtained solid was taken into ethyl acetate (125 ml) and the slurry was heated to 70-75° C., stirred for 15-20 min, cooled to 25-30° C. and filtered.
- reaction mass was cooled to below 20° C., quenched with 25 ml methanol to decompose the excess sodium hydride. Further methanol (125 ml) was added and the resulting slurry was stirred for 30 min at 25-30° C. and filtered. The obtained solid was taken into ethyl acetate (125 ml) and heated to 70-75° C. The slurry was stirred for 15-20 min, cooled to 25-30° C. and filtered.
- Methyl amine solution 50 g was added to a mixture of methanol (100 ml), DM water (400 ml) and (5S) 2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione (100 g 0.235 moles) at a temperature of 25-30° C.
- the reaction mixture was stirred and the temperature was slowly raised to 80-85° C. and maintained for 2-3 hours.
- the reaction mixture was allowed to cool to 25-30° C., dichloromethane (500 ml) was added and the mixture was stirred for 15 min to separate the layers.
- Purified water 500 ml was added to the MDC layer and the mixture was acidified to pH 2.0-3.0 with dilute hydrochloric acid and stirred for 10-15 min. The two layers were separated and basified with aqueous ammonia to pH 10.0-11.0 to separate the MDC layer. The solvent of the isolated organic layer was distilled off completely under atmospheric pressure to get the residual product of (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one. Dichloroinethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at 25-30° C. over a period of 60 min.
- the reaction mixture was stirred for 60 min at 25-30° C. After completion of reaction, 5% aqueous sodium bicarbonate solution was slowly added to the reaction mixture, which was stirred for 15 min. The two layers were separated and the dichloromethane layer was washed with DM Water (200 ml). The dichloromethane layer was filtered through hiflo and dichloromethane was distilled off completely under vacuum below 40° C. Cyclohexane (500 ml) was added to the residue and the mixture was heated to 45-50° C. The slurry obtained was cooled to 20-25° C. and stirred for 60 min. The solid obtained was filtered, washed with cyclohexane (200 ml) and dried at 45-55° C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
where Roxa is phenyl substituted with one fluoro and one substituted amino group, wherein the substituted amino groups include 4-(benzyloxycarbonyl)-1-piperazinyl, 4-morpholinyl and 4-hydroxyacetylpiperazinyl
- X1 is C1-C20 alkyl;
- X2 is CI, Br
- RN is C1-C5 alkyl
# indicates that the atoms marked with a (#) are bonded to each other resulting in the formation of ring
and RING is
2-[(2)-Oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (I) was first mentioned in Compt. rend. 1930, 190, 495-6, which describes a process for the preparation of 2-[(2)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione comprising the reaction of potassium phthalimide with epibromohydrin in the presence of gaseous or aqueous hydrohalogen acids. This process is schematically shown below:
wherein R represents hydrogen, C1-C5 alkyl, aryl, aralkyl; with (S)-glycidyl phthalimide of formula (IX)
in the presence of alkali metal iodides (or) metal hydrides (or)
in the presence of lithium tertiary butoxide in the range 0.2-0.4 mole equivalents based on carbamate compound of formula (III)
-
- a) reacting the compound of formula (III) with (S)-Glycidyl Phthalimide of formula (IX) in the presence of alkali metal iodides (or) metal hydrides to give a compound of formula (VI)
- b) subjecting the compound of formula (VI) with aqueous methyl amine or hydrazine hydrate,
- c) acylating the product of step b), and
- d) isolating the compound of formula (I).
-
- a) reacting 1H-isoindole-1,3(2H)-dione or phthalimide with (S)-epichlorohydrin in the presence of an organic base in an organic solvent to obtain (S)-1-chloro-3-phthalimido-2-propanol.
-
-
- Wherein, the organic base is a primary or a secondary alkyl amine having 1-5 carbon atoms.
- b) (S)-1-chloro-3-phthalimido-2-propanol is cyclized in the presence of an alkali metal alkoxide to obtain 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione
-
wherein R represents hydrogen, C1-C5 alkyl, aryl, aralkyl; with (S)-glycidyl phthalimide of formula (IX)
in the presence of alkali metal iodides (or) metal hydrides (or)
in the presence of lithium tertiary butoxide used in the range 0.2-0.4 mole equivalents based on the carbamate compound of formula (III)
-
- a) reacting the compound of formula (III) with (S)-Glycidyl phthalimide of formula (IX) in the presence of an alkali metal iodide or a metal hydride to give a compound of formula (VI),
- b) subjecting the compound of formula (VI) with aqueous methyl amine or hydrazine hydrate,
- c) acylating the product of step b), and
- d) isolating the compound of formula (I).
-
- a) reacting phthalimide with (S)-(+)-Epichlorohydrin in the presence of an organic base in an organic solvent at a temperature of 60° C. to obtain (S)-1-chloro-3-phthalimido-2-propanol.
-
-
- wherein, the organic base is a primary or a secondary alkyl amine having 1-5 carbon atoms.
- The organic base is selected from a primary or a secondary alkyl amine having 1-5 Carbon atoms such as methylamine, ethylamine, ethyl methylamine, diethylamine, dipropylamine, dibutylamine, preferably diethylamine.
- The organic solvent is selected from the group comprising alcohols, ethers, esters, nitriles having C1-C4 carbon atoms; preferably alcohols.
- The alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol; the ether solvents are selected from diethyl ether, tetrahydrofuran etc.; the ester solvents are selected from ethyl acetate, methyl acetate, etc.; nitriles are selected from acetonitrile, propionitrile, butyronitrile etc.
- b) (S)-1-chloro-3-phthalimido-2-propanol is cyclized in the presence of an alkali metal alkoxide to obtain 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione
-
-
-
- Cyclization of (S)-1-chloro-3-phthalimide-2-propanol will produce 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3-(2H)-dione.
- Cyclization is carried out in the presence of an alkali metal alkoxide as described in U.S. Pat. No. 6,875,875.
-
-
- 1. The present invention is a simple, operation friendly and industrially applicable process.
- 2. The process is commercially viable and provides the compounds in high yield, which makes the process cost effective
- 3. The reaction sequence of the present invention is carried out in a shorter time span
- 4. The present invention provides the compounds of formulas (I), (VI) and (IX) with high purity and less impurities.
Claims (3)
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US5608110A (en) | 1993-06-15 | 1997-03-04 | Bracco International B.V. | Heteroatom-bearing ligands and metal complexes thereof |
US5688792A (en) | 1994-08-16 | 1997-11-18 | Pharmacia & Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
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