TWI535715B - 製備利奈唑烷（ｌｉｎｅｚｏｌｉｄ）之方法 - Google Patents
製備利奈唑烷（ｌｉｎｅｚｏｌｉｄ）之方法 Download PDFInfo
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- TWI535715B TWI535715B TW100115216A TW100115216A TWI535715B TW I535715 B TWI535715 B TW I535715B TW 100115216 A TW100115216 A TW 100115216A TW 100115216 A TW100115216 A TW 100115216A TW I535715 B TWI535715 B TW I535715B
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- 238000000034 method Methods 0.000 title claims description 119
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title claims description 30
- 229960003907 linezolid Drugs 0.000 title claims description 27
- -1 tributylphosphine oxide Nitride Chemical class 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 34
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 27
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 16
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 11
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- 239000012190 activator Substances 0.000 claims description 9
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- FPENCTDAQQQKNY-UHFFFAOYSA-N 3,4-difluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(F)=C1 FPENCTDAQQQKNY-UHFFFAOYSA-N 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- QPIBHIXKUQKNFP-UHFFFAOYSA-N 4-chloro-3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(F)=C1 QPIBHIXKUQKNFP-UHFFFAOYSA-N 0.000 claims description 2
- CIVQCUDGGGGDCR-UHFFFAOYSA-N FC1N(CCOC1)C1=CC=CC=C1C(=O)O Chemical compound FC1N(CCOC1)C1=CC=CC=C1C(=O)O CIVQCUDGGGGDCR-UHFFFAOYSA-N 0.000 claims 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 101
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 238000006243 chemical reaction Methods 0.000 description 84
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000013078 crystal Substances 0.000 description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 238000003756 stirring Methods 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- 238000010992 reflux Methods 0.000 description 49
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 45
- 239000000203 mixture Substances 0.000 description 45
- 239000007787 solid Substances 0.000 description 36
- 238000001914 filtration Methods 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- 125000003277 amino group Chemical group 0.000 description 26
- 239000010410 layer Substances 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 23
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 22
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- 239000003921 oil Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- KYDFICMLDMOOJX-UHFFFAOYSA-N 3-fluoro-2-morpholin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1N1CCOCC1 KYDFICMLDMOOJX-UHFFFAOYSA-N 0.000 description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 10
- 229940078552 o-xylene Drugs 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- CSSSAKOGRYYMSA-UHFFFAOYSA-N 1-chloro-2-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(F)=C1 CSSSAKOGRYYMSA-UHFFFAOYSA-N 0.000 description 7
- MNZAKDODWSQONA-UHFFFAOYSA-N 1-dibutylphosphorylbutane Chemical compound CCCCP(=O)(CCCC)CCCC MNZAKDODWSQONA-UHFFFAOYSA-N 0.000 description 7
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 7
- RVPOFXBMBJKJJK-UHFFFAOYSA-N 4-(2-fluoro-6-nitrophenyl)morpholine Chemical compound [O-][N+](=O)C1=CC=CC(F)=C1N1CCOCC1 RVPOFXBMBJKJJK-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical group ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 150000001540 azides Chemical class 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 150000002924 oxiranes Chemical class 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000002198 insoluble material Substances 0.000 description 6
- 239000012948 isocyanate Substances 0.000 description 6
- 150000002513 isocyanates Chemical class 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 6
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- RUBQQRMAWLSCCJ-UHFFFAOYSA-N 1,2-difluoro-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(F)C(F)=C1 RUBQQRMAWLSCCJ-UHFFFAOYSA-N 0.000 description 4
- FQGIBHQUVCGEAC-UHFFFAOYSA-N 3-Fluoro-4-morpholinoaniline Chemical compound FC1=CC(N)=CC=C1N1CCOCC1 FQGIBHQUVCGEAC-UHFFFAOYSA-N 0.000 description 4
- 244000248349 Citrus limon Species 0.000 description 4
- 235000005979 Citrus limon Nutrition 0.000 description 4
- 229920000742 Cotton Polymers 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000005484 gravity Effects 0.000 description 4
- 239000012456 homogeneous solution Substances 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000006146 oximation reaction Methods 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 235000010378 sodium ascorbate Nutrition 0.000 description 4
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 4
- 229960005055 sodium ascorbate Drugs 0.000 description 4
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000006418 Brown reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
- MTMNJFGEKOYMIV-UHFFFAOYSA-N carbonyl dichloride;toluene Chemical compound ClC(Cl)=O.CC1=CC=CC=C1 MTMNJFGEKOYMIV-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical group 0.000 description 2
- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- MWDNZMWVENFVHT-UHFFFAOYSA-L (2-decoxy-2-oxoethyl)-[2-[2-[(2-decoxy-2-oxoethyl)-dimethylazaniumyl]ethylsulfanyl]ethyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCOC(=O)C[N+](C)(C)CCSCC[N+](C)(C)CC(=O)OCCCCCCCCCC MWDNZMWVENFVHT-UHFFFAOYSA-L 0.000 description 1
- WMASLRCNNKMRFP-UHFFFAOYSA-N 1-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(F)=C1 WMASLRCNNKMRFP-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- JFDMLXYWGLECEY-UHFFFAOYSA-N 2-benzyloxirane Chemical compound C=1C=CC=CC=1CC1CO1 JFDMLXYWGLECEY-UHFFFAOYSA-N 0.000 description 1
- MNNZINNZIQVULG-UHFFFAOYSA-N 2-chloroethylbenzene Chemical compound ClCCC1=CC=CC=C1 MNNZINNZIQVULG-UHFFFAOYSA-N 0.000 description 1
- JFYQLZHULWIALT-UHFFFAOYSA-N 4-(2-fluoro-4-isocyanatophenyl)morpholine Chemical compound FC1=CC(N=C=O)=CC=C1N1CCOCC1 JFYQLZHULWIALT-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- 229940125782 compound 2 Drugs 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- HQFQTTNMBUPQAY-UHFFFAOYSA-N cyclobutylhydrazine Chemical compound NNC1CCC1 HQFQTTNMBUPQAY-UHFFFAOYSA-N 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 229910052744 lithium Inorganic materials 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- JGZKUKYUQJUUNE-UHFFFAOYSA-L magnesium;ethoxyethane;dibromide Chemical compound [Mg+2].[Br-].[Br-].CCOCC JGZKUKYUQJUUNE-UHFFFAOYSA-L 0.000 description 1
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- 229960003085 meticillin Drugs 0.000 description 1
- HBTVZPMDLRPWKZ-YFKPBYRVSA-N n-[[(2s)-oxiran-2-yl]methyl]acetamide Chemical compound CC(=O)NC[C@H]1CO1 HBTVZPMDLRPWKZ-YFKPBYRVSA-N 0.000 description 1
- TYZROVQLWOKYKF-CYBMUJFWSA-N n-[[(5r)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-CYBMUJFWSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
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- 230000020477 pH reduction Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| US32989210P | 2010-04-30 | 2010-04-30 | |
| US35985110P | 2010-06-30 | 2010-06-30 | |
| US37557610P | 2010-08-20 | 2010-08-20 | |
| US38953410P | 2010-10-04 | 2010-10-04 | |
| US42144210P | 2010-12-09 | 2010-12-09 |
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|---|---|
| TW201144301A TW201144301A (en) | 2011-12-16 |
| TWI535715B true TWI535715B (zh) | 2016-06-01 |
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|---|---|
| US (2) | US9206141B2 (enExample) |
| EP (2) | EP2563781B1 (enExample) |
| JP (1) | JP5865898B2 (enExample) |
| KR (1) | KR20130108975A (enExample) |
| CN (1) | CN103025730A (enExample) |
| AU (1) | AU2011245302A1 (enExample) |
| BR (1) | BR112012027901A2 (enExample) |
| CA (1) | CA2798101A1 (enExample) |
| IL (1) | IL222770A0 (enExample) |
| MX (1) | MX2012012627A (enExample) |
| RU (1) | RU2012151303A (enExample) |
| SG (1) | SG185103A1 (enExample) |
| TW (1) | TWI535715B (enExample) |
| WO (1) | WO2011137222A1 (enExample) |
| ZA (1) | ZA201208382B (enExample) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103025730A (zh) * | 2010-04-30 | 2013-04-03 | 印第安纳大学研究及科技有限公司 | 制备利奈唑胺的方法 |
| SI2595968T1 (sl) | 2011-02-24 | 2016-01-29 | Lee Pharma Limited | Novi postopek za pripravo linezolida in njegovih novih intermediatov |
| WO2013072923A1 (en) * | 2011-09-19 | 2013-05-23 | Cadila Healthcare Limited | Process for the preparation of crystalline linezolid |
| CN103254148B (zh) * | 2012-02-15 | 2016-04-13 | 浙江海正药业股份有限公司 | 利奈唑胺中间体的制备方法 |
| CN103288814B (zh) * | 2012-02-24 | 2016-07-06 | 国药集团国瑞药业有限公司 | 一种利伐沙班中间体的制备方法 |
| EP2834235A1 (en) * | 2012-04-06 | 2015-02-11 | Indiana University Research and Technology Corporation | Processes for preparing rivaroxaban |
| ITMI20120655A1 (it) * | 2012-04-19 | 2013-10-20 | Bioindustria Lab Italiano M Edicinali Spa | Procedimento per la preparazione di linezolid |
| AR090844A1 (es) * | 2012-04-27 | 2014-12-10 | Actelion Pharmaceuticals Ltd | Proceso para elaborar derivados de naftiridina |
| CN103626712B (zh) * | 2012-08-23 | 2016-06-01 | 重庆药友制药有限责任公司 | 一种用于制备利奈唑胺的中间体及其制备方法 |
| WO2014045292A1 (en) * | 2012-09-20 | 2014-03-27 | Symed Labs Limited | Improved process for the preparation of linezolid intermediate |
| WO2014170908A1 (en) * | 2013-04-18 | 2014-10-23 | Nosch Labs Private Limited | Process for preparation of oxazolidinone derivatives |
| WO2017182853A1 (en) * | 2016-04-21 | 2017-10-26 | Optimus Drugs Pvt Ltd | An improved process for the preparation of linezolid |
| CN110194750A (zh) * | 2019-06-19 | 2019-09-03 | 四川美大康华康药业有限公司 | 一种利奈唑胺的制备方法及精制方法 |
| CN112159368A (zh) * | 2020-07-07 | 2021-01-01 | 杭州杜易科技有限公司 | 一种利奈唑胺中间体的合成方法 |
| RU2760198C1 (ru) * | 2020-12-16 | 2021-11-22 | Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт по изысканию новых антибиотиков имени Г.Ф. Гаузе" | Однореакторный способ получения полупродукта для синтеза линезолида |
| CN115684399B (zh) * | 2022-10-27 | 2024-12-20 | 贵州健安德科技有限公司 | 一种氯醇亚胺的高效液相检测及含量测定方法 |
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| US3725450A (en) * | 1970-10-05 | 1973-04-03 | Gen Mills Chem Inc | Process for the preparation of isocyanates from acyl azides |
| US4937331A (en) | 1988-03-25 | 1990-06-26 | President And Fellows Of Harvard College | Chiral azetidinone epoxides |
| DE4119611A1 (de) * | 1991-06-14 | 1992-12-17 | Bayer Ag | Mittel zur bekaempfung von schaedlingen auf basis substituierter oxazolidinone, neue substituierte oxazolidinone, deren herstellung und verwendung |
| TW380137B (en) * | 1994-03-04 | 2000-01-21 | Merck & Co Inc | Process for making an epoxide |
| DE19542148A1 (de) * | 1995-11-11 | 1997-05-15 | Hoechst Ag | Verfahren zur Herstellung von fluorierten Aromaten |
| CA2304100A1 (en) | 1997-11-07 | 1999-05-20 | Pharmacia & Upjohn Company | Process to produce oxazolidinones |
| US6921825B2 (en) | 1998-09-16 | 2005-07-26 | King Pharmaceuticuals Research & Development, Inc. | Adenosine A3 receptor modulators |
| US6444813B2 (en) * | 2000-02-02 | 2002-09-03 | Pharmacia & Upjohn Company | Linezolid-crystal form II |
| AR027261A1 (es) | 2000-02-02 | 2003-03-19 | Upjohn Co | Linezolid forma cristalina ii |
| SE0001866D0 (sv) * | 2000-05-18 | 2000-05-18 | Astrazeneca Ab | A new process |
| NZ525923A (en) | 2000-10-17 | 2005-11-25 | Upjohn Co | Methods of producing oxazolidinone compounds |
| MXPA03011006A (es) | 2001-06-05 | 2004-02-27 | Boehringer Ingelheim Pharma | Compuestos de cicloalquil urea benzo-fusionados 1,4-disustituidos. |
| ES2294494T3 (es) | 2004-04-19 | 2008-04-01 | Symed Labs Limited | Un nuevo procedimiento para la preparacion de linezolid y compuestos relacionados. |
| US7429661B2 (en) | 2004-07-20 | 2008-09-30 | Symed Labs Limited | Intermediates for linezolid and related compounds |
| US7291614B2 (en) | 2005-02-24 | 2007-11-06 | Teva Pharmaceutical Industries Ltd. | Processes for the preparation of linezolid intermediate |
| EP1910443A2 (en) | 2005-07-15 | 2008-04-16 | Cyclics Corporation | Macrocyclic polyester oligomers as carriers and/or flow modifier additives for thermoplastics |
| RU2008139612A (ru) * | 2006-04-07 | 2010-04-20 | Пфайзер Продактс Инк. (Us) | Способ получения линезолида |
| CN101220001A (zh) | 2008-01-25 | 2008-07-16 | 浙江博泰化工有限公司 | 一种利奈唑酮的合成方法 |
| CN101638392B (zh) * | 2009-08-24 | 2012-05-16 | 浙江工业大学 | 一种列奈唑酮的制备方法 |
| CN103025730A (zh) * | 2010-04-30 | 2013-04-03 | 印第安纳大学研究及科技有限公司 | 制备利奈唑胺的方法 |
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2011
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- 2011-04-28 WO PCT/US2011/034278 patent/WO2011137222A1/en not_active Ceased
- 2011-04-28 AU AU2011245302A patent/AU2011245302A1/en not_active Abandoned
- 2011-04-28 SG SG2012080321A patent/SG185103A1/en unknown
- 2011-04-28 MX MX2012012627A patent/MX2012012627A/es not_active Application Discontinuation
- 2011-04-28 RU RU2012151303/04A patent/RU2012151303A/ru not_active Application Discontinuation
- 2011-04-28 EP EP11775554.6A patent/EP2563781B1/en not_active Not-in-force
- 2011-04-28 BR BR112012027901A patent/BR112012027901A2/pt not_active IP Right Cessation
- 2011-04-28 EP EP14197369.3A patent/EP2899185B1/en not_active Not-in-force
- 2011-04-28 KR KR1020127029523A patent/KR20130108975A/ko not_active Withdrawn
- 2011-04-28 US US13/695,211 patent/US9206141B2/en not_active Expired - Fee Related
- 2011-04-28 JP JP2013508243A patent/JP5865898B2/ja not_active Expired - Fee Related
- 2011-04-28 CA CA2798101A patent/CA2798101A1/en not_active Abandoned
- 2011-04-29 TW TW100115216A patent/TWI535715B/zh not_active IP Right Cessation
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2012
- 2012-10-30 IL IL222770A patent/IL222770A0/en unknown
- 2012-11-07 ZA ZA2012/08382A patent/ZA201208382B/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| US20160024032A1 (en) | 2016-01-28 |
| TW201144301A (en) | 2011-12-16 |
| EP2899185A1 (en) | 2015-07-29 |
| CN103025730A (zh) | 2013-04-03 |
| SG185103A1 (en) | 2012-12-28 |
| EP2899185B1 (en) | 2018-01-31 |
| BR112012027901A2 (pt) | 2015-09-08 |
| ZA201208382B (en) | 2015-06-24 |
| WO2011137222A1 (en) | 2011-11-03 |
| IL222770A0 (en) | 2012-12-31 |
| EP2563781B1 (en) | 2016-10-26 |
| US9206141B2 (en) | 2015-12-08 |
| EP2563781A1 (en) | 2013-03-06 |
| JP5865898B2 (ja) | 2016-02-17 |
| AU2011245302A1 (en) | 2012-11-22 |
| KR20130108975A (ko) | 2013-10-07 |
| MX2012012627A (es) | 2013-05-09 |
| EP2563781A4 (en) | 2013-11-06 |
| CA2798101A1 (en) | 2011-11-03 |
| RU2012151303A (ru) | 2014-06-10 |
| JP2013525454A (ja) | 2013-06-20 |
| US20130053557A1 (en) | 2013-02-28 |
| US9656973B2 (en) | 2017-05-23 |
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