CN1155585C - 3, 5-substituted oxazolidinone derivative and preparation method and application thereof - Google Patents
3, 5-substituted oxazolidinone derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN1155585C CN1155585C CNB011446137A CN01144613A CN1155585C CN 1155585 C CN1155585 C CN 1155585C CN B011446137 A CNB011446137 A CN B011446137A CN 01144613 A CN01144613 A CN 01144613A CN 1155585 C CN1155585 C CN 1155585C
- Authority
- CN
- China
- Prior art keywords
- compound
- morpholinyl
- oxazolidinyl
- oxo
- phenyl
- 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.)
- Expired - Lifetime
Links
- -1 5-substituted oxazolidinone Chemical class 0.000 title claims abstract description 216
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 178
- 238000006243 chemical reaction Methods 0.000 claims description 79
- RKXFFOKVCXWANY-UHFFFAOYSA-N 1-ethyl-8,8-dimethyl-3-azabicyclo[3.2.1]octane-2,4-dione Chemical compound CCC12C(=O)NC(C(C1(C)C)CC2)=O RKXFFOKVCXWANY-UHFFFAOYSA-N 0.000 claims description 28
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- 241000894006 Bacteria Species 0.000 claims description 14
- 125000002757 morpholinyl group Chemical group 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 230000000941 anti-staphylcoccal effect Effects 0.000 claims 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims 2
- KAJJUFUPJGVIFJ-UHFFFAOYSA-N 3-methylpyrrolidine-2,5-dione Chemical compound CC1CC(=O)NC1=O KAJJUFUPJGVIFJ-UHFFFAOYSA-N 0.000 claims 1
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 1
- 125000005544 phthalimido group Chemical group 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 241000192125 Firmicutes Species 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 84
- 239000002585 base Substances 0.000 description 74
- 238000010189 synthetic method Methods 0.000 description 68
- 239000013078 crystal Substances 0.000 description 64
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 59
- 239000000243 solution Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- 239000007787 solid Substances 0.000 description 43
- 238000001953 recrystallisation Methods 0.000 description 38
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- ABCGRFHYOYXEJV-UHFFFAOYSA-N 4-methylisoindole-1,3-dione Chemical compound CC1=CC=CC2=C1C(=O)NC2=O ABCGRFHYOYXEJV-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 20
- NRQVXWNPFZZDMQ-UHFFFAOYSA-N 5,8,8-trimethyl-3-azabicyclo[3.2.1]octane-2,4-dione Chemical compound O=C1NC(=O)C2(C)CCC1C2(C)C NRQVXWNPFZZDMQ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 238000005406 washing Methods 0.000 description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 230000000845 anti-microbial effect Effects 0.000 description 14
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000003810 ethyl acetate extraction Methods 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 108010059993 Vancomycin Proteins 0.000 description 9
- 229960004756 ethanol Drugs 0.000 description 9
- 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 9
- 229960003165 vancomycin Drugs 0.000 description 9
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- VIKSTSDUVSJVFX-UHFFFAOYSA-N O=C(N(C(OCC1=CC=CC=C1)=O)C(C=C1)=CC(F)=C1N1CCOCC1)OCC1=CC=CC=C1 Chemical compound O=C(N(C(OCC1=CC=CC=C1)=O)C(C=C1)=CC(F)=C1N1CCOCC1)OCC1=CC=CC=C1 VIKSTSDUVSJVFX-UHFFFAOYSA-N 0.000 description 8
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 8
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 7
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 238000010907 mechanical stirring Methods 0.000 description 7
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229930182555 Penicillin Natural products 0.000 description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 241000193996 Streptococcus pyogenes Species 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
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- 150000003254 radicals Chemical class 0.000 description 6
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- DOYDZSBFIRXZDY-UHFFFAOYSA-N N-chloro-4-morpholin-4-ylaniline Chemical compound ClNc1ccc(cc1)N1CCOCC1 DOYDZSBFIRXZDY-UHFFFAOYSA-N 0.000 description 5
- 241000191963 Staphylococcus epidermidis Species 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
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- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 5
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- PHNDZBFLOPIMSM-UHFFFAOYSA-N 4-morpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCOCC1 PHNDZBFLOPIMSM-UHFFFAOYSA-N 0.000 description 4
- CCUHUZRFMGXPKE-UHFFFAOYSA-N C1COCCN1C2=CC=C(C=C2)N(C(=O)OCC3=CC=CC=C3)C(=O)OCC4=CC=CC=C4 Chemical compound C1COCCN1C2=CC=C(C=C2)N(C(=O)OCC3=CC=CC=C3)C(=O)OCC4=CC=CC=C4 CCUHUZRFMGXPKE-UHFFFAOYSA-N 0.000 description 4
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- JKPONZOFJIWGCE-UHFFFAOYSA-N morpholin-4-yl methanesulfonate Chemical compound CS(=O)(=O)ON1CCOCC1 JKPONZOFJIWGCE-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
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- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical class [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- SOOARYARZPXNAL-UHFFFAOYSA-N methyl-thiophenol Natural products CSC1=CC=CC=C1O SOOARYARZPXNAL-UHFFFAOYSA-N 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
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- 239000011259 mixed solution Substances 0.000 description 1
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- JJUSTAVGGFEOJN-UHFFFAOYSA-N morpholin-4-yl acetate Chemical compound CC(=O)ON1CCOCC1 JJUSTAVGGFEOJN-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- BOTNYLSAWDQNEX-UHFFFAOYSA-N phenoxymethylbenzene Chemical compound C=1C=CC=CC=1COC1=CC=CC=C1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- MXLUQLPDHXJJGL-UHFFFAOYSA-N piperidin-1-yl methanesulfonate Chemical compound CS(=O)(=O)ON1CCCCC1 MXLUQLPDHXJJGL-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000004708 ribosome subunit Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Landscapes
- 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
The invention relates to a 3, 5-substituted oxazolidinone derivative with antibacterial effect and a salt thereof, which have strong gram-positive bacteria resisting activity and are shown as a general formula I, a preparation method of the 3, 5-substituted oxazolidinone derivative and the salt thereof, application of the 3, 5-substituted oxazolidinone derivative and the salt thereof in preparation of an antibacterial agent, and an antibacterial medicament containing the 3, 5-substituted oxazolidinone derivative and the salt thereof as effective components.
Description
Technical field
The present invention relates to have 3 of anti-microbial effect, 5-substituted oxazolidinone derivative and salt thereof.The invention still further relates to this 3, the preparation method of 5-substituted oxazolidinone derivative and salt thereof.In addition, the invention still further relates to this 3,5-substituted oxazolidinone derivative and salt thereof is in the application of preparation in the antiseptic-germicide, and contain this 3,5-substituted oxazolidinone derivative and salt thereof are as the antibacterials of effective constituent.
Background technology
In recent years; all kinds ofly antibioticly constantly be developed and come out; make the treatment of bacterial infection disease that a lot of specific aim medicines arranged; certainly seeing that also a large amount of resistant organisms at antiseptic-germicide also are that development is rapid in its positively effect; for example; methicillin-resistant staphylococcus aureus (MRSA); methicillin-resistant staphylococcus epidermidis (MRSE); penicillin resistant streptococcus pneumoniae (PRSP); the multi-drug resistant tubercule bacillus; especially the appearance of vancomycin-resistant enterococcus (VRE); after these bacterium contact antibacterials; morph by plasmid or karyomit(e) mediation; obtain resistance, caused new difficulty to clinical treatment.Because these drug-fast bacteria infections of the still difficult effectively control of currently reported antibacterials impel Pharmaceutical Chemist to make great efforts development novel anti drug tolerant bacteria medicine, design and screening have the new antimicrobial drug of new chemical structure, new role mechanism or new role target position.
As far back as 1978, (the EI Dupont de Nemours ﹠amp of E.I.Du Pont Company; Co., Inc) Fugitt discloses 5-monochloromethyl-3-Fang oxazolidinone the certain plants germ has been had anti-microbial activity in US 4128654 patents.1984, Gregory etc. reported that 5 methylols, 5-ethanoyl and 5-Jia Yang methyl oxazolidinone series compound also have anti-microbial activity.
U.S. Pharmacia﹠amp; Upjohn company with one's early years E.I.Du Pont Company be found to be lead compound, use for reference the structural modification experience of quinolones, synthesized a series of 5-(S)-kharophen methyl oxazolidinone compound, therefrom selected linezolid (Linezolid, L), and March calendar year 2001 go on the market in first EU member country Britain.Linezolid is used for the treatment of the infection that gram-positive microorganism (resistance and sensitivity) causes, comprise staphylococcus, suis and faecalis, especially the gram-positive microorganism to penicillin resistant, Macrolide, glycopeptide class and other antibacterials has good activity.
But, in order to solve the problem of resistance and anti-microbial activity better, people wish to develop a kind ofly have no drug resistance, effect is more outstanding, anti-microbial activity is higher microbiotic.
Summary of the invention
The invention provides a kind of 3 of anti-microbial effect that has, 5-substituted oxazolidinone derivative and salt thereof, this 3, the structure of 5-substituted oxazolidinone derivative is represented by general formula (I):
In the formula, R
1Expression hydrogen atom, halogen atom, alkyl or haloalkyl, R
2The piperazinyl that expression morpholinyl, replacement or unsubstituted piperidyl, 4-position replace, R
3Expression hydroxyl, sulfydryl, replacement or unsubstituted acyloxy, replacement or unsubstituted alkylsulfonyl oxygen base, replacement or unsubstituted acyl amino, replacement or unsubstituted diacyl imino-, replacement or unsubstituted five-membered ring group, wherein R
1During for fluorine atom, R
2, R
3Be not morpholinyl, acetylamino simultaneously.
The present invention also provide this 3, the preparation method of 5-substituted oxazolidinone derivative and salt thereof.
In addition, the present invention also provide this 3,5-substituted oxazolidinone derivative and salt thereof is in the application of preparation in the antiseptic-germicide, and contain this 3,5-substituted oxazolidinone derivative and salt thereof are as the antibacterial combination of effective constituent.
According to formula provided by the invention (I) compound, R
1Can be " halogen atom ", comprise fluorine atom, chlorine atom, bromine is former gives and the iodine atom, wherein preferred fluorine atom, chlorine atom; R
1It is 1～6 alkyl or cycloalkyl that " alkyl " of expression can be selected from carbonatoms, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.; R
1The carbonatoms that " haloalkyl " of expression can be replaced by identical or different halogen atom more than 1 or 1 is 1～6 a alkyl, as fluoro methyl, difluoromethyl, trifluoromethyl, chloro methyl, dichloromethyl, trichloromethyl, 2,2,2-three fluoro ethyls etc.
R
3In the group of representative:
" acyloxy " expression carbonatoms is 1～6 an alkyloyl oxygen base, as formyl radical oxygen base, ethanoyl oxygen base, positive propionyl oxygen base, different propionyl oxygen base, positive butyryl radicals oxygen base, isobutyryl oxygen base, secondary butyryl radicals oxygen base, uncle's butyryl radicals oxygen base, positive pentanoyl oxygen base, isovaleryl oxygen base, secondary pentanoyl oxygen base, pivaloyl oxygen base, valeryl oxygen base, positive caproyl oxygen base etc., wherein preferred ethanoyl oxygen base;
" alkylsulfonyl oxygen base " be methylsulfonyl oxygen base, ethylsulfonyl oxygen base, benzenesulfonyl oxygen base, p-toluenesulfonyl oxygen base etc. for example, wherein preferred methylsulfonyl oxygen base, p-toluenesulfonyl oxygen base;
" acyl amino ", be selected from carbonatoms and be 1～6 alkyl amido, as formamido group, kharophen, positive propionamido, different propionamido, positive butyrylamino, isobutyryl amino, secondary butyrylamino, tert-butyl-carboxamide, positive valeryl amino, isovaleryl amino, secondary valeryl amino, pivalyl amino, pivalyl amino, positive hexanamido etc., wherein preferred kharophen;
" diacyl imino-", as succinimido, glutaryl imino-, hexanedioyl imino-, pimeloyl imino-, phthaloyl imino, camphorimide base, wherein preferred as succinimido, glutaryl imino-, hexanedioyl imino-, phthaloyl imino, camphorimide base;
" five-membered ring group " comprises that then having 1～4 is selected from Sauerstoffatom, sulphur atom, the total atom number of the heteroatoms of nitrogen-atoms and formation ring is 5 a heterocyclic group, as furyl, the dihydrofuran base, tetrahydrofuran base, thienyl, benzothienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, pyrazolidyl, triazolyl, tetrazyl, the benzotriazole base, the benzo tetrazyl, benzimidazolyl-oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, thiazolyl, thiazolidyl, isothiazolyl, isothiazole alkyl etc., wherein preferred imidazolyl, thiazolyl, thiadiazolyl group, triazolyl, tetrazyl, the benzotriazole base.
R
2, R
3In substituting group can comprise for example halogen atoms such as fluorine, chlorine, bromine; C such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl
1～C
5Alkyl; C such as phenmethyl, styroyl, menaphthyl
7～C
15Aralkyl; Trifluoromethyl; C such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, isopentyloxy
1～C
5Alkoxyl group; C such as benzyloxy, benzene oxyethyl group, naphthalene methoxyl group
7～C
15Aralkyl oxy; C such as methylene radical dioxy base, ethylidene dioxy base, propylidene dioxy base
1～C
5Alkylenedioxy group; Hydroxyl; Nitro; C such as acetoxyl group, propionyloxy, butyryl acyloxy, penta acyloxy
2～C
6Alkyloyl oxygen base; Carboxyl; C such as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl
2～C
6Alkoxy carbonyl; C such as benzyloxy carbonyl, benzene ethoxy carbonyl, naphthalene methoxycarbonyl
7～C
15Aromatic alkoxy carbonyl; The oxygen base; C such as ethanoyl, propionyl, butyryl radicals, pentanoyl
2～C
6Alkyloyl; Amino; C such as methylamino, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, isobutylamino, tertiary butyl amino, amyl group amino, isopentyl amino
1～C
5Alkyl monosubstituted amino; C such as dimethylamino, ethylmethylamino, diethylamino, methyl-propyl amino, diisopropylaminoethyl
2～C
10Dialkyl amido; C such as kharophen, propionamido, different propionamido, butyrylamino, valeryl amino
2～C
6Alkanoylamino; C such as methoxycarbonyl amino, ethoxy carbonyl amino, propoxycarbonyl amino, isopropoxy carbonyl amino, butoxy carbonyl amino, isobutoxy carbonyl amino, tert-butoxycarbonyl amino, pentyloxy carbonyl amino
2～C
6Alkoxycarbonyl amino; C such as benzyloxy carbonylamino, benzene ethoxy carbonyl amino, naphthalene methoxycarbonyl amino
7～C
15Aromatic alkoxy carbonyl amino; Formamyl; C such as methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, butyl formamyl, tertiary butyl formamyl, amyl group formamyl
2～C
6Alkyl-carbamoyl and C such as phenyl, naphthyl
6～C
12Aryl; And heterocyclic group etc.
Of the present invention 3, in the 5-substituted oxazolidinone derivative, preferably, R
2During for morpholinyl, R
3For replacing or unsubstituted diacyl imino-or five-membered ring group; R
2During the piperazinyl that replaces for the 4-position, R
3Be kharophen, replacement or unsubstituted diacyl imino-or five-membered ring group; Or R
2During for replacement or unsubstituted piperidyl, R
3Kharophen, replacement or unsubstituted diacyl imino-or five-membered ring group.
Compound of the present invention, itself can have anti-microbial activity, simultaneously can also be as the raw material of synthetic other The compounds of this invention, it is as shown in table 1 to be fit to part particular compound of the present invention.
Table 1
| Compound number | R 1 | R 2 | R 3 |
| 4 | F | Morpholinyl | Hydroxyl |
| 5 | F | Morpholinyl | Methylsulfonyl oxygen base |
| 8* | F | Morpholinyl | Kharophen |
| 11 | F | Morpholinyl | P-toluenesulfonyl oxygen base |
| 12 | F | Morpholinyl | Ethanoyl oxygen base |
| 13 | F | Morpholinyl | Imidazolyl |
| 14 | F | Morpholinyl | 1,3,4-thiadiazolyl group sulfydryl |
| 15 | F | Morpholinyl | 1,2, the 4-1H-triazol radical |
| 16 | F | Morpholinyl | 1H-tetrazole base |
| 17 | F | Morpholinyl | The camphorimide base |
| 18 | F | Morpholinyl | Tetrazole base sulfydryl |
| 19 | F | Morpholinyl | Phthaloyl imino |
| 20 | F | Morpholinyl | Benzoglyoxaline 2-sulfydryl |
| 21 | F | Morpholinyl | Succinimido |
| 22 | F | Morpholinyl | The benzotriazole base |
| 26 | H | Morpholinyl | Hydroxyl |
| 27 | H | Morpholinyl | Methylsulfonyl oxygen base |
| 28 | H | Morpholinyl | Phthaloyl imino |
| 30 | H | Morpholinyl | Acetylamino |
| 31 | H | Morpholinyl | 1,2, the 4-1H-triazol radical |
| 32 | H | Morpholinyl | The camphorimide base |
| 33 | H | Morpholinyl | Succinimido |
| 37 | Cl | Morpholinyl | Hydroxyl |
| 38 | Cl | Morpholinyl | Methylsulfonyl oxygen base |
| 39 | Cl | Morpholinyl | Phthaloyl imino |
| 41 | Cl | Morpholinyl | Acetylamino |
| 42 | Cl | Morpholinyl | 1,2, the 4-1H-triazol radical |
| 43 | Cl | Morpholinyl | The camphorimide base |
| 44 | Cl | Morpholinyl | Succinimido |
| 48 | CF 3 | Morpholinyl | Hydroxyl |
| 49 | CF 3 | Morpholinyl | Methylsulfonyl oxygen base |
| 50 | CF 3 | Morpholinyl | Phthaloyl imino |
| 52 | CF 3 | Morpholinyl | Acetylamino |
| 53 | CF 3 | Morpholinyl | 1,2, the 4-1H-triazol radical |
| 54 | CF 3 | Morpholinyl | The camphorimide base |
| 55 | CF 3 | Morpholinyl | Succinimido |
| 59 | F | The 4-Phenylpiperazinyl | Hydroxyl |
| 60 | F | The 4-Phenylpiperazinyl | Methylsulfonyl oxygen base |
| 61 | F | The 4-Phenylpiperazinyl | Phthaloyl imino |
| 63 | F | The 4-Phenylpiperazinyl | Acetylamino |
| 64 | F | The 4-Phenylpiperazinyl | 1,2, the 4-1H-triazol radical |
| 65 | F | The 4-Phenylpiperazinyl | The camphorimide base |
| 66 | F | The 4-Phenylpiperazinyl | Succinimido |
| 70 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | Hydroxyl |
| 71 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | Methylsulfonyl oxygen base |
| 72 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | Phthaloyl imino |
| 74 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | Acetylamino |
| 75 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | 1,2, the 4-1H-triazol radical |
| 76 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | The camphorimide base |
| 77 | F | 4-(4 '-methoxyl group) Phenylpiperazinyl | Succinimido |
| 81 | F | 4-benzyl piepridine base | Hydroxyl |
| 82 | F | 4-benzyl piepridine base | Methylsulfonyl oxygen base |
| 83 | F | 4-benzyl piepridine base | Phthaloyl imino |
| 85 | F | 4-benzyl piepridine base | Acetylamino |
| 86 | F | 4-benzyl piepridine base | 1,2, the 4-1H-triazol radical |
| 87 | F | 4-benzyl piepridine base | The camphorimide base |
| 88 | F | 4-benzyl piepridine base | Succinimido |
| 92 | F | Piperidyl | Hydroxyl |
| 93 | F | Piperidyl | Methylsulfonyl oxygen base |
| 94 | F | Piperidyl | Phthaloyl imino |
| 95 | F | Piperidyl | 1,2, the 4-1H-triazol radical |
| 96 | F | Piperidyl | The camphorimide base |
| 97 | F | Piperidyl | Succinimido |
* compound 8 is a known compound, but the contriver synthesizes by method of the present invention.
Wherein preferred compound has:
(S)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (30),
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (31),
(S)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (41),
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (55),
(S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (63),
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (65),
(S)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (74),
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (76),
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (95),
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (96).
The present invention 3, and the synthetic method of 5-substituted oxazolidinone derivative comprises that the compound of representing with general formula (II) is as raw material, with R
3 -The process that substitution reaction obtains the compound of general formula (I) expression takes place,
In the formula, R
1, R
2And R
3Definition as hereinbefore.
Under 60～100 ℃,, in dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, propionitrile etc. or their any mixture, make methanesulfonate ester Compound I I and radicals R at non-proton property polar solvent
3 -Reaction correspondingly can obtain having radicals R
3 -Compound I.For the carrying out that promotes to react, can also in reaction system, add a spot of alkali, for example yellow soda ash, sodium bicarbonate, Anhydrous potassium carbonate, triethylamine, pyridine etc.The time that this substitution reaction is carried out is not particularly limited, and preferred 0.5～18 hour, more preferably 1～2 hour.
Has anti-microbial activity by the synthetic product that obtains of above-mentioned substitution reaction itself, can be used as the object of the invention product, also can be used as simultaneously intermediate, more can realize the antimicrobial compounds of the object of the invention through the appropriate reaction path of preparing, preparation for this part compound, the technician can design reaction scheme in conjunction with the conventional synthetic method of the open source literature before the present invention and this area fully, and the present invention is not particularly limited at this.
The preferable methods according to the present invention is at preparation R
3During for the compound of amido, can at first make the methanesulfonates compound and the phthalic imidine salt of general formula (II) expression (promptly have radicals R
3 -Compound III) reaction obtains the compound of general formula (IV) expression; then make the compound of general formula (IV) expression that the primary amine that the Gabriel reaction can access general formula (V) expression takes place again; to lead to the compound that primary amine acidylate that formula V represents can obtain general formula (I) expression at last, concrete reaction process is shown below:
In the formula, R
1, R
2Definition same as described above, R
3The expression amido.
In above-mentioned reaction process, by Compound I I prepare compound IV reaction can 60～100 ℃ (2 times, at non-proton property polar solvent, as carrying out in dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, propionitrile etc. or their any mixture.For the carrying out that promotes to react, can also in reaction system, add a spot of alkali, for example yellow soda ash, sodium bicarbonate, (anhydrous) salt of wormwood, triethylamine, pyridine etc.The time that reaction is carried out is not particularly limited, and preferred 0.5～18 hour, more preferably 1～2 hour.Wherein phthalic imidine salt can be sylvite, sodium salt etc., most preferably preferred sylvite.
The reaction that is prepared compound V by compound IV is to obtain primary amine by the Gabriel reaction.In not hindering any solvent of carrying out of reaction,, under the reflux temperature of-5 ℃～solvent, make compound IV and C as ethanol etc.
1～C
4Primary amine reaction 0.5 hour～2 hours, can obtain compound V.Wherein, C
1～C
4The preferred methylamine of primary amine, more preferably 25% methylamine solution, with respect to raw material, the additional proportion of primary amine can be in the scope of 7: 1～13: 1 (mol ratio), most preferably the ratio with 10: 1 (mol ratio) adds.In addition, for the ease of the separation and purification reaction product, can also in reaction system, add an amount of dilute hydrochloric acid and make reaction product---compound V becomes hydrochloride and changes water over to, be beneficial to carry out next step reaction, this dilute hydrochloric acid most preferably uses 5% hydrochloric acid soln, and reaction can be finished in reflux.
Can adopt routine to carry out the method for acidylate, V prepares Compound I by compound.For example, under 0～5 ℃, in the water equal solvent, make reaction preparation in 10～30 minutes Compound I such as compound IV and carboxylic acid anhydride or acyl chlorides, preferably use acetic anhydride.In addition, for the carrying out that promotes to react, a spot of alkali can also be added, in reaction system as sodium hydroxide, yellow soda ash, sodium bicarbonate etc.
In addition, methanesulfonates Compound I I can adopt any feasible ordinary method or literature method preparation.For example can be prepared according to following method:
In the formula, R
1, R
2Identical with above-mentioned definition.
Below aforesaid method is elaborated.
Step a: adopt ordinary method that compd A is reduced into compd B, for example use 10%Pd/C the shortening method, use the reduction method of iron powder and acid (as acetate) etc.Wherein, compd A can be purchased, also can be by ordinary method or literature method preparation.
Step b: adopt ordinary method, by making compd B and ClCOOCH
2Substitution reaction takes place and obtains Compound C in ph.
Wherein, can be that solvent reacts with methylene dichloride or tetrahydrofuran (THF), in reaction system, add the acetate that a small amount of triethylamine comes neutralization reaction to generate simultaneously; Also can be with acetone: the mixed solution of water=2: 1 be a solvent, adds a small amount of yellow soda ash or sodium bicarbonate simultaneously and promote the carrying out that react, wherein preferred yellow soda ash in reaction system; Also can finish the back and filter the high purity white mother liquor crystals that obtains earlier, obtain carrying out suction filtration in the filtrate impouring mixture of ice and water then in reaction.Reaction times is not particularly limited, preferred 0.5～1 hour.
Step c: under-78 ℃, anhydrous condition, in nitrogen environment, make Compound C and butyllithium and (R)-Racemic glycidol butyl ester reaction obtain Compound D.Preferred 50～90 minutes of reaction times.
Steps d: adopt ordinary method, make Compound D and methylsulfonyl chloride generation substitution reaction, can obtain Compound I I.
Above-mentioned general formula (I) expression of the present invention 3, the 5-substituted oxazolidinone derivative can form pharmacologically acceptable salt.Described salt is specifically as ammonium salts such as metal-salt such as lithium salts, sodium salt, sylvite, magnesium salts, calcium salt or ammonium salt, methyl ammonium salt, dimethyl ammonium, leptodactyline, dicyclohexyl ammonium salts, perhaps forms organic acid salts such as inorganic acid salt such as hydrochloride, hydrobromate, vitriol, phosphoric acid salt or mesylate, benzene sulfonate, tosilate, acetate, propionic salt, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactic acid salt.In addition, the De oxazolidone derivative of the present invention of above-mentioned general formula (I) expression can exist with the form of solvate or hydrate.
3 of the invention described above, 5-substituted oxazolidinone derivative or its salt are by combining with 50S ribosomal subunit, can suppress the transhipment of gram-positive microorganism messenger RNA(mRNA), suppress bacterioprotein synthetic earliest stages, because this derivative can stop protein synthesis, even before beginning, protein synthesis will have an effect, can limit the resistance that it causes and can reduce trend with other antimicrobial drug crossing drug resistant risk thereby have, of the present invention thus 3,5-substituted oxazolidinone derivative and salt thereof are a kind of antibacterial agents that has clinical value.Of the present invention 3, the 5-substituted oxazolidinone derivative mainly can suppress gram positive bacterium (comprising sensitive organism and resistant organism), as streptococcus aureus (MRSA), staphylococcus epidermidis (MRSE), faecalis, suis etc.
So described 3 according to a further aspect of the invention, the 5-substituted oxazolidinone derivative can be used for preparing the medicine of resisting gram-positive bacterium, in particular for preparing the medicine of anti-streptococcus aureus, staphylococcus epidermidis, faecalis and suis etc.
The present invention also further provides a kind of antibacterial combination, wherein contains 3 of above-mentioned general formula (I) expression for the treatment of significant quantity, and 5-substituted oxazolidinone derivative or its salt are as effective constituent.As the effective constituent of medicine of the present invention, can use the above-claimed cpd that is selected from free form and pharmacologically acceptable salt and the material of crystalline form, solvate and their hydrates arbitrarily thereof, also can use the combination of material more than 2 kinds.As medicine of the present invention, can directly use above-mentioned substance itself, but usually wish to provide with the form of the above-mentioned substance that contains significant quantity and the pharmaceutical composition that preparation is formed with additive more than a kind or 2 kinds.
The formulation of aforementioned pharmaceutical compositions is not particularly limited, as being prepared into oral Preparations such as capsule, tablet, granula subtilis, granule, powder, syrup, perhaps non-oral Preparations such as injection, suppository, eye drops, ointment, ear drop, the agent of transdermal mucosal absorption, inhalation or external composition for skin.These preparations can add the additive of pharmacology, pharmaceutics permission, adopt the ordinary method preparation.That is to say, for oral Preparation and suppository, use vehicle (lactose, D-N.F,USP MANNITOL, crystalline cellulose etc.), disintegrating agent (carboxymethyl cellulose, calcium carboxymethylcellulose etc.), tackiness agent (hydroxypropylcellulose, Vltra tears etc.), lubricant (Magnesium Stearate, talcum etc.), Drug coating (Vltra tears, white sugar etc.), softening agent (polyoxyethylene glycol etc.), matrix preparation compositions such as (polyoxyethylene glycol etc.), for injection, eye drops, ear drop, nasal drop, use the solvating agent and the dissolving auxiliary (distilled water for injection that constitute water-based or time spent lysotype formulation, physiological saline, propylene glycol etc.), pH regulator agent (inorganic or organic acid or alkali), isotonic agent (salt, glucose, glycerine etc.), preparations such as stablizer composition, in addition, for the eye ointment, external composition for skin uses as ointment, paste, suitable preparation composition (the white Vaseline of patch, glycerine, whiteruss etc.).
Medicine of the present invention can be used as antiseptic-germicide, for treating or prevent to comprise people's mammiferous infection disease administration.The dosage of medicine of the present invention is not particularly limited, and can select suitable dosage corresponding to the degree of the kind of pathogenic bacteria, patient's age, body weight, disease etc.Be generally when adult, for example 1 day amount is 0.1～1000mg during oral administration when being 1～2000mg, non-oral administration, can 1 day 1 time to being divided into administration for several times.But, wish suitably to increase and decrease corresponding to purpose, the position of infection and kind, patient's age and the symptom of pathogenic bacteria of treatment or prevention.
Embodiment
Further specify enforcement of the present invention below by embodiment, but do not constitute qualification practical range.In an embodiment, measure fusing point and use accurate fusing point instrument of X6 and RY-1 type fusing point instrument (capillary tube technique) to measure, thermometer is not calibrated.Infrared spectra is measured with the infrared instrument of Tianjin, island IR-435 type, and mass spectrum is measured with ZAB-2F and Autospect-UltimaETOF mass spectrograph, nuclear magnetic resonance spectrum WYS-300 type nmr determination, and TMS is interior mark.What thin-layer chromatography (TLC) adopted E.Merck company overlays silica gel aluminum foil coil (DC-alurolle Kieselgel 60GF254,0.2mm is thick).The silica gel H that the decompression column chromatography is produced with Haiyang Chemical Plant, Qingdao.
Embodiment 1
The preparation (1) of 3-fluoro-4-morpholinyl oil of mirbane
In the 500ml four-hole bottle, add ethyl acetate (110ml), morpholine (19.07ml, 0.218mol), diisopropyl ethyl amine (37.4ml, 0.215mol), mechanical stirring under the room temperature, slowly drip 3, and the 4-difluoro nitrobenzene (22.0ml, 0.199mol), stirred 72 hours, after reactant is used ethyl acetate extraction (250ml), with saturated NaCl solution washing (250ml * 3), through anhydrous MgSO
4Drying, evaporate to dryness obtains yellow solid, uses the acetone-water recrystallization, obtains yellow crystals (42.70g), yield 95.0%.
M.p.112-113 ℃ (document, 98%, 111-112 ℃)
1H-NMR(CDCl
3，300MHz)δ：7.982(dd，1H)，7.894(dd，1H)，6.921(t，1H)，3.874(t，4H)，3.279(t，4H)
Embodiment 2
The preparation (2) of 3-fluoro-4-morpholinyl aniline
In the 500ml there-necked flask, add reduced iron powder (8.40g, 0.150mol), water (30ml, 1.67mol), glacial acetic acid (1.4ml, 24.27mmol), mechanical stirring, activation 30min refluxes, (12.305g, ethanol solution 50mmol) react about 30min again after adding slowly to drip compound (1), filtered while hot, evaporate to dryness obtains shallow white solid, with ethyl acetate washing leaching cake (50ml * 3), merging filtrate, with ethyl acetate extraction (250ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (250ml * 3)
4Drying, evaporate to dryness obtains shallow white solid (9.71g), and yield 90.98% is directly used in the next step.
1H-NMR(CDCl
3，300MHz)δ：6.784(t，1H)，6.456(d，1H)，6.393(d，1H)，3.851(t，4H)，3.023(t，4H)
Embodiment 3
N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline (3)
In the 1000ml four-hole bottle, (9.71g, 49.47mmol), acetone (166ml), water (84ml), 0 ℃ adds NaHCO down to add compound (2)
3(7.77g, 92.50mmol), mechanical stirring, (6.63ml 50.95mmol), stirs 16h to drip chloroformic acid benzyl ester, suction filtration obtains white solid (5.47g), with (550ml in the filtrate impouring mixture of ice and water, the light red floss v/v), is separated out in ice/water=1/2, suction filtration, obtain solid (6.83g), the gained solid merges back yield 76.10% all through the acetone-water recrystallization.
M.p.123-124.5 ℃ (document, 70%, 123-124 ℃)
FAB-MS：330[M
+]
IR(film)cm
-1：3321，2848，1705，1591，1533，1435，1238，930，744
1H-NMR(CDCl
3，300MHz)δ：7.362(m，5H)，6.957(t，2H)，6.669(s，1H)，5.189(s，2H)，3.873(t，4H)，3.043(t，4H)
Embodiment 4
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] preparation of methyl alcohol (4)
In the 100ml there-necked flask (120 ℃ baking 2h more than) add compound (3) (4.12g, 12.63mmol), anhydrous tetrahydro furan (50ml), under-78 ℃, N
2Protection, and dropping 2M butyl lithium solution (6.24ml, 12.48mmol); under-78 ℃, stir 50min, (R)-glycerine butyl ester (1.80ml contracts in dropping; 12.75mmol; anhydrous THF 5ml), uniform temp is reaction 1h down, removes acetone bath; be warming up to room temperature; stir 16h, a large amount of yellow mercury oxides occur, add saturated NH successively
4Cl solution (2ml slowly adds), ethyl acetate (30m1), saturated NH
4Cl solution (30ml), water (30ml) with ethyl acetate extraction (50ml * 3), with saturated NaCl solution washing (50ml * 3), are used anhydrous MgSO
4Drying, evaporate to dryness obtains light yellow solid, with ethyl acetate-normal hexane recrystallization, gets white amorphous solid (2.64g), yield 70.56%.
M.p.112-113 ℃ (document, 85%, 112-114 ℃)
FAB-MS：m/z 297.1[M+H
+](100)
IR(film)cm
-1：3560，3357，2954，2860，1751，1518，1448，1414，1246，1115
1H-NMR(CDCl
3，300MHz)δ：
7.429(dd，1H)，7.094(dd，1H)，6.957(t，1H)，4.731(m，1H)，4.018(m，3H)，3.874(t，4H)，3.758(d，1H，4-H)，3.057(t，4H)
Embodiment 5
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (5)
In the l00ml there-necked flask, add anhydrous methylene chloride (50ml), compound (4) (2.62g, 8.84mmol), triethylamine (2.43ml, 17.43mmol), under 0 ℃, (0.954ml 12.32mmol), reacts 20min to drip methylsulfonyl chloride, a large amount of white precipitates appear, with dichloromethane extraction (50ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (50ml * 3)
4Drying, evaporate to dryness obtains white solid, uses the acetonitrile-water recrystallization, obtains white crystal (3.21g), yield 96.97% (document, 100%).
FAB-MS：m/z 374.1[M
+]
IR(film)cm
-1：3097，2966，2823，1751，1516，1421，1356，1320，1128，999，976，831，746，526
1H-NMR(CDCl
3，300MHz)δ：7.455(dd，1H)，7.116(m，2H)，4.926(m，1H)，4.473(m，2H)，4.125(t，1H)，3.949(d，1H)，3.103(t，7H)，3.080(t，4H)
Embodiment 6
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol p-toluenesulfonic esters (11)
In the 50ml there-necked flask, add methylene dichloride (10ml), compound (4) (0.3126g, 1.06mmol), diisopropyl ethyl amine (0.363ml, 2.09mmol), 0 ℃ drips down Tosyl chloride (0.28g, 1.47mmol), produce a large amount of white cigarettes, reaction is spent the night, with dichloromethane extraction (50ml * 3), with saturated NaCl solution washing (50ml * 3), use anhydrous MgSO
4Drying, evaporate to dryness, silica gel column chromatography with ethyl acetate-normal hexane recrystallization, obtains white crystal (311.2mg), yield 65.98%.
m.p.138-140℃
FAB-MS：m/z 451.3[M+H
+]
IR(film)cm
-1：3099，2962，2833，1745，1597，1516，1369，1228，993，760，661
1H-NMR(CDCl
3，300MHz)δ：7.800(d，2H)，7.500(dd，1H)，7.380(d，2H)，7.150(t，1H)，7.071(dd，1H)，4.820(m，1H)，4.249(dd，2H)，4.040(t，1H)，3.936(t，4H)，3.878(dd，1H)，3.092(t，4H)，2.458(s)
Embodiment 7
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methanol acetic acid ester (12)
The synthetic method of reference compound (11), (0.131g, 0.4422mmol), (34.8 μ l 0.6147mmol), get white crystal (76.0mg), yield 50.8% to dripping acetyl chloride to use compound (4).
m.p.115-117℃
FAB-MS：m/z 339.1[M+H
+]
IR(fi lm)em
-1：3442，2966，2862，2829，1747，1520，1230，1115，1047，748
1H-NMR(CDCl
3，300MHz)δ：7.640(d，1H)，7.383(m，1H)，7.090(d，1H)，4.883(m，1H)，4.249(ddd，2H)，4.102(t，1H)，4.011(t，4H)，3.796(dd，1H)，3.223(t，4H)，2.104(s，3H)
Embodiment 8
(S)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] Methylimidazole (13)
In the 50ml there-necked flask, add DMF (10.0ml), compound (5) (0.1131g, 0.3027mmol), imidazoles (20.61mg, 0.3027mmol), (83.68mg 0.6055mmol), is heated to about 80 ℃ Anhydrous potassium carbonate, reaction 15h, with ethyl acetate extraction (50ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (50ml * 3)
4Drying, evaporate to dryness, silica gel column chromatography with ethyl acetate-normal hexane recrystallization, gets white crystal (16.0mg), yield 15.22%.
m.p.145-147℃
FAB-MS：m/z347.3[M
+](100)
1H-NMR(CDCl
3，300MHz)δ：8.291(s，1H)，7.373(d，1H)，7.324(m，1H)，7.181(d，1H)，4.883(m，1H)，4.249(ddd，2H)，4.102(t，1H)，4.011(t，4H)，3.796(dd，1H)，3.223(t，4H)
Embodiment 9
The 5-methyl-2-[(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl] sulfydryl-1,3,4-thiadiazoles (14)
The synthetic method of reference compound (13) is used compound (5) and 5-methyl-2-sulfydryl-1,3, and (59.56mg, 0.4505mmol), the mol ratio of reactant is 1: 1 to the 4-thiadiazoles, about reaction 2h, gets yellow semisolid (10.0mg), yield 5.0%.
FAB-MS：m/z 411.0[M
+]
1H-NMR(CDCl
3，300MHz)δ：7.530(d，1H)，7.183(m，1H)，7.080(dd，1H)，5.190(m，1H)，4.653(ddd，2H)，4.090(t，1H)，3.979(t，1H)，3.938(t，4H)，3.143(t，4H)，2.481(s)
Embodiment 10
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (15)
The synthetic method of reference compound (13) is a raw material with compound (5), adds 1,2, and the 4-1H-triazole (12.5mg, 0.1811mmol), the mol ratio of reactant is 1: 1, reaction 3.5h gets white crystal (40.4mg), yield 64.22%.
m.p.164-166℃
FAB-MS：m/z 348.0[M
+](100)，349.0[M+H
+]
IR(film)cm
-1：3438，3118，2954，1753，1516，1236，1115，1049，906，683
1H-NMR(CDCl
3，300MHz)δ：8.242(s，1H)，7.956(s，1H)，7.458(d，1H)，7.323(m，1H)，7.025(dd，1H)，5.033(m，1H)，4.561(dd，2H)，4.141(t，1H)，4.014(m，1H)，3.982(t，4H)，3.197(t，4H)
Embodiment 11
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid H-tetrazole (16)
The synthetic method of reference compound (13), and adding 1H-tetrazole (13.68mg, 0.1954mmol), the mol ratio of reactant is about 1: 1, reaction 11h, evaporate to dryness, silica gel column chromatography, with ethyl acetate-normal hexane recrystallization, get yellow crystals (5.4mg), yield 8.7%.
FAB-MS：m/z 349.0[M
+](100)，350.0[M+H
+]
IR(film)cm
-1：3438，3103，2852，1751，1518，1238，1119，746
1H-NMR(CDCl
3，300MHz)δ：7.834(s，1H)，7.367(d，1H)，7.001(m，2H)，5.071(m，1H)，4.827(ddd，2H)，4.215(t，1H)，3.919(m，1H)，3.888(t，4H)，3.197(t，4H)
Embodiment 12
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (17)
The synthetic method of reference compound (13), the imide that camphorates (33.26mg, 0.1866mmol), the mol ratio of itself and compound (5) is 1.2: 1, reaction 2h, white cotton-shaped crystal (47.6mg), yield 66.72%.
m.p.178-180℃
FAB-MS：m/z，460.0[M
+](100)，461.0[M+H
+]
IR(film)cm
-1：3437，2962，2858，1755，1750，1678，1518，1225，1117，752
1H-NMR(CDCl
3，300MHz)δ：7.540(d，1H)，7.087(dd，2H)，4.861(m，1H)，4.294(dd，1H)，3.949(ddd，2H)，3.897(t，4H)，3.728(dd，1H)，3.155(t，4H)，2.790(d，1H)，1.977(m，1H)，1.928(t，2H)，1.788(m，1H)，1.212(s，3H)，1.010(s，3H)，0.984(s，3H)
Embodiment 13
1-methyl-5-(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl mercapto tetrazole (18)
The synthetic method of reference compound (13) is a raw material with compound (5), and (27.82mg, 0.1598mmol), the mol ratio of reactant is 1: 1, reaction 6h, yellow crystals (28.4mg), yield 54.08% to add methyl mercapto tetrazole sodium salt.
m.p.146-147℃
FAB-MS：m/z 395.1[M+H
+](100)
IR(film)cm
-1：3435，2960，2856，1749，1520，1242，1109，1022，937
1H-NMR(CDCl
3，300MHz)δ：7.595(d，1H)，7.448(m，1H)，7.087(dd，1H)，5.140(m，1H)，4.206(dd，1H)，3.949(bs，4H)，3.920(s，1H)，3.887(dd，1H)，3.783(ddd，2H)，3.243(bs，4H)
Embodiment 14
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (19)
In the 100ml there-necked flask, add compound (5) (800mg, 2.139mmol), potassium phthalimide (475.43mg, 2.567mmol), Anhydrous potassium carbonate (591mg, 4.278mmol), 80 ℃ are reacted 1.5h down, with ethyl acetate extraction (150ml * 3), with saturated NaCl solution washing (150ml * 3), use anhydrous MgS0
4Drying, evaporate to dryness obtains white solid, without separation, is directly used in down-goes on foot reaction.
m.p.197-199℃
FAB-MS：m/z 426.1[M+H
+]
IR(film)cm
-1：3479，2952，2852，1738，1714，1516，1048，1236，1115，723
1H-NMR(CDCl
3，300MHz)δ：7.896(m，2H)，7.774(m，2H)，7.457(d，1H)，7.237(m，2H)，4.988(m，1H)，4.134(ddd，2H)，3.989(dd，1H)，3.942(t，4H)，3.846(t，1H)，3.243(t，4H)
Embodiment 15
(S)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (8)
In the 250ml there-necked flask, add above-claimed cpd (19), dehydrated alcohol (100ml), 25% aqueous methylamine solution (4.63ml, 21.39mmol), the mol ratio of this 25% aqueous methylamine solution and compound (19) is 10: 1, backflow 1h, evaporate to dryness obtains compound (7)---(S)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylamine.
This product extracts with 0.1M HCl (50ml), with twice of ethyl acetate extraction, water is transferred in the 100ml there-necked flask, transfers to weakly alkaline (pH=8-9), add diacetyl oxide (0.61ml with an amount of NaOH, 6.417mmol), with the mol ratio of starting compound be 3: 1, reaction 10min is with ethyl acetate extraction (100ml * 3), with saturated NaCl solution washing (100ml * 3), use anhydrous MgSO
4Drying, evaporate to dryness, column chromatography with ethyl acetate-sherwood oil recrystallization, obtains white solid (429.8mg), yield 55.0%.
M.p.182-183.5 ℃ (document, 70%, m.p.181.5-182.5 ℃)
FAB-MS：m/z 338.1[M+H+](85％)
IR(film)cm-1：3338，2968，2862，1743，1664，1518，1425，1228，1117，937
1H-NMR(CDCl3，300MHz)δ：7.474(dd，1H)，7.061(dd，1H)，6.999(t，1H)，6.133(bs，t，1H)，4.769(m，1H)，4.018(t，1H)，3.881(t，4H)，3.747(dd，1H)，3.650(m，2H)，3.092(t，4H)，2.019(s，3H)
13C-NMR(CDCl3，75.46MHz)δ：171.102，157.257，154.396(d)，136.768，133.156，119.080，114.124，107.917(d)，72.130，67.228，51.331(d)，47.968，42.316，23.500
Embodiment 16
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl thiophenol (20)
The synthetic method of reference compound (13) is a raw material with compound (5), and the adding 2-mercaptobenzimidazole (16mg, 0.1069mmol), the mol ratio of reactant is 1: 1, reaction 4h, silica gel column chromatography gets yellow crystals 11.2mg, yield 24.46%.
m.p.145-148℃
FAB-MS：m/z 429.1[M+H
+](100)
IR(fi lm)cm
-1：2958，2854，1751，130，1516，1227，1117，744
1H-NMR(CDCl
3，300MHz)δ：7.677(s，H)，7.457(m，4H)，7.138(m，1H)，7.027(m，1H)，6.888(d，1H)，5.155(m，1H)，4.166(dd，2H)，3.989(t，4H)，3.769(dd，1H)，3.584(dd，1H)，3.049(t，4H)
Embodiment 17
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (21)
The synthetic method of reference compound (13), add succimide (12.7mg, 0.0890mmol), its mol ratio with compound (5) is 1: 1, reaction 2.5h must white cotton-shaped crystal (22.2mg), yield 67.0%.
m.p.196-198℃
FAB-MS：m/z 378.1[M+H
+](100)
IR(film)cm
-1：3444，2964，1749，1703，1516，1406，1227，1115，667
1H-NMR(CDCl
3，300MHz)δ：7.527(d，1H)，7.180(m，1H)，7.071(d，1H)，4.931(m，1H)，4.294(dd，2H)，3.999(t，4H)，3.788(dd，1H)，3.741(dd，1H)，3.155(t，4H)，2.792(s，4H)
Embodiment 18
(R)-[N-3-(3 '-fluoro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl benzotriazazole (22)
The synthetic method of reference compound (13) is a raw material with compound (5), and the adding benzotriazole (12.7mg, 0.1069mmol), the mol ratio of reactant is 1: 1, reaction 2.5h, silica gel column chromatography gets yellow solid (10mg), yield 23.56%.
m.p.156-158℃
FAB-MS：m/z 398.3[M+H
+]
1H-NMR(CDCl
3，300MHz)δ：7.865(m，2H)，7.411(m，2H)，7.011(m，3H)，5.302(m，1H)，5.134(dd，1H)，5.011(dd，1H)，4.100(ddd，2H)，3.880(t，4H)，3.065(t，4H)
Embodiment 19
4-morpholinyl oil of mirbane (23)
In the 250ml there-necked flask, add ethyl acetate (100ml), morpholine (13.0ml, 148.6mmol), diisopropyl ethyl amine (25.5ml, 146.5mmol), mechanical stirring under the room temperature slowly drips 4-fluoronitrobenzene (19.1ml, 135.5mmol), reflux 48h is cooled to room temperature, suction filtration, obtain mother liquor crystals, with ethyl acetate extraction (100ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (100ml * 3)
4Drying, evaporate to dryness, yellow solid, silica gel column chromatography use the acetone-water recrystallization, common yellow crystals (23.70g), yield 84.09%.
m.p.144-146℃
1H-NMR(CDCl
3，300MHz)δ：8.164(dd，2H)，6.869(dd，2H)，3.871(t，4H)，3.373(t，4H)
Embodiment 20
4-morpholinyl aniline (24)
The synthetic method of reference compound (2), the ethanol solution (200ml) of dropping compound (23) (16.69g, 81. 54mmol) reacts about 30min again after adding, get shallow white solid, is directly used in the next step.
Embodiment 21
N-carbobenzoxy-(Cbz)-4-morpholinyl aniline (25)
The synthetic method of reference compound (3) adds above-claimed cpd (24) (81.54mmol), gets light gray solid, uses the acetone-water recrystallization, obtains brilliant violet look crystal 17.83g, yield 70.1%.
m.p.150-152℃
FAB-MS：m/z 313.2[M+H
+](100)
IR(fi lm)cm
-1：3330，2852，1689，152，1228，1124，1063，924，818，741，696
1H-NMR(CDCl
3，300MHz)δ：7.390(m，5H)，6.957(m，2H)，6.669(bs，1H)，5.192(s，2H)，3.881(bs，4H)，3.140(t，4H)
Embodiment 22
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (26)
The synthetic method of reference compound compound (4), and adding compound (25) (3.12g, 10.0mmol), drip 2 M butyl lithium solutions (5.0ml, 10.0mmol) ,-78 ℃, stir 90min, (R)-glycerine butyl ester (1.41ml, 10.3mmol contract in dropping, anhydrous THF 5ml) ,-78 ℃, reaction 1h, get shallow white solid, column chromatography gets white crystal (1.699g), yield 61.56%.
m.p.165-167℃
FAB-MS：m/z 279.1[M+H
+](100)
IR(film)cm
-1：3427，2956，2823，1741，1703，1520，1450，1230，1122，928，820
1H-NMR(CDCl
3，300MHz)δ：7.449(d，2H)，6.941(d，2H)，4.734(m，1H)，3.970(m，3H)，3.880(t，4H)，3.735(m，1H)，3.123(t，4H)
Embodiment 23
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (27)
The synthetic method of reference compound compound (5), (1.4564g, 5.27mmol), reaction 20min gets shallow white solid, with ethyl acetate-sherwood oil recrystallization, gets white crystal (1.7579g), yield 94.37% to add compound (26).
m.p.146-148℃
FAB-MS：m/z 357.2[M+H
+]
1H-NMR(CDCl
3，300MHz)δ：7.435(dd，2H)，7.966(d，2H)，4.909(m，1H)，4.447(ddd，2H)，4.135(t，1H)，3.959(d，1H)，3.926(t，4H)，3.145(t，4H)，3.106(s，1H)
Embodiment 24
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (28)
The synthetic method of reference compound (19), use compound (27) (800mg, 2.247mmol) with the potassium phthalimide (mol of potassium phthalimide and compound (27) was than 1.2: 1) of 2.696mmol, reaction 1.5h, get white solid, do not add separation, be directly used in next step reaction.
1H-NMR(CDCl
3，300MHz)δ：7.893(m，2H)，7.777(m，2H)，7.449(d，1H)，6.987(m，2H)，4.977(m，1H)，4.140(ddd，2H)，4.072(dd，1H)，3.942(t，4H)，3.856(t，1H)，3.138(t，4H)
Embodiment 25
(S)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (30)
The synthetic method of reference compound (8) adds above-claimed cpd (28), obtains white solid (57.8mg), yield 8.06%.
m.p.136-138℃
FAB-MS：m/z 320.2[M
+](100)，321.2[M+H
+]
IR(fi lm)cm
-1：3300，2827，1747，1730，1665，1520，1228，1117，930，814
1H-NMR(CDCl
3，300MHz)δ：7.341(dd，2H)，6.885(dd，2H)，6.771(bs，t，1H)，4.721(m，1H)，3.985(t，1H)，3.881(t，4H)，3.812(t，1H)，3.591(m，2H)，3.087(t，4H)，2.022(s，3H)
13C-NMR(CDCl
3，75.46MHz)δ：171.458，155.064，148.424，130.652，120.267，116.420，72.256，67.080，49.843，48.303，42.301，23.364
Embodiment 26
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (31)
The synthetic method of reference compound (15), (170.6mg, 0.4972mmol) with 1,2,4-1H-triazole (mol ratio of reactant is 1: 1) reacts 1.5h, obtains white crystal (127.1mg), yield 80.62% to use compound (27).
m.p 189-191℃
FAB-MS：m/z 330.1[M+H
+]
IR(film)cm
-1：3454，2856，1743，1697，1518，1402，1225，1117，924，822，665
1H-NMR(CDCl
3，300MHz)δ：8.238(s，1H)，7.953(s，1H)，7.353(d，2H)，6.967(d，2H)，5.012(m，1H)，4.558(d，2H)，4.138(t，1H)，3.973(dd，1H)，3.888(t，4H)，3.146(t，4H)
Embodiment 27
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (32)
The synthetic method of reference compound (17), (200mg, 0.5618mmol) with camphorimide reaction (mol of compound (27) and camphorimide is than 1: 1.2), reaction 2.5h gets white crystal (167.7mg), yield 66.19% to use compound (27).
m.p.182-184℃
FAB-MS：m/z 441.2[M
+](100)，442.0[M+H
+]
IR(film)cm
-1：2994，2852，1749，1676，1518，1412，1223，1124，930，822，752
1H-NMR(CDCl
3，300MHz)δ：7.431(d，2H)，6.957(d，2H)，4.821(m，1H)，4.282(dd，1H)，4.030(t，1H)，3.919(t，4H)，3.737(dd，2H)，3.138(t，4H)，2.787(d，1H)，2.238(m，1H)，1.958(t，2H)，1.812(m，1H)，1.215(s，3H)，1.013(s，3H)，0.982(s，3H)
Embodiment 28
(R)-[N-3-(4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (33)
The synthetic method of reference compound (21), (200mg, 0.5618mmol) with succimide (its mol ratio 1: 1), reaction 1.5h obtains white crystal (101.6mg), yield 50.94% to use compound (27).
m.p.149-151℃
FAB-MS：m/z 359[M
+](100)
IR(film)cm
-1：3514，2819，1736，1716，1522，1236，1144，1119，926，827，681
1H-NMR(CDCl
3，300MHz)δ：7.472(d，2H)，7.091(m，2H)，4.933(m，1H)，4.062(dd，2H)，3.950(t，4H)，3.735(m，2H)，3.107(t，4H)，2.783(s，4H)
Embodiment 29
3-chloro-4-morpholinyl oil of mirbane (34)
In the 500ml there-necked flask, add ethyl acetate (100ml), morpholine (15.0ml, 0.171mol), diisopropyl ethyl amine (25.5ml, 0.147mol), mechanical stirring under the room temperature, add 3, and the 4-dichloronitrobenzene (27.4g, 0.156mol), refluxed 105 hours, with ethyl acetate extraction (200ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (200ml * 3)
4Drying, evaporate to dryness obtains yellow solid, uses the acetone-water recrystallization, obtains yellow crystals (22.81g), yield 66.0%.
m.p.123-125℃
1H-NMR(CDCl
3，300MHz)δ：8.137(d，1H)，8.106(dd，1H)，7.040(d，1H)，3.896(t，4H)，3.216(t，4H)
Embodiment 30
3 chloro-4-morpholinyl aniline (35)
The synthetic method of reference compound (2) slowly drips compound (34) (22.305g, ethanol solution 84.95mmol), the mol of reduced iron powder and compound (34) was than 3: 1, get white solid (9.71g), yield 90.98% is directly used in the next step.
1H-NMR(CDCl
3，300MHz)δ：6.912(d，1H)，6.764(d，1H)，6.558(dd，1H)，3.855(t，4H)，2.948(t，4H)
Embodiment 31
N-carbobenzoxy-(Cbz)-3-chloro-4-morpholinyl aniline (36)
In the 500ml four-hole bottle, add methylene dichloride (160ml), compound crude product (35) (20.63g), adding diisopropyl ethyl amine under 0 ℃ (32.8ml, 0.188mol), mechanical stirring, drip chloroformic acid benzyl ester (15.3ml, 0.170mol), stir 16h under the room temperature, with dichloromethane extraction (100ml * 3), with saturated NaCl solution washing (100ml * 3), use anhydrous MgSO
4Drying, evaporate to dryness gets shallow white solid, uses the acetone-water recrystallization, obtains white crystal (22.81g), yield 77.46%.
m.p.122-124℃
FAB-MS：347.1[M+H
+]
IR(film)cm
-1：3246，2947，1728，1591，1531，1221，1107，1066，895，741
1H-NMR(CDCl
3，300MHz)δ：7.52l(s，1H)，7.402(m，5H)，7.210(dd，lH)，7.064(d，1H)，6.559(s，1H)，5.192(s，2H)，3.895(t，4H)，3.05l(t，4H)
Embodiment 32
(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (37)
The synthetic method of reference compound (4), and adding compound (36) (7.53g, 21.72mmol) ,-78 ℃, N
2A large amount of white precipitates appear in protection, drip 2M butyl lithium solution (10.86ml; 21.72mmol);-78 ℃ are stirred 50min down, and system flavescence gradually is green, and more and more rarer; (R)-glycerine butyl ester (3.14ml contracts in dropping; 22.20mmol, anhydrous THF5ml), become settled solution very soon under-78 ℃; reaction 1h; remove acetone bath, be warming up to room temperature, stir 16h; the minute quantity precipitation appears; get light yellow solid, silica gel column chromatography is with ethyl acetate-normal hexane recrystallization; get white solid (0.38g), yield 5.6%.
m.p.108-110℃
FAB-MS：m/z 313.1[M+H+]
IR(film)cm-1：3413，2864，1701，1502，1437，1324，1109，704
1H-NMR(CDCl3，300MHz)δ：7.647(d，1H)，7.416(dd，1H)，7.181(m，1H)，4.773(m，1H)，4.018(m，3H)，3.930(t，4H)，3.751(dd，1H)，3.103(t，4H)
Embodiment 33
(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (38)
The synthetic method of reference compound (5), (0.56g 1.79mmol), gets white solid (0.3744g), yield 53.50% to add compound (37).
m.p.169-171℃
IR(film)cm
-1：2966，1741，1502，1356，1232，1182，1001，812，706
1H-NMR(CDCl
3，300MHz)δ：7.650(bs，1H)，7.386(dd，2H)，4.926(m，1H)，4.483(m，2H)，4.141(t，1H)，3.936(t，4H)，3.585(d，1H)，3.122(t，4H)，3.109(s，1H)
Embodiment 34
(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (39)
The synthetic method of reference compound (19), (237.4mg is 0.581mmol) with potassium phthalimide (mol of compound (38) and potassium phthalimide was than 1: 1.2) for compound (38), reaction 1.5h, obtain white solid,, be directly used in next step reaction without separation.
m.p.272-274℃
FAB-MS：m/z 442.0[M+H
+](100)
IR(film)cm
-1：3469，2939，1745，1714，1500，1396，1217，1111，1043，935，729
1H-NMR(CDCl
3，300MHz)δ：7.896(m，2H)，7.768(m，2H)，7.581(d，1H)，7.418(m，1H)，7.122(d，1H)，4.980(m，1H)，4.132(ddd，2H)，3.989(dd，2H)，3.942(t，4H)，3.243(t，4H)
Embodiment 35
(S)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (41)
The synthetic method of reference compound (8) adds above-claimed cpd (39), obtains white crystal (66.7mg), yield 33.89%.
m.p.186-188℃
FAB-MS：m/z 354.3[M+H
+]
IR(fi lm)cm
-1：3344，2970，2819，1739，1662，1502，1320，1115，935，704
1H-NMR(CDCl
3，300MHz)δ：7.587(d，1H)，7.366(dd，1H)，7.040(d，1H)，6.289(bs，t，1H)，4.770(m，1H)，4.020(t，1H)，3.866(t，4H)，3.760(dd，1H)，3.651(m，2H)，3.013(t，4H)，2.038(s，3H)
13C-NMR(CDCl
3，75.46MHz)δ：171.231，154.498，145.711，133.926，129.259，121.034，117.824，72.256，67.380，47.950，42.244，23.470
Embodiment 36
(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (42)
The synthetic method of reference compound (15), (40mg, 0.1024mmol) with 1,2,4-1H-triazole (mol ratio 1: 1) reaction 1.5h gets crude product (28.0mg) to compound (38), with ethyl acetate-normal hexane recrystallization, does not grow crystal, yield 75.16%.
FAB-MS：m/z 364.0[M+H
+]
1H-NMR(CDCl
3，300MHz)δ：8.243(s，1H)，7.944(s，1H)，7.465(d，1H)，7.321(m，1H)，7.02 7(dd，1H)，5.007(m，1H)，4.558(d，2H)，4.118(t，1H)，3.979(dd，1H)，3.855(t，4H)，3.006(t，4H)
Embodiment 37
(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (43)
The synthetic method of reference compound (17), (30mg 0.0768mmol) with camphorimide (compound (38) with camphorimide mol than 1: 1.2), reacts 6h to compound (38), obtains white crystal (10.0mg), yield 27.39%.
m.p.168-170℃
FAB-MS：m/z 476.1[M+H
+]
1H-NMR(CDCl
3，300MHz)δ：7.548(d，1H)，7.424(dd，1H)，7.088(s，1H)，4.841(m，1H)，4.292(dd，1H)，4.028(t，1H)，3.882(t，4H)，3.725(dd，2H)，3.037(t，4H)，2.788(d，1H)，2.254(m，1H)，1.979(t，2H)，1.819(m，1H)，1.213(s，3H)，1.010(s，3H)，0.981(s，3H)
Embodiment 38
(R)-[N-3-(3 '-chloro-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (44)
The synthetic method of reference compound (21), and compound (38) (30mg, 0.077mmol) with succimide (mol was than 1: 1), reaction 2.5h.With ethyl acetate-normal hexane recrystallization, do not go out crystal, obtain product (20.0mg), yield 66.16%.
FAB-MS：m/z 394.0[M+H
+](100)
1H-NMR(CDCl
3，300MHz)δ：7.530(d，1H)，7.381(dd，1H)，7.029(d，1H)，4.888(m，1H)，4.029(dd，2H)，3.929(t，4H)，3.705(dd，2H)，3.002(t，4H)，2.724(s，4H)
Embodiment 39
3-trifluoromethyl-4-morpholinyl oil of mirbane (45)
In the 50ml there-necked flask, add ethyl acetate (15ml), morpholine (2.28ml, 26.08mmol), diisopropyl ethyl amine (4.86ml, 25.84mmol), magnetic stirs under the room temperature, add 3-trifluoromethyl-4-fluoronitrobenzene (5.0g, 23.92mmol), reacted 120 hours, with ethyl acetate extraction (50ml * 3), with saturated NaCl solution washing (50ml * 3), use anhydrous MgSO
4Drying, evaporate to dryness obtains yellow solid, uses the acetone-water recrystallization, obtains yellow crystals (5.40g), yield 81.7%.
m.p.108-110℃
1H-NMR(CDCl
3，300MHz)δ：8.529(d，1H)，8.363(dd，1H)，7.285(d，1H)，3.861(t，4H)，3.122(t，4H)
Embodiment 40
3-trifluoromethyl-4-morpholinyl aniline (46)
The synthetic method of reference compound (2) slowly drips compound (45) (10.15g, ethanol solution 36.77mmol), wherein the mol of reduced iron powder and compound (45) was than 3: 1, react about 5min after adding again, get shallow white solid crude product (9.50g), be directly used in the next step.
1H-NMR(CDCl
3，300MHz)δ：7.214(d，1H)，6.916(d，1H)，6.830(dd，1H)，3.797(t，4H)，2.830(t，4H)
Embodiment 41
N-carbobenzoxy-(Cbz)-3-trifluoromethyl-4-morpholinyl aniline (47)
The synthetic method of reference compound (3) adds compound (46) (9.50g), gets white crystal (12.07g), yield 86.39%.
m.p.159-161℃
FAB-MS：m/z 380.2[M
+]
IR(film)cm
-1：3249，2945，1738，1541，1504，1329，1227，1132，899，741，698
1H-NMR(CDCl
3，300MHz)δ：7.617(dd，2H)，7.416(m，5H)，7.341(dd，1H)，6.790(s，1H)，5.210(s，2H)，3.816(t，4H)，2.872(t，4H)
Embodiment 42
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (48)
The synthetic method of reference compound (4), (6.23g, 16.395mmol), evaporate to dryness obtains light yellow dope (2.8982g), with ethyl acetate-normal hexane recrystallization, does not separate out crystal, yield 51.09% to use compound (47).
FAB-MS：m/z 347.1[M+H
+]
1H-NMR(CDCl
3，300MHz)δ：7.863(dd，1H)，7.684(d，1H)，7.410(d，1H)，4.770(m，1H)，4.049(m，3H)，3.809(t，4H)，3.744(dd，1H)，2.889(t，4H)
Embodiment 43
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (49)
The synthetic method of reference compound (5), (2.8982g 8.3763mmol), obtains yellow oil (3.9912g), yield 112.38% to use compound (48).
1H-NMR(CDCl
3，300MHz)δ：7.826(dd，1H)，7.688(d，1H)，7.424(d，1H)，4.943(m，1H)，4.492(m，2H)，4.188(t，1H)，3.992(dd，1H)，3.828(t，4H)，3.122(s，3H)，2.884(t，4H)
Embodiment 44
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (50)
The synthetic method of reference compound (19), (583.1mg is 1.38mmol) with potassium phthalimide (mol of compound (49) and potassium phthalimide was than 1: 1.2) for compound (49), reaction 2h, obtain white solid,, be directly used in next step reaction without separation.
1H-NMR(CDCl
3，300MHz)δ：7.897(m，2H)，7.858(dd，1H)，7.758(m，2H)，7.647(d，1H)，7.385(d，1H)，5.009(m，1H)，4.130(dd，2H)，3.984(dd，2H)，3.829(t，4H)，2.897(t，4H)
Embodiment 45
(S)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (52)
The synthetic method of reference compound (8) adds above-claimed cpd (50), obtains white crystal (87.5mg), yield 16.38%.
m.p.205-207.5℃
FAB-MS：m/z 388.2[M+H
+](100)
IR(film)cm
-1：3346，2956，1741，1664，1541，1510，1415，1130，931，847，679
1H-NMR(CDCl
3，300MHz)δ：7.758(m，2H)，7.375(d，1H)，6.122(bs，t，1H)，4.803(m，1H)，4.084(t，1H)，3.808(t，4H)，3.733(dd，1H)，3.695(m，2H)，2.888(t，4H)，2.069(s，3H)
13C-NMR(CDCl
3，75.46MHz)δ：171.113，154.426，148.340，135.106，128.645，125.473(d)，122.806，121.849，117.727(d)，72.256，67.581，54.074，47.912，42.270，23.497
Embodiment 46
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (53)
The synthetic method of reference compound (15), and compound (49) (494.3mg, 1.166mmol) with 1,2,4-1H-triazole (mol was than 1: 1), reaction 2h with ethyl acetate-sherwood oil recrystallization, obtains white crystal (206.5g), yield 44.62%.
m.p 101-103℃
FAB-MS：m/z 398.2[M+H
+](100)
IR(fi lm)cm
-1：3114，2958，2854，1763，1508，1414，1336，1228，1119，931，679
1H-NMR(CDCl
3，300MHz)δ：8.282(s，1H)，7.974(s，1H)，7.734(dd，1H)，7.581(d，1H)，7.367(dd，1H)，5.060(m，1H)，4.708(d，2H)，4.162(t，1H)，4.085(dd，1H)，3.823(t，4H)，2.889(t，4H)
Embodiment 47
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (54)
The synthetic method of reference compound (17), (650.1mg 1.53mmol) with camphorimide (mol of compound (49) and camphorimide is than 1: 1.2), reacts 6h to compound (49), obtains white crystal (424.7mg), yield 54.55%.
m.p.137-139℃
FAB-MS：m/z 509.2[M
+]
IR(fi lm)cm
-1：2970，2823，1761，1730，1676，1508，1334，1225，1130，1039，933，752，679
1H-NMR(CDCl
3，300MHz)δ：7.842(dd，1H)，7.638(d，1H)，7.385(d，1H)，4.885(m，1H)，4.310(dd，1H)，4.095(t，1H)，3.894(t，4H)，3.725(dd，2H)，2.982(t，4H)，2.772(d，1H)，2.238(m，1H)，1.967(t，2H)，1.809(m，1H)，1.219(s，3H)，1.019(s，3H)，0.987(s，3H)
Embodiment 48
(R)-[N-3-(3 '-trifluoromethyl-4 '-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (55)
The synthetic method of reference compound (21), (552.1mg, 1.30mmol) with succimide (mol was than 1: 1), reaction 1.5h obtains white crystal (283.2mg), yield 50.93% to compound (49).
m.p 68-69℃
FAB-MS：m/z 427.2[M
+]
IR(film)cm
-1：2960，2858，1755，1705，1508，1408，1334，1228，1130，1039，933，752，676
1H-NMR(CDCl
3，300MHz)δ：7.848(dd，1H)，7.687(dd，1H)，7.419(d，1H)，4.938(m，1H)，4.168(dd，2H)，4.054(dd，1H)，3.831(t，4H)，3.784(dd，1H)，2.912(t，4H)，2.800(s，4H)
Embodiment 49
3-fluoro-4-(4-Phenylpiperazinyl) oil of mirbane (56)
In the 250ml there-necked flask, add ethyl acetate (50ml), 4-phenylpiperazine (13.5ml, 89.10mmol), diisopropyl ethyl amine (15.30ml, 89.10mmol), magnetic stirs under the room temperature, add 3, and the 4-difluoro nitrobenzene (9.0ml, 81.30mmol), reacted 105 hours, with ethyl acetate extraction (150ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (150ml * 3)
4Drying, evaporate to dryness gets orange/yellow solid, uses the acetone-water recrystallization, obtains orange-yellow crystal (23.66g), yield 96.33%.
m.p.154-156℃
1H-NMR(CDCl
3，300MHz)δ：8.027d，1H)，7.920(d，1H)，7.315(d，1H)，6.940(m，5H)，3.861(t，4H)，3.122(t，4H)
Embodiment 50
3-fluoro-4-(4-Phenylpiperazinyl) aniline (57)
The synthetic method of reference compound (2), the activation 80min (using reduced iron powder 0.12mol) that refluxes slowly drips compound (56) (12.0g, 39.82mmol) ethanol solution, react about 10min after adding again, get shallow white solid, be directly used in the next step.
1H-NMR(CDCl
3，300MHz)δ：7.304(dd，1H)，7.060(d，1H)，6.923(t，1H)，6.433(m，5H)，3.387(t，4H)，3.193(t，4H)
Embodiment 51
N-carbobenzoxy-(Cbz)-3-fluoro-4-(4-Phenylpiperazinyl) aniline (58)
The synthetic method of reference compound (36) adds compound (57) 35.81g, and stirred overnight at room temperature gets shallow white solid, uses the acetone-water recrystallization, gets shallow white crystal (11.45g), yield 76.66%.
m.p.166-168℃
FAB-MS：m/z 406.2[M+H
+]
1H-NMR(CDCl
3，300MHz)δ：7.394(m，5H)，7.325(d，2H)，6.969(m，1H)，6.790(s，1H)，5.189(s，2H)，3.385(t，4H)，3.235(t，4H)
Embodiment 52
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (59)
In 100ml there-necked flask (120 ℃ baking 2h more than), add compound (58) (3.40g, 8.395mmol), anhydrous tetrahydro furan (50ml), under-78 ℃, N
2Protection, and dropping 1.6M butyl lithium solution (6.60ml, 8.395mmol) ,-78 ℃; stir 80min, system is the flavescence green solution gradually, and (R)-glycerine butyl ester (1.21ml, 8.58mmol contract in dropping; anhydrous THF5ml) ,-78 ℃, become settled solution very soon, reaction 1h; remove acetone bath, be warming up to room temperature, stir 16h; small amount of precipitate occurs, get white solid, silica gel column chromatography; with ethyl acetate-sherwood oil recrystallization, separate out white crystal (2.34g), yield 77.21%.
m.p.189-191℃
FAB-MS：m/z 372.2[M+H
+]
IR(fi lm)cm
-1：3413，2825，1732，1599，1520，1230，947，760，692
1H-NMR(CDCl
3，300MHz)δ：7.500(dd，1H)，7.328(d，1H)，7.410(d，1H)，6.960(m，5H)，4.743(m，1H)，3.982(m，3H)，3.367(t，4H)，3.235(t，4H)
Embodiment 53
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (60)
The synthetic method of reference compound (5), (1.74g, 4.82mmol), reaction 65min obtains white crystal (1.6065g), yield 75.92% to add compound (59).
m.p.170-172℃
1H-NMR(CDCl
3，300MHz)δ：7.501(dd，1H)，7.351(dt，2H)，7.135(m，5H)，4.915(m，1H)，4.479(ddd，2H)，4.175(t，1H)，3.937(dd，1H)，3.884(t，4H)，3.288(t，4H)，3.107(s，3H)
Embodiment 54
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl) methyl phthalimide (61)
The synthetic method of reference compound (19), (686.3mg, 1.563mmol) with potassium phthalimide (mol of the two was than 1: 1.2), reaction 3h obtains white solid to compound (60), without separation, is directly used in next step reaction.
m.p.238-239.5℃
1H-NMR(CDCl
3，300MHz)δ：7.862(m，2H)，7.797(dd，2H)，7.455(dd，1H)，7.326(dd，1H)，7.262(d，1H)，6.950(m，5H)，4.986(m，1H)，4.165(dd，2H)，3.994(dd，1H)，3.873(dd，1H)，3.362(t，4H)，3.218(t，4H)
Embodiment 55
(S)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (63)
The synthetic method of reference compound (8) adds above-claimed cpd (61), obtains white crystal (183.5mg), yield 29.49%.
m.p.177-179℃
FAB-MS：m/z 413.2[M+H
+]
IR(fi lm)cm
-1：3311，2831，1730，1657，1520，1429，1232，947，862，762，690
1H-NMR(CDCl
3，300MHz)δ：7.4888(m，1H)，7.304(dd，2H)，7.010(m，5H)，6.101(bs，t，1H)，4.781(m，1H)，3.970(t，1H)，3.778(m，2H)，3.685(dd，1H)，3.372(t，4H)，3.241(t，4H)，2.027(s，3H)
13C-NMR(CDCl
3，75.46MHz)δ：170.974，156.974，154.215(d)，150.839，136.333，132.881，129.094，120.227，119.070(d)，116.365，113.849(d)，107.953(d)，71.908，50.657，49.625，47.675，41.983，23.153
Embodiment 56
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, and 2,4-1H-triazole (64)
The synthetic method of reference compound (15), and compound (60) (109.9mg, 0.25mmol) with 1,2,4-1H-triazole (mol was than 1: 1), reaction 1.5h with ethyl acetate-sherwood oil recrystallization, obtains white crystal (78.0g), yield 75.62%.
m.p 196-198℃
FAB-MS：m/z 423.2[M+H
+](100)
IR(film)cm
-1：3118，2952，2839，1755，1599，1516，1452，1415，1323，1232，943，758，676
1H-NMR(CDCl
3，300MHz)δ：8.238(s，1H)，7.960(s，1H)，7.393(m，3H)，7.032(m，5H)，5.030(m，1H)，4.569(d，2H)，4.136(t，1H)，3.992(dd，1H)，3.382(t，4H)，3.249(t，4H)
Embodiment 57
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (65)
The synthetic method of reference compound (17), (100mg, 0.2278mmol) with camphorimide (mol was than 1: 1.2), reaction 4h with ethyl acetate-sherwood oil recrystallization, obtains white crystal (78.8mg), yield 66.02% to compound (60).
m.p.191-193℃
FAB-MS：m/z 535.3[M+H
+]
IR(fi lm)cm
-1：3438，2958，2839，1739，1676，1518，1450，1404，1325，1232，943，833，764，694
1H-NMR(CDCl
3，300MHz)δ：7.467(dd，1H)，7.315(m，1H)，7.130(d，1H)，6.990(m，5H)，4.856(m，1H)，4.300(dd，1H)，4.029(t，1H)，3.908(dd，1H)，3.716(dd，1H)，3.980(t，4H)，3.241(t，4H)，2.771(d，1H)，2.243(m，1H)，1.842(t，2H)，1.811(m，1H)，1.259(s，3H)，1.015(s，3H)，0.986(s，3H)
Embodiment 58
(R)-[N-3-(3 '-fluoro-4 '-(4 " Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (66)
The synthetic method of reference compound (21), (100mg, 0.2278mmol) with succimide (mol was than 1: 1), reaction 1.5h obtains white crystal (72.4mg), yield 70.34% to compound (60).
m.p 223-225℃
FAB-MS：m/z 453.2[M+H
+]
IR(fi lm)cm
-1：3462，2959，2287，1766，1747，1705，1599，1518，1404，1 323，1227，945，814，762，696，663
1H-NMR(CDCl
3，300MHz)δ：7.469(dd，1H)，7.334(dd，1H)，7.132(d，1H)，6.991(m，5H)，4.928(m，1H)，4.050(dd，2H)，3.787(m，2H)，3.374(t，4H)，3.379(t，4H)，2.791(s，4H)
Embodiment 59
3-fluoro-4-(4 '-(4 " methoxyl group) Phenylpiperazinyl) oil of mirbane (67)
In the 500ml there-necked flask, add ethyl acetate (200ml), 4-(4-methoxyl group) phenylpiperazine (15.71g, 81.72mmol), triethylamine (11.22ml, 81.73mmol), magnetic stirs under the room temperature, adds 3,4-difluoro nitrobenzene (8.25ml, 81.30mmol), reaction 21h, suction filtration, obtain yellow mother crystal (12.89g), with ethyl acetate extraction filtrate (150ml * 3),, use anhydrous MgSO with saturated NaCl solution washing (150ml * 3)
4Drying, evaporate to dryness gets yellow solid, uses the acetone-water recrystallization, gets yellow crystals (13.31g), merges yield 76.09%.
m.p.140-142
1H-NMR(CDCl
3，300MHz)δ：8.032(dd，1H)，8.002(dd，2H)，6.896(m，4H)，3.790(s，3H)，3.497(t，4H)，3.263(t，4H)
Embodiment 60
3-fluoro-4-(4 '-(4 " methoxyl group) Phenylpiperazinyl) aniline (68)
The synthetic method of reference compound (2), the activation 50min (using reduced iron powder 0.118mol) that refluxes slowly adds compound (67) (13.0g, 39.24mmol) ethanol solution, react about 10min after adding again, get shallow white solid crude product, be directly used in the next step.
1H-NMR(CDCl
3，300MHz)δ：6.845(m，4H)，6.433(m，3H)，3.779(s，3H)，3.241(t，4H)，3.151(t，4H)
Embodiment 61
N-carbobenzoxy-(Cbz)-3-fluoro-4-(4 '-(4 " methoxyl group) Phenylpiperazinyl) aniline (69)
The synthetic method of reference compound (3) adds compound (68), and a large amount of white precipitates appear in stirred overnight at room temperature, and suction filtration gets shallow white solid, uses the acetone-water recrystallization, gets white (the band point is light green) crystal (13.87g), yield 81.32%.
m.p.178-179.5℃
FAB-MS：m/z 436.1[M+H
+]
IR(film)cm
-1：3332，2958，2819，1701，1589，1525，154，1227，1149，1061，1036，941，820，735，696
1H-NMR(CDCl
3，300MHz)δ：7.393(m，3H)，6.957(m，4H)，6.588(s，1H)，5.197(s，2H)，3.782(s，3H)，3.293(t，4H)，3.216(t，4H)
Embodiment 62
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (70)
In 100ml there-necked flask (120 ℃ baking 2 h more than), add compound (69) (5.0g, 11.49mmol), anhydrous tetrahydro furan (70ml), under-78 ℃, N
2A large amount of white precipitates appear in protection, and adding 2.0M butyl lithium solution (5.80ml, 11.49mmol);-78 ℃, stir 90min, system becomes blackish green solution gradually, and (R)-glycerine butyl ester (1.79ml contracts in dropping; 11.83mmol, anhydrous THF5ml) ,-78 ℃; become yellow settled solution very soon, reaction 1h removes acetone bath; be warming up to room temperature, stir 16h, small amount of precipitate occurs; with ethyl acetate-sherwood oil recrystallization, separate out white crystal (1.6131g), yield 35.00%.
m.p.156-158℃
FAB-MS：m/z 402.3[M+H
+](100)
IR(film)cm
-1：3415，2954，2831，1747，1514，1228，1032，949，825，752
1H-NMR(CDCl
3，300MHz)δ：7.496(dd，1H)，7.149(d，1H)，7.023(m，4H)，6.858(d，1H)，4.752(m，1H)，3.985(m，3H)，3.787(s，3H)，3.737(d，1H)，3.256(t，8H)
Embodiment 63
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (71)
The synthetic method of reference compound (5), (1.3187g, 3.29mmol), reaction 40min obtains white crystal (1.9603g), yield 124.44% to add compound (70).
m.p.135-136℃
1H-NMR(CDCl
3，300MHz)δ：7.500(dd，1H)，7.100(m，4H)，6.873(d，2H)，4.926(m，1H)，4.478(ddd，2H)，4.132(t，1H)，3.936(d，1H)，3.793(s，3H)，3.299(s，8H)，3.109(s，3H)
Embodiment 64
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl) methyl phthalimide (72)
The synthetic method of reference compound (19), (700.0mg 1.4614mmol) with potassium phthalimide (mol ratio of the two 1: 1.2), obtains white solid to compound (71), without separation, is directly used in next step reaction.
Embodiment 65
(S)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (74)
The synthetic method of reference compound (8) adds above-claimed cpd (72), with ethyl acetate-sherwood oil recrystallization, obtains white crystal (149.0mg), yield 23.07%.
m.p.174-176℃
FAB-MS：m/z 443.2[M+H
+]
IR(film)cm
-1：3307，2952，2831，1751，1732，1665，1514，1448，1421，1230，1034，947，823，750
1H-NMR(CDCl
3，300MHz)δ：7.478(dd，1H)，7.094(dd，1H)，6.948(m，4H)，6.851(d，1H)，6.169(bs，t，1H)，4.768(m，1H)，4.023(t，1H)，3.764(s，3H)，3.730(m，3H)，3.245(t，8H)，2.004(s，3H)
13C-NMR(CDCl
3，75.46MHz)δ：171.170，157.287，154.438(d)，154.024，136.673，133.152(d)，119.395(d)，118.894，114.747(d)，114.094，107.887(d)，73.041，72.138，63.081，55.891，51.467(d)，47.996，46.732，46.144，42.335，27.272，23.493
Embodiment 66
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, and 2,4-1H-triazole (75)
The synthetic method of reference compound (15), and compound (71) (150.0mg, 0.313mmol) with 1,2,4-1H-triazole (mol was than 1: 1), reaction 2.5h with ethyl acetate-sherwood oil recrystallization, obtains white crystal (100.9g), yield 71.28%.
m.p 222-224℃
FAB-MS：m/z 453.2[M+H
+]
IR(fi lm)cm
-1：3109，2945，2833，1743，1514，1423，1242，1227，1038，943，862，831，750，681
1H-NMR(CDCl
3，300MHz)δ：8.236(s，1H)，7.961(s，1H)，6.951(m，7H)，5.029(m，1H)，4.567(d，2H)，4.134(t，1H)，3.992(dd，1H)，3.795(s，3H)，3.257(t，8H)
Embodiment 67
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (76)
The synthetic method of reference compound (17), (200mg, 0.4175mmol) with camphorimide (mol of the two was than 1: 1.2), reaction 2.5h with ethyl acetate-sherwood oil recrystallization, obtains white crystal (126.96mg), yield 53.76% to compound (71).
m.p.186-188℃
FAB-MS：m/z 565.2[M+H
+]
IR(fi lm)cm
-1：2974，2833，1736，1678，1512，1540，1406，1323，1240，1230，1039，945，818，752，592
1H-NMR(CDCl
3，300MHz)δ：7.458(dd，1H)，7.015(m，1H)，6.986(m，4H)，6.862(d，1H)，4.841(m，1H)，4.275(dd，1H)，4.021(t，1H)，3.907(dd，1H)，3.786(s，3H)，3.712(dd，1H)，3.266(s，8H)，2.790(d，1H)，2.235(m，1H)，1.941(t，2H)，1.824(m，1H)，1.414(s，3H)，1.013(s，3H)，0.984(s，3H)
Embodiment 68
(R)-[N-3-(3 '-fluoro-4 '-(4 " (4-methoxyl group) Phenylpiperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (77)
The synthetic method of reference compound (21), compound (71) (200mg, 0.2278 mmol) and succimide (mol was than 1: 1), reaction 2h with ethyl acetate-sherwood oil recrystallization, obtains white crystal (43.1mg), yield 21.37%.
m.p 155-157℃
FAB-MS：m/z 483.2[M+H
+]
IR(film)cm
-1：2956，2831，1766，1749，1703，1514，1421，1232，1227，1030，947，748，661
1H-NMR(CDCl
3，300MHz)δ：7.474(d，1H)，6.992(m，4H)，6.872(d，1H)，4.922(m，1H)，4.073(dd，2H)，4.044(dt，2H)，3.790(s，3H)，3.282(t，8H)，2.791(s，4H)
Embodiment 69
3-fluoro-4-(4 '-the benzyl piepridine base) oil of mirbane (78)
In the 250ml there-necked flask, add ethyl acetate (150ml), 4-benzyl piepridine (15.84ml, 89.16mmol), triethylamine (12.30ml, 89.16mmol), magnetic stirs under the room temperature, adds 3, (9.0ml 81.30mmoI), reacted 33 hours the 4-difluoro nitrobenzene.Evaporate to dryness gets yellow solid, uses the acetone-water recrystallization, obtains yellow crystals (24.35g), yield 93.12%.
m.p 109-110℃
1H-NMR(CDCl
3，300MHz)δ：7.976(dd，1H)，7.898(dd，1H)，7.283(m，5H)，6.913(d，1H)，3.708(d，2H)，2.834(t，2H)，2.616(d，2H)，1.708(m，3H)，1.442(m，2H)
Embodiment 70
3-fluoro-4-(4 '-the benzyl piepridine base) aniline (79)
The synthetic method of reference compound (2), the activation 1h (using reduced iron powder 0.158mol) that refluxes slowly drips compound (78) (16.53g, 52.58mmol) ethanol solution, react about 10min after adding again, get shallow white solid, be directly used in the next step.
Embodiment 71
N-carbobenzoxy-(Cbz)-3-fluoro-4-(4 '-the benzyl piepridine base) aniline (80)
The synthetic method of reference compound (3) adds above-claimed cpd (79), and a large amount of white precipitates appear in stirred overnight at room temperature, and suction filtration with 25% aqueous acetone solution washing leaching cake, is used the acetone-water recrystallization, gets white crystal (15.68g), yield 71.43%.
m.p.114-116℃
FAB-MS：m/z 418.1[M+H
+](100)
IR(fi lm)cm
-1：3356，2292，1701，1586，1529，1435，1388，1279，1234，1086，926，868，748，731，699
1H-NMR(CDCl
3，300MHz)δ：7.393(m，5H)，7.294(m，5H)，6.920(d，2H)，6.861(m，1H)，6.570(s，1H)，5.182(s，2H)，3.363(d，2H)，2.834(m，4H)，1.711(m，1H)，1.442(d，4H)
Embodiment 72
(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (81)
In 100ml there-necked flask (120 ℃ baking 2 h more than), add compound (80) (4.12g, 9.40mmol), anhydrous tetrahydro furan (80ml), under-78 ℃, N
2The protection, splash into 1.6M butyllithium hexane solution (5.93ml, 9.40mmol);-78 ℃, stir 50min, system is virescence solution gradually; add (the R)-glycerine butyl ester that contracts (1.47ml, 9.68mmol, anhydrous THF5ml);-78 ℃, become yellow clear liquor very soon, reaction 1h; remove acetone bath; be warming up to room temperature, stir 16h, small amount of precipitate occurs.Evaporate to dryness, silica gel column chromatography with ethyl acetate-sherwood oil recrystallization, is separated out white crystal (1.2962g), yield 35.15%.
m.p.105-107℃
FAB-MS：m/z 385.2[M+H
+](100)
IR(fi lm)cm
-1：3392，2924，1734，1520，1326，1099，750，700
1H-NMR(CDCl
3，300MHz)δ：7.393(m，5H)，7.294(m，5H)，7.109(dd，1H)，6.935(d，2H)，4.720(m，1H)，3.944(m，3H)，3.766(d，1H)，3.358(d，2H)，2.834(t，4H)，1.724(m，1H)，1.623(d，4H)
Embodiment 73
(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (82)
The synthetic method of reference compound (5), (1.2962g, 3.2834mmol), reaction 30min with ethyl acetate-sherwood oil recrystallization, obtains white crystal (1.7177g), yield 111.11% to add compound (81).
m.p.121-123℃
1H-NMR(CDCl
3，300MHz)δ：7.319(m，5H)，7.082(m，5H)，7.053(dd，1H)，6.938(m，2H)，4.910(m，1H)，4.437(ddd，2H)，4.109(t，1H)，3.909(dd，1H)，3.376(d，2H)，3.098(s，3H)，2.613(d，4H)，1.775-1.387(m，5H)
Embodiment 74
(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (83)
The synthetic method of reference compound (19), compound (82) (309.4mg, 0.671mmol) with potassium phthalimide (mol of the two was than 1: 1.2), reaction 2h,, obtain white solid, be directly used in next step reaction.
1H-NMR(CDCl
3，300MHz)δ：7.887(m，2H)，7.747(dd，2H)，7.355(m，5H)，7.201(m，5H)，7.073(dd，1H)，6.912(m，2H)，4.967(m，1H)，4.150(dd，2H)，3.950(dd，1H)，3.846(dd，1H)，3.394(d，2H)，2.586(d，4H)，1.767-1.470(m，5H)
Embodiment 75
(S)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methylacetamide (85)
The synthetic method of reference compound (8) adds above-claimed cpd (83), obtains white crystal (128.8mg), yield 45.27%.(in the operating process, the mol of 25% aqueous methylamine solution and compound (83) is than 10: 1, and the mol of diacetyl oxide and starting compound was than 3: 1.)
m.p.105-107℃
FAB-MS：m/z 426.2[M+H
+](100)
IR(film)cm
-1：3288，3086，2916，1735，1728，1646，1518，1228，872，748，700
1H-NMR(CDCl
3，300MHz)δ：7.346(m，5H)，7.196(m，5H)，7.007(dd，1H)，6.900(m，2H)，6.353(bs，t，1H)，4.746(m，1H)，3.991(t，1H)，3.717(t，1H)，3.632(m，2H)，33.384(d，2H)，2.579(d，4H)，1.760-1.459(m，5H)
13C-NMR(CDCl
3，75.46MHz)δ：170.879，154.177，140.268，129.007，128.096，125.770，113.781，107.513(d)，71.840，51.552，43.186，41.987，37.723，32.305，23.157
Embodiment 76
(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, and 2,4-1H-triazole (86)
The synthetic method of reference compound (15), (150.0mg, 0.3253mmol) with 1,2,4-1H-triazole (mol was than 1: 1) obtains white crystal (115.8g), yield 81.43% to compound (81).
m.p 140-142℃
FAB-MS：m/z 436.2[M+H
+](100)
IR(film)cm
-1：3438，2916，1743，1516，1326，1099，860，748，700
1H-NMR(CDCl
3，300MHz)δ：8.226(s，1H)，7.949(s，1H)，7.292(m，5H)7.220(m，5H)，6.992(dd，1H)，6.908(m，2H)，5.007(m，1H)，4.548(d，2H)，4.105(t，1H)，3.946(dd，1H)，3.399(d，2H)，2.608(d，4H)，1.765-1.502(m，5H)
Embodiment 77
(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (87)
The synthetic method of reference compound (17), (150mg, 0.3253mmol) with camphorimide (mol of the two was than 1: 1.2), reaction 6h gets white crystal (39.8mg), yield 21.84% to compound (81).
m.p.78-80℃
FAB-MS：m/z 548.3[M+H
+]
IR(fi lm)cm
-1：2929，1757，1732，1678，1516，1226，1011，928，748，700
1H-NMR(CDCl
3，300MHz)δ：7.293(m，5H)，7.199(m，5H)，7.093(d，1H)，6.913(m，2H)，4.834(m，1H)，4.308(dd，1H)，3.971(t，1H)，3.861(dd，1H)，3.758(dd，1H)，3.392(d，2H)，2.759(d，1H)，2.608(d，4H)，2.232(d，1H)，1.946(t，2H)，1.764(m，1H)，1.765-1.502(m，5H)，1.207(s，3H)，1.004(s，3H)，0.977(s，3H)
Embodiment 78
(R)-[N-3-(3 '-fluoro-4 '-(4 " the benzyl piepridine base)) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (88)
The synthetic method of reference compound (21), (150mg, 0.3253mmol) with succimide (mol was than 1: 1), reaction 2h obtains white crystal (37.6mg), yield 24.90% to compound (81).
m.p 217-219℃
FAB-MS：m/z 466.2[M+H
+]
IR(fi lm)cm
-1：2918，1743，1705，1518，1327，1230，860，820，752，700
1H-NMR(CDCl
3，300MHz)δ：7.292(m，5H)，7.178(m，5H)，7.054(d，1H)，6.914(m，2H)，4.903(m，1H)，4.018(dd，2H)，3.757(m，2H)，3.360(d，2H)，2.774(s，4H)，2.585(d，4H)，1.765-1.499(m，5H)
Embodiment 79
3-fluoro-4-piperidyl oil of mirbane (89)
In the 250ml there-necked flask, add ethyl acetate (70ml), piperidines (6.71ml, 67.83mmol), triethylamine (12.56ml, 90.33mmol), magnetic stirs under the room temperature, add 3, (5.0ml 45.16mmol), reacted 15 hours the 4-difluoro nitrobenzene, get colorless oil (10.50g), yield 100%.
1H-NMR(CDCl
3，300MHz)δ：7.979(dd，1H)，7.897(dd，1H)，6.898(t，1H)，3.269(t，4H)，1.703(m，6H)
Embodiment 80
3-fluoro-4-piperidyl aniline (90)
The synthetic method of reference compound (2), the activation 1h (using reduced iron powder 0.14mol) that refluxes slowly drips compound (89) (10.44g, 46.60mmol) ethanol solution, react about 20min after adding again, get shallow white solid, be directly used in the next step.
1H-NMR(CDCl
3，300MHz)δ：6.817(t，1H)，6.397(m，2H)，2.895(t，4H)，1.723(m，4H)，1.511(m，2H)
Embodiment 81
N-carbobenzoxy-(Cbz)-3-fluoro-4-piperidyl aniline (91)
In the 250ml four-hole bottle, add THF (100ml) and compound (90), 0 ℃ adds sodium bicarbonate (5.0g down, 59.52mmol), mechanical stirring, and the adding chloroformic acid benzyl ester (7.56ml, 53.6lmmol), stir under the room temperature and spend the night, a large amount of white precipitates appear, suction filtration, and filtrate extracts (200ml * 3) with THF, with saturated NaCl solution washing (100ml * 3), use anhydrous MgSO
4Drying, evaporate to dryness is used the acetone-water recrystallization, obtains white needle-like crystals (12.00g), yield 78.52%.
m.p.116-118℃
FAB-MS：m/z 328.2[M+H
+](100)
IR(film)cm
-1：3303，2933，1701，1589，1537，1518，1419，1038，1254，1227，1126，1066，957，816，860，686
1H-NMR(CDCl
3，300MHz)δ：7.357(m，5H)，6.920(m，3H)，6.553(s，1H)，5.184(s，2H)，2.954(t，4H)，1.728(m，4H)，1.551(m，2H)
Embodiment 82
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (92)
The synthetic method of reference compound (4), and adding compound (91) (3.28g, 10.0mmol), splash into 1.6M butyllithium hexane solution (6.67ml, 10.0mmol) ,-78 ℃, stir 50min, system is virescence solution gradually, and (R)-glycerine butyl ester (1.50ml contracts in adding, 10.59mmol, anhydrous THF5ml) ,-78 ℃, become light yellow clarifying liquid very soon, reaction 1h removes acetone bath, be warming up to room temperature, stir 16h, small amount of precipitate occurs.Silica gel column chromatography with ethyl acetate-sherwood oil recrystallization, is separated out white crystal (0.4391g), merges yield 14.53%.
m.p.135-137℃
FAB-MS：m/z 295.2[M
+](100)
IR(fi lm)cm
-1：3408，2935，1712，1520，1414，1246，1236，881，752，611
1H-NMR(CDCl
3，300MHz)δ：7.426(dd，1H)，7.109(dd，1H)，6.966(t，1H)，4.724(m，1H)，3.957(m，3H)，3.766(d，1H)，2.987(t，4H)，1.730(m，4H)，1.566(m，2H)
Embodiment 83
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (93)
The synthetic method of reference compound (5), (0.4271g 1.45mmol), obtains white crystal (0.5665g), yield 104.8% to add compound (92).
m.p.141-143℃
1H-NMR(CDCl
3，300MHz)δ：7.460(m，1H)，7.066(d，2H)，4.920(m，1H)，4.473(ddd，2H)，4.122(t，1H)，3.912(dd，1H)，3.122(s，3H)，3.037(t，4H)，1.730-1.386(m，6H)
Embodiment 84
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (94)
The synthetic method of reference compound (19), (90mg, 0.242mmol) with potassium phthalimide (mol was than 1: 1.2), reaction 2h obtains white solid (71.1mg), yield 69.87% to compound (93).
m.p 167-169℃
1H-NMR(CDCl
3，300MHz)δ：7.895(m，2H)，7.779(dd，2H)，7.369(m，1H)，7.105(m，1H)，6.933(m，1H)，4.967(m，1H)，4.131(dd，2H)，3.957(dd，1H)，3.857(dd，1H)，2.892(t，4H)，1.740(m，4H)，1.553(m，2H)
Embodiment 85
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl isophthalic acid, 2,4-1H-triazole (95)
The synthetic method of reference compound (15), (100.0mg, 0.2688mmol) with 1,2,4-1H-triazole (mol of the two was than 1: 1) reacts 1h to add compound (93).With ethyl acetate-sherwood oil recrystallization, obtain white crystal (89.0g), yield 95.96%.
m.p 136-138℃
FAB-MS：m/z 346.2[M
+](100)
IR(film)cm
-1：3107，2941，1739，1516，1421，1331，1273，1230，1140，864，752，685
1H-NMR(CDCl
3，300MHz)δ：8.232(s，1H)，7.955(s，1H)，7.254(m，1H)，6.990(m，2H)，5.032(m，1H)，4.551(d，2H)，4.134(t，1H)，3.995(m，1H)，3.052(t，4H)，1.778(m，4H)，1.562(m，2H)
Embodiment 86
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl camphorimide (96)
The synthetic method of reference compound (17), (90mg, 0.2419mmol) with camphorimide (mol was than 1: 1.2), reaction 6h gets white crystal (83.0mg), yield 75.07% to compound (93).
m.p.159-161℃
FAB-MS：m/z 458.2[M+H
+](100)
IR(film)cm
-1：2941，1745，1682，1516，1417，1213，930，862，752
1H-NMR(CDCl
3，300MHz)δ：7.325(dd，1H)，7.083(dd，1H)，6.936(t，1H)，4.840(m，1H)，4.289(dd，1H)，4.010(t，1H)，3.870(dd，1H)，3.729(dd，1H)，2.979(t，4H)，2.787(d，1H)，2.240(d，1H)，1.937(dt，2H)，1.822(m，1H)，1.742(m，4H)，1.581(m，2H)，1.551(s，3H)，1.010(s，3H)，0.982(s，3H)
Embodiment 87
(R)-[N-3-(3 '-fluoro-4 '-piperidyl) phenyl-2-oxo-5-oxazolidinyl] methyl succimide (97)
The synthetic method of reference compound (21), (100.3mg, 0.2696mmol) with succimide (mol was than 1: 1), reaction 1.5h obtains white crystal (49.5mg), yield 48.95% to compound (93).
m.p 146-148℃
FAB-MS：m/z 376.2[M+H
+](100)
IR(film)cm
-1：2937，1714，1705，1518，1402，1329，1236，1111，858，818，652
1H-NMR(CDCl
3，300MHz)δ：7.424(m，1H)，7.026(m，2H)，4.937(m，1H)，4.043(dd，2H)，3.786(m，2H)，2.774(s，4H)，1.785(t，4H)，1.545(m，6H)
Experimental example
Bacteriostatic experiment
1, laboratory sample
With the present invention 3,5-substituted oxazolidinone derivative 8,12,15,17,21,30,31,32,33,41,52,53,54,55,63,64,65,66,74,75,76,77,85,86,87,88,95,96,97 is as laboratory sample.
With Ciprofloxacin (Ciprofloxacin, CIP), sultamicillin (Sultamicillin, SUL) and vancomycin (Vancomycin, VCO) sample in contrast.
Test with bacterium is:
Golden yellow grape ball resistant organism (Staphylococcus aureus MRSA) 20 strains
Golden yellow grape ball sensitive organism (Staphylococcus aureus MSSA) 20 strains
Percentage of methicillin-resistant staphylococcus epidermidis (Streptococcus epidermidis Oxacillin resistant) 20 strains
Responsive staphylococcus epidermidis (Streptococcus epidermidis Oxacillin susceptible) 20 strains of Oxazacillin
Drug resistance of vancomycin enterococcus faecalis (Enterococcus faecium Vancomycin resistant) 10 strains
Responsive enterococcus faecalis (Enterococcus faecium Vancomycin susceptible) 20 strains of vancomycin
Penicillin resistance streptococcus pyogenes (Streptococcus pyogenes Penicillin resistant) 10 strains
Penicillin sensitization Streptococcus pyrogenes (Streptococcus pyogenes Penicillin susceptible) 10 strains
2, experimental technique
Take by weighing above-mentioned 32 compound 25.6mg respectively, with small amount of N aOH hydrotropy, complement to 5ml with distilled water again, fully behind the mixing, the preceding Guan Banliang of taking-up adds equivalent aquae destillata two-fold dilution and becomes 16 concentration, after each concentration is got the 1ml soup and added 19mlMueller-Hinton Agar and train basic mixing, pour plate into and get final product after cooling.Golden yellow grape ball Portugal bacterium, faecalis are tested with above-mentioned training base, and include 5% sheep blood.
Experimental bacteria is seeded in (10ml/ pipe) in the common nutrient broth, and streptococcus pyogenes is seeded in and contains in the 2% deactivation calf serum, and above-mentioned inoculation bacterium was hatched under 37 ℃ 18 hours, is diluted to 10 next day
6/ cfu uses bacteria concentration as experiment, and bacterium is added in the microwell plate, on the medicine plate of different concns, after waiting to do, hatches observations after 18 hours with multiple spot inoculation method kind bacterium under 37 ℃.
3, experimental result:
The present invention 3, and 5-substituted oxazolidinone derivative antimicrobial MIC (μ g/ml) result is as shown in table 2.
Table 2
Drug MSSA MRSA S.epi.R(S) S.pyo.R(S) E.fae.R(S)
8 MIC
50 0.5 1 0.5(0.25) 0.062(0.016) 1(0.5)
MIC
90 1 2 1(0.5) 0.25(0.031) 1(0.5)
12 MIC
50 16 32 4(0.25) 32(16) 32(8)
MIC
90 32 64 16(1) 4(16) 64(16)
15 MIC
50 2 4 2(0.062) 2(0.5) 4(1)
MIC
90 8 64 4(2) 2(1) 8(2)
17 MIC
50 16 16 32(0.125) 8(0.062) 4(＜0.008)
MIC
90 16 256 128(1) 16(0.25) 8(0.062)
21 MIC
50 ＞256 ＞256 0.5(0.25) 32(0.125) 32(4)
MIC
90 ＞256 ＞256 1(1) 128(1) 64(16)
30 MIC
50 ＜0.008 ＜0.008 4(0.5) ＜0.008(＜0.008) 16(8)
MIC
90 ＜0.008 1 8(2) ＜0.016(＜0.008) 16(16)
31 MIC
50 ＜0.008 ＜0.008 256(4) 0.008(＜0.008) ＞256(＞256)
MIC
90 ＜0.008 ＜0.008 256(16) ＜0.008(＜0.008) ＞256(＞256)
32 MIC
50 256 256 64(2) ＜0.008(＜0.008) 128(32)
MIC
90 ＞256 ＞256 256(8) ＜0.008(＜0.008) 256(64)
33 MIC
50 32 32 32(1) 32(16) 256(32)
MIC
90 64 64 64(4) 64(32) 256(64)
41 MIC
50 1 1 0.062(0.031) 1(0.5) 0.25(0.062)
MIC
90 1 1 1(0.125) 1(1) 1(0.25)
52 MIC
50 16 32 1(0.031) 8(0.031) 8(1)
MIC
90 64 64 2(0.5) 8(4) 16(1)
53 MIC
50 ＞256 ＞256 32(0.5) 0.016(＜0.008) 256(128)
MIC
90 ＞256 ＞256 128(4) 0.125(＜0.008) ＞256(128)
54 MIC
50 ＜0.008 ＜0.008 4(0.5) 8(0.031) 64(8)
MIC
90 ＜0.008 0.016 8(2) 8(4) 128(16)
55 MIC
50 ＜0.008 ＜0.008 ＜0.008(＜0.008) 4(1) 0.25(0.016)
MIC
90 ＜0.008 ＜0.008 0.25(＜0.008) 8(2) 0.5(0.062)
63 MIC
50 0.016 0.016 0.031(0.016) 0.031(0.016) 0.062(0.031)
MIC
90 0.5 0.5 0.125(0.031) 0.062(0.031) 0.125(0.062)
64 MIC
50 ＞256 ＞256 ＞256(16) ＞256(＞256) 256(128)
MIC
90 ＞256 ＞256 ＞256(32) 256(128) ＞256(128)
65 MIC
50 ＜0.008 ＜0.008 2(1) ＜0.008(＜0.008) ＞256(256)
MIC
90 ＜0.008 ＜0.008 8(4) ＜0.008(＜0.008) ＞256(＞256)
66 MIC
50 64 128 64(16) ＜0.008(＜0.008) 256(0.5)
MIC
90 128 256 128(32) 0.016(＜0.008) ＞256(8)
74 MIC
50 1 1 0.5(0.25) ＜0.008(＜0.008) 2(1)
MIC
90 2 4 1(0.5) ＜0.008(＜0.008) 4(2)
75 MIC
50 32 32 1(0.5) 16(0.062) 256(32)
MIC
90 32 32 8(1) 32(4) ＞256(32)
76 MIC
50 ＜0.008 ＜0.008 (0.016) 0.062(0.008) 0.016(＜0.008)
MIC
90 ＜0.008 ＜0.008 (0.125) 16(0.016) 0.062(＜0.008)
77 MIC
50 32 32 4(1) 64(32) 64(8)
MIC
90 64 128 8(2) 64(32) 64(16)
85 MIC
50 8 64 8(0.5) 16(4) 32(2)
MIC
90 16 128 32(1) 32(8) 128(8)
86 MIC
50 ＜0.008 1 256(1) 32(16) ＞256(＞256)
MIC
90 0.5 32 ＞256(64) 256(32) ＞256(＞256)
87 MIC
50 ＜0.008 ＜0.008 64(8) 32(32) 256(128)
MIC
90 ＜0.008 32 256(128) 128(32) 256(256)
88 MIC
50 256 256 32(16) 64(32) 128(128)
MIC
90 ＞256 ＞256 128(32) 64(64) ＞256(128)
95 MIC
50 16 32 4(0.5) 16(4) 16(4)
MIC
90 32 32 16(2) 32(16) 32(8)
96 MIC
50 ＜0.008 ＜0.008 16(2) ＜0.008(＜0.008) 32(16)
MIC
90 ＜0.008 0.5 32(4) ＜0.008(＜0.008) 64(32)
97 MIC
50 ＜0.008 0.125 1(0.125) 4(1) 8(1)
MIC
90 2 64 4(＜0.008) 8(2) 16(4)
CIP MIC
50 0.5 16 2(0.25) 0.5(0.5) 32(8)
MIC
90 4 64 16(0.125) 0.5(0.5) 32(16)
SUL MIC
50 0.25 8 1(0.062) 0.25(0.016) 8(0.062)
MIC
90 0.5 32 16(0.125) 0.5(0.031) 32(2)
VCO MIC
50 0.25 1 1(1) 1(0.25) 1(0.25)
MIC
90 1 2 2(1) 2(0.5) 2(0.5)
As can be seen from the above table, of the present invention 3, the antibacterial activity in vitro experimental result of 5-substituted oxazolidinone derivative shows that most compounds have potent anti-microbial activity, especially 41,55,63,74,76 pairs of four kinds of test organismss of compound all have very strong anti-microbial activity, relatively MIC
90Value is better than vancomycin 2-250 doubly to four kinds of resistant organisms, is better than sultamicillin 2-8000 doubly, is better than Ciprofloxacin 32-8000 doubly.
In addition, 30,31,65,96 pairs of golden Portugal bacterium of compound and streptococcus pyogenes (resistance) have very strong anti-microbial activity, are better than vancomycin 2-250 doubly, are better than sultamicillin 4-2000 doubly, are better than Ciprofloxacin 32-2000 doubly.And 95 pairs of four kinds of test organismss of compound also have the moderate anti-microbial effect respectively.
4, with the comparing result of linezolid
As can be seen from Table 2, for gram-positive microorganism, The compounds of this invention and linezolid (compound 8) relatively have bacteriostatic activity better.
Claims (15)
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-
2001
- 2001-12-19 CN CNB011446137A patent/CN1155585C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014530232A (en) * | 2011-10-11 | 2014-11-17 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | Sila analogs of oxazolidinone derivatives and their synthesis |
| CN111925343A (en) * | 2020-08-12 | 2020-11-13 | 石家庄四药有限公司 | Synthesis method of linezolid degradation impurities |
| CN111925343B (en) * | 2020-08-12 | 2021-11-23 | 石家庄四药有限公司 | Synthesis method of linezolid degradation impurities |
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| CN1355165A (en) | 2002-06-26 |
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