CN106928214A - The preparation method of Yi Zhong oxazolidinone compounds and its intermediate - Google Patents
The preparation method of Yi Zhong oxazolidinone compounds and its intermediate Download PDFInfo
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- CN106928214A CN106928214A CN201710227928.7A CN201710227928A CN106928214A CN 106928214 A CN106928214 A CN 106928214A CN 201710227928 A CN201710227928 A CN 201710227928A CN 106928214 A CN106928214 A CN 106928214A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 129
- 238000006243 chemical reaction Methods 0.000 claims description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 77
- -1 phenylsulfonyloxy group Chemical group 0.000 claims description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 51
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 21
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 229910052763 palladium Inorganic materials 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
- 239000011630 iodine Substances 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 7
- 238000005360 mashing Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 229910019213 POCl3 Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- GQKOIYMLDFEQGP-UHFFFAOYSA-N methylsulfonyloxy trifluoromethanesulfonate Chemical compound CS(=O)(=O)OOS(=O)(=O)C(F)(F)F GQKOIYMLDFEQGP-UHFFFAOYSA-N 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- 241000165940 Houjia Species 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- 239000008213 purified water Substances 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 239000012634 fragment Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 150000002431 hydrogen Chemical group 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000003223 protective agent Substances 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VRESBNUEIKZECD-UHFFFAOYSA-N 2-methyltetrazole Chemical compound CN1N=CN=N1 VRESBNUEIKZECD-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 0 CC1(C)C(C)(C)O**1 Chemical compound CC1(C)C(C)(C)O**1 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004327 boric acid Substances 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 4
- 229940073608 benzyl chloride Drugs 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000006178 methyl benzyl group Chemical group 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000005103 alkyl silyl group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 150000001642 boronic acid derivatives Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- OMAFFHIGWTVZOH-UHFFFAOYSA-O 1-methyl-2h-tetrazol-1-ium Chemical compound C[N+]1=CN=NN1 OMAFFHIGWTVZOH-UHFFFAOYSA-O 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- YLNSNVGRSIOCEU-ZCFIWIBFSA-N [(2r)-oxiran-2-yl]methyl butanoate Chemical class CCCC(=O)OC[C@H]1CO1 YLNSNVGRSIOCEU-ZCFIWIBFSA-N 0.000 description 2
- FECNWVGSNARTFE-UHFFFAOYSA-M [Cl+].[O-]I(=O)=O Chemical compound [Cl+].[O-]I(=O)=O FECNWVGSNARTFE-UHFFFAOYSA-M 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005257 alkyl acyl group Chemical group 0.000 description 2
- 150000005215 alkyl ethers Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- ROBFUDYVXSDBQM-UHFFFAOYSA-N hydroxymalonic acid Chemical compound OC(=O)C(O)C(O)=O ROBFUDYVXSDBQM-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- FUTZDFOAPDCBHZ-UHFFFAOYSA-N n-bromo-3-fluoroaniline Chemical class FC1=CC=CC(NBr)=C1 FUTZDFOAPDCBHZ-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
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- 238000004587 chromatography analysis Methods 0.000 description 1
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- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 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
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- 239000002184 metal Substances 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical group CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- YLNSNVGRSIOCEU-UHFFFAOYSA-N oxiran-2-ylmethyl butanoate Chemical compound CCCC(=O)OCC1CO1 YLNSNVGRSIOCEU-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910021332 silicide Inorganic materials 0.000 description 1
- FVBUAEGBCNSCDD-UHFFFAOYSA-N silicide(4-) Chemical compound [Si-4] FVBUAEGBCNSCDD-UHFFFAOYSA-N 0.000 description 1
- 230000036548 skin texture Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 description 1
- 229960003947 tedizolid phosphate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- RSKHNOFGQRATRE-UHFFFAOYSA-N trifluoromethylsilicon Chemical compound FC(F)(F)[Si] RSKHNOFGQRATRE-UHFFFAOYSA-N 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical class CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
The present invention relates to Yi Zhong oxazolidinone compounds and its preparation method of intermediate.Specifically, be coupled for two fragments using Suzuki reactions by the present invention, Oxazolidinone derivative is prepared, the method process is simple, the reaction time is short, high income, be adapted to industrialized production.Also, the preparation method of this invention Ti Gong oxazolidinone compounds intermediates has simple to operate, high income, the advantage of low cost.
Description
The present invention is that number of patent application is 201410819173.6, and the applying date is 2014.12.25, entitled " a kind of
The divisional application of the preparation method of oxazolidinone compounds and its intermediate ".
Technical field
The present invention relates to pharmaceutical chemistry synthesis field, and in particular to the system of Yi Zhong oxazolidinone compounds and its intermediate
Preparation Method.
Background technology
Oxazolidone finds treating and preventing such as bacterium infection and atherosclerosis as a class chemical composition
It is widely used in the medicine of medical conditions.The various structures of oxazolidinone derivative are known.Such as US4461773,
The monosubstituted or disubstituted derivatives of 3- phenyl -2- oxazolidones are disclosed in US4476136, US4250318 etc..
Safe ground azoles amine (Tedizolid) is a kind of novel oxazolidinone antibiotics, its phosphate (tedizolid
Phosphate FDA) has been obtained and has ratified for treating staphylococcus aureus that (including methicillin resistant strains, methicillin is quick
Sense bacterial strain) and the gram-positive bacterium such as various streptococcuses and enterococcus faecalis the acute bacterial skin and skin texture that cause
Infection (ABSSSI).Safe ground azoles amine structure formula as shown in following formula TD,
Chemical name：(R) -3- (4- (2- (2- methyl tetrazolium -5- bases) pyridine -5- bases) -3- fluorophenyls) -5- Qiang Jia Ji oxazoles
Alkane -2- ketone.
Chinese patent CN102516238A and CN102702184A disclose safe ground azoles amine and phosphoric acid safe ground azoles amine is generalized
The preparation method of compound, such as reaction equation (1)：
The method first replaces the hydrogen atom on the phenyl of Qiang methyl oxazolidinones derivative (II) with halogen atom, and generation is spread out
Biological (III)；Being subsequently adding palladium catalyst makes derivative (III) replace with hexa methyl ditin or tri-butyl tin hydride, and generation is spread out
Biological (IV), the step yield about 61%；3rd step, the pyrrole for making derivative (IV) under the conditions of palladium catalyst and being replaced by bromine or iodine
Piperidine derivatives react, and generation has pyridine ring oxazolidinone derivatives (V).The method prepares safe ground azoles amine, it is necessary to use twice
To palladium catalyst, and three-step reaction is by (R) -3- (4- tributyl tinbase -3- fluorophenyls) -2- oxo -5- oxazole alkyl first
Alcohol is only capable of reaching 26% with 2- (2- methyl tetrazolium -5- bases) -5- bromopyridines reaction generation safe ground azoles amine, yield.Whole piece route into
This height, yield is low, is not suitable for industrialized production；On the other hand, this method is related to the route of synthesis that organotin is coupled, and is easily caused
The residual of tin in finished product, is not suitable for preparing patent medicine.
US8604209B2 discloses the preparation method of the safe ground azoles amine shown in following reaction equation (2)：
Wherein Y is from ZnCl, BF3And BR3R4, wherein R3And R4Independently selected from the OH and C of any substitution1-C6Unitary and
Dihydroxylic alcohols, wherein R3And R4Together can be with cyclization.
After compound 1 and compound 2 are first carried out coupling reaction by the method, will obtain compound 3 in the basic conditions with
Glycidyl Butyrate reacts, generation safe ground azoles amine (TD).Wherein, the purity of intermediate 3 and yield that prepared by first step reaction are equal
Relatively low (HPLC：89.8%, yield：66%)；Final step coupling reaction, is caused secondary anti-using highly basic (lithium silicide of hexamethyl two)
Ying Duo, introducing impurity is more, and post processing is difficult, cumbersome；The final step reaction time is long, and the safe ground azoles amine for preparing is pure
Degree is low, it is necessary to by repeatedly purifying, cumbersome, Pd residual quantities are still higher after purifying；Reaction needs to use anhydrous solvent,
Be not suitable for industrialization generation.
Fewer, the existing method of the preparation method document report at present on safe ground azoles amine, complex operation, reaction time
Long, production cost is high, and total recovery is low, and purity is relatively low, is not suitable for industrialization generation.
The content of the invention
Simple to operate it is an object of the present invention to provide a kind of low production cost, yield and purity are higher, and the reaction time is short, fit
The method for closing the oxazolidinones class compound processed of industrialized production, and in particular to the method for preparing safe ground azoles amine.
To achieve the above object, the present invention provides following technical scheme：
The preparation method of compound shown in a kind of following formula TD
Including by compound shown in following formula I
With compound shown in Formula II
Reaction, compound shown in generation following formula TD-1
Wherein, R is hydrogen or hydroxyl protecting group；L and R1In one be leaving group, another is BF3Or BR2R3, wherein R2
And R3The independent C selected from by OH and any substitution1~C6The group of unitary and dihydroxylic alcohols composition, wherein R2And R3Together can be into
Ring；Optional, slough the hydroxyl protecting group R of compound shown in TD-1, compound shown in generation TD.
In one embodiment, preferably L is leaving group, R1It is BF3Or BR2R3, wherein R2And R3It is independent selected from by OH
With the C of any substitution1~C6The group of unitary and dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization.
In another embodiment, preferential L is BF3Or BR2R3, wherein R2And R3It is independent selected from by OH and any substitution
C1~C6The group of unitary and dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization, R1It is leaving group.
Wherein, the leaving group includes halogen such as chlorine, bromine, iodine, sulfonyloxy such as trifluoro-methanesulfonyl oxy, methylsulfonyl oxygen
Base, phenylsulfonyloxy, or the phenylsulfonyloxy being substituted by one or more substituents, the substitution base are selected from：Halogen, C1~6Alkane
Base and C1~6The group of alkoxy composition；It is preferred that leaving group is chlorine, bromine, iodine；More preferably leaving group is bromine or iodine.
Wherein, the R is hydrogen, or hydroxyl protecting group, the hydroxyl protecting group includes：Alkyl, acyl group, alkyl silyl is excellent
The described hydroxyl protecting group of choosing is benzyl, the benzyl being substituted by one or more substituents, C1~4Alkyl acyl, or trimethyl silicane
Base, the substitution base is selected from by C1~6Alkyl, C1~6The group of alkoxy and halogen composition.It is further that preferably R is hydrogen, benzyl,
To methyl-benzyl, acetyl group, propiono, or bytyry.
Wherein, the BR2R3, preferably B (OH)2Or
In another embodiment, preferably L is bromine or iodine, R1It is BF3、B(OH)2OrFormula TD shownization
Shown in the following reaction equation of preparation method of compound：
Compound shown in Formulas I and compound shown in Formula II react, preferably under palladium catalyst catalytic condition, alkalescence (such as carbon
Sour sodium, potassium carbonate, NaOH or potassium hydroxide etc.) react under environment, solvent is preferably toluene, THF, DMF, DMSO, dioxy
Six rings, isopropanol or ethanol etc., reaction temperature are about 60~80 DEG C, coupling obtain compound TD-1 (R is hydroxyl protecting group) or
TD (R is hydrogen)；Optional sloughs hydroxyl protecting group R by compound TD-1, obtains compound TD.Wherein intermediate Formula II shownization
Compound：
Wherein R1It is BF3、B(OH)2OrCan prepare by the following method：
Intermediate ii, wherein X are chlorine, bromine or iodine, highly basic (such as C with 2 equivalents1~6Lithium alkylide such as n-BuLi or the tert-butyl group
Lithium) reaction, it is subsequently adding suitable electrophilic reagent such as B (OR2)3, specifically, such as C1~6(such as boric acid three is different for tri-alkoxy borate
Propyl ester), preferred solvent is THF or toluene, and reaction temperature is about -75 DEG C~-65 DEG C.Electrophilic reagent is tri-alkoxy borate
When, gained reactant mixture is post-treated to obtain boric acid IIa.The dianion of intermediate ii and ring borate are reacted, and
Afterwards can isolated ring borate IIb.Boronic acid compounds IIa can also refer to " the pyrimidine chloro thing of palladium chtalyst and pyridine boron
The Suzuki coupling reactions of acid esters " (Xiao Wenjing, 2011- Zhengzhou University：Pharmaceutical chemistry, master thesis) disclosed in method system
It is standby to obtain.Or diborate (such as two pinacols of hypoboric acid) is coupled on halogenated hydrocarbons (ii) under palladium catalyst effect,
The borate IIb of generation can be hydrolyzed as boric acid IIa in sour water；Trifluoro boronic acid derivatives IIc can be by IIa and KF
And/or KHF2Reaction generation；Or trifluoro boronic acid derivatives IIc passes through formula ii with borate (such as triisopropyl borate ester) in alkalescence
Under the conditions of (such as n-BuLi) reaction, solvent is preferably THF, generates boric acid triisopropyl lithium salts, then again with KHF2Reaction system
Standby to obtain, specific method can be found in " Suzuki-Miyaura idols of the potassium fluoborate of 2- pyridines three and fragrant miscellaneous halides under palladium chtalyst
Connection reaction " (appoints big, 2011- Zhengzhou University：Organic chemistry, Master's thesis), the document is incorporated by reference into this patent.
Specifically, the IIa can be prepared by method shown in following reaction equation：
Wherein compound shown in formula (1-4) refers to method disclosed in CN1894242B and prepares, disclosed in the patent
Content is incorporated by reference into the present invention.For example, including but is not limited to compound shown in (1-4) in strong basicity (such as normal-butyl
Lithium) under the conditions of with boric acid ester compound reaction, prepare compound shown in Formula II a, preferably reaction dissolvent is THF, reaction
Temperature is about -70 DEG C~-65 DEG C.
In another embodiment, preferential R1It is bromine or iodine, L is BF3、B(OH)2OrFormula TD shownization
The following reaction equation of preparation method of compound：
Compound shown in Formulas I reacts with compound shown in Formula II, is reacted preferably under palladium catalyst catalytic condition, and solvent is excellent
Elect DMF as, reaction temperature is about 60~80 DEG C, prepare compound TD-1 (R is hydroxyl protecting group) or TD (R is hydrogen), appoint
Choosing, compound TD-1 is sloughed into hydroxyl protecting group R, obtain compound TD.Compound wherein shown in intermediate Formulas I：
Wherein, L is BF3、B(OH)2OrPreparation method and previously described formula II institutes
Show that compound works as R1It is borate or BF3When preparation method be similar to, specific reaction equation is as follows：
X is chlorine, bromine or iodine in wherein formula i；The R be hydrogen, benzyl, to methyl-benzyl, acetyl group, propiono, or butyryl
Base.Further preferred X is bromine or iodine, and R is hydrogen.
In another embodiment, preferably described L is bromine or iodine, and the R is hydrogen, specifically, formula TD shownization
Shown in the following reaction process of preparation method of compound：
The reaction is reacted preferably under palladium catalyst catalytic condition, and solvent is preferably DMF, and reaction temperature is about 60~80
DEG C, preferable reaction temperature is 70 DEG C.
Halogen of the present invention is to include fluorine, chlorine, bromine, iodine；The alkyl includes straight or branched alkyl, and (such as ethyl, different
Propyl group etc.), the moieties (such as benzyl) of aryl substitution.
Compound shown in the Formulas I is preferably coupled with compound shown in Formula II a under the catalytic condition of palladium catalyst
Reaction, described palladium catalyst can include double (triphenylphosphine) palladiums (II) of dichloro, tetrakis triphenylphosphine palladium (0), palladium carbon, Pd
(OAc)2And PCy3/Pd2(dba)3(dba=benzalacetones) etc., the preferably reaction dissolvent are dimethylformamide
(DMF), 1-Methyl-2-Pyrrolidone, tetrahydrofuran (THF), toluene, dimethyl sulfoxide, toluene, isopropanol, ethanol etc., temperature is
About 60 DEG C~150 DEG C.
When R is hydroxyl protecting group, according to the method for the conventional dehydroxylation protection group in this area, protection group R is sloughed, obtained
Compound shown in formula TD.For example, Pb-C/H may be selected when R is benzyl or substituted benzyl2The method of catalytic hydrogenation sloughs protection
Base, reaction dissolvent is preferably THF, methyl alcohol, toluene or hexane etc.；When R is alkyl silyl (such as trimethyl silicon substrate), preferably in acid
Property under the conditions of in organic solvent (such as HCl-MeOH, HCl- dioxane system, or AcOH-THF systems) slough alkyl silyl guarantor
Shield base；When R is alkyl acyl (acetyl group, propiono, bytyry etc.), may be selected to be hydrolyzed under pickling or alkalescence condition
Slough, such as under the conditions of sodium methoxide, corresponding alkyl acyl is sloughed as solvent is stirred at room temperature with methyl alcohol.
On the other hand, the invention provides compound shown in Formulas I, preferably L be chlorine, preparation method during bromine or iodine, its by
Compound shown in formula III is changed into carbonyl dimidazoles reaction,
The reaction dissolvent is preferably dichloromethane, DMF, and isopropanol or THF etc., reaction temperature are for about 25 DEG C~40 DEG C.
After reaction terminates, optional the compound I and hydroxyl protecting group (such as benzyl chloride, diethylaminoethanol, C1 that will be free of protection group
~6 alkyl carboxylic acids, dimethyl tertiary butyl silicon chloride, trimethylsilyl chloride or dimethyl tertiary butyl silicon chloride etc.) reaction, obtain right
Answer the compound I that R is hydroxyl protecting group；Wherein preferred R is hydrogen, benzyl, to methyl-benzyl, acetyl group, and propiono, bytyry,
Dimethyl tertiary butyl silicon chloride, trimethylsilyl chloride or dimethyl tertiary butyl silicon chloride.
Further, compound shown in formula IV shown in the formula III
With the reaction of glycidol butyl ester, generate, wherein, L is chlorine, bromine or iodine；The reaction is carried out preferably in isopropanol
Reaction is back to terminate.
In certain embodiments, the method for the invention also includes, the formula TD prepared using the method for the invention
Shown compound, with POCl3、POCl(OBn)2Or P (N-iPr2)(O-tBu)2Compound shown in TD-P is generated at reaction conditions
Further, methods described also includes reacting generation following formula with alkali at reaction conditions using compound shown in TD-P
Compound shown in TD-PN
Wherein, M is PO (OH)2Pharmaceutically acceptable salt.The technical staff of medicinal chemistry art is it will be appreciated that term
" pharmaceutically acceptable salt " refers to the salt generated with the cation and/or anion of suitable bio-compatible.Described sun from
Attached bag includes metallic element cation, such as the quaternary ammonium cation of sodium, lithium, potassium, magnesium, aluminium, calcium, zinc and alkaloid includes metal
Thanide cation, such as N, N- dibenzyl-ethylenediamins.Chloroprocanine, choline, diethyl hydramine, ethylenediamine, procaine and
N- methyl glucose osamines etc..The anion of the anion including inorganic acid, the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
Phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic, formic acid, lactic acid, maleic acid, tartaric acid, lemon
Lemon acid, palmitic acid, malonic acid, tartronic acid, phenylacetic acid, glutamic acid, benzoic acid salicylic acid, toluenesulfonic acid, malic acid and class
Acidoid.It is preferred that described alkali is the alkali containing sodium, preferably described M is PO3Na2。
The third aspect, the invention provides following formula: compound
Wherein, L is bromine or iodine.
On the other hand, compound (during R=H) shown in formula i ' of the present invention, can also be by following reaction equation (4) Suo Shi
Method is prepared：
Reaction equation (4)
Step 1) the bromo- 3- fluoroanilines of 4- and benzyl chloroformate are reacted under the conditions of alkaline (such as sodium acid carbonate), prepare benzyl
Aminocarbamic acid ester type compound (1-7)；Step 2) by Benzylcarbamate class compound (1-7) in strong basicity (such as positive fourth
Base lithium) under the conditions of with glycidol butyl ester reaction, obtain compound shown in formula (1-9)；Finally, the different choice according to X is anti-
By compound shown in the conversion accepted way of doing sth of compound shown in formula (1-9) i ' under the conditions of answering.Optional, by compound and hydroxyl shown in formula i '
Protective agent reaction prepares the compound of hydroxyl protection group R.
Specifically, when X is halogen (that is, when preferably L is bromine or iodine), compound shown in formula (1-9) is with halide reagent (such as
ICl/CF3COOAg、BrCl/CF3COOAg) react, solvent is preferably acetonitrile, chemical combination shown in formula i ' is reacted under room temperature condition
Thing.
Compound i ' it is optional with hydroxy-protecting agent (such as benzyl chloride, diethylaminoethanol, C1~6Alkyl carboxylic acid etc.) it is anti-
Should, it is the compound I of hydroxyl protecting group to obtain correspondence R,
On the other hand, halogen X can change into methanesulfonic acid anhydride group by this area conventional method in compound I ', then
Compound TD is obtained by coupling reaction with compound IIa again.
In the present invention, described " hydroxy-protecting agent " refer to can with hydroxyl reaction generate esters protection group, silicon ether protection group,
The reagent of alkyl ether protection group, for example, the hydroxy-protecting agent of esters protection group can be generated with hydroxyl reaction, including but not limited to,
Formic acid, acetic acid, butyric acid, propionic acid etc.；The hydroxy-protecting agent for forming silicon ethers protection group, including but not limited to, trifluoromethyl
Silicon substrate, trimethyl silicon substrate, 3,5-dimethylphenyl silicon substrate, dimethyl tertiary butyl silicon substrate etc.；The hydroxyl that alkyl ether can be formed with hydroxyl
Base protective agent, including but not limited to, benzyl, to methyl-benzyl etc..
Heretofore described " optional ", refers to that, according to reaction needs, can select yes or no, illustration, this
The process of compound I and compound II reaction prepare compounds TD in invention, when R is H, TD-1 is identical with the structure of TD, then
TD-1 need not further slough hydroxyl protecting group and prepare TD；When R is benzyl or silicon-based protecting group, compound I and compound
II reactions obtain compound TD-1 first, then need selection further to slough hydroxyl protecting group R in TD-1, prepare TD.
The invention provides a kind of new synthetic method of safe ground azoles amine (TD), methods described has compared with prior art
Significant technique effect, first, the raw material used in the present invention is easy to get, compound shown in the used Formulas I of the present invention, can be by many
The method of kind is prepared, and yield is higher；Compound shown in Formula II used in the present invention, preparation method is simple, easily obtains
；Secondly, compound coupling prepares safe ground azoles amine (compound TD) as shown in compound shown in this Formulas I and Formula II, and yield is notable
Improve (being not less than 87%), the reaction time significantly shortens.3rd, the method that the present invention is provided, agents useful for same is easy to get, cost
Low, each intermediate of preparation is solid, and post processing is simple.
Specific embodiment
In order that technical problem solved by the invention, technical scheme and beneficial effect become more apparent, below in conjunction with
Specific embodiment, the present invention is further illustrated, and given specific embodiment is the preferred embodiments of the present invention.
Embodiment 1：The preparation of compound shown in Formula II a
(1), the preparation of 2- cyano group -5- bromopyridines：
100 grams of 2,5- dibromo pyridines are dissolved in 1 liter of dimethylformamide, at room temperature by 32 grams of copper cyaniders and 17.8 grams
Cymag is added in solution, is reacted within 7 hours solution stirring at being 150 DEG C in temperature.After being cooled to room temperature, reaction mixing
Water is added in thing, and is extracted with ethyl acetate.Organic layer salt water washing is simultaneously dehydrated, filters and is concentrated in vacuo, and obtains 54 grams of marks
Topic compound, yield 70%.
1H-NMR(CDCl3) δ 8.76 (s, 1H), 7.98 (dd, 1H), 7.58 (dd, 1H).
(2), the preparation of 2- (tetrazolium -5- bases) -5- bromopyridines：
10 grams of 2- cyano group -5- bromopyridines are dissolved in 100 milliliters of dimethylformamides, at room temperature by 5.33 grams of Azides
Sodium and 4.4 grams of ammonium chlorides are added in solution, and solution is stirred at being 110 DEG C in temperature and reacted for 3 hours.In reactant mixture
Water is added, is then extracted with ethyl acetate, separating obtained organic layer salt water washing, be dehydrated, filter and be concentrated in vacuo, thus
Obtain 10.5 grams of title compounds, yield 85%.
(3), the preparation of 2- (1- methyl tetrazolium -5- bases) -5- bromopyridines and 2- (2- methyl tetrazolium -5- bases) -5- bromopyridines
10.5 grams of 2- (tetrazolium -5- bases) -5- bromopyridines are dissolved in 100 milliliters of dimethylformamides, then by 6.5 grams of hydrogen
Sodium oxide molybdena is added in solution, and 9.3 grams of iodomethanes are slowly added in solution at 0 DEG C.Solution is stirred at room temperature 6
Hour, water is subsequently adding, and be extracted with ethyl acetate.Then organic layer salt water washing, dehydration, filtering, vacuum concentration obtained by
And by chromatography over CC, obtain 4 grams of 2- (1- methyl tetrazolium -5- bases) -5- bromopyridines and 5 grams of 2- (2- methyl tetrazolium -5- bases) -
5- bromopyridines.
(4), the preparation of compound shown in Formula II a：
Under nitrogen protection, 240 grams of 2- (2- methyl tetrazolium -5- bases) -5- bromopyridines are dissolved in 2.4 liters of tetrahydrofurans, plus
Enter 207g triisopropyl borate esters, -75 DEG C are cooled in liquid nitrogen/ethanol bath, be slowly added dropwise the n-BuLi four of 840ml 2.5M
Hydrogen tetrahydrofuran solution, control temperature reacts 2h, HPLC detection reactions, until completely in -75~-65 DEG C below -65 DEG C.It is added dropwise
The aqueous ammonium chloride solutions of 1.3L 20%, below 0 DEG C, drop finishes control temperature, stirs 0.5h, stratification, the anhydrous sulphur of organic layer
Sour sodium is dried, and draws dry, adds 600ml ethyl acetate mashing 2h, and filtering is dried, and obtains 149.7g target compounds, and yield is
73%.
Embodiment 2：(R) -3- (4- iodo -3- fluorophenyls) -2- oxo -5- oxazoles alkyl methanol (that is, compound i ')
Prepare：
(1), the preparation of N- carbobenzyloxies -3- fluoroanilines (1-7)：
100 grams of 3- fluoroanilines are dissolved in 1 liter of tetrahydrofuran (THF), and by 150 grams of (1.8 moles) sodium acid carbonates
(NaHCO3) be added in the solution, after being cooled to 0 DEG C, 154 milliliters of N- carbobenzoxy chlorides (CbzCl) are slowly added to solution
In reacted.Under agitation by reactant mixture at 0 DEG C sustained response 2 hours, extracted with 0.5 liter of ethyl acetate afterwards
Reaction system is taken, after separation, organic layer salt water washing, with anhydrous magnesium sulfate (MgSO4) dry and be concentrated in vacuo, residue is used
N-hexane is washed twice, and obtains 132 grams of title compounds for white crystal, yield 85%.
(2), the preparation of (R) -3- (3- fluorophenyls) -2- oxos -5- oxazoles alkyl methanol (1-9)：
132 grams of N- carbobenzyloxy -3- fluoroanilines are dissolved in 1.3 liters of tetrahydrofurans, and solution is cooled to -78
℃.370 milliliters of n-BuLis (1.6 mol/Ls, n-hexane) are slowly added in solution in a nitrogen atmosphere, are then stirred
10 minutes.84 milliliters of (R)-(-)-Glycidyl butyrates are slowly added in reactant mixture, are stirred at that same temperature
Mix 2 hours, then react 24 hours at room temperature.After the completion of reaction, ammonium chloride solution is added toward solution, and use at room temperature
0.5 liter of ethyl acetate extraction.With the separating obtained organic layer of salt water washing, and dried with anhydrous magnesium sulfate, vacuum concentration.By institute
Obtain residue to be dissolved in 100 milliliters of ethyl acetate and washed with n-hexane, obtain white crystal, white crystal purifying is 80 grams
Title compound, yield 70%.
1H-NMR(DMSO-d6) δ 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.02 (t,
1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).
(3), the system of (R) -3- (4- iodo -3- fluorophenyls) -2- oxo -5- oxazoles alkyl methanol (compound shown in formula i ')
It is standby：
30 grams of (R) -3- (3- fluorophenyls) -2- oxo -5- oxazole alkyl methanols are dissolved in 300 milliliters of acetonitriles, and by 46
Gram trifluoroacetic acid silver salt (CF3COOAg) it is added in solution with 43 grams of iodate chlorine, after being stirred at room temperature 1 day, is added toward solution
Enter water, and be extracted with ethyl acetate, separating obtained organic layer salt water washing is simultaneously dehydrated.Then by residue filtering, vacuum
It is concentrated and dried, thus obtains 44 grams of title compounds, yield 94%.
1H-NMR(DMSO-d6) δ 7.77 (t, 1H), 7.56 (dd, 1H), 7.20 (dd, 1H), 5.20 (m, 1H), 4.70 (m,
1H), 4.07 (t, 1H), 3.80 (m, 1H), 3.67 (m, 2H), 3.56 (m, 3H).
(R) -3- (4- bromo -3- fluorophenyls) -2- oxo -5- oxazoles alkyl methanol (Formulas I ' shown in compound, when L be bromine)
Similar (R) -3- (4- iodo -3- the fluorophenyls) -2- oxo -5- oxazole alkyl methanols of preparation method preparation method, difference
Place is to replace the iodide (iodate chlorine) in step (3) with the bromide of response.
Embodiment 3：The preparation on safe ground azoles amine (compound shown in TD)：
In the there-necked flask of the 500ml of reflux condensing tube and thermometer is configured with, 1.57g Pd (OAc) is added2, 3.7g
PPh3150ml DMF are dissolved in, nitrogen is replaced as, 33.75ml triethylamines are subsequently adding, stirring at 70 DEG C is until solution is changed into red-black
Color, (R) -3- (4- iodo -3- the fluorophenyls) -2- oxo -5- oxazole alkyl methanol (compounds for adding 47.2g embodiments 2 to prepare
I ') and compound shown in the Formula II a of the preparation of 34.4g embodiments 1,100ml DMF solutions are dissolved in, under nitrogen protection, stirred at 90 DEG C
Reaction 2h, TLC monitoring reaction is mixed, is filtered through diatomite while hot.50ml is concentrated at 70 DEG C, 500ml purified waters, stirring is added
1.0h, filtering, filter cake is washed with the methanol aqueous solutions of 50ml 50% (volumetric concentration), and 50 DEG C dry 8h.Added in gained solid
The methanol aqueous solutions of 430ml 50% (volumetric concentration), is heated to 70 degree of mashing 2h, is cooled to room temperature, filters, 30ml methanol rinses,
Compound 45g shown in TD is dried to obtain in 50 degree, yield is 87%, and purity is 98.6%.
1H-NMR(DMSO-d6)δ8.89(s,1H),8.16(m,2H),7.69(m,2H),7.49(dd,1H),5.25(t,
1H),4.73(m,1H),4.45(s,3H),4.13(t,1H),3.86(dd,1H),3.67(m,1H),3.58(m,1H)。
Embodiment 4：The preparation of (2R)-(4- bromine-3-fluorophenyls amino) -2- hydrox y-propanols butyrate (compound III ')
The bromo- 3- fluoroanilines of 19.0g 4- are dissolved in 200ml isopropanols, 14.4g (R)-Glycidyl butyrate is added,
It is heated to reflux, insulation reaction 12h.Remove solvent under reduced pressure, obtain product (2R)-(4- bromine-3-fluorophenyls amino) -2- hydroxyls-the third
Alcohol butyrate, product can be directly used for next step reaction without purifying.
Embodiment 5：(R) preparation of -3- (4- bromo -3- fluorophenyls) -2- oxo -5- oxazoles alkyl methanol (compound I ")
33.4g (2R)-(4- bromine-3-fluorophenyls amino) -2- hydrox y-propanol butyrates are dissolved in 150ml dichloromethane
In, 17.8g carbonyl dimidazoles are added, it is heated to 30~35 DEG C, insulation reaction 16h.100ml water is added, 0.5h is stirred, separated
Machine layer, anhydrous sodium sulfate drying, concentration.100ml methyl alcohol dissolving residue is added, after dissolving clarification, 5.94g sodium methoxides is added,
2h is stirred at room temperature, solvent is removed under reduced pressure, 200ml dichloromethane is added, respectively with the watery hydrochloric acid of 50ml 5%, the carbon of 50ml 7%
Sour hydrogen sodium water solution, 50ml purifying water washings, organic layer anhydrous sodium sulfate drying are filtered, are concentrated to give title compound
31.5g, yield is 85%.
Using the method for embodiment 5 prepare (R) -3- (4- bromo -3- fluorophenyls) -2- oxos -5- oxazoles alkyl methanols with
Compound reaction shown in Formula II prepared by the method for embodiment 1, the method for azoles amine (compound shown in TD) is similar with preparing Thailand implements
Example 3.
Embodiment 6：The preparation of compound shown in following formula (I-2)
(2R)-(4- bromine-3-fluorophenyls amino) -2- hydrox y-propanol butyrates prepared by 33.4g embodiments are dissolved in
In 150ml dichloromethane, 17.8g carbonyl dimidazoles are added, be heated to 30~35 DEG C, insulation reaction 16h.100ml water is added, is stirred
0.5h is mixed, organic layer is separated, anhydrous sodium sulfate drying, concentration obtains title compound 31.5g, and yield is 85%.
Embodiment 7：The preparation of safe ground azoles amine
In the there-necked flask of the 500ml of reflux condensing tube and thermometer is configured with, 1.57g Pd (OAc) is added2, 3.7g
PPh3150ml DMF are dissolved in, nitrogen is replaced as, 33.75ml triethylamines are subsequently adding, stirring at 70 DEG C is until solution is changed into red-black
Color, adds compound shown in the Formula II of compound shown in the formula (I-2) of the preparation of 47.2g embodiments 6 and the preparation of 34.4g embodiments 1,
100ml DMF solutions are dissolved in, under nitrogen protection, in 90 DEG C of stirring reaction 2h, TLC monitoring reactions, are filtered through diatomite while hot.
70 DEG C are concentrated into 50ml, add 500ml purified waters, stir 1.0h, and filtering, filter cake 100ml methyl alcohol dissolves, and adds 5.94g first
Sodium alkoxide, stirs 2h at room temperature, removes solvent under reduced pressure, and filter cake is washed with the methanol aqueous solutions of 50ml 50% (volumetric concentration), 50 DEG C
Dry 8h.The methanol aqueous solutions of 430ml 50% (volumetric concentration) is added in gained solid, 70 degree of mashing 2h are heated to, is cooled to
Room temperature, filtering, 30ml methanol rinses are dried to obtain compound 45g shown in TD in 50 DEG C, and yield is 87%, and purity is 98.6%,
Pd contents：＜ 2ppm.
The preparation of the following formula: compound TD-1 of embodiment 8
1) preparation of compound (I-3)：
By 14.5g chemical compounds Is " it is dissolved in 70mL tetrahydrofurans (THF), and 6.33g (1.2eq.) benzyl chloride is added to
In the solution, after being cooled to 0 DEG C, 1.2g (1.0eq) sodium hydride is slowly dividedly in some parts.Under agitation by reactant mixture liter
Temperature to sustained response at 40 DEG C 5 hours, step-down concentration adds 300mL ethyl acetate, and organic layer salt water washing uses anhydrous sulphur
Sour sodium is dried, filtered, concentration, obtains the 15.6g title compounds for white crystal, yield 82%.
2) chemical combination TD-1, is prepared by compound (I-3)
In the there-necked flask of 250ml, 11.41g compounds 1-3,6.46g (1.05eq.) compound ii a, 1.14g Pd/C is added,
9.09g triethylamines, 80ml DMF, nitrogen protection are heated to 80 DEG C, and insulation reaction 3h is filtered by diatomite, adds 400ml
7% sodium bicarbonate aqueous solution, stirs 10min, is extracted with 150ml*3 ethyl acetate, successively with 150ml distilled water, 150ml saturations
Sodium-chloride water solution washing, anhydrous sodium sulfate drying, filter, be concentrated to give target compound TD-1 9.26g, yield is 67%.
By compound (I-3) and the method class of compound IIa reaction prepare compounds TD-1 (hydroxyl protecting group R is benzyl)
Like compound (I-2) in embodiment 7 and the method for IIa reaction prepare compounds TD-1 (R is positive bytyry).
Embodiment 9：The preparation (in compound shown in TD-1 during R=benzyls) of safe ground azoles amine：
By TD-1 (during R=benzyls):10g TD-1 are dissolved in 80ml methyl alcohol, 0.5gPb-C/H is added2, nitrogen displacement 3 times,
Hydrogen is replaced three times, and Hydrogen Vapor Pressure is 0.5Mpa, is heated to reflux, and HPLC monitoring reactions, reaction is complete, room temperature is cooled to, through micro-
Twice, concentration is dried hole membrane filtration, obtains compound described in title.
Embodiment 10：Following formula I ' shown in compound preparation
Compound (1-9) (0.9eq) is dissolved in 1L tetrahydrofurans (THF), sodium hydrogen (1.1eq) is added to the solution
In, after being cooled to about 0 DEG C, benzyl chloride (1.0eq) being added in reaction solution, stirring to reaction terminates, ethyl acetate extraction, point
From obtaining benzyl oxide after concentration.Subsequent similar embodiment 2 step (3) (R) -3- (4- iodo -3- fluorophenyls) -2- oxo -5- oxazoles
The preparation method of alkyl methanol, 4 iodine for acting on phenyl ring through silver trifluoroacetate and iodine monochloride in acetonitrile replace, and obtain 4
Position replaces , oxazolidones hydroxyl compound shown in the formula (1-9) of benzyl protection by iodine, referring next to the step of embodiment 1 (4)
Synthetic method prepares corresponding boric acid, and benzyl is finally removed in the concentrated hydrochloric acid obtains target compound Formulas I ' shown in compound, MS
ESI[M]+：255.
Embodiment 11：The preparation on safe ground azoles amine (compound shown in TD)
In the there-necked flask of the 500ml of reflux condensing tube and thermometer is configured with, 1.83g Pd are added2(dba)3, 1.12g
PCy3400ml DMF are dissolved in, nitrogen is replaced as, 0.5h is stirred at room temperature, be subsequently adding 60.6g triethylamines, add 51.0g formulas I '
Shown compound and compound shown in 57.6g formulas II ', under nitrogen protection, in 70 DEG C of stirring reactions, HPLC monitorings are reacted, while hot
Filtered through diatomite.50ml is concentrated at 70 DEG C, 500ml purified waters are added, is extracted with dichloromethane 400ml*2, anhydrous slufuric acid
Sodium is dried, filtering, is concentrated to give solid, and the methanol aqueous solutions of 500ml 50% (volumetric concentration), heating are added in gained solid
To 70 degree of mashing 2h, room temperature is cooled to, filtered, 40ml methanol rinses are dried to obtain compound 65.9g shown in TD in 50 DEG C, receive
Rate is 89%, and purity is 98.8%.
Embodiment 12：The preparation of phosphoric acid safe ground azoles amine (TD-P)
The round-bottomed flask of the jacket of 5L, the machine mixer equipped with top, additional funnel, thermocouple, nitrogen inlet and follows
Ring cooling unit.Compound (70.0g, 0.189mol), THF (1.4L, 20 volumes) and triethylamine shown in TD are added in flask
(58.2g, 0.575mol).Slurry is stirred, and jacket temperature is set as 0 DEG C.Added in additional funnel and be dissolved in THF (70mL, 1 body
Product) POCl3 (87.0g, 0.567mol).When internal temperature reaches 1 DEG C, POCl3Solution is to be added dropwise in 44min.
The mixture is stirred 3 hours at 1-2 DEG C.To in three neck round bottom, water (1.4L) is added, 3.8 are cooled in ice, brine bath
℃.Reactant mixture pumped into 1 hour and water surface is quenched.Maximum temperature during being quenched is 11.9 DEG C.Yellow syrup is stirred
Overnight, filter, filter cake is rinsed with water (700mL) and methyl alcohol (700mL).Product is being dried under vacuum to constant weight at room temperature.Obtain
Target product, yield be 83.4g (98.1%), purity is 96.5%.
Embodiment 13：The preparation of safe ground azoles amine disodic alkaliine
Phosphoric acid safe ground azoles amine (30.0g) prepared by embodiment 9 is added in the reactor of 1L, adds methyl alcohol (360mL), slurry
Body is stirred at room temperature, and methyl alcohol (43.1g) solution of 25% sodium methoxide is added dropwise in 10min.Slurry is stirred at room temperature
Filtered after 1h.Reactor and filter cake are rinsed with methyl alcohol (150mL) and acetone (150mL).Product is done in 50-60 DEG C in vacuum tank
It is dry, obtain 32.6g crude products safe ground azoles amine disodic alkaliine.Crude product is dissolved in water (325mL), adds activated carbon, stirs at room temperature
30 minutes.2N NaOH adjust slurry pH to 11.Slurry is filtered by diatomite, and filtrate is filtered again with the filter membrane of 0.45 μ.
Filtrate is added dropwise in acetone (1.3L), and gained slurry is stirred overnight, then slurry by filtration, is rinsed with acetone (320mL), in 50
Dry DEG C in vacuum tank, be redissolved in water (230mL), add sodium hydroxide solution that pH value is adjusted into 10, the solution leads to
The membrane filtration for crossing 0.45 μ removes color, and filtrate is added dropwise in acetone (950ml), filters, and is then rushed with acetone (230mL)
Wash.After product is dried, weight is 25.8g (total recovery is 79%), HPLC：99.6%.
Embodiment 14：The preparation of following formula: compound Ib
In the there-necked flask of the 500ml of reflux condensing tube and thermometer is configured with, 14.5g compounds i, 13.97g are added
(1.1eq.) pinacol diborate, 1.83g (0.05eq.) PdCl2(dppf) 2,110ml DMF, under nitrogen protection, at 70 DEG C
Stirring reaction, HPLC monitoring reactions, filters through diatomite while hot.50ml is concentrated at 70 DEG C, 400ml purified waters is added, with two
Chloromethanes 400ml*2 is extracted, anhydrous sodium sulfate drying, filtering, is concentrated to give compound Ib 12.74g, and yield is 74%, purity
It is 99.3%；1H-NMR(DMSO-D6)：1.32 (s, 12H), 4.45 (s, 3H), 8.13 (d, 1H), 8.18 (d, 1H), 8.90 (s,
1H)。
The preparation of safe ground azoles amine of embodiment 15 (TD)
In the there-necked flask of the 500ml of reflux condensing tube and thermometer is configured with, 1.83g Pd are added2(dba)3, 1.12g
PCy3400ml DMF are dissolved in, nitrogen is replaced as, 0.5h is stirred at room temperature, be subsequently adding 60.6g triethylamines, add 51.0g chemical combination
Thing i and 85.2g compound lb, under nitrogen protection, in 70 DEG C of stirring reactions, HPLC monitoring reactions are filtered through diatomite while hot.
70 DEG C are concentrated into 50ml, add 500ml purified waters, are extracted with dichloromethane 400ml*2, anhydrous sodium sulfate drying, filtering, concentration
Solid is obtained, the methanol aqueous solutions of 500ml 50% (volumetric concentration) is added in gained solid, be heated to 70 degree of mashing 2h, cooling
To room temperature, filtering, 40ml methanol rinses are dried to obtain compound 61.2g shown in TD in 50 DEG C, and yield is 82.7%, and purity is
98.9%.
It should be noted that the foregoing is only presently preferred embodiments of the present invention, it is not intended to limit the invention, it is all
Any modification, equivalent and improvement for being made within the spirit and principles in the present invention etc., should be included in guarantor of the invention
Within the scope of shield.
Claims (8)
1. a kind of preparation method of compound shown in following formula TD, comprises the following steps：
(1) by compound IV and glycidol butyl ester back flow reaction in isopropanol, compound III is generated, is directly used in next
Step reaction,
(2) the compound III for obtaining step (1) and dicarbapentaborane imidazoles are in organic solvent dichloromethane, DMF, isopropanol or THF
In in 25 DEG C~40 DEG C reactions, generation compound I：
(3) by compound shown in following formula I and compound shown in Formula Il in the presence of palladium catalyst, chemical combination shown in reaction generation TD
Thing, described palladium catalyst is double (triphenylphosphine) palladiums (II) of dichloro, tetrakis triphenylphosphine palladium (0), palladium carbon, Pd (OAc) 2 or
PCy3/Pd2 (dba) 3 (dba=benzalacetones)：
Wherein, L is leaving group, R1It is BF3Or BR2R3, wherein R2And R3The independent C selected from by OH and any substitution1~C6One
Unit and the group of dihydroxylic alcohols composition, wherein R2And R3Together can be with cyclization.
2. method according to claim 1, wherein the leaving group L is selected from halogen, trifluoro-methanesulfonyl oxy, methylsulfonyl oxygen
Base, and the group that substituted or unsubstituted phenylsulfonyloxy group is constituted；The R1It is BF3、B(OH)2Or
3. method according to claim 2, wherein the leaving group L is selected from chlorine, bromine and iodine.
4. method according to claim 3, wherein, be added to palladium catalyst in organic solvent DMF by step (3), Ran Houjia
Enter triethylamine, 60~80 DEG C of stirrings add compound of formula I to be reacted with Formula II compound to dissolving, generation compound TD.
5. method according to claim 4, wherein the compound of formula I is reacted with Formula II compound, generates compound
TD, after reaction terminates, filters through diatomite while hot, and concentration adds purified water, is extracted with dichloromethane or ethyl acetate, anhydrous
Sodium sulphate is dried, filtering, is concentrated to give solid, to 50% methanol aqueous solution (volumetric concentration) is added in gained solid, is heated to
70 DEG C of mashing, are cooled to room temperature, filter, and methanol rinses are dried to obtain compound shown in high-purity TD in 50 DEG C.
6. a kind of method for preparing compound shown in following formula TD-P, it is characterised in that usage right 1~5 any side of requirement
Compound shown in the formula TD that method is prepared, with POCl3、POCl(OBn)2Or P (N-iPr2)(O-tBu)2Give birth at reaction conditions
Into：
7. method according to claim 6, it is characterised in that also including using compound shown in TD-P at reaction conditions with
Compound shown in alkali reaction generation following formula TD-PN
Wherein, M is PO (OH)2Pharmaceutically acceptable salt.
8. a kind of following formula: compound
Wherein, L is bromine or iodine.
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| CN106928214A (en) * | 2014-09-17 | 2017-07-07 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of Yi Zhong oxazolidinone compounds and its intermediate |
| CN104530128B (en) * | 2014-12-30 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | A kind of Tedizolid Phosphate disodium salt and preparation method thereof |
| CN104892592A (en) * | 2015-03-30 | 2015-09-09 | 成都惟新医药科技有限公司 | Preparation method for tedizolid |
| CN106146559B (en) * | 2015-04-10 | 2019-08-09 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of Oxazolidinone derivative |
| CN106279281B (en) * | 2015-05-15 | 2018-08-03 | 重庆圣华曦药业股份有限公司 | The process for purification of oxazolidone antibiotics safe ground azoles amine phosphate |
| CN106045934A (en) * | 2015-10-27 | 2016-10-26 | 博瑞生物医药（苏州）股份有限公司 | Crystal form of intermediate used for synthesis of tedizolid |
| CN106632298B (en) * | 2015-11-03 | 2021-06-01 | 上海科胜药物研发有限公司 | Preparation method and intermediate of tedizolid |
| CN105418681A (en) * | 2015-12-15 | 2016-03-23 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of tedizolid phosphate |
| CN107382995A (en) * | 2017-09-01 | 2017-11-24 | 杭州新博思生物医药有限公司 | One pot process safe ground azoles amine |
| CN111116652A (en) * | 2019-12-06 | 2020-05-08 | 山东中医药大学 | Preparation method of high-purity tedizolid phosphate |
| BR112022025918A2 (en) | 2020-06-18 | 2023-03-14 | Akagera Medicines Inc | OXAZOLIDINONE COMPOUNDS, LIPOSOMAL COMPOSITIONS COMPRISING OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF |
| CN112500433A (en) * | 2020-12-23 | 2021-03-16 | 桂林南药股份有限公司 | Preparation method of tedizolid phosphate |
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