CN111808041B - 一种对二氟烷基的芳基噁唑烷酮类化合物及其制备方法 - Google Patents
一种对二氟烷基的芳基噁唑烷酮类化合物及其制备方法 Download PDFInfo
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- CN111808041B CN111808041B CN202010827489.5A CN202010827489A CN111808041B CN 111808041 B CN111808041 B CN 111808041B CN 202010827489 A CN202010827489 A CN 202010827489A CN 111808041 B CN111808041 B CN 111808041B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 aryl oxazolidinone compound Chemical class 0.000 title abstract description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 33
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 239000011574 phosphorus Substances 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 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 claims 3
- 125000003118 aryl group Chemical group 0.000 abstract description 20
- 229910052731 fluorine Inorganic materials 0.000 abstract description 6
- 239000011737 fluorine Substances 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 5
- 238000009509 drug development Methods 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 22
- 125000000217 alkyl group Chemical group 0.000 description 17
- 229910052736 halogen Inorganic materials 0.000 description 15
- 150000002367 halogens Chemical class 0.000 description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000004404 heteroalkyl group Chemical group 0.000 description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 8
- 238000012986 modification Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 description 2
- NCTCGHLIHJJIBK-UHFFFAOYSA-N 3-phenyl-1,3-oxazolidin-2-one Chemical compound O=C1OCCN1C1=CC=CC=C1 NCTCGHLIHJJIBK-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- LTVOKYUPTHZZQH-UHFFFAOYSA-N difluoromethane Chemical group F[C]F LTVOKYUPTHZZQH-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 238000006772 olefination reaction Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical group O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical compound O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- UPULOMQHYQDNNT-UHFFFAOYSA-N 5h-1,3-oxazol-2-one Chemical group O=C1OCC=N1 UPULOMQHYQDNNT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DDBBRNIXHXSDEL-UHFFFAOYSA-N P(=O)(O)(O)C=C1N=C2C=CC=CC2=C1 Chemical class P(=O)(O)(O)C=C1N=C2C=CC=CC2=C1 DDBBRNIXHXSDEL-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000002751 aliphatic alkane group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910021419 crystalline silicon Inorganic materials 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- ZXKWUYWWVSKKQZ-UHFFFAOYSA-N cyclohexyl(diphenyl)phosphane Chemical compound C1CCCCC1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZXKWUYWWVSKKQZ-UHFFFAOYSA-N 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DPYMFVXJLLWWEU-UHFFFAOYSA-N desflurane Chemical compound FC(F)OC(F)C(F)(F)F DPYMFVXJLLWWEU-UHFFFAOYSA-N 0.000 description 1
- 229960003537 desflurane Drugs 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007350 electrophilic reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 150000002941 palladium compounds Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 230000008685 targeting Effects 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
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- FQLSDFNKTNBQLC-UHFFFAOYSA-N tris(2,3,4,5,6-pentafluorophenyl)phosphane Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1P(C=1C(=C(F)C(F)=C(F)C=1F)F)C1=C(F)C(F)=C(F)C(F)=C1F FQLSDFNKTNBQLC-UHFFFAOYSA-N 0.000 description 1
- JQKHNBQZGUKYPX-UHFFFAOYSA-N tris(2,4,6-trimethoxyphenyl)phosphane Chemical compound COC1=CC(OC)=CC(OC)=C1P(C=1C(=CC(OC)=CC=1OC)OC)C1=C(OC)C=C(OC)C=C1OC JQKHNBQZGUKYPX-UHFFFAOYSA-N 0.000 description 1
- UYUUAUOYLFIRJG-UHFFFAOYSA-N tris(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 UYUUAUOYLFIRJG-UHFFFAOYSA-N 0.000 description 1
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明公开了一种对二氟烷基的芳基噁唑烷酮类化合物及其制备方法，本发明以本身就具有广泛生物活性的噁唑啉酮片段为导向基团，通过钯催化实现了芳基对位的二氟烷基化反应，高效、便捷地制得了一系列对位氟取代的芳基噁唑烷酮类衍生物，为进一步地药物开发奠定基础。
Description
技术领域
本发明涉及对二氟烷基芳基噁唑烷酮类化合物领域，特别是涉及一种对二氟烷基的芳基噁唑烷酮类化合物及其制备方法。
背景技术
噁唑烷酮骨架，广泛存在于具有生物活性的天然产物及药物分子中，例如抗菌药物利奈唑胺和泰迪唑啉，抗凝剂利伐沙班和抗抑郁药物托洛沙星。近年来关于此类杂环化合物的合成以及结构修饰受到广泛的关注，其骨架结构的修饰对于结构多样性也具有重要意义。
二氟亚甲基(CF2)，可作为亲脂性氢键供体提高生物活性分子的膜透性和结合亲和力，会显著改变分子的物理和生物活性，因此功能化的二氟甲基化芳烃是一类非常重要的化学结构，广泛存在于药物分子中，因此，通过有机合成在反应后期将氟烷基引入到具有生物活性的分子中显得尤为重要。
在过去的几十年中，热反应、亲电反应和光化学反应已被广泛地研究用于C-H氟烷基化反应。然而，多取代苯环上位置选择性引入氟烷基团的反应仍然很少见。因此发明一种高位置选择性氟烷基化反应显得尤为重要。
近年来，导向基团辅助的过渡金属催化的选择性C-H官能团化已经成为生物活性分子合成或结构修饰的重要策略。然而，大多数导向基团仅限于吡啶，嘧啶以及其他含氮的基团，此类导向基团比较难以消除或者转化，极大的限制了产物的多样性和后续的应用。而含有噁唑啉酮片段的化合物本身就是一类具有广泛生物活性化合物，以此结构作为导向基团进行结构修饰可以为药物的后阶段修饰提供一条方便快捷的路径。
目前，对于噁唑啉酮弱配位导向的碳氢官能化的报道很少，2005年Sanford教授报道了钯催化3-芳基噁唑烷酮邻位的芳基化反应。2016年，Frost课题组报道了钌催化的芳基噁唑烷酮邻位选择性烯基化反应。该类方法条件缓和，产率较高且化学选择性较好，但是这些反应仅限于芳基邻位的官能团化反应，且仅仅限于芳基化和烯基化反应，应用非常局限。而过渡金属催化弱配位导向基团辅助的芳基噁唑烷酮对位选择性二氟烷基化反应方法未见文献报道。
CF2CO2Et作为一种功能化的二氟甲基化基团，为各种含二氟亚甲基的生物活性化合物的转化提供了机会。传统上的合成二氟甲基化羧酸衍生物的方法是将二羰基化合物与SF4或三氟化二烷基胺(DAST或DeoxoFluor)还原(脱氧)氟化，这些合成路线不仅步骤多而且受到反应条件苛刻和官能团相容性差的限制。
因此，构建一种高效、便捷地合成对位氟取代的芳基噁唑烷酮类衍生物反应方法具有重要意义。
发明内容
本发明解决的主要技术问题是提供一种对二氟烷基的芳基噁唑烷酮类化合物及其制备方法，能高效合成一系列对二氟烷基的芳基噁唑烷酮类化合物。
为了解决上述的技术问题，本发明所采用的技术方案是：
提供一种化合物，一种化合物，其结构如式III所示：
Z选自C或O；
R1、R2每次出现时独立地选自H、卤素、硝基、羟基、巯基、氨基、氰基、酰基、酯基、酰胺基、非取代或取代的磺酰基、非取代或取代的烷基、非取代或取代的杂烷基、非取代或取代的环烷基、非取代或取代的杂环烷基、非取代或取代的芳基、非取代或取代的杂芳基、非取代或取代的酚氧基，其中，取代基选自卤素、硝基、羟基、巯基、氨基、氰基、酰胺基、酰基、磺酰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、酚氧基；
R3选自F、非取代或被氟取代的烷基；
R4选自烷基；
n选自0、1、2、3、4，m选自0、1、2、3、4；
上述基团的取代基选自卤素、硝基、羟基、巯基、氨基、氰基、酰胺基、酰基、磺酰基、烷基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、酚氧基。
“R1每次出现时独立地选自”，是指当限定R1数量的n大于1时，不同的R1可以选自相同或不同的基团。例如，n＝2，一个R1可以选自取代或非取代的烷基，另一个R1可以选自卤素；或者，n＝2，两个R1可以均选自取代或非取代的烷基；R2同理。
进一步地，R1每次出现时独立地选自H、卤素、氨基、氰基、酰基、酯基、酰胺基、非取代或取代的C1～C10烷基、非取代或取代的C1～C10杂烷基、非取代或取代的3～10元环烷基、非取代或取代的3～10元杂环烷基、非取代或取代的6～10元芳基、非取代或取代的5～6元杂芳基；
R2每次出现时独立地选自H、卤素、非取代或取代的C1～C10烷基、非取代或取代的C1～C10杂烷基、非取代或取代的3～10元环烷基、非取代或取代的3～10元杂环烷基、非取代或取代的6～10元芳基、非取代或取代的5～6元杂芳基；
上述基团的取代基选自于卤素、羟基、硝基、氨基、巯基、氰基、酯基、酰胺基、酰基、磺酰基、C1～C10烷基或杂烷基、3～10元环烷基或杂环烷基、芳基、杂芳基；
进一步地，
R1每次出现时独立地选自H、卤素、氨基、氰基、酰基、酯基、酰胺基、非取代或取代的C1～C6烷基、非取代或取代的C1～C6杂烷基、非取代或取代的3～6元环烷基、非取代或取代的3～6元杂环烷基；
R2每次出现时独立地选自H、卤素、非取代或取代的C1～C6烷基、非取代或取代的C1～C6杂烷基、非取代或取代的3～6元环烷基、非取代或取代的3～6元杂环烷基、非取代或取代的6～10元芳基、非取代或取代的5～6元杂芳基；
上述基团的取代基选自卤素、羟基、硝基、氨基、巯基、氰基、酯基、酰胺基、酰基、磺酰基、C1～C6烷基或杂烷基、3～6元环烷基或杂环烷基、芳基、杂芳基。
进一步地，R1每次出现时独立地选自H、卤素、氰基、非取代或取代的C1～C6烷基、非取代或取代的C1～C6杂烷基；
R2每次出现时独立地选自H、非取代或取代的C1～C6烷基、非取代或取代的C1～C6杂烷基、非取代或取代的6～10元芳基；
上述基团的取代基选自卤素、C1～C6烷基或杂烷基、芳基；
R3选自F、非取代或被氟取代的C1～C6烷基；
R4选自C1～C6烷基。
进一步地，R1每次出现时独立地选自H、卤素、氰基、非取代或取代的C1～C6烷基、非取代或取代的C1～C6烷氧基、非取代或取代的C1～C6烷硫基；
R2每次出现时独立地选自H、非取代或取代的C1～C6烷基、非取代或取代的苯基；
n选自0、1、2，m选自0、1、2；
上述基团的取代基选自卤素、C1～C6烷基或杂烷基、芳基；
R3选自F、非取代或被氟取代的C1～C3烷基；
R4选自C1～C3烷基。
进一步地，R1每次出现时独立地选自H、卤素、氰基、C1～C6烷基、甲氧基、MeS-、BnO-；
R2每次出现时独立地选自H、C1～C6烷基、
苄基、苯基、对氟苯基；
R3选自F、三氟甲基；
R4选自甲基、乙基。
在本发明的具体实施方式中，所述化合物选自如下结构之一：
本发明还提供了上述化合物的制备方法，包含以下内容：使化合物I与化合物II发生如下反应得到：
其中，Z，R1，R2，R3，R4，n，m如上述任一项中所定义；
进一步地，是将化合物I、化合物II、钯催化剂、配体、碱、溶剂混合；所述钯催化剂选自钯化合物和/或钯络合物；所述配体选自磷配体；
更进一步地，所述钯催化剂选自Pd(TFA)2、Pd(OAc)2、PdCl2、Pd2(dba)2、Pd(PPh3)4、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、1,3-双二苯基膦丙烷氯化钯、(2,2-联吡啶)二氯钯(II)中的一种或几种，优选Pd(TFA)2；
所述磷配体选自三苯基膦、三(4-甲氧基苯基)膦、二苯基环己基膦、三环己基膦、三(2-呋喃基)膦、1,1'-双(二苯基膦)二茂铁、4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,4-双(二苯基膦基)丁烷、三(2,4,6-三甲氧基苯基)磷、三(五氟苯基)膦、BINAP中的一种或几种，优选BINAP。
进一步地，所述化合物I：化合物II的摩尔比为1：1～7，优选1：2～5，更优选为1：4；
所述化合物I：钯催化剂的摩尔比为1：0.05～0.5，优选1：0.05～0.2，更优选为1：0.1；
所述化合物I：配体的摩尔比为1：0.1～1，优选1：0.1～0.5，更优选为1：0.2。
进一步地，所述碱选自K2CO3，KOAc，NaOAc，CsCO3，NaHCO3，Et3N中的一种或几种，优选碳酸钾；
进一步地，所述化合物I：碱的摩尔比为1：1～5，优选1：1～3，更优选为1：2。
进一步地，所述溶剂选自正己烷、TBME、CF3CH2OH、DCE、1,4-dioxane、CH3CN中的一种或几种，优选正己烷；进一步地，所述溶剂的用量为每毫摩尔化合物I使用溶剂2～6mL，优选4mL。
TBME是指甲基叔丁基醚，DCE是指1,2-二氯乙烷。
进一步地，反应的温度为100～160℃，优选140℃；
进一步地，所述反应在保护气体氛围下进行，所述保护气体为惰性气体和/或氮气。
在本发明的具体实施方式中，所述保护气体为氩气。
“烷基”，是指脂肪族烷烃基团，是饱和烃基。其中，烷基可以是直链烷基或支链烷基。
本发明中所使用的C1～Cn烷基包括C1～C2、C1～C3……C1～Cn。n是大于或等于一的整数，表示主链上的碳原子数。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等等。
“酰胺”是具有式-C(O)NHR或-NHC(O)R的化学结构，其中R选自烷基、环烷基、芳基。
“酰基”是具有式-C(O)R的化学结构，其中R选自烷基、环烷基、芳基。
“磺酰基”是指具有式-SO2R的化学结构，其中R选自烷基、非取代或取代的芳基。
“烷硫基”是指具有式-SR的化学结构，其中R选自烷基。
“环”是指任意的共价封闭结构，其中包括如下结构：碳环(如环烷基或芳基)、杂环(如杂环烷基或杂芳基)。环可以是单环、多环或任意取代的环。典型的多环一般有二环、三环。
“元”是指构成环的骨架原子的个数。其中，典型的3元环是环丙基；典型的5元环包括但不限环戊基、咪唑、噻唑、呋喃、吡咯和噻吩等；典型的6元环包括但不限苯、环己基、吡喃、吡啶、噻喃、哒嗪、吡嗪、嘧啶等。此外，骨架原子中含有杂原子的环，即为杂环；由杂环构成的非芳香性基团，为杂环烷基；由杂环构成的芳基，为杂芳基。
“杂烷基”是指含有杂原子的烷基，其中，杂原子包括但不限于N、O、S、P等；氨烷基、硫烷基、烷氧基等都属于杂烷基。
“杂原子”是指除了碳或氢以外的其它原子。杂原子可独立地选自于N、O、S、P或Si，但不限于此。
典型的杂环烷基包括但不限于：
典型的杂芳香基或杂芳基包括但不限于：
“芳香基”是指平面环具有离域的π电子系统且含有4n+2个π电子，n为整数。芳香基环可以由五、六、七、八、九或九个以上的原子构成，芳香基包括但不限于噻吩基、苯基、萘基、菲基等等。
“环烷基”是指单环或多环的烃基，其结构式中只含有原子和氢原子，可以是饱和的也可以是不饱和的。典型的环烷基结构包括但不限于：
“卤素”是指氟、氯、溴或碘。
文中所述的氨基、酯基、酰基、酰胺基、磺酰基等既可以是取代的也可以是非取代的。
本发明的有益效果是：
(1)本发明方法通过钯催化剂催化，采用噁唑烷酮做导向基，实现了芳基对位的二氟烷基化，为药物分子后期的合成、修饰提供了新的方法，为药物开发奠定了基础。
(2)本发明中噁唑烷酮骨架既作为导向基也作为活性分子的一部分，更高效、方便。
(3)本发明方法反应条件温和、操作简便易行，对具有各种官能团的底物兼容性高，底物耐受性好，衍生范围广，丰富了此类化合物的结构多样性。
(6)本发明化合物是一种含有噁唑烷酮和二氟烷基取代的多官能团化合物，可发生进一步官能团化，在合成具有生物活性的化合物中具有重要的应用价值。
具体实施方式
以下对本发明的技术方案进行清晰、完整地描述，显然，此处所描述的实施例仅是本发明中的一部分，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明的保护范围。
本发明实施例中所使用的化合物1可通过现有技术合成，参考文献：
[1]Mahy,W.；Plucinski,P.K.；Frost,C.G.Org.Lett.2014,16,5020-5023.
[2]Mallesham,B.；Rajesh,B.M.；Reddy,P.R.；Srinivas,D.；Trehan,S.Org.Lett.2003,5(7),963-965.
[3]Hosseinzadeh,R.；Tajbakhsh,M.；Mohadjerani,M.；Mehdinejad,H.Synlett.2004,9,1517-1520.
本发明实施例中所用的化合物2、催化剂、配体、溶剂等都可通过商业购买获得。
本发明系列C2-膦酰基亚甲基吲哚化合物的合成通式如下：
在本发明中部分缩写表示的含义如下：
Me：甲基；Et：乙基；Bn：苄基；
OTBS：(CH3)3C-Si(CH3)2-O-，叔丁基二甲基硅氧基；
BINAP：2,2'-双-(二苯膦基)-1,1'-联萘，结构如下：
实施例1对二氟烷基的芳基噁唑烷酮类化合物的合成
式中R1、R2的取代基个数不限。
将0.25mmol 3-芳基噁唑烷酮底物1和4equiv二氟溴乙酸乙酯2混合，加入10mol％催化剂、20mol％配体和2equiv碱到反应管中，在氩气保护下加入干燥的正己烷(1mL)，140℃反应24h得混合液体，反应结束后添加水和乙酸乙酯萃取三次，合并有机层，无水Na2SO4干燥有机层，过滤，浓缩，硅胶柱层析(石油醚/乙酸乙酯＝50/1—1/1)分离纯化得到对位二氟烷基化的芳基噁唑烷酮类化合物3。
按照以上方法，根据所需要合成的对位二氟烷基化芳基噁唑烷酮类化合物的具体结构式，选择相应的芳基噁唑烷酮类底物和二氟溴乙酸乙酯进行反应，如制备化合物3aa，反应物为1a和2a，反应式如下：
化合物3aa的制备:在反应管中加入3-苯基恶唑烷-2-酮(1a)(40.7mg,0.25mmol)，二氟溴乙酸乙酯(2a)(203.0mg,1.0mmol)，Pd(TFA)2(8.3mg,0.025mmol),BINAP(31.1mg,0.05mmol)，K2CO3(69.1mg,0.5mmol)，在氩气保护下加入干燥正己烷(1mL)，140℃反应24h得混合液体，反应结束后添加水和乙酸乙酯萃取三次，合并有机层，无水Na2SO4干燥有机层，过滤，浓缩，硅胶柱层析(石油醚/乙酸乙酯＝50/1—1/1)分离纯化得到3aa(63mg,88％)。
其余产物的反应物以此类推，通过带有不同取代基的底物1和2制得如下化合物3，产物和产率如下：
产物的结构鉴定：
Ethyl 2,2-difluoro-2-(4-(2-oxooxazolidin-3-yl)phenyl)acetate：1H NMR(600MHz)δ＝7.63(q,J＝9.0Hz,4H),4.52(t,J＝7.9Hz,2H),4.30(q,J＝7.2Hz,2H),4.09(t,J＝7.9Hz,2H),1.30(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.1(t,J＝35.6Hz),155.0,140.6,128.1(t,J＝26.3Hz),126.5(t,J＝5.8Hz),117.8,113.2(t,J＝252.0Hz),63.2,61.4,45.0,13.9.19F NMR(565MHz)δ＝-103.34(s).HR-MS(ESI)m/z calcd for:C13H14F2NO4 +[M+H+]286.0885,found 286.0878.
Ethyl 2,2-difluoro-2-(2-methyl-4-(2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.57(d,J＝8.6Hz,1H),7.49(s,1H),7.41(dd,J＝8.7,1.9Hz,1H),4.50(t,J＝7.9Hz,2H),4.31(q,J＝7.2Hz,2H),4.07(t,J＝7.9Hz,2H),2.44(s,3H),1.30(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.1(t,J＝35.3Hz),155.0,140.2,137.8,127.2(t,J＝8.8Hz),126.6(t,J＝23.9Hz),120.9,115.0,114.1(t,J＝251.9Hz),63.2,61.3,45.0,20.0,13.9.19FNMR(565MHz)δ＝-99.81(s).HR-MS(ESI)m/z calcd for:C14H16F2NO4 +[M+H+]300.1042,found 300.1036.
Ethyl 2,2-difluoro-2-(2-methoxy-4-(2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.72(s,1H),7.61(d,J＝8.6Hz,1H),6.79(dd,J＝8.4,1.9Hz,1H),4.50(t,J＝7.9Hz,2H),4.32(q,J＝7.2Hz,2H),4.05(t,J＝7.9Hz,2H),3.84(s,3H),1.30(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝34.2Hz),157.5,155.0,142.1,126.9(t,J＝7.3Hz),117.5(t,J＝24.8Hz),112.2(t,J＝248.0Hz),108.7,101.9,62.7,61.3,55.9,45.1,14.0.19FNMR(565MHz)δ＝-102.16(s).HR-MS(ESI)m/z calcd for:C14H16F2NO4 +[M+H+]316.0991,found 316.0987.
Ethyl 2,2-difluoro-2-(2-fluoro-4-(2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.65–7.59(m,2H),7.29(dd,J＝8.7,1.9Hz,1H),4.53(t,J＝7.9Hz,2H),4.35(q,J＝7.2Hz,2H),4.08(t,J＝7.9Hz,2H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝163.2(t,J＝34.2Hz),160.1(d,J＝251.4Hz),154.6,142.4(d,J＝10.9Hz),127.8,116.18–115.75(m),112.7(d,J＝2.6Hz),111.5(t,J＝250.9Hz),106.1(d,J＝26.5Hz),63.4,61.3,44.9,13.8.19F NMR(565MHz)δ＝-101.45(d,J＝7.9Hz),-111.68–-111.74(m).HR-MS(ESI)m/z calcd for:C13H13F3NO4 +[M+H+]304.0791,found304.0784.
Ethyl 2-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.78(d,J＝1.6Hz,1H),7.73(d,J＝8.8Hz,1H),7.52(dd,J＝8.7,2.2Hz,1H),4.53(t,J＝7.9Hz,2H),4.35(q,J＝7.2Hz,2H),4.08(t,J＝7.9Hz,2H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝163.1(t,J＝34.0Hz),154.6,141.3,132.8,128.0(t,J＝8.4Hz),126.3(t,J＝25.1Hz),119.5,115.6,112.1(t,J＝250.9Hz),63.4,61.4,44.8,13.8.19FNMR(565MHz)δ＝-101.69(s).HR-MS(ESI)m/z calcd for:C13H13ClF2NO4 +[M+H+]320.0496,found 320.0495.
Ethyl 2,2-difluoro-2-(2-(methylthio)-4-(2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.94(s,1H),7.66(d,J＝8.6Hz,1H),7.25(dd,J＝8.3,2.1Hz,1H),4.52(t,J＝7.9Hz,2H),4.34(q,J＝7.2Hz,2H),4.09(t,J＝7.9Hz,2H),2.46(s,3H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝163.8(t,J＝34.3Hz),154.9,140.8,138.4,128.1(t,J＝23.8Hz),127.1(t,J＝8.7Hz),119.3,114.7,113.0(t,J＝250.3Hz),63.1,61.4,44.9,18.1,13.9.19F NMR(565MHz)δ＝-98.84(s).HR-MS(ESI)m/z calcd for:C14H16F2NO4S+[M+H+]332.0763,found 332.0757.
Ethyl 2-(2-(benzyloxy)-4-(2-oxooxazolidin-3-yl)phenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.80(s,1H),7.62(d,J＝8.3Hz,1H),7.42–7.36(m,4H),7.34–7.30(m,1H),6.78(d,J＝8.3Hz,1H),5.11(s,2H),4.46(t,J＝7.9Hz,2H),4.06(q,J＝7.2Hz,2H),4.04(t,J＝7.9Hz,2H),1.12(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝33.9Hz),156.5(t,J＝4.1Hz),155.0,141.9,135.7,128.5,128.2,127.6,127.0(t,J＝7.4Hz),117.6(t,J＝24.6Hz),112.3(t,J＝249.0Hz),108.8,102.7,70.6,62.7,61.4,45.1,13.7.19F NMR(565MHz)δ＝-102.07(s).HR-MS(ESI)m/z calcd for:C20H20F2NO5 +[M+H+]392.1304,found 392.1299.
Ethyl 2,2-difluoro-2-(2-methoxy-6-methyl-4-(2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.50(s,1H),6.62(s,1H),4.47(t,J＝7.9Hz,2H),4.32(q,J＝7.2Hz,2H),4.04(t,J＝7.9Hz,2H),3.78(s,3H),2.51(t,J＝4.5Hz,3H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.4(t,J＝33.4Hz),158.2(t,J＝5.7Hz),155.0,141.0,140.1,123.1,114.3(t,J＝248.4Hz),113.3,99.8,62.6,61.3,56.1,45.0,21.6,14.0.19F NMR(565MHz)δ＝-95.76(s).HR-MS(ESI)m/z calcd for:C15H18F2NO5 +[M+H+]330.1148,found 330.1143.
Ethyl 2-(2,6-dimethyl-4-(2-oxooxazolidin-3-yl)phenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.25(s,2H),4.48(t,J＝7.9Hz,2H),4.31(q,J＝7.2Hz,2H),4.04(t,J＝7.9Hz,2H),2.47(t,J＝4.1Hz,6H),1.31(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.3(t,J＝35.6Hz),155.0,139.2,139.1,125.4(t,J＝22.7Hz),119.2,115.9(t,J＝253.3Hz),63.1,61.3,44.9,22.0(t,J＝5.7Hz),13.9.19F NMR(565MHz)δ＝-94.59(s).HR-MS(ESI)m/z calcd for:C15H18F2NO4 +[M+H+]314.1198,found 314.1194.
Ethyl 2-(2-chloro-6-methoxy-4-(2-oxooxazolidin-3-yl)phenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.68(s,1H),6.81(d,J＝1.9Hz,1H),4.52(t,J＝7.9Hz,2H),4.34(q,J＝7.2Hz,2H),4.06(t,J＝7.9Hz,2H),3.82(s,3H),1.33(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝163.7(t,J＝33.1Hz),159.1,154.7,141.6,134.5,114.8(t,J＝23.2Hz),112.5(t,J＝250.8Hz),112.4,100.4,62.8,61.4,56.5,44.8,14.0.19F NMR(565MHz)δ＝-97.25(s).HR-MS(ESI)m/z calcd for:C14H15ClF2NO5 +[M+H+]350.0601,found350.0594.
Ethyl 2,2-difluoro-2-(2-fluoro-6-methoxy-4-(2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.44(s,1H),6.63(dd,J＝13.1,1.8Hz,1H),4.52(t,J＝7.9Hz,2H),4.34(q,J＝7.2Hz,2H),4.05(t,J＝7.9Hz,2H),3.83(s,3H),1.33(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝163.6(t,J＝32.7Hz),161.5(d,J＝253.2Hz),158.9(d,J＝6.8Hz),154.6,142.4(d,J＝14.0Hz),112.1(t,J＝249.7Hz),105.3–104.8(m),98.4(d,J＝28.7Hz),97.3,62.9,61.3,56.5,44.9,14.0.19F NMR(565MHz)δ＝-98.46(d,J＝34.8Hz),-110.75–-110.95(m).HR-MS(ESI)m/z calcd for:C14H15F3NO5 +[M+H+]334.0897,found334.0891.
Ethyl 2-(2-cyano-6-methoxy-4-(2-oxooxazolidin-3-yl)phenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝8.07(s,1H),7.08(d,J＝2.1Hz,1H),4.57(t,J＝7.9Hz,2H),4.34(q,J＝7.2Hz,2H),4.11(t,J＝7.9Hz,2H),3.87(s,3H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝162.8(t,J＝33.1Hz),158.4,154.6,142.3,119.0(t,J＝23.8Hz),116.3,114.5,111.7,111.38(t,J＝253.5Hz),105.6,63.2,61.5,56.5,44.8,14.0.19F NMR(565MHz)δ＝-99.24(s).HR-MS(ESI)m/z calcd for:C15H15F2N2O5 +[M+H+]341.0944,found341.0940.
Ethyl 2,2-difluoro-2-(4-(2-oxopyrrolidin-1-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.73(d,J＝8.7Hz,2H),7.60(d,J＝8.8Hz,2H),4.29(q,J＝7.2Hz,2H),3.88(t,J＝7.0Hz,2H),2.63(t,J＝8.0Hz,2H),2.22–2.16(m,2H),1.30(t,J＝7.2Hz,3H).13CNMR(150MHz)δ＝174.6,164.2(t,J＝35.6Hz),141.7,128.3(t,J＝26.1Hz),126.2(t,J＝5.9Hz),119.4,113.3(t,J＝251.8Hz),63.1,48.5,32.8,17.9,13.9.19FNMR(565MHz)δ＝-103.42(s).HR-MS(ESI)m/z calcd for:C14H16F2NO3 +[M+H+]284.1093,found284.1089.
Ethyl 2,2-difluoro-2-(2-methoxy-4-(2-oxopyrrolidin-1-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.83(s,1H),7.60(d,J＝8.6Hz,1H),6.91(dd,J＝8.4,2.0Hz,1H),4.32(q,J＝7.2Hz,2H),3.89(t,J＝7.0Hz,2H),3.83(s,3H),2.64(t,J＝8.0Hz,2H),2.22–2.15(m,2H),1.30(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝174.7,164.1(t,J＝34.0Hz),157.2,143.2,126.6(t,J＝7.4Hz),117.7(t,J＝24.6Hz),112.2(t,J＝247.8Hz),110.2,103.4,62.7,55.8,48.7,33.0,17.8,14.0.19FNMR(565MHz)δ＝-102.15(s).HR-MS(ESI)m/z calcd for:C15H18F2NO4 +[M+H+]314.1198,found 314.1195.
Ethyl 2,2-difluoro-2-(2-methoxy-4-(5-methyl-2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.72(s,1H),7.60(d,J＝8.5Hz,1H),6.76(dd,J＝8.5,1.9Hz,1H),4.84–4.78(m,1H),4.32(q,J＝7.2Hz,2H),4.14(dd,J＝8.4,7.2Hz,1H),3.83(s,3H),3.64(dd,J＝8.4,7.2Hz,1H),1.55(d,J＝6.2Hz,3H),1.30(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝34.1Hz),157.4,154.6,142.2,126.8(t,J＝7.3Hz),117.3(t,J＝24.7Hz),112.2(t,J＝247.8Hz),108.6,101.9,69.7,62.7,55.9,51.8,20.7,14.0.19F NMR(565MHz)δ＝-102.13(d,J＝25.1Hz).HR-MS(ESI)m/z calcd for:C15H18F2NO5 +[M+H+]330.1148,found 330.1143.
Ethyl
2-(4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooxazolidin-3-yl)-2-methoxyphenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.75(s,1H),7.60(d,J＝8.5Hz,1H),6.78(dd,J＝8.4,1.8Hz,1H),4.73–4.67(m,1H),4.32(q,J＝7.2Hz,2H),4.06(dd,J＝8.6,5.7Hz,1H),3.98(dd,J＝8.6,5.7Hz,1H),3.92(dd,J＝11.2,4.0Hz,1H),3.83(s,3H),3.80(dd,J＝11.2,4.0Hz,1H),1.30(t,J＝7.2Hz,3H),0.85(s,9H),0.09(s,6H).13CNMR(150MHz)δ＝164.1(t,J＝34.0Hz),157.4,154.6,142.2,126.8(t,J＝7.2Hz),117.3(t,J＝24.6Hz),112.2(t,J＝247.8Hz),108.7,101.8,72.5,63.4,62.7,55.8,46.6,25.7,18.2,14.0,-5.4,-5.5.19F NMR(565MHz)δ＝-102.11(d,J＝3.4Hz).HR-MS(ESI)m/z calcdfor:C21H32F2NO6Si+[M+H+]460.1961,found 460.1959.
Ethyl 2-(4-(5,5-bis(4-fluorophenyl)-2-oxooxazolidin-3-yl)-2-methoxyphenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.68(s,1H),7.60(d,J＝8.5Hz,1H),7.44–7.39(m,4H),7.12–7.07(m,4H),6.79(dd,J＝8.7,2.0Hz,1H),4.58(s,2H),4.31(q,J＝7.2Hz,2H),3.83(s,3H),1.29(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝163.9(t,J＝34.1Hz),162.7(d,J＝248.8Hz),157.5,153.4,141.6,137.4(d,J＝2.6Hz),127.5(d,J＝8.3Hz),127.0(t,J＝7.2Hz),117.9(t,J＝24.9Hz),115.9(d,J＝21.9Hz),112.1(t,J＝247.9Hz),108.8,102.2,82.1,62.8,57.8,55.9,14.0.19F NMR(565MHz)δ＝-102.29(s),-112.34–-112.55(m).HR-MS(ESI)m/z calcd for:C26H22F4NO5 +[M+H+]504.1429,found504.1425.
Ethyl 2,3,3,3-tetrafluoro-2-(2-methoxy-4-(2-oxooxazolidin-3-yl)phenyl)propanoate:1H NMR(600MHz)δ＝7.74(s,1H),7.54(d,J＝8.4Hz,1H),6.79(dd,J＝8.7,2.0Hz,1H),4.50(t,J＝7.9Hz,2H),4.39–4.28(m,2H),4.08(t,J＝7.9Hz,2H),3.82(s,3H),1.30(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.2(d,J＝23.5Hz),157.9(d,J＝3.7Hz),155.0,141.8,128.8(d,J＝9.1Hz),121.7(qd,J＝285.4,30.0Hz),115.2(d,J＝21.6Hz),109.1,102.2,91.1(dq,J＝195.8,32.0Hz),62.8,61.4,56.0,45.1,14.0.19FNMR(565MHz)δ＝-75.44(d,J＝9.2Hz),-162.16(q,J＝9.0Hz).HR-MS(ESI)m/z calcd for:C15H16F4NO5 +[M+H+]366.0959,found 366.0953.
Ethyl
(R)-2,2-difluoro-2-(4-(4-isopropyl-2-oxooxazolidin-3-yl)-2-methoxyphenyl)acetate:1H NMR(600MHz)δ＝7.61(d,J＝8.4Hz,1H),7.55(s,1H),6.85(dd,J＝8.5,1.6Hz,1H),4.46(dd,J＝8.5,3.7Hz,1H),4.45–4.40(m,1H),4.33(q,J＝7.2Hz,2H),4.28(dd,J＝8.5,3.7Hz,1H),3.84(s,3H),2.28–2.21(m,1H),1.31(t,J＝6.9Hz,3H),0.94(d,J＝7.0Hz,3H),0.86(d,J＝6.7Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝34.0Hz),157.6,155.5,140.8,126.8(t,J＝7.4Hz),118.2(t,J＝24.2Hz),112.1(t,J＝248.1Hz),111.7,105.0,62.8,62.3,60.2,55.9,27.4,17.8,14.2,14.0.19F NMR(565MHz)δ＝-101.27(d,J＝273.3Hz),-103.07(d,J＝273.3Hz).HR-MS(ESI)m/z calcd for:C17H22F2NO5 +[M+H+]358.1461,found 358.1457.
Ethyl 2,2-difluoro-2-(2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.62(d,J＝8.5Hz,1H),7.53(s,1H),6.83(dd,J＝8.4,1.5Hz,1H),4.58(d,J＝4.6Hz,2H),4.33(q,J＝7.2Hz,2H),4.09–4.04(m,1H),3.83(s,3H),1.41(d,J＝5.4Hz,3H),1.31(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝34.0Hz),157.5,155.1,140.7,126.9(t,J＝7.3Hz),118.1(t,J＝24.5Hz),112.1(t,J＝248.3Hz),111.2,104.7,68.6,62.8,55.9,52.1,18.5,14.0.19F NMR(565MHz)δ＝-101.58(d,J＝273.3Hz),-102.77(d,J＝273.3Hz).HR-MS(ESI)m/z calcd for:C15H18F2NO5 +[M+H+]330.1148,found 330.1144.
Ethyl 2,2-difluoro-2-(2-methoxy-4-(2-oxo-4-phenyloxazolidin-3-yl)phenyl)acetate:1H NMR(600MHz)δ＝7.51(s,1H),7.44(d,J＝8.5Hz,1H),7.42–7.37(m,2H),7.37–7.28(m,3H),6.75(dd,J＝8.6,1.6Hz,1H),5.39(dd,J＝8.6,5.5Hz,1H),4.79(t,J＝8.7Hz,1H),4.29(q,J＝7.2Hz,2H),4.22(dd,J＝8.6,5.5Hz,1H),3.74(s,3H),1.27(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝34.1Hz),157.2,155.5,141.0,138.1,129.6,129.1,126.7(t,J＝7.2Hz),125.9,117.6(t,J＝24.6Hz),112.1(t,J＝248.1Hz),111.0,103.7,69.8,62.7,60.5,55.8,13.9.19F NMR(565MHz)δ＝-101.68(d,J＝273.3Hz),-102.64(d,J＝273.3Hz).HR-MS(ESI)m/z calcd for:C20H20F2NO5 +[M+H+]392.1304,found392.1300.
Ethyl(R)-2-(4-(4-benzyl-2-oxooxazolidin-3-yl)-2-methoxyphenyl)-2,2-difluoroacetate:1H NMR(600MHz)δ＝7.68(d,J＝8.5Hz,1H),7.63(s,1H),7.37–7.32(m,2H),7.28(dd,J＝13.3,5.8Hz,1H),7.14(d,J＝7.2Hz,2H),6.96(dd,J＝8.5,1.6Hz,1H),4.73–4.65(m,1H),4.39–4.32(m,3H),4.25(dd,J＝8.8,3.9Hz,1H),3.85(s,3H),3.20(dd,J＝13.9,3.1Hz,1H),2.82(dd,J＝13.9,9.3Hz,1H),1.32(t,J＝7.2Hz,3H).13C NMR(150MHz)δ＝164.0(t,J＝34.0Hz),157.7,155.0,140.7,134.9,129.2,129.1,127.5,127.1(t,J＝7.2Hz),118.2(t,J＝24.7Hz),112.1(t,J＝248.3Hz),110.9,104.5,65.9,62.8,57.0,55.9,37.6,14.0.19F NMR(565MHz)δ＝-101.58(d,J＝273.3Hz),-102.78(d,J＝273.3Hz).HR-MS(ESI)m/z calcd for:C21H22F2NO5 +[M+H+]406.1461,found406.1458.
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。
Claims (2)
1.式III化合物的制备方法，其特征在于，式III化合物结构如下：
所述式III化合物选自如下化合物中的任意一种：
所述制备方法为：
使化合物I与化合物II发生如下反应得到：
Z，R1，R2，R3，R4，n，m如上述式III化合物所定义；
将化合物I、化合物II、钯催化剂、磷配体、碱、溶剂混合制得式III化合物；所述钯催化剂为Pd(TFA)2；
所述磷配体为2,2'-双-(二苯膦基)-1,1'-联萘；碱为K2CO3；溶剂为正己烷；
所述化合物I：化合物II的摩尔比为1：4；
所述化合物I：钯催化剂的摩尔比为1：0.1；
所述化合物I：磷配体的摩尔比为1：0.2；所述化合物I：碱的摩尔比为1：2；所述溶剂的用量为每毫摩尔化合物I使用溶剂4mL；反应的温度为140℃；所述反应在保护气体氛围下进行，所述保护气体为惰性气体和/或氮气。
2.根据权利要求1所述的制备方法，其特征在于，所述保护气体为氩气。
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