CN116813643A - 一种手性氧桥噁唑辛杂环化合物及制备方法 - Google Patents
一种手性氧桥噁唑辛杂环化合物及制备方法 Download PDFInfo
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- CN116813643A CN116813643A CN202310557737.2A CN202310557737A CN116813643A CN 116813643 A CN116813643 A CN 116813643A CN 202310557737 A CN202310557737 A CN 202310557737A CN 116813643 A CN116813643 A CN 116813643A
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- -1 oxazolyl heterocyclic compound Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 239000003446 ligand Substances 0.000 claims abstract description 27
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 11
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 11
- 150000003624 transition metals Chemical class 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 239000003480 eluent Substances 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 8
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- ZQBFAOFFOQMSGJ-UHFFFAOYSA-N hexafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1F ZQBFAOFFOQMSGJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 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 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- 239000010948 rhodium Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 2
- KGUDSELBPWEAKU-UHFFFAOYSA-N 1,1,2,2-tetrafluoroethanol Chemical compound OC(F)(F)C(F)F KGUDSELBPWEAKU-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NXLACVVNHYIYJN-UHFFFAOYSA-N 1-phenyl-n-(1-phenylethyl)ethanamine Chemical compound C=1C=CC=CC=1C(C)NC(C)C1=CC=CC=C1 NXLACVVNHYIYJN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- VXFKMKXTPXVEMU-UHFFFAOYSA-N 2-diphenylphosphanyl-n-[2-[(2-diphenylphosphanylnaphthalene-1-carbonyl)amino]cyclohexyl]naphthalene-1-carboxamide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C=1C=CC2=CC=CC=C2C=1C(=O)NC1CCCCC1NC(=O)C(C1=CC=CC=C1C=C1)=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VXFKMKXTPXVEMU-UHFFFAOYSA-N 0.000 claims description 2
- HLHBIMJNCKZZQO-UHFFFAOYSA-N 4-phenyl-2-[6-(4-phenyl-4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound C1OC(C=2N=C(C=CC=2)C=2OCC(N=2)C=2C=CC=CC=2)=NC1C1=CC=CC=C1 HLHBIMJNCKZZQO-UHFFFAOYSA-N 0.000 claims description 2
- CSGQGLBCAHGJDR-UHFFFAOYSA-N 4-propan-2-yl-2-[6-(4-propan-2-yl-4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound CC(C)C1COC(C=2N=C(C=CC=2)C=2OCC(N=2)C(C)C)=N1 CSGQGLBCAHGJDR-UHFFFAOYSA-N 0.000 claims description 2
- DPMGLJUMNRDNMX-UHFFFAOYSA-N 4-tert-butyl-2-[2-(4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl)propan-2-yl]-4,5-dihydro-1,3-oxazole Chemical compound CC(C)(C)C1COC(C(C)(C)C=2OCC(N=2)C(C)(C)C)=N1 DPMGLJUMNRDNMX-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.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 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 claims description 2
- 239000012954 diazonium Substances 0.000 claims description 2
- OKUTYUNUKKPYJS-UHFFFAOYSA-N diphenyl-[2-(4-phenyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]phosphane Chemical compound C1OC(C=2C(=CC=CC=2)P(C=2C=CC=CC=2)C=2C=CC=CC=2)=NC1C1=CC=CC=C1 OKUTYUNUKKPYJS-UHFFFAOYSA-N 0.000 claims description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 claims description 2
- UEEXRMUCXBPYOV-UHFFFAOYSA-N iridium;2-phenylpyridine Chemical compound [Ir].C1=CC=CC=C1C1=CC=CC=N1.C1=CC=CC=C1C1=CC=CC=N1.C1=CC=CC=C1C1=CC=CC=N1 UEEXRMUCXBPYOV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims description 2
- OJLCQGGSMYKWEK-UHFFFAOYSA-K ruthenium(3+);triacetate Chemical compound [Ru+3].CC([O-])=O.CC([O-])=O.CC([O-])=O OJLCQGGSMYKWEK-UHFFFAOYSA-K 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 238000006352 cycloaddition reaction Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000000758 substrate Substances 0.000 abstract description 3
- 239000000376 reactant Substances 0.000 abstract description 2
- 230000036632 reaction speed Effects 0.000 abstract description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 7
- 238000007110 [4+3]-cycloaddition reaction Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- SYBXSZMNKDOUCA-UHFFFAOYSA-J rhodium(2+);tetraacetate Chemical compound [Rh+2].[Rh+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O SYBXSZMNKDOUCA-UHFFFAOYSA-J 0.000 description 6
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 3
- 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 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- RJDZFUUSXRDFCZ-UHFFFAOYSA-N 2h-oxazocine Chemical compound C1=CC=CONC=C1 RJDZFUUSXRDFCZ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical class C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
一种手性氧桥噁唑辛杂环化合物及制备方法,属于化合物的制备技术领域。化合物结构式
Description
技术领域
本发明涉及一种手性氧桥噁唑辛杂环化合物及制备方法,属于化合物的制备技术领域。
背景技术
噁唑辛杂环化合物具有独特的N,O-八元杂环片段,是优势的药物分子骨架,具有抗肿瘤、抗血栓、抗老年痴呆和抗炎等生物活性,可作为先导结构,用于各类靶向性药物的研制和开发。目前,文献报道的噁唑辛类似物大多为单环或苯环稠合结构,而杂环稠合的手性氧桥噁唑辛类似物报道极少,在区域选择性和立体选择性合成方面发展空间巨大。更需要指出的是,选取α-重氮羰基化合物和杂环亲偶极体和作为合成子,通过构建原创性的[4+3]环加成反应,区域选择性和立体选择性合成杂环稠合的手性氧桥噁唑辛类似物的方法学研究还完全没有文献报道。因此,选取α-重氮羰基化合物和吡唑啉酮为反应底物,设计和发展新型高效的环状羰基叶立徳中间体参与的手性[4+3]环加成反应,不仅能够丰富和发展过渡金属催化的α-重氮羰基化合物立体选择性有机合成方法学研究,而且为杂环稠合的手性氧桥噁唑辛类药性分子骨架的高效简洁构建提供了先进的有机合成方法和技术手段,有利于推动该类候选药物的研制和开发。
α-重氮羰基化合物是重要的多功能有机合成砌块,已广泛用于生物活性天然产物和类药性分子骨架的高效简洁构建。在过渡金属的催化作用下,α-重氮羰基化合物可脱去一分子氮气,原位生成游离卡宾或金属卡宾,这些卡宾可参与插入、环加成、偶联和重排等反应。尤为重要的是,原位生成的金属卡宾可通过和碳基官能团的亲电加成作用,产生高反应活性的环状羰基叶立徳。环状羰基叶立徳的环加成反应已成为构建各类含氧杂环的重要手段之一。目前,环状羰基叶立徳的环加成反应主要集中[3+2]环加成的研究,而用于构建中等杂环的[4+3]环加成的研究并不多见。该发明选取α-重氮羰基化合物和吡唑啉酮作为起始原料,通过构建基于环状羰基叶立徳合成子的[4+3]环加成反应,首次实现了类药性骨架手性氧桥噁唑辛类似物的非对映体选择性合成。该反应具有操作简单、化学收率高和非对映体选择性高等特点。通过该有机合成方法获得的手性氧桥噁唑辛类似物,骨架结构新颖独特,化学结构类药性极强,具有潜在的生物活性和药用开发价值。
发明内容
本发明目的在于提供一种手性氧桥噁唑辛杂环化合物及制备方法。
为达到上述发明目的,本发明采取的技术方案是:
该手性氧桥噁唑辛杂环化合物的结构式为:
其中,R1为氢原子、烷基、烷酰基中的一种;n代表环的大小,可为0,1,2,3,4。
上述的Ar1、Ar2为芳基,所述芳基是萘基、吡啶基、苯基或具有1~2个取代基的苯基。例如:一取代苯基、二取代苯基;上述苯基上的取代基选自:烷基、甲氧基、三氟甲基、氟、氯、溴、硝基中的一种或两种。烷基选自甲基、乙基、丙基、丁基等。
Ar1为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基等;Ar2为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴-苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基等;
上述手性氧桥噁唑辛杂环化合物的制备方法,所述制备方法为:以α-重氮羰基化合物、吡唑啉酮化合物为反应物,加入过渡金属催化剂以及含氮和/或膦配体,在极性为2-7的有机溶剂中,在一定温度条件下,得到该手性氧桥噁唑辛杂环化合物,目标产物的非对映体选择性和化学产率为均优秀;优选所述α-重氮羰基化合物、吡唑啉酮化合物的摩尔比为1.5:1。
上述技术方案中,所述有机溶剂为二氯甲烷、氯仿、四氢呋喃、1,2-二氯乙烷、苯、甲苯、二甲苯、三氟甲苯、氯苯、六氟苯、DMF、六氟异丙醇、三氟乙醇、四氟乙醇、乙腈、1,4-二氧六环、乙醚等。
上述技术方案中,所述过渡金属催化剂选自:四(三苯基膦)钯、醋酸钯、三(二亚苄基丙酮)二钯、三(二亚苄基丙酮)二钯-氯仿加合物、FAC-三(2-苯基吡啶)合铱、(三苯基膦)氯化金、辛酸铑聚合物、氯化金、醋酸钌、醋酸铑聚合物、六氟锑酸银、双(三氟甲烷磺酰基)酰亚银等其中的一种或几种;
含膦配体选自三苯基膦(PPh3)、三环己基膦(PCy3)、1,3-双(二苯基膦)丙烷(Dppp)、1,4-双(二苯基膦)丁烷(Dppb)、1,1'-双(二苯基膦)二茂铁(Dppf)等;
基于联二萘酚(BINOL)为骨架的手性磷酸配体或手性联萘型双磷配体(BINAP),例如:(±)-1,1'-联萘-2,2'-双二苯膦、(±)-1,1'-联萘-2,2'-双二苯膦等。
含氮配体选自(±)-N,N'-1,2-二氨基环己烷二基双(2-吡啶甲酰胺)、(±)-2,6-二[4-苯基-2-恶唑啉基]吡啶、(±)-2,2'-异丙叉双(4-特丁基-2-噁唑啉)、(±)-2,6-双(4-异丙基-2-恶唑啉-2-基)吡啶等。
含氮和膦配体选自(±)-(3,5-二氧杂-4-磷环庚并[2,1-a:3,4-a']二萘-4-基)双(1-苯基乙基)胺、(±)-(3,5-二氧杂-4-磷环庚并[2,1-a:3,4-a']二萘-4-基)双(1-苯基乙基)、(±)-1,2-二胺基环己基-N,N'-双(2'-二苯基磷基苯甲酰)、(±)-N,N'-双(2-二苯基膦基-1-萘酰基)-1,2-环己二胺、(±)-2-[2-(二苯基膦)苯基]-4-苯基-2-噁唑啉、(±)-2-[2-二苯基膦]苯基]-4-异丙基-2-噁唑啉等。
上述技术方案中,所述反应时间为1小时~4小时。
上述技术方案中,所述过渡金属催化剂用量为吡唑啉酮摩尔量的10%;含氮和/或膦配体的用量为吡唑啉酮摩尔量的20%。
上述技术方案中,反应过程包括向反应瓶中加入α-重氮羰基化合物、吡唑啉酮化合物以及有机溶剂,加入过渡金属催化剂和含氮和/或膦配体并搅拌,使用TLC监测反应进程,当吡唑啉酮消耗完,结束反应,将粗产物通过简单的柱层析分离(洗脱剂选为体积比2:1~5:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物。
本发明中,α-重氮羰基化合物的制备方法属于现有技术,其结构式如下所示:
R1为氢原子,烷基,酰基等;n代表环的大小,可为0,1,2,3,4。
本发明中,吡唑啉酮化合物的制备方法属于现有技术,其结构式如下所示:
Ar1为为芳基,如苯基、4-甲氧基-苯基、4-氟-苯基、4-氯-苯基、4-溴-苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基等;Ar2为苯基、4-甲氧基-苯基、4-氟-苯基、4-氯-苯基、4-溴-苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基等。
本发明公开的反应过程如下所示:
由于上述技术方案运用,本发明与现有技术相比具有下列优点:
1.本发明以α-重氮羰基化合物和吡唑啉酮化合物为合成砌块,在过渡金属和含氮和/或膦配体的协同催化作用下,通过构建环状羰基叶立徳的[4+3]环加成反应,实现了类药性分子骨架手性氧桥噁唑辛类似物的非对映体选择性合成。该合成方法具有高效简洁、操作简单、反应条件温和、化学产率高和立体选择性优秀等优点。
2.本发明所公开的制备方法中采用过渡金属和含氮和/或膦配体进行协同催化,反应速率快,区域选择性和立体选择性良好,分离纯化操作过程简单。
3.本发明所公开的方法对α-重氮羰基化合物和吡唑啉酮底物变换的普适性好,[4+3]环加成反应的反应速度、化学产率、区域和立体选择性均良好,实现了目标骨架结构的复杂性和多样性变化。
4.本发明所涉及的原料容易制备,成本低,无污染。
5.本发明构建的目标化合物类药性结构特征显著,具有潜在的生物活性及药用价值。
具体实施方式
下面结合实施例对本发明作进一步描述,但本发明并不限于以下实施例。
实施例1:
称取1a(29.2mg,0.15mmol)、2a(26.2mg,0.1mmol)溶于1.0mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),反应混合液用80℃油浴加热并搅拌,用TLC监测反应,待2a反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产endo/anti-3aa(43.4mg),化学产率为98%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.64(d,J=7.7Hz,2H),7.54-7.48(br,1H),7.45(t,J=7.6Hz,2H),7.30(t,J=7.4Hz,3H),7.28-7.25(br,1H)),7.20-7.14(br,1H),5.12(s,1H),3.92-3.81(m,1H),3.50-3.38(m,1H),2.68-2.56(m,1H),2.47-2.24(m,3H),2.16(s,3H),1.56(s,3H)ppm;13C NMR(100MHz,CDCl3):δ198.3,169.4,148.9,145.3,138.6,135.8,128.8,128.0,127.7,126.3,122.6,119.7,100.2,93.4,47.5,42.8,35.4,29.7,26.7,25.0,14.3ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C25H23N3O4430.1761;实测值430.1759.
实施例2:
称取1a(29.2mg,0.15mmol)、2b(34.0mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2b反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3ab(37.0mg),得率为73%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.63(d,J=8.7Hz,2H),7.47(s,1H),7.46(s,2H),7.44(s,1H),7.38(d,J=8.2Hz,1H),7.32(t,J=7.4Hz,1H),7.02(d,J=8.3Hz,1H),5.12(s,1H),3.93-3.84(m,1H),3.47-3.38(m,1H),2.67-2.56(m,1H),2.46-2.25(m,3H),2.59(s,3H)ppm;13C NMR(100MHz,CDCl3):δ198.1,169.3,148.6,145.3,138.5,135.2,131.2,131.1,128.8,126.4,122.6,121.8,120.0,99.7,93.1,46.3,42.9,35.4,26.4,25.0,14.4ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C25H22BrN3O4 508.0866;实测值508.0867.
实施例3:
称取1a(29.2mg,0.15mmol)、2c(29.6mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2c反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3ac(33.3mg),得率为72%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.60(dd,J=8.8,2.0Hz,2H),7.5-7.47(br,1H),7.41(dt,J=8.9,2.7Hz,2H),7.34-7.22(br,3H),7.18-7.08(br,1H),5.12(s,1H),3.91-3.81(m,1H),3.46-3.37(m,1H),2.64-2.56(m,1H),2.42-2.56(m,3H),2.15(s,3H),1.55(s,3H)ppm;13C NMR(100MHz,CDCl3):δ198.2,169.3,149.3,145.4,137.2,135.6,131.7,131.5,128.9,128.0,127.8,123.6,119.8,100.4,93.4,47.4,42.9,35.5,26.7,25.0,14.3ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C25H22ClN3O4464.1371;实测值464.1369.
实施例4:
称取1a(29.2mg,0.15mmol)、2d(27.6mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2d反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3ad(34.3mg),得率为73%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.50(d,J=8.4Hz,3H),7.36-7.26(br,2H),7.26(t,J=7.8Hz,3H),7.21-7.12(br,1H),5.12(s,1H),3.90-3.82(m,1H),3.45-3.37(m,1H),2.65-2.55(m,1H),2.41(s,3H),2.40-2.25(m,3H),2.15(s,3H)ppm;13C NMR(100MHz,CDCl3):δ198.5,169.4,148.6,145.3,136.2,135.9,131.5,129.7,129.4,128.6,127.7,122.7,120.0,100.0,93.5,47.6,42.8,35.5,26.8,25.0,21.1,14.3ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C26H25N3O4 444.1917;实测值444.1920.
实施例5:
称取1b(19.0mg,0.15mmol)、2b(34.2mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2b反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3bb(41.8mg),得率为90%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.63(d,J=7.8Hz,2H),7.53(dd,J=8.1,1.8Hz,1H),7.50-7.41(m,3H),7.31(d,J=7.4Hz,1H),7.25(dd,J=8.0,2.0Hz,1H),7.15(dd,J=8.4,2.1Hz,1H),4.74(dd,J=14.9,6.6Hz,2H),3.78-3.69(m,1H),3.35-3.27(m,1H),2.57-2.45(m,1H),2.36-2.21(m,3H),1.63(s,3H)ppm;13C NMR(100MHz,CDCl3):δ170.8,148.3,146.5,138.6,134.2,131.7,131.6,131.3,131.0,128.9,126.5,122.7,122.0,120.9,99.3,85.7,47.2,42.2,35.0,29.7,26.9,24.8,21.1,15.0,14.2ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C23H20BrN3O3 466.0760;实测值466.0769.
实施例6:
称取1c(27.4mg,0.15mmol)、2e(30.9mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2e反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3ce(39.0mg),得率为80%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ8.15(d,J=8.7Hz,2H),7.66(d,J=8.0Hz,2H),7.53(d,J=8.7Hz,2H),7.47(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H),4.95(s,1H),3.91(dd,J=13.2,4.5Hz,1H),2.79(d,J=13.2Hz,1H),2.56(td,J=13.0,3.0Hz,1H),2.03(d,J=13.5Hz,1H),1.98(s,6H),1.91(dd,J=13.3,4.1Hz,1H),1.86-1.68(m,2H),1.56-1.42(m,1H)ppm;13CNMR(100MHz,CDCl3):δ200.0,164.9,147.9,147.4,145.2,144.5,138.0,130.8,129.0,126.9,123.5,122.5,110.8,100.2,91.5,46.8,39.2,34.4,27.2,23.2,20.8,12.9ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C26H24N4O6489.1768;实测值489.1773.
实施例7:
称取1d(29.5mg,0.15mmol)、2b(34.2mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2b反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3db(32.1mg),得率为60%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.63(d,J=7.5Hz,2H),7.47(t,J=7.6Hz,2H),7.40(d,J=8.4Hz,2H),7.32(t,J=7.4Hz,1H),7.20(d,J=8.5Hz,2H),4.77(s,1H),3.86(dd,J=13.3,4.6Hz,1H),2.91-2.75(m,2H),2.37-2.29(m,1H),2.00(s,3H),1.97(s,3H),1.96-1.88(m,2H),1.79-1.71(m,1H),1.54-1.39(m,3H)ppm;13C NMR(100MHz,CDCl3):δ200.5,166.1,148.0,145.3,138.3,136.1,131.5,131.4,129.0,126.6,122.5,121.8,115.6,100.3,91.4,47.1,40.6,38.4,29.7,29.5,28.5,27.7,22.6,12.9ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C27H26BrN3O4 536.1179;实测值536.1189.
实施例8:
称取1e(31.6mg,0.15mmol)、2d(29.4mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2d反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3ed(42.5mg),得率为85%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.62(d,J=7.5Hz,2H),7.43(t,J=7.6Hz,2H),7.28(t,J=7.4Hz,1H),7.21(d,J=8.4Hz,2H),6.80(d,J=11.6Hz,2H),4.75(s,1H),3.76(s,3H),3.85(dt,J=14.4,4.0Hz,1H),2.78(td,J=11.9,3.5Hz,1H),2.64(dt,J=15.7,4.3Hz,1H),2.48(td,J=10.9,4.3Hz,1H),1.98(s,3H),1.97(s,3H),1.86-1.71(m,3H),1.70-1.55(m,3H),1.54-1.33(m,2H)ppm;13C NMR(100MHz,CDCl3):δ200.8,167.0,158.9,148.1,145.1,138.5,130.7,128.9,128.8,126.4,122.3,114.1,113.7,101.1,91.6,60.4,55.2,47.7,40.3,31.7,27.7,27.0,25.0,23.8,22.1,21.1,14.2,12.9ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C29H31N3O5 502.2336;实测值502.2341.
实施例9:
称取1C(27.4mg,0.15mmol)、2C(29.8mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2c反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3cc(38.1mg),得率为80%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.64(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,2H),7.33-7.22(m,5H),4.79(s,1H),3.89(dd,J=13.3,4.6Hz,1H),2.76(d,J=13.2Hz,1H),2.52(td,J=13.0,3.0Hz,1H),2.08(d,J=13.4Hz,1H),1.98(s,3H),1.94(s,3H),1.92-1.64(m,3H),1.57-1.39(m,1H)ppm;13C NMR(100MHz,CDCl3):δ200.3,165.4,148.7,145.2,136.9,136.5,132.0129.6,129.1,128.4,127.7,123.3,110.6,101.5,91.8,48.0,39.0,34.4,34.1,27.4,23.2,22.4,20.9,14.2,14.1,12.9ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C26H24ClN3O4 478.1528;实测值478.1532.
实施例10:
称取1c(27.4mg,0.15mmol)、2d(27.8mg,0.1mmol)溶于1mL干燥的1,2二氯乙烷,再加入二聚醋酸铑(4.4mg,0.01mmol)和配体(±)-2,2'-双(二苯膦基)-1,1'-联萘(12.4mg,0.02mmol),混合液在油浴80℃下搅拌,用TLC监测反应,待2d反应完全后,粗产物经过柱层析(洗脱剂选为体积比4:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物endo/anti-3cd(38.3mg),得率为84%。
目标物的表征及分析:白色固体,1H NMR(400MHz,CDCl3):δ7.53(d,J=8.4Hz,2H),7.31(td,J=8.5,1.6Hz,2H),7.29-7.22(m,5H),4.80(s,1H),3.89(dd,J=13.3,4.6Hz,1H),2.75(d,J=13.2Hz,1H),2.52(td,J=13.0,3.0Hz,1H),2.41(s,3H),2.04-1.99(m,1H),1.98(s,3H),1.94(s,3H),1.92-1.68(m,3H),1.53-1.39(m,1H)ppm;13C NMR(100MHz,CDCl3):δ200.6,165.5,147.9,145.0,136.8,136.4,135.8,129.7,129.5,128.3,127.6,122.4,110.3,101.0,91.9,60.4,48.0,38.9,34.4,27.4,23.3,21.1,20.8,14.2,12.9ppm;HRMS(ESI-TOF)m/z:[M+H]+理论计算值C27H27N3O4 458.2074;实测值458.2079.
以上结果可以看出,本发明公开的制备方法反应条件温和,后处理简单,立体选择性优秀,目标产物的化学产率均良好。
Claims (6)
1.一种手性氧桥噁唑辛杂环化合物,所述手性氧桥噁唑辛杂环化合物的结构式为:
其中,其中,R1为氢原子、烷基、烷酰基中的一种;n代表环的大小,为0,1,2,3,4;
Ar1为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基;Ar2为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴-苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基;烷基选自甲基、乙基、丙基、丁基。
2.制备权利要求1所述的一手性氧桥噁唑辛杂环化合物的制备方法,其特征在于:反应过程包括向反应瓶中加入α-重氮羰基化合物、吡唑啉酮化合物以及有机溶剂,加入过渡金属催化剂和含氮和/或膦配体,反应混合物在80℃油浴中搅拌,用TLC检测反应进程,当吡唑啉酮化合物消耗完时,结束反应,粗产物通过简单的柱层析分离(洗脱剂选为体积比2:1~5:1的石油醚/乙酸乙酯混合溶液)即可得到目标产物;
3.按照权利要求2所述的方法,其特征在于,所述α-重氮羰基化合物和吡唑啉酮化合物的摩尔比为1.5:1。
4.按照权利要求2所述的方法,其特征在于,有机溶剂为二氯甲烷、氯仿、四氢呋喃、1,2-二氯乙烷、苯、甲苯、二甲苯、三氟甲苯、氯苯、六氟苯、DMF、六氟异丙醇、三氟乙醇、四氟乙醇、乙腈、1,4-二氧六环、乙醚等。
5.按照权利要求2所述的方法,其特征在于,所述过渡金属催化剂选自:四(三苯基膦)钯、醋酸钯、三(二亚苄基丙酮)二钯、三(二亚苄基丙酮)二钯-氯仿加合物、FAC-三(2-苯基吡啶)合铱、(三苯基膦)氯化金、辛酸铑聚合物、氯化金、醋酸钌、醋酸铑聚合物、六氟锑酸银、双(三氟甲烷磺酰基)酰亚银等其中的一种或几种;
含膦配体选自三苯基膦(PPh3)、三环己基膦(PCy3)、1,3-双(二苯基膦)丙烷(Dppp)、1,4-双(二苯基膦)丁烷(Dppb)、1,1’-双(二苯基膦)二茂铁(Dppf);
基于联二萘酚(BINOL)为骨架的手性磷酸配体或手性联萘型双磷配体(BINAP),例如:(±)-1,1'-联萘-2,2'-双二苯膦、(±)-1,1'-联萘-2,2'-双二苯膦;
含氮配体选自(±)-N,N'-1,2-二氨基环己烷二基双(2-吡啶甲酰胺)、(±)-2,6-二[4-苯基-2-恶唑啉基]吡啶、(±)-2,2'-异丙叉双(4-特丁基-2-噁唑啉)、(±)-2,6-双(4-异丙基-2-恶唑啉-2-基)吡啶;
含氮和膦配体选自(±)-(3,5-二氧杂-4-磷环庚并[2,1-a:3,4-a']二萘-4-基)双(1-苯基乙基)胺、(±)-(3,5-二氧杂-4-磷环庚并[2,1-a:3,4-a']二萘-4-基)双(1-苯基乙基)、(±)-1,2-二胺基环己基-N,N'-双(2'-二苯基磷基苯甲酰)、(±)-N,N'-双(2-二苯基膦基-1-萘酰基)-1,2-环己二胺、(±)-2-[2-(二苯基膦)苯基]-4-苯基-2-噁唑啉、(±)-2-[2-二苯基膦]苯基]-4-异丙基-2-噁唑啉。
6.按照权利要求2所述的方法,其特征在于,α-重氮羰基化合物结构式如下所示:
R1为氢原子,烷基,酰基等;n代表环的大小,可为0,1,2,3,4。
本发明中,吡唑啉酮化合物化合物的制备方法属于现有技术,其结构式如下所示:
Ar1为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4溴苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基等;Ar2为苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、4-溴苯基、4-甲基苯基、4-硝基苯基,4-甲氧基苯基、2-甲氧基苯基、2-氯苯基、2-溴苯基、萘基、噻吩基等。
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