CN114989072B - A method of asymmetric catalytic synthesis of chiral 1,4-dihydropyridine compounds and its application - Google Patents
A method of asymmetric catalytic synthesis of chiral 1,4-dihydropyridine compounds and its application Download PDFInfo
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- CN114989072B CN114989072B CN202210586317.2A CN202210586317A CN114989072B CN 114989072 B CN114989072 B CN 114989072B CN 202210586317 A CN202210586317 A CN 202210586317A CN 114989072 B CN114989072 B CN 114989072B
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- compound
- chiral
- otf
- triflate
- dihydropyridine
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- 238000000034 method Methods 0.000 title claims abstract description 22
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000007036 catalytic synthesis reaction Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- -1 2-substituted-3-oxo-butyrate Chemical class 0.000 claims abstract description 29
- 150000001412 amines Chemical class 0.000 claims abstract description 28
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims abstract description 20
- 229960005425 nitrendipine Drugs 0.000 claims abstract description 20
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims abstract description 19
- 229960003580 felodipine Drugs 0.000 claims abstract description 18
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims abstract description 17
- 229960000715 nimodipine Drugs 0.000 claims abstract description 17
- 150000002736 metal compounds Chemical class 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 11
- WYRSPTDNOIZOGA-UHFFFAOYSA-K neodymium(3+);trifluoromethanesulfonate Chemical compound [Nd+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WYRSPTDNOIZOGA-UHFFFAOYSA-K 0.000 claims description 11
- 238000001308 synthesis method Methods 0.000 claims description 9
- 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 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 2
- UCYRAEIHXSVXPV-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)indiganyl trifluoromethanesulfonate Chemical compound [In+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F UCYRAEIHXSVXPV-UHFFFAOYSA-K 0.000 claims description 2
- OSHOQERNFGVVRH-UHFFFAOYSA-K iron(3+);trifluoromethanesulfonate Chemical compound [Fe+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F OSHOQERNFGVVRH-UHFFFAOYSA-K 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 claims description 2
- BZQRBEVTLZHKEA-UHFFFAOYSA-L magnesium;trifluoromethanesulfonate Chemical compound [Mg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BZQRBEVTLZHKEA-UHFFFAOYSA-L 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JPJIEXKLJOWQQK-UHFFFAOYSA-K trifluoromethanesulfonate;yttrium(3+) Chemical compound [Y+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F JPJIEXKLJOWQQK-UHFFFAOYSA-K 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- FKOASGGZYSYPBI-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)alumanyl trifluoromethanesulfonate Chemical compound [Al+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F FKOASGGZYSYPBI-UHFFFAOYSA-K 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- GSOLWAFGMNOBSY-UHFFFAOYSA-N cobalt Chemical compound [Co][Co][Co][Co][Co][Co][Co][Co] GSOLWAFGMNOBSY-UHFFFAOYSA-N 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 20
- 239000003814 drug Substances 0.000 abstract description 20
- 239000000758 substrate Substances 0.000 abstract description 5
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 abstract description 4
- 229960000528 amlodipine Drugs 0.000 abstract description 4
- 230000018044 dehydration Effects 0.000 abstract description 4
- 238000006297 dehydration reaction Methods 0.000 abstract description 4
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 abstract description 4
- 229960000227 nisoldipine Drugs 0.000 abstract description 4
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 abstract description 3
- UKVYVZLTGQVOPX-IHWYPQMZSA-N (z)-3-aminobut-2-enoic acid Chemical compound C\C(N)=C\C(O)=O UKVYVZLTGQVOPX-IHWYPQMZSA-N 0.000 abstract description 3
- KJEBULYHNRNJTE-DHZHZOJOSA-N Cinalong Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC\C=C\C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KJEBULYHNRNJTE-DHZHZOJOSA-N 0.000 abstract description 3
- 229960002992 barnidipine Drugs 0.000 abstract description 3
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 abstract description 3
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 abstract description 3
- 229960004916 benidipine Drugs 0.000 abstract description 3
- 229960003020 cilnidipine Drugs 0.000 abstract description 3
- 229960004427 isradipine Drugs 0.000 abstract description 3
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 230000004913 activation Effects 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- YPMPTULBFPFSEQ-PLNGDYQASA-N ethyl (z)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)N YPMPTULBFPFSEQ-PLNGDYQASA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 5
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 5
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 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 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 229960005235 piperonyl butoxide Drugs 0.000 description 5
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000010276 construction Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- BVLXNPRUOXPBII-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)gallanyl trifluoromethanesulfonate Chemical compound [Ga+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BVLXNPRUOXPBII-UHFFFAOYSA-K 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- PHSMPGGNMIPKTH-UHFFFAOYSA-K cerium(3+);trifluoromethanesulfonate Chemical compound [Ce+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PHSMPGGNMIPKTH-UHFFFAOYSA-K 0.000 description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 2
- XSVCYDUEICANRJ-UHFFFAOYSA-K dysprosium(3+);trifluoromethanesulfonate Chemical compound [Dy+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F XSVCYDUEICANRJ-UHFFFAOYSA-K 0.000 description 2
- GLQOFBCJADYRKR-UHFFFAOYSA-K erbium(3+);trifluoromethanesulfonate Chemical compound [Er+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F GLQOFBCJADYRKR-UHFFFAOYSA-K 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- TWNOVENTEPVGEJ-UHFFFAOYSA-K europium(3+);trifluoromethanesulfonate Chemical compound [Eu+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F TWNOVENTEPVGEJ-UHFFFAOYSA-K 0.000 description 2
- DYOBTPTUHDTANY-UHFFFAOYSA-K gadolinium(3+);trifluoromethanesulfonate Chemical compound [Gd+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F DYOBTPTUHDTANY-UHFFFAOYSA-K 0.000 description 2
- DBPDCYACEYLEMY-UHFFFAOYSA-K holmium(3+);trifluoromethanesulfonate Chemical compound [Ho+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F DBPDCYACEYLEMY-UHFFFAOYSA-K 0.000 description 2
- NRMNRSCGHRWJAK-UHFFFAOYSA-K lutetium(3+);trifluoromethanesulfonate Chemical compound [Lu+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NRMNRSCGHRWJAK-UHFFFAOYSA-K 0.000 description 2
- DMFBPGIDUUNBRU-UHFFFAOYSA-N magnesium;bis(trifluoromethylsulfonyl)azanide Chemical compound [Mg+2].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F DMFBPGIDUUNBRU-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- DDCWGUIPLGMBPO-UHFFFAOYSA-K samarium(3+);trifluoromethanesulfonate Chemical compound [Sm+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F DDCWGUIPLGMBPO-UHFFFAOYSA-K 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- JLYAVYSVLLIWEK-UHFFFAOYSA-K terbium(3+);trifluoromethanesulfonate Chemical compound [Tb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F JLYAVYSVLLIWEK-UHFFFAOYSA-K 0.000 description 2
- PBASUZORNBYVFM-UHFFFAOYSA-K thulium(3+);trifluoromethanesulfonate Chemical compound [Tm+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PBASUZORNBYVFM-UHFFFAOYSA-K 0.000 description 2
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 2
- CMWINYFJZCARON-UHFFFAOYSA-N 6-chloro-2-(4-iodophenyl)imidazo[1,2-b]pyridazine Chemical compound C=1N2N=C(Cl)C=CC2=NC=1C1=CC=C(I)C=C1 CMWINYFJZCARON-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- 241000157855 Cinchona Species 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 1
- 229910018597 Ni(BF4)2 Inorganic materials 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- VFUSIQAHVPEYFD-UHFFFAOYSA-N bis(trifluoromethylsulfonyl)azanide;nickel(2+) Chemical compound [Ni+2].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F VFUSIQAHVPEYFD-UHFFFAOYSA-N 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
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- MPMSMUBQXQALQI-UHFFFAOYSA-N cobalt phthalocyanine Chemical compound [Co+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 MPMSMUBQXQALQI-UHFFFAOYSA-N 0.000 description 1
- RDLMYNHWUFIVQE-UHFFFAOYSA-L cobalt(2+);trifluoromethanesulfonate Chemical compound [Co+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RDLMYNHWUFIVQE-UHFFFAOYSA-L 0.000 description 1
- UQENANCFJGYGSY-UHFFFAOYSA-N copper;bis(trifluoromethylsulfonyl)azanide Chemical compound [Cu+2].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F UQENANCFJGYGSY-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- PGJLOGNVZGRMGX-UHFFFAOYSA-L iron(2+);trifluoromethanesulfonate Chemical compound [Fe+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PGJLOGNVZGRMGX-UHFFFAOYSA-L 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- WHGYCGOFTBFDLW-UHFFFAOYSA-L nickel(2+);diperchlorate;hexahydrate Chemical compound O.O.O.O.O.O.[Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O WHGYCGOFTBFDLW-UHFFFAOYSA-L 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ROUBZIWQWFQCHU-UHFFFAOYSA-K praseodymium(3+);trifluoromethanesulfonate Chemical compound [Pr+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F ROUBZIWQWFQCHU-UHFFFAOYSA-K 0.000 description 1
- YCKAGGHNUHZKCL-UHFFFAOYSA-N propan-2-yl 3-aminobut-2-enoate Chemical compound CC(C)OC(=O)C=C(C)N YCKAGGHNUHZKCL-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical group [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
-
- 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
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
Description
技术领域technical field
本发明属于化学合成技术领域，具体涉及一种不对称催化合成手性1,4-二氢吡啶化合物的方法及其应用。The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for asymmetric catalytic synthesis of chiral 1,4-dihydropyridine compounds and an application thereof.
背景技术Background technique
1,4-二氢吡啶化合物作为一种高效的钙离子通道阻滞剂而被广泛的用于心血管疾病的临床治疗，目前市面在售用于治疗高血压的1,4-二氢吡啶药物分子包括：非洛地平、氨氯地平、尼群地平、尼莫地平、尼索地平等，这类药物分子C-4位取代基的立体化学极大的影响该类结构的药理活性。因此，合成光学纯的1,4-二氢吡啶药物分子将有利于增强该类药物分子的临床治疗效果。目前，已公开了手性诱导、拆分以及不对称催化合成该类手性药物分子的策略。1,4-Dihydropyridine compounds are widely used in the clinical treatment of cardiovascular diseases as efficient calcium ion channel blockers. The 1,4-dihydropyridine drug molecules currently on the market for the treatment of hypertension include: felodipine, amlodipine, nitrendipine, nimodipine, nisoldipine, etc. The stereochemistry of the C-4 substituents of these drug molecules greatly affects the pharmacological activity of such structures. Therefore, the synthesis of optically pure 1,4-dihydropyridine drug molecules will be beneficial to enhance the clinical therapeutic effect of such drug molecules. Currently, strategies for chiral induction, resolution, and asymmetric catalytic synthesis of such chiral drug molecules have been published.
拆分：Split:
F.Dollé等人利用手性高效液相色谱(HPLC)实现了钙通道拮抗剂S11568的拆分反应，能分别以50％的收率得到两种构型的产物(Bioorg.Med.Chem.1997,5,749)；尹永梅和郗日沫等人利用手性超临界流体色谱(SFC)实现了对1,4-二氢吡啶药物分子的手性拆分，通过对流速以及溶剂的调节，完成了对尼莫地平、氨氯地平、阿折地平、贝尼地平、西尼地平、尼索地平和非洛地平药物分子的拆分(J.ofSupercriticalFluids2016,107,129)。F.Dollé et al. realized the resolution reaction of calcium channel antagonist S11568 by chiral high-performance liquid chromatography (HPLC), and obtained two configurations of products with a yield of 50% (Bioorg.Med.Chem.1997,5,749); Yin Yongmei and Xi Rimo et al. used chiral supercritical fluid chromatography (SFC) to realize the chiral resolution of 1,4-dihydropyridine drug molecules. By adjusting the flow rate and solvent, the Separation of nimodipine, amlodipine, azeldipine, benidipine, cilnidipine, nisoldipine and felodipine drug molecules (J.ofSupercriticalFluids2016, 107, 129).
S.P.Sonawane等人利用(+)-L-酒石酸盐对氨氯地平药物分子进行拆分(Org.Process Res.Dev.2010,14,640)。在该反应中，以DMF/水(v/v＝85:15)作为混合溶剂，(S)-氨氯地平与(+)-L-酒石酸盐以共结晶的形式析出，而(R)-氨氯地平则溶解在DMF/水混合溶液中。随后(S)-氨氯地平在异丙醇/水的混合溶剂中与苯磺酸在室温下即可转换成手性药物分子(S)-苯磺酸氨氯地平。S.P. Sonawane et al. used (+)-L-tartrate to resolve amlodipine drug molecules (Org. Process Res. Dev. 2010, 14, 640). In this reaction, DMF/water (v/v=85:15) was used as a mixed solvent, (S)-amlodipine and (+)-L-tartrate were precipitated in the form of co-crystals, while (R)-amlodipine was dissolved in the DMF/water mixed solution. Then (S)-amlodipine can be converted into a chiral drug molecule (S)-amlodipine besylate in a mixed solvent of isopropanol/water and benzenesulfonic acid at room temperature.
F.Rebolledo等人利用脂肪酶实现了1,4-二氢吡啶药物分子衍生物的动力学拆分(Tetrahedron2015,71,3976)。产物以34-51％的转换率得到58-98％ee对映选择性的水解产物。F. Rebolledo et al. used lipase to realize the kinetic resolution of 1,4-dihydropyridine drug molecule derivatives (Tetrahedron 2015, 71, 3976). The product was hydrolyzed with 58-98% ee enantioselectivity at 34-51% conversion.
手性诱导：Chiral induction:
S.Sundell课题组利用手性醇为原料，先后经历上保护基、酯化、加成脱水串联反应、去保护基、水解再酯化六步反应，以37％的收率得到手性felodipine药物分子(Tetrahedron Lett.1989,30,6423)。S. Sundell's research group used chiral alcohol as a raw material, and went through six steps of protecting group, esterification, addition and dehydration series reaction, removing protecting group, hydrolysis and re-esterification, and obtained chiral felodipine drug molecule with a yield of 37% (Tetrahedron Lett. 1989, 30, 6423).
H.-Y.Lee等人利用手性缩水甘油为起始原料，同样经历多步衍生，最终以22％的总收率得到(S)-felodipine(Tetrahedron2011,67,10222)。H.-Y.Lee et al. used chiral glycidol as a starting material, also underwent multi-step derivatization, and finally obtained (S)-felodipine with a total yield of 22% (Tetrahedron2011, 67, 10222).
不对称催化：Asymmetric Catalysis:
龚流柱等人利用手性联萘磷酸为催化剂、苯甲腈为溶剂、在50℃下反应24h，以31–93％的收率以及66–98％ee的对映选择性得到一系列手性1,4-二氢吡啶化合物(Angew.Chem.Int.Ed.2008,47,2458)。然而该类1,4-二氢吡啶产物难以转换成3,5-二羧酸酯基取代的手性1,4-二氢吡啶药物分子。Gong Liuzhu et al. used chiral binaphthyl phosphoric acid as a catalyst, benzonitrile as a solvent, and reacted at 50°C for 24 hours to obtain a series of chiral 1,4-dihydropyridine compounds with a yield of 31–93% and an enantioselectivity of 66–98% ee (Angew.Chem.Int.Ed.2008, 47, 2458). However, such 1,4-dihydropyridine products are difficult to convert into chiral 1,4-dihydropyridine drug molecules substituted with 3,5-dicarboxylate groups.
C.Bressy，X.Bugaut以及J.Rodriguez等人利用硫脲衍生物为手性有机小分子催化剂，二氯甲烷为反应溶剂，在37℃下反应24h，最终以25–71％的收率以及58–96％ee的对映选择性得到手性1,4-二氢吡啶化合物，该化合物结构同样难以转换为3,5-二羧酸酯取代的手性1,4-二氢吡啶药物分子(Angew.Chem.Int.Ed.2016,55,1401)。在氧化剂的作用下，该类1,4-二氢吡啶结构被氧化为吡啶，实现中心手性到轴手性的转变。C.Bressy, X.Bugaut and J.Rodriguez et al. used thiourea derivatives as chiral organic small molecule catalysts, dichloromethane as the reaction solvent, and reacted at 37°C for 24 hours, and finally obtained chiral 1,4-dihydropyridine compounds with a yield of 25–71% and an enantioselectivity of 58–96%ee. .Int.Ed.2016,55,1401). Under the action of an oxidizing agent, the 1,4-dihydropyridine structure is oxidized to pyridine, realizing the transformation from central chirality to axial chirality.
吴建一课题组利用金鸡纳碱衍生的手性小分子催化剂实现了尼群地平分子的不对称构建(AdvancedMaterialsResearch,2012,518-523,3943)。由于产物手性中心两端取代基分别为区分度较小的甲酯以及乙酯，因此该产物的手性控制较差，只能以41％ee的对映选择性得到尼群地平，且与该产物结构类似的其它1,4-二氢吡啶药物家族的不对称合成并未有涉及。Wu Jianyi's research group used cinchona base-derived chiral small molecule catalysts to realize the asymmetric construction of nitrendipine molecules (Advanced Materials Research, 2012, 518-523, 3943). Since the substituents at both ends of the chiral center of the product are methyl ester and ethyl ester with less discrimination, the chiral control of this product is poor, and nitrendipine can only be obtained with an enantioselectivity of 41% ee, and the asymmetric synthesis of other 1,4-dihydropyridine drug families similar to the product structure has not been involved.
综上所述，目前关于直接合成手性1,4-二氢吡啶药物分子及其衍生物的策略主要依靠拆分以及手性诱导。然而拆分最高只能做到50％的收率，原子经济性差；而手性诱导则需要提前制备底物，步骤冗长，收率较低，原子经济性差。虽然目前有一些小分子催化剂能够实现1,4-二氢吡啶化合物的不对称构建，并且有不错的手性控制，然而该类1,4-二氢吡啶化合物结构特殊，难以转换为真正的手性1,4-二氢吡啶药物分子。关于催化不对称合成手性1,4-二氢吡啶药物分子只有一例报道，但是手性控制较差，且只局限于尼群地平药物分子的合成。因此，有必要发展一种简单、高效、环境友好、底物普适性好的合成手性1,4-二氢吡啶化合物及其药物分子的方法。In summary, the current strategies for the direct synthesis of chiral 1,4-dihydropyridine drug molecules and their derivatives mainly rely on resolution and chiral induction. However, resolution can only achieve a maximum yield of 50%, which is poor in atom economy; while chiral induction needs to prepare substrates in advance, the steps are tedious, the yield is low, and atom economy is poor. Although there are currently some small molecule catalysts that can realize the asymmetric construction of 1,4-dihydropyridine compounds and have good chiral control, such 1,4-dihydropyridine compounds have special structures and are difficult to convert into real chiral 1,4-dihydropyridine drug molecules. There is only one report on the catalytic asymmetric synthesis of chiral 1,4-dihydropyridine drug molecules, but the chiral control is poor, and it is limited to the synthesis of nitrendipine drug molecules. Therefore, it is necessary to develop a method for synthesizing chiral 1,4-dihydropyridine compounds and their drug molecules that is simple, efficient, environmentally friendly and has good substrate universality.
发明内容Contents of the invention
本发明的目的在于通过2-取代-3-氧代丁酸酯与3-氨基巴豆酸酯的不对称1,4-加成/亲核加成/脱水串联反应一步构建1,4-二氢吡啶化合物，为合成一系列手性1,4-二氢吡啶药物分子提供一种高效、高选择性不对称催化新方法。The purpose of the present invention is to construct a 1,4-dihydropyridine compound in one step through the asymmetric 1,4-addition/nucleophilic addition/dehydration cascade reaction of 2-substituted-3-oxobutyrate and 3-aminocrotonate, and provide a new efficient and highly selective asymmetric catalytic method for synthesizing a series of chiral 1,4-dihydropyridine drug molecules.
本发明的目的是通过以下技术方案来实现的：The purpose of the present invention is achieved through the following technical solutions:
一种不对称催化合成手性1,4-二氢吡啶化合物的方法，包括以下步骤：A method for the asymmetric catalytic synthesis of chiral 1,4-dihydropyridine compounds, comprising the following steps:
以化合物Ⅰ和化合物Ⅱ为原料，手性氧化胺与金属化合物形成的配合物为催化剂，手性氧化胺与金属化合物在有机溶剂中搅拌即可形成配合物，优选的搅拌时间是10-60min，在有机溶剂中反应得到所述手性1,4-二氢吡啶化合物；Using compound I and compound II as raw materials, a complex formed by a chiral amine oxide and a metal compound as a catalyst, the chiral amine oxide and the metal compound are stirred in an organic solvent to form a complex, the preferred stirring time is 10-60 minutes, and the chiral 1,4-dihydropyridine compound is obtained by reacting in an organic solvent;
反应式如下：The reaction formula is as follows:
式中，R1为芳基、杂环芳基或烷基；In the formula, R 1 is an aryl group, a heterocyclic aryl group or an alkyl group;
R2为芳基、杂环芳基或烷基；R 2 is aryl, heterocyclic aryl or alkyl;
R3为芳基、杂环芳基或烷基；R 3 is aryl, heterocyclic aryl or alkyl;
R4为芳基、杂环芳基或烷基；R 4 is aryl, heterocyclic aryl or alkyl;
R5为芳基、杂环芳基或烷基；R is aryl , heterocyclic aryl or alkyl;
R1，R2，R3，R4，R5中所述芳基、杂环芳基或烷基分别被一个或多个各自独立的Rx的取代基取代；所述Rx为氢原子、卤素、烷基、氟取代基、硝基、氰基、酯基、烯基、炔基、烷氧基、取代氨基、芳基、羟基、氨基、酰胺基和磺酰胺中的一种或多种；R 1 , R 2 , R 3 , R 4 , R 5 said aryl, heterocyclic aryl or alkyl are respectively substituted by one or more independent substituents of R x ; said R x is one or more of hydrogen atom, halogen, alkyl, fluorine substituent, nitro, cyano, ester, alkenyl, alkynyl, alkoxy, substituted amino, aryl, hydroxyl, amino, amido and sulfonamide;
所述手性氧化胺的结构式为：The structural formula of the chiral amine oxide is:
中的一种或多种； one or more of
式中，R为烷基、芳基或杂环，所述烷基、芳基和杂环分别被一个或多个各自独立的Ry所取代；所述Ry为氢原子、烷基、烷氧基、酯基、芳基以及卤素中的一种或多种；m＝0～6；优选的，手性氧化胺为m＝1，R为2,3,4,5,6-Me5C6，记为L3-PiMe5；优选的，手性氧化胺为m＝1，R为2,6-Et2C6H3，记为L3-PeEt2；In the formula, R is an alkyl group, an aryl group or a heterocycle, and the alkyl group, aryl group and heterocycle are respectively substituted by one or more independent R y ; the R y is one or more of a hydrogen atom, an alkyl group, an alkoxy group, an ester group, an aryl group and a halogen; m=0~6; preferably, the chiral amine oxide is m=1, and R is 2,3,4,5,6-Me 5 C 6 , denoted as L 3 -PiMe 5 ; preferably, the chiral amine oxide is m =1, R is 2,6-Et 2 C 6 H 3 , denoted as L 3 -PeEt 2 ;
所述金属化合物为：三氟甲磺酸镁[Mg(OTf)2]、高氯酸镁[Mg(ClO4)2]、双(三氟甲基磺酰)亚胺镁[Mg(NTf2)2]、三氟甲磺酸钪[Sc(OTf)3]、三氟甲磺酸亚铁[Fe(OTf)2]、三氟甲磺酸铁[Fe(OTf)3]、三氟甲磺酸镍[Ni(OTf)2]、镍二(三氟甲基磺酰基)亚胺[Ni(NTf2)2]、六水合四氟硼酸镍[Ni(BF4)2]·6H2O、六水合高氯酸镍[Ni(ClO4)2]·6H2O、三氟甲磺酸铜[Cu(OTf)2]、双(三氟甲基磺酰基)酰亚胺铜[Cu(NTf2)2]、三氟甲磺酸锌[Zn(OTf)2]，三氟甲磺酸钇[Y(OTf)3]、三氟甲磺酸镧[La(OTf)3]、三氟甲磺酸铈[Ce(OTf)3]、三氟甲磺酸镨[Pr(OTf)3]、三氟甲磺酸钕[Nd(OTf)3]、三氟甲磺酸钐[Sm(OTf)3]、三氟甲磺酸铕[Eu(OTf)3]、三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸铽[Tb(OTf)3]、三氟甲磺酸镝[Dy(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸铒[Er(OTf)3]、三氟甲磺酸铥[Tm(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸镥[Lu(OTf)3]、三氟甲磺酸钴[Co(OTf)2]和双(三氟甲基磺酰基)亚钴[Co(NTf2)2]、三氟甲磺酸铝[Al(OTf)3]、三氟甲磺酸铟[In(OTf)3]、三氟甲磺酸镓[Ga(OTf)3]中的一种或多种。The metal compound is: magnesium trifluoromethanesulfonate [Mg(OTf)2], magnesium perchlorate [Mg(ClO4)2], magnesium bis(trifluoromethylsulfonyl)imide [Mg(NTf2)2], scandium trifluoromethanesulfonate [Sc(OTf)3], ferrous trifluoromethanesulfonate [Fe(OTf)2], iron trifluoromethanesulfonate [Fe(OTf)3], nickel trifluoromethanesulfonate [Ni(OTf)2], nickel bis(trifluoromethylsulfonyl)imide [Ni(NTf2)2], nickel tetrafluoroborate hexahydrate [Ni(BF4)2]·6H2O, nickel perchlorate hexahydrate [Ni(ClO4)2]·6H2O, copper trifluoromethanesulfonate [Cu(OTf)2], bis(trifluoromethylsulfonyl)imide copper [Cu(NTf2)2], zinc trifluoromethanesulfonate [Zn(OTf)2], yttrium triflate [Y(OTf)3], lanthanum trifluoromethanesulfonate [La(OTf)3], cerium trifluoromethanesulfonate [Ce(OTf)3], praseodymium trifluoromethanesulfonate [Pr(OTf)3], neodymium trifluoromethanesulfonate [Nd(OTf)3], samarium trifluoromethanesulfonate [Sm(OTf)3], europium trifluoromethanesulfonate [Eu(OTf)3], gadolinium trifluoromethanesulfonate [Gd(OTf)3], terbium trifluoromethanesulfonate [Tb(OTf)3], dysprosium trifluoromethanesulfonate [Dy(OTf)3], holmium trifluoromethanesulfonate [Ho(OTf)3], erbium trifluoromethanesulfonate [Er(OTf)3], thulium trifluoromethanesulfonate [Tm(OTf)3], ytterbium trifluoromethanesulfonate [Yb(OTf)3], lutetium trifluoromethanesulfonate [Lu(OTf)3], cobalt trifluoromethanesulfonate [Co(OTf)2] and bis(trifluoromethylsulfonyl)cobaltous [Co(NTf2)2], aluminum trifluoromethanesulfonate [Al(OTf)3], indium trifluoromethanesulfonate [In(OTf)3], gallium trifluoromethanesulfonate [Ga(OTf)3] in one or more.
进一步的，式中，Further, in the formula,
R1为C6H5，2F-C6H4，3F-C6H4，4F-C6H4，2CF3-C6H4，2CF3-C6H4，2CF3-C6H4，2Cl-C6H4，3Cl-C6H4，4Cl-C6H4，2BrC6H4，3BrC6H4，4BrC6H4，2Me-C6H4，3Me-C6H4，4Me-C6H4，2OMe-C6H4，3OMe-C6H4，4OMe-C6H4，2NO2-C6H4，3NO2-C6H4，4NO2-C6H4，4OEt-C6H4，4Ph-C6H4，2CN-C6H4，3CN-C6H4，4CN-C6H4，2CO2Me-C6H4，3CO2Me-C6H4，4CO2Me-C6H4，3,4-Me2-C6H3，3Cl-4F-C6H3，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl2-C6H3，2NMe2C6H4，3NMe2C6H4，4NMe2C6H4，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl，R1for C6h5, 2F-C6h4, 3F-C6h4, 4F-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2Cl-C6h4, 3Cl-C6h4, 4Cl-C6h4, 2BrC6h4, 3BrC6h4, 4BrC6h4, 2Me-C6h4, 3Me-C6h4, 4Me-C6h4, 2OMe-C6h4, 3OMe-C6h4, 4OMe-C6h4, 2NO2-C6h4, 3NO2-C6h4, 4NO2-C6h4, 4OEt-C6h4, 4Ph-C6h4, 2CN-C6h4, 3CN-C6h4, 4CN-C6h4, 2CO2Me-C6h4, 3CO2Me-C6h4, 4CO2Me-C6h4, 3,4-Me2-C6h3, 3Cl-4F-C6h3, 2-Thienyl, 3-Thienyl, Piperonyl, 2-Naphthyl, 1-Naphthyl, 2,3-Cl2-C6h3, 2NMe2C6h4, 3NMe2C6h4, 4NMe2C6h4, 4-(Methylsulfonyl)-benzonyl, 2-(Methylsulfonyl)-benzonyl,
3-(Methylsulfonyl)-benzenyl，Me，Et，Isopropyl，Tertiarybutyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl， 3-(Methylsulfonyl)-benzonyl, Me, Et, Isopropyl, Tertiarybutyl, Isobutyl, Cyclopropyl, Cyclopentyl, Cyclohexyl, Cycloheptyl,
和/或，R2为CH3，Et，Isopropyl，Tertiarybutyl，Isobutyl，C6H5,2F-C6H4，3F-C6H4，4F-C6H4，2CF3-C6H4，2CF3-C6H4，2CF3-C6H4，2Cl-C6H4，3Cl-C6H4，4Cl-C6H4，2BrC6H4，3BrC6H4，4BrC6H4，2Me-C6H4，3Me-C6H4，4Me-C6H4，2OMe-C6H4，3OMe-C6H4，4OMe-C6H4，2NO2-C6H4，3NO2-C6H4，4NO2-C6H4，4OEt-C6H4，4Ph-C6H4，2CN-C6H4，3CN-C6H4，4CN-C6H4，2CO2Me-C6H4，3CO2Me-C6H4，4CO2Me-C6H4，3,4-Me2-C6H3，3Cl-4F-C6H3，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl2-C6H3，2NMe2C6H4，3NMe2C6H4，4NMe2C6H4，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl，3-(Methylsulfonyl)-benzenyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，CH2CO2 nPr，C2H4OMe， and/or, R2for CH3, Et, Isopropyl, Tertiarybutyl, Isobutyl, C6h5,2F-C6h4, 3F-C6h4, 4F-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2Cl-C6h4, 3Cl-C6h4, 4Cl-C6h4, 2BrC6h4, 3BrC6h4, 4BrC6h4, 2Me-C6h4, 3Me-C6h4, 4Me-C6h4, 2OMe-C6h4, 3OMe-C6h4, 4OMe-C6h4, 2NO2-C6h4, 3NO2-C6h4, 4NO2-C6h4, 4OEt-C6h4, 4Ph-C6h4, 2CN-C6h4, 3CN-C6h4, 4CN-C6h4, 2CO2Me-C6h4, 3CO2Me-C6h4, 4CO2Me-C6h4, 3,4-Me2-C6h3, 3Cl-4F-C6h3, 2-Thienyl, 3-Thienyl, Piperonyl, 2-Naphthyl, 1-Naphthyl, 2,3-Cl2-C6h3, 2NMe2C6h4, 3NMe2C6h4, 4NMe2C6h4, 4-(Methylsulfonyl)-benzonyl, 2-(Methylsulfonyl)-benzonyl, 3-(Methylsulfonyl)-benzonyl, Cyclopropyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, CH2CO2 noPr, C2h4OMe,
和/或，R3为CH3，Et，Isopropyl，Tertiarybutyl，Isobutyl，C2H4OMe，C6H5,2F-C6H4，3F-C6H4，4F-C6H4，2CF3-C6H4，2CF3-C6H4，2CF3-C6H4，2Cl-C6H4，3Cl-C6H4，4Cl-C6H4，2BrC6H4，3BrC6H4，4BrC6H4，2Me-C6H4，3Me-C6H4，4Me-C6H4，2OMe-C6H4，3OMe-C6H4，4OMe-C6H4，2NO2-C6H4，3NO2-C6H4，4NO2-C6H4，4OEt-C6H4，4Ph-C6H4，2CN-C6H4，3CN-C6H4，4CN-C6H4，2CO2Me-C6H4，3CO2Me-C6H4，4CO2Me-C6H4，3,4-Me2-C6H3，3Cl-4F-C6H3，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl2-C6H3，2NMe2C6H4，3NMe2C6H4，4NMe2C6H4，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl，3-(Methylsulfonyl)-benzenyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl， and/or, R3for CH3, Et, Isopropyl, Tertiarybutyl, Isobutyl, C2h4OMe, C6h5,2F-C6h4, 3F-C6h4, 4F-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2Cl-C6h4, 3Cl-C6h4, 4Cl-C6h4, 2BrC6h4, 3BrC6h4, 4BrC6h4, 2Me-C6h4, 3Me-C6h4, 4Me-C6h4, 2OMe-C6h4, 3OMe-C6h4, 4OMe-C6h4, 2NO2-C6h4, 3NO2-C6h4, 4NO2-C6h4, 4OEt-C6h4, 4Ph-C6h4, 2CN-C6h4, 3CN-C6h4, 4CN-C6h4, 2CO2Me-C6h4, 3CO2Me-C6h4, 4CO2Me-C6h4, 3,4-Me2-C6h3, 3Cl-4F-C6h3, 2-Thienyl, 3-Thienyl, Piperonyl, 2-Naphthyl, 1-Naphthyl, 2,3-Cl2-C6h3, 2NMe2C6h4, 3NMe2C6h4, 4NMe2C6h4, 4-(Methylsulfonyl)-benzonyl, 2-(Methylsulfonyl)-benzonyl, 3-(Methylsulfonyl)-benzonyl, Cyclopropyl, Cyclopentyl, Cyclohexyl, Cycloheptyl,
和/或，R4为CH3，Et，Isopropyl，Tertiarybutyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，C6H5,2F-C6H4，3F-C6H4，4F-C6H4，2CF3-C6H4，2CF3-C6H4，2CF3-C6H4，2Cl-C6H4，3Cl-C6H4，4Cl-C6H4，2BrC6H4，3BrC6H4，4BrC6H4，2Me-C6H4，3Me-C6H4，4Me-C6H4，2OMe-C6H4，3OMe-C6H4，4OMe-C6H4，2NO2-C6H4，3NO2-C6H4，4NO2-C6H4，4OEt-C6H4，4Ph-C6H4，2CN-C6H4，3CN-C6H4，4CN-C6H4，2CO2Me-C6H4，3CO2Me-C6H4，4CO2Me-C6H4，3,4-Me2-C6H3，3Cl-4F-C6H3，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl2-C6H3，2NMe2C6H4，3NMe2C6H4，4NMe2C6H4，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl或3-(Methylsulfonyl)-benzenyl；and/or, R4for CH3, Et, Isopropyl, Tertiarybutyl, Isobutyl, Cyclopropyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, C6h5,2F-C6h4, 3F-C6h4, 4F-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2CF3-C6h4, 2Cl-C6h4, 3Cl-C6h4, 4Cl-C6h4, 2BrC6h4, 3BrC6h4, 4BrC6h4, 2Me-C6h4, 3Me-C6h4, 4Me-C6h4, 2OMe-C6h4, 3OMe-C6h4, 4OMe-C6h4, 2NO2-C6h4, 3NO2-C6h4, 4NO2-C6h4, 4OEt-C6h4, 4Ph-C6h4, 2CN-C6h4, 3CN-C6h4, 4CN-C6h4, 2CO2Me-C6h4, 3CO2Me-C6h4, 4CO2Me-C6h4, 3,4-Me2-C6h3, 3Cl-4F-C6h3, 2-Thienyl, 3-Thienyl, Piperonyl, 2-Naphthyl, 1-Naphthyl, 2,3-Cl2-C6h3, 2NMe2C6h4, 3NMe2C6h4, 4NMe2C6h4, 4-(Methylsulfonyl)-benzonyl, 2-(Methylsulfonyl)-benzonyl or 3-(Methylsulfonyl)-benzonyl;
和/或，R5为CH3，Et，Isopropyl，Tertiary butyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，C6H5,2F-C6H4，3F-C6H4，4F-C6H4，2CF3-C6H4，2CF3-C6H4，2CF3-C6H4，2Cl-C6H4，3Cl-C6H4，4Cl-C6H4，2BrC6H4，3BrC6H4，4BrC6H4，2Me-C6H4，3Me-C6H4，4Me-C6H4，2OMe-C6H4，3OMe-C6H4，4OMe-C6H4，2NO2-C6H4，3NO2-C6H4，4NO2-C6H4，4OEt-C6H4，4Ph-C6H4，2CN-C6H4，3CN-C6H4，4CN-C6H4，2CO2Me-C6H4，3CO2Me-C6H4，4CO2Me-C6H4，3,4-Me2-C6H3，3Cl-4F-C6H3，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl2-C6H3，2NMe2C6H4，3NMe2C6H4，4NMe2C6H4，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl或3-(Methylsulfonyl)-benzenyl。And/or, R 5 is CH 3 , Et，Isopropyl，Tertiary butyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，C 6 H 5 ,2F-C 6 H 4 ，3F-C 6 H 4 ，4F-C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2Cl-C 6 H 4 ，3Cl-C 6 H 4 ，4Cl-C 6 H 4 ，2BrC 6 H 4 ，3BrC 6 H 4 ，4BrC 6 H 4 ，2Me-C 6 H 4 ，3Me-C 6 H 4 ，4Me-C 6 H 4 ，2OMe-C 6 H 4 ，3OMe-C 6 H 4 ，4OMe-C 6 H 4 ，2NO 2 -C 6 H 4 ，3NO 2 -C 6 H 4 ，4NO 2 -C 6 H 4 ，4OEt-C 6 H 4 ，4Ph-C 6 H 4 ，2CN-C 6 H 4 ，3CN-C 6 H 4 ，4CN-C 6 H 4 ，2CO 2 Me-C 6 H 4 ，3CO 2 Me-C 6 H 4 ，4CO 2 Me-C 6 H 4 ，3,4-Me 2 -C 6 H 3 ，3Cl-4F-C 6 H 3 ，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl 2 -C 6 H 3 ，2NMe 2 C 6 H 4 ，3NMe 2 C 6 H 4 ，4NMe 2 C 6 H 4 ，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl或3-(Methylsulfonyl)-benzenyl。
进一步的，所述化合物Ⅰ与化合物Ⅱ的摩尔比为1:0.5-5；优选的，所述化合物Ⅰ与化合物Ⅱ的摩尔比为1:1.2；Further, the molar ratio of compound I to compound II is 1:0.5-5; preferably, the molar ratio of compound I to compound II is 1:1.2;
和/或，所述化合物Ⅰ与催化剂的摩尔比为1:0.01-1；优选的，所述化合物Ⅰ与催化剂的摩尔比为1:0.1；And/or, the molar ratio of the compound I to the catalyst is 1:0.01-1; preferably, the molar ratio of the compound I to the catalyst is 1:0.1;
和/或，所述手性氧化胺与金属化合物的摩尔比为0.5-2:1；优选的，所述手性氧化胺与金属化合物的摩尔比为1:1。And/or, the molar ratio of the chiral amine oxide to the metal compound is 0.5-2:1; preferably, the molar ratio of the chiral amine oxide to the metal compound is 1:1.
进一步的，当所述化合物Ⅰ和化合物Ⅱ反应时，且R1不为2-Ar时，还使用有添加剂NaBAr4 F；2-Ar的含义为2-位有取代基的芳基，即式中N表示取代基。Further, when the compound I and compound II are reacted, and R 1 is not 2-Ar, an additive NaBAr 4 F is also used; 2-Ar means an aryl group with a substituent at the 2-position, namely In the formula, N represents a substituent.
更进一步的，使用NaBAr4 F的作用为：标准反应不添加添加剂NaBAr4 F也可以反应，也有较好的手性控制，只是加了添加剂后产物ee值更高。NaBAr4 F的加入可能主要起到抗衡离子交换的作用，它可以帮助催化剂形成更好的手性环境，更好的屏蔽反应的其中一个面，实现产物更好的手性控制。Furthermore, the effect of using NaBAr 4 F is: the standard reaction can also be performed without the addition of NaBAr 4 F , and it also has better chiral control, but the ee value of the product is higher after the addition of the additive. The addition of NaBAr 4 F may mainly play the role of counter ion exchange, which can help the catalyst to form a better chiral environment, better shield one side of the reaction, and achieve better chiral control of the product.
所述化合物Ⅰ与添加剂NaBAr4 F的摩尔比为1:0.01-1，优选地，所述化合物Ⅰ与添加剂NaBAr4 F的摩尔比为1:0.1。The molar ratio of the compound I to the additive NaBAr 4 F is 1:0.01-1, preferably, the molar ratio of the compound I to the additive NaBAr 4 F is 1:0.1.
进一步的，当R1为2-Ar时，所述金属化合物为三氟甲磺酸钕[Nd(OTf)3]，所述手性氧化胺为L3-PeEt2，所述催化剂为L3-PeEt2和三氟甲磺酸钕[Nd(OTf)3]形成的配合物；当R1不为2-Ar时，所述金属化合物为三氟甲磺酸镍[Ni(OTf)2]，所述手性氧化胺为L3-PiMe5，所述催化剂为L3-PiMe5和三氟甲磺酸镍[Ni(OTf)2]形成的配合物。Further, when R 1 is 2-Ar, the metal compound is neodymium trifluoromethanesulfonate [Nd(OTf) 3 ], the chiral amine oxide is L 3 -PeEt 2 , and the catalyst is a complex formed by L 3 -PeEt 2 and neodymium trifluoromethanesulfonate [Nd(OTf) 3 ]; when R 1 is not 2-Ar, the metal compound is nickel trifluoromethanesulfonate [Ni(OTf) 2 ], The chiral amine oxide is L 3 -PiMe 5 , and the catalyst is a complex formed between L 3 -PiMe 5 and nickel trifluoromethanesulfonate [Ni(OTf) 2 ].
进一步的，所述有机溶剂的种类包括：二氯甲烷、三氯甲烷、1,2-二氯乙烷、1,1,2-三氯乙烷、1,1,2,2-四氯乙烷、甲苯、乙苯、异丙苯、乙醚、甲基叔丁基醚、四氢呋喃、乙酸乙酯或乙酸异丙酯。Further, the types of the organic solvent include: methylene chloride, chloroform, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, toluene, ethylbenzene, cumene, ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate or isopropyl acetate.
更进一步的，当R1为2-Ar时，所述有机溶剂为乙酸乙酯。当R1不为2-Ar时，所述有机溶剂为二氯甲烷。Further, when R 1 is 2-Ar, the organic solvent is ethyl acetate. When R 1 is not 2-Ar, the organic solvent is dichloromethane.
和/或，所述有机溶剂和化合物Ⅰ的摩尔比为：1:0.01-1。And/or, the molar ratio of the organic solvent to compound I is: 1:0.01-1.
进一步的，所述反应的温度为0-100℃，和/或，所述反应的时间为2-240h；优选地，所述反应的温度为10–30℃，和/或，所述反应的时间为72–96h。Further, the reaction temperature is 0-100°C, and/or, the reaction time is 2-240h; preferably, the reaction temperature is 10-30°C, and/or, the reaction time is 72-96h.
本发明还提供一种上述的方法在合成所述手性1,4-二氢吡啶化合物的应用。The present invention also provides an application of the above-mentioned method in synthesizing the chiral 1,4-dihydropyridine compound.
进一步的，所述的手性1,4-二氢吡啶化合物包括尼群地平、尼莫地平、伊拉地平、氨氯地平、尼索地平、巴尼地平、阿泽尼地平、贝尼地平、西尼地平和非洛地平中的一种或多种。Further, the chiral 1,4-dihydropyridine compound includes one or more of nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azenidipine, benidipine, cilnidipine and felodipine.
进一步的，所述尼群地平的合成方法包括：选择化合物Ⅰ为化合物Ⅱ为/>即可合成所述尼群地平；Further, the synthesis method of nitrendipine includes: selecting compound I as Compound Ⅱ is /> The nitrendipine can be synthesized;
进一步的，所述尼群地平的合成方法包括：取三氟甲磺酸镍、手性氧化胺、2-取代-3-氧代丁酸酯、NaBAr4 F和二氯甲烷进行活化反应，再加入3-氨基巴豆酸乙酯反应即可得到所述尼群地平；Further, the synthesis method of nitrendipine comprises: taking nickel trifluoromethanesulfonate, chiral amine oxide, 2-substituted-3-oxobutyrate, NaBAr 4 F and dichloromethane for an activation reaction, and then adding ethyl 3-aminocrotonate to react to obtain the nitrendipine;
更进一步的，合成方法具体包括：取三氟甲磺酸镍[Ni(OTf)2](0.01mmol)、手性氧化胺L3-PiMe5(0.01mmol)，2-取代-3-氧代丁酸酯(0.10mmol)以及NaBAr4 F(0.10mmol)；加入二氯甲烷2.0mL，于30℃下活化30min后，将反应转移至20℃继续搅拌10min；在20℃下缓慢加入3-氨基巴豆酸乙酯(0.12mmol)，并继续在20℃下反应72h，经石油醚/乙酸乙酯柱层析分离纯化得产物尼群地平Nitrendipine，产物的对映体过量用高效液相色谱(Daicelchiralcel IG，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定；Further, the synthesis method specifically includes: taking nickel trifluoromethanesulfonate [Ni(OTf)2] (0.01mmol), chiral amine oxide L3-PiMe5(0.01mmol), 2-substituted-3-oxobutyrate (0.10mmol) and NaBAr4 f(0.10mmol); add dichloromethane 2.0mL, after activation at 30°C for 30min, transfer the reaction to 20°C and continue to stir for 10min; slowly add ethyl 3-aminocrotonate (0.12mmol) at 20°C, and continue to react at 20°C for 72h, and obtain the product Nitrendipine through separation and purification by petroleum ether/ethyl acetate column chromatography, and the enantiomeric excess of the product is determined by high performance liquid chromatography (Daicelchiral cel IG, V n-hexane: V isopropanol=95:5, flow rate 1.0mL/min) measurement;
反应式如下：The reaction formula is as follows:
进一步的，所述尼莫地平的合成方法包括：选择化合物Ⅰ为化合物Ⅱ为/>即可合成所述尼莫地平；Further, the synthetic method of nimodipine includes: selecting compound I as Compound Ⅱ is /> The nimodipine can be synthesized;
进一步的，所述尼莫地平的合成方法包括：取三氟甲磺酸镍、手性氧化胺、2-取代-3-氧代丁酸酯、NaBAr4 F和二氯甲烷进行活化反应，再加入3-氨基巴豆酸异丙酯反应即可得到所述尼莫地平；Further, the synthesis method of nimodipine comprises: taking nickel trifluoromethanesulfonate, chiral amine oxide , 2-substituted-3-oxobutyrate, NaBAr4F and dichloromethane for an activation reaction, and then adding 3-amino crotonate for reaction to obtain the nimodipine;
更进一步的，合成方法具体包括：取三氟甲磺酸镍[Ni(OTf)2](0.01mmol)、手性氧化胺L3-PiMe5(0.01mmol)，2-取代-3-氧代丁酸酯(0.10mmol)以及NaBAr4 F(0.10mmol)；加入二氯甲烷2.0mL，于30℃下活化30min后，缓慢加入3-氨基巴豆酸异丙酯(0.12mmol)，并继续在30℃下反应96h，经石油醚/乙酸乙酯柱层析分离纯化得产物尼莫地平Nimodipine，产物的对映体过量用高效液相色谱(Daicel chiralcel IF，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定；Further, the synthesis method specifically includes: taking nickel trifluoromethanesulfonate [Ni(OTf)2] (0.01mmol), chiral amine oxide L3-PiMe5(0.01mmol), 2-substituted-3-oxobutyrate (0.10mmol) and NaBAr4 f(0.10mmol); add 2.0mL of dichloromethane, after activation at 30°C for 30min, slowly add isopropyl 3-aminocrotonate (0.12mmol), and continue to react at 30°C for 96h, the product Nimodipine was obtained by separation and purification by petroleum ether/ethyl acetate column chromatography, and the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IF, V n-hexane:V isopropanol=95 :5, flow rate 1.0mL/min) measurement;
反应式如下：The reaction formula is as follows:
进一步的，所述非洛地平的合成方法包括：选择化合物Ⅰ为化合物Ⅱ为/>可合成所述非洛地平；Further, the synthesis method of felodipine includes: selecting compound I as Compound Ⅱ is /> The felodipine can be synthesized;
进一步的，所述非洛地平的合成方法包括：取三氟甲磺酸钕、手性氧化胺L3-PeEt2、2-取代-3-氧代丁酸酯和乙酸乙酯进行活化反应，再加入3-氨基巴豆酸乙酯反应即可得到所述非洛地平；Further, the synthesis method of felodipine comprises: taking neodymium trifluoromethanesulfonate, chiral amine oxide L 3 -PeEt 2 , 2-substituted-3-oxobutyrate and ethyl acetate for an activation reaction, and then adding ethyl 3-aminocrotonate to react to obtain the felodipine;
更进一步的，合成方法具体包括：取三氟甲磺酸钕[Nd(OTf)3](0.01mmol)、手性氧化胺L3-PeEt2(0.01mmol)以及2-取代-3-氧代丁酸酯1d(0.10mmol)；加入乙酸乙酯2.0mL，于30℃下活化30min后，将反应转移至20℃继续搅拌10min；在20℃下加入3-氨基巴豆酸乙酯2a(0.12mmol)，并继续在20℃下反应72h，经石油醚/乙酸乙酯柱层析分离纯化得产物非洛地平Felodipine，产物的对映体过量用高效液相色谱(Daicel chiralcel IC，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定；Further, the synthesis method specifically includes: taking neodymium trifluoromethanesulfonate [Nd(OTf)3] (0.01mmol), chiral amine oxide L3-PeEt2(0.01mmol) and 2-substituted-3-oxobutyrate 1d (0.10mmol); add ethyl acetate 2.0mL, activate at 30°C for 30min, then transfer the reaction to 20°C and continue to stir for 10min; add 3-aminocrotonate ethyl ester 2a (0.12mmol) at 20°C, and continue to react at 20°C for 72h, and the product felodipine Fel was separated and purified by petroleum ether/ethyl acetate column chromatography odipine, the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IC, V n-hexane:V isopropanol=95:5, flow rate 1.0mL/min);
反应式如下：The reaction formula is as follows:
本发明的有益效果是：The beneficial effects of the present invention are:
1、本发明利用手性氧化胺-三氟甲磺酸镍/三氟甲磺酸钕配合物催化2-取代-3-氧代丁酸酯与3-氨基巴豆酸酯的不对称1,4-加成/亲核加成/脱水串联反应，以高收率、高对映选择性的实现1,4-二氢吡啶化合物及其药物分子的一步构建，底物普适性好；1. The present invention utilizes the chiral amine oxide-nickel trifluoromethanesulfonate/neodymium trifluoromethanesulfonate complex to catalyze the asymmetric 1,4-addition/nucleophilic addition/dehydration series reaction of 2-substituted-3-oxobutyrate and 3-aminocrotonate to realize the one-step construction of 1,4-dihydropyridine compound and its drug molecule with high yield and high enantioselectivity, and the substrate has good universality;
2、本发明的产物易与催化剂以及原料分离；2. The product of the present invention is easy to separate from the catalyst and raw materials;
3、本发明的反应体系简单清洁，符合绿色化学原子经济性；3. The reaction system of the present invention is simple and clean, and conforms to the atom economy of green chemistry;
4、运用该方法能以高收率以及对应选择上实现一系列具有潜在生物活性的手性1,4-二氢吡啶化合物的一步构建，如尼群地平、尼莫地平、伊拉地平、氨氯地平、尼索地平、巴尼地平、阿泽尼地平、贝尼地平、西尼地平或非洛地平，特别是手性药物分子非洛地平、尼群地平和尼莫地平。4. Using this method can realize the one-step construction of a series of chiral 1,4-dihydropyridine compounds with potential biological activity with high yield and corresponding selection, such as nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azendipine, benidipine, cilnidipine or felodipine, especially the chiral drug molecules felodipine, nitrendipine and nimodipine.
附图说明Description of drawings
图1为实施例3制备的尼群地平的核磁谱图；Fig. 1 is the nuclear magnetic spectrum of the nitrendipine prepared by embodiment 3;
图2为实施例4制备的尼莫地平的核磁谱图；Fig. 2 is the nuclear magnetic spectrum of the nimodipine prepared by embodiment 4;
图3为实施例5制备的非洛地平的核磁谱图。Fig. 3 is the nuclear magnetic spectrum of the felodipine prepared in embodiment 5.
具体实施方式Detailed ways
为了更好的理解本发明的内容，下面结合具体实例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, the following will be further described in conjunction with specific examples, but the specific implementation is not a limitation to the content of the present invention.
实施例1不同金属化合物的效果对比The effect contrast of embodiment 1 different metal compounds
在反应瓶中分别加入金属盐[Al(OTf)3、In(OTf)3、Zn(OTf)2、Sc(OTf)3、Fe(OTf)3、Fe(OTf)2、La(OTf)3、Y(OTf)3、Cu(OTf)2、Mg(OTf)2、Ni(OTf)2、Co(OTf)2(0.01mmol)]、手性氧化胺L3-PiEt2(0.01mmol)、2-取代-3-氧代丁酸酯1a(0.1mmol)、搅拌子以及1,2-二氯乙烷(1.0mL)，于30℃下搅拌30min，在30℃下加入底物2a(0.12mmol)并继续在此温度下反应24h，经石油醚/乙酸乙酯柱层析分离纯化，产物的对映体过量用高效液相色谱(DaicelchiralcelIC，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定。反应式结构如下：在反应瓶中分别加入金属盐[Al(OTf) 3 、In(OTf) 3 、Zn(OTf) 2 、Sc(OTf) 3 、Fe(OTf) 3 、Fe(OTf) 2 、La(OTf) 3 、Y(OTf) 3 、Cu(OTf) 2 、Mg(OTf) 2 、Ni(OTf) 2 、Co(OTf) 2 (0.01mmol)]、手性氧化胺L 3 -PiEt 2 (0.01mmol)、2-取代-3-氧代丁酸酯1a(0.1mmol)、搅拌子以及1,2-二氯乙烷(1.0mL)，于30℃下搅拌30min，在30℃下加入底物2a(0.12mmol)并继续在此温度下反应24h，经石油醚/乙酸乙酯柱层析分离纯化，产物的对映体过量用高效液相色谱(DaicelchiralcelIC，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定。 The reactive structure is as follows:
a标准反应条件下1.0mL二氯甲烷做反应溶剂。 a. Under standard reaction conditions, 1.0 mL of dichloromethane was used as the reaction solvent.
实施例2不同手性氧化胺的效果对比The effect contrast of embodiment 2 different chiral amine oxides
在反应瓶中加入三氟甲磺酸镍[Ni(OTf)2](0.01mmol)、手性氧化胺(0.01mmol)、NaBAr4 F(0.01mmol)、2-取代-3-氧代丁酸酯1a(0.1mmol)、搅拌子以及二氯甲烷(2.0mL)，于30℃下活化30min，将反应转移至20℃下继续搅拌10min，加入底物2a(0.12mmol)并在此温度下反应48h。反应完成后，产物经石油醚/乙酸乙酯柱层析分离纯化，产物的对映体过量用高效液相色谱(Daicelchiralcel IC，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定。反应式和手性氧化胺配体结构如下：Nickel trifluoromethanesulfonate [Ni(OTf) 2 ] (0.01mmol), chiral amine oxide (0.01mmol), NaBAr 4 F (0.01mmol), 2-substituted-3-oxobutyrate 1a (0.1mmol), a stirrer and dichloromethane (2.0mL) were added to the reaction flask, activated at 30°C for 30min, the reaction was transferred to 20°C and stirred for 10min, and substrate 2a was added ( 0.12mmol) and reacted at this temperature for 48h. After the reaction was completed, the product was separated and purified by petroleum ether/ethyl acetate column chromatography, and the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicelchiralcel IC, V n-hexane:V isopropanol=95:5, flow rate 1.0 mL/min). The reaction formula and chiral amine oxide ligand structure are as follows:
a 10℃下反应72h。 a Reaction at 10°C for 72h.
实施例3手性药物分子尼群地平(Nitrendipine)的合成Example 3 Synthesis of Chiral Drug Molecule Nitrendipine (Nitrendipine)
在反应瓶中加入三氟甲磺酸镍[Ni(OTf)2](0.01mmol)、手性氧化胺L3-PiMe5(0.01mmol)，2-取代-3-氧代丁酸酯1b(0.10mmol)以及NaBAr4 F(0.10mmol)；加入二氯甲烷2.0mL，于30℃下活化30min后，将反应转移至20℃继续搅拌10min；在20℃下缓慢加入3-氨基巴豆酸乙酯2a(0.12mmol)，并继续在20℃下反应72h，经石油醚/乙酸乙酯柱层析分离纯化得产物Nitrendipine(98％yield,92％ee)，产物的对映体过量用高效液相色谱(Daicelchiralcel IG，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定。Add nickel trifluoromethanesulfonate [Ni(OTf)2] (0.01mmol), chiral amine oxide L3-PiMe5(0.01mmol), 2-substituted-3-oxobutyrate 1b (0.10mmol) and NaBAr4 f(0.10mmol); add 2.0mL of dichloromethane, activate at 30°C for 30min, transfer the reaction to 20°C and continue to stir for 10min; slowly add 3-aminocrotonate ethyl ester 2a (0.12mmol) at 20°C, and continue to react at 20°C for 72h, separated and purified by petroleum ether/ethyl acetate column chromatography to obtain the product Nitrendipine (98%yield, 92%ee), the enantiomeric excess of the product It was determined by high performance liquid chromatography (Daicelchiralcel IG, V n-hexane: V isopropanol = 95:5, flow rate 1.0 mL/min).
实施例4手性药物分子尼莫地平(Nimodipine)的合成Synthesis of Example 4 Chiral Drug Molecule Nimodipine (Nimodipine)
在反应瓶中加入三氟甲磺酸镍[Ni(OTf)2](0.01mmol)、手性氧化胺L3-PiMe5(0.01mmol)，2-取代-3-氧代丁酸酯1c(0.10mmol)以及NaBAr4 F(0.10mmol)；加入二氯甲烷2.0mL，于30℃下活化30min后，在此温度下加入3-氨基巴豆酸异丙酯2b(0.12mmol)，并继续在30℃下反应96h，经石油醚/乙酸乙酯柱层析分离纯化得产物Nimodipine(75％yield,87％ee)，产物的对映体过量用高效液相色谱(Daicel chiralcel IF，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定。Add nickel trifluoromethanesulfonate [Ni(OTf)2] (0.01mmol), chiral amine oxide L3-PiMe5(0.01mmol), 2-substituted-3-oxobutyrate 1c (0.10mmol) and NaBAr4 f(0.10mmol); add 2.0mL of dichloromethane, activate at 30°C for 30min, add 3-aminocrotonate isopropyl 2b (0.12mmol) at this temperature, and continue to react at 30°C for 96h, and obtain the product Nimodipine (75% yield, 87%ee) through petroleum ether/ethyl acetate column chromatography. , V n-hexane:V isopropanol=95:5, flow rate 1.0mL/min) determination.
实施例5：手性药物分子非洛地平(Felodipine)的合成Embodiment 5: the synthesis of chiral drug molecule Felodipine (Felodipine)
在反应瓶中加入三氟甲磺酸钕[Nd(OTf)3](0.01mmol)、手性氧化胺L3-PeEt2(0.01mmol)以及2-取代-3-氧代丁酸酯1d(0.10mmol)；加入乙酸乙酯2.0mL，于30℃下活化30min后，将反应转移至20℃继续搅拌10min；在20℃下加入3-氨基巴豆酸乙酯2a(0.12mmol)，并继续在20℃下反应72h，经石油醚/乙酸乙酯柱层析分离纯化得产物Felodipine(65％yield,91％ee)，产物的对映体过量用高效液相色谱(Daicel chiralcelIC，V正己烷:V异丙醇＝95:5，流速1.0mL/min)测定。Add neodymium trifluoromethanesulfonate [Nd(OTf)3] (0.01mmol), chiral amine oxide L3-PeEt2(0.01mmol) and 2-substituted-3-oxobutyrate 1d (0.10mmol); add ethyl acetate 2.0mL, after activation at 30°C for 30min, transfer the reaction to 20°C and continue to stir for 10min; add 3-aminocrotonate ethyl ester 2a (0.12mmol) at 20°C, and continue to react at 20°C for 72h, and the product Felodipine was separated and purified by petroleum ether/ethyl acetate column chromatography ( 65% yield, 91% ee), the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcelIC, V n-hexane: V isopropanol = 95:5, flow rate 1.0 mL/min).
以上所述仅是本发明的优选实施方式，应当理解本发明并非局限于本文所披露的形式，不应看作是对其他实施例的排除，而可用于各种其他组合、修改和环境，并能够在本文所述构想范围内，通过上述教导或相关领域的技术或知识进行改动。而本领域人员所进行的改动和变化不脱离本发明的精神和范围，则都应在本发明所附权利要求的保护范围内。The above are only preferred implementations of the present invention, and it should be understood that the present invention is not limited to the forms disclosed herein, and should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be modified within the scope of the ideas described herein through the above teachings or technology or knowledge in related fields. However, changes and changes made by those skilled in the art do not depart from the spirit and scope of the present invention, and should all be within the protection scope of the appended claims of the present invention.
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