CN111205288B - 一种(1S,12bS)内酰胺酯化合物的合成方法 - Google Patents
一种(1S,12bS)内酰胺酯化合物的合成方法 Download PDFInfo
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- CN111205288B CN111205288B CN202010102390.9A CN202010102390A CN111205288B CN 111205288 B CN111205288 B CN 111205288B CN 202010102390 A CN202010102390 A CN 202010102390A CN 111205288 B CN111205288 B CN 111205288B
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- organic solvent
- hydrogen
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- -1 lactam ester compound Chemical class 0.000 title claims abstract description 58
- 238000001308 synthesis method Methods 0.000 title description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 99
- 150000002367 halogens Chemical class 0.000 claims abstract description 87
- 239000000654 additive Substances 0.000 claims abstract description 54
- 239000001257 hydrogen Substances 0.000 claims abstract description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 49
- 230000000996 additive effect Effects 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003446 ligand Substances 0.000 claims abstract description 24
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 23
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000010930 lactamization Methods 0.000 claims abstract description 14
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 12
- 239000012298 atmosphere Substances 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 3
- 230000015572 biosynthetic process Effects 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 40
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 39
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 34
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 33
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 30
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- 239000012685 metal catalyst precursor Substances 0.000 claims description 12
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003495 polar organic solvent Substances 0.000 claims description 10
- 235000009518 sodium iodide Nutrition 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- COTJKXKUWHUMIR-UHFFFAOYSA-N (s,s)-f-binaphane Chemical compound [Fe+2].[CH]1[CH][CH][CH][C]1P1CC(C=CC=2C3=CC=CC=2)=C3C2=C3C=CC=CC3=CC=C2C1.[CH]1[CH][CH][CH][C]1P1CC(C=CC=2C3=CC=CC=2)=C3C2=C3C=CC=CC3=CC=C2C1 COTJKXKUWHUMIR-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 6
- 125000005011 alkyl ether group Chemical group 0.000 claims description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical group C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 claims description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- ARYZCSRUUPFYMY-UHFFFAOYSA-N methoxysilane Chemical group CO[SiH3] ARYZCSRUUPFYMY-UHFFFAOYSA-N 0.000 claims description 2
- RBCYCMNKVQPXDR-UHFFFAOYSA-N phenoxysilane Chemical group [SiH3]OC1=CC=CC=C1 RBCYCMNKVQPXDR-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- 125000003545 alkoxy group Chemical group 0.000 description 31
- 125000000623 heterocyclic group Chemical group 0.000 description 26
- 125000002877 alkyl aryl group Chemical group 0.000 description 18
- 125000003368 amide group Chemical group 0.000 description 18
- 125000002843 carboxylic acid group Chemical group 0.000 description 18
- 125000004185 ester group Chemical group 0.000 description 18
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 125000004104 aryloxy group Chemical group 0.000 description 13
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 9
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 229910000039 hydrogen halide Inorganic materials 0.000 description 7
- 239000012433 hydrogen halide Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- JJQVHODEIZDXSW-UHFFFAOYSA-N cycloocta-1,5-diene iridium Chemical compound [Ir].C1CC=CCCC=C1 JJQVHODEIZDXSW-UHFFFAOYSA-N 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical class C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 3
- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- SHWINQXIGSEZAP-UHFFFAOYSA-N dimethyl heptanedioate Chemical compound COC(=O)CCCCCC(=O)OC SHWINQXIGSEZAP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-L pimelate(2-) Chemical compound [O-]C(=O)CCCCCC([O-])=O WLJVNTCWHIRURA-UHFFFAOYSA-L 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- WPVJFYKTUIJEEP-PKTZIBPZSA-N propan-2-yl 3-[(1S,12bS)-1-ethyl-4-oxo-2,3,6,7,12,12b-hexahydroindolo[2,3-a]quinolizin-1-yl]propanoate Chemical compound C(C)[C@]1(CCC(N2CCC3=C([C@H]12)NC1=CC=CC=C13)=O)CCC(=O)OC(C)C WPVJFYKTUIJEEP-PKTZIBPZSA-N 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- JAAGVIUFBAHDMA-UHFFFAOYSA-M rubidium bromide Chemical compound [Br-].[Rb+] JAAGVIUFBAHDMA-UHFFFAOYSA-M 0.000 description 2
- FGDZQCVHDSGLHJ-UHFFFAOYSA-M rubidium chloride Chemical compound [Cl-].[Rb+] FGDZQCVHDSGLHJ-UHFFFAOYSA-M 0.000 description 2
- AHLATJUETSFVIM-UHFFFAOYSA-M rubidium fluoride Chemical compound [F-].[Rb+] AHLATJUETSFVIM-UHFFFAOYSA-M 0.000 description 2
- WFUBYPSJBBQSOU-UHFFFAOYSA-M rubidium iodide Chemical compound [Rb+].[I-] WFUBYPSJBBQSOU-UHFFFAOYSA-M 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 1
- ZFOUGNAJKPZBPO-AUUWQFPRSA-N (1z,5z)-cycloocta-1,5-diene;iridium;tetrakis[3,5-bis(trifluoromethyl)phenyl]boranuide Chemical group [Ir].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1.FC(F)(F)C1=CC(C(F)(F)F)=CC([B-](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)(C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=C1 ZFOUGNAJKPZBPO-AUUWQFPRSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- RNDNSYIPLPAXAZ-UHFFFAOYSA-N 2-Phenyl-1-propanol Chemical compound OCC(C)C1=CC=CC=C1 RNDNSYIPLPAXAZ-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ZPUIMDHWHIASSK-UHFFFAOYSA-N C(C)C1(C=CC=C1)[Ir]C1=CC=CCC1.[Ir] Chemical compound C(C)C1(C=CC=C1)[Ir]C1=CC=CCC1.[Ir] ZPUIMDHWHIASSK-UHFFFAOYSA-N 0.000 description 1
- GFFAGXUXQQQSBV-UHFFFAOYSA-N C12=CC=C(CC1)C2.C21=CC=C(CC2)C1.C12=CC=C(CC1)C2.[Ir] Chemical compound C12=CC=C(CC1)C2.C21=CC=C(CC2)C1.C12=CC=C(CC1)C2.[Ir] GFFAGXUXQQQSBV-UHFFFAOYSA-N 0.000 description 1
- ZECJHXWYQJXFQQ-UHFFFAOYSA-L CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C ZECJHXWYQJXFQQ-UHFFFAOYSA-L 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000191368 Chlorobi Species 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical group C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- KFNNIILCVOLYIR-UHFFFAOYSA-N Propyl formate Chemical compound CCCOC=O KFNNIILCVOLYIR-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- WUZLQPAWFINOFB-UHFFFAOYSA-K [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1.[Ir] Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1.[Ir] WUZLQPAWFINOFB-UHFFFAOYSA-K 0.000 description 1
- OLIWQDQTJVIVPA-UHFFFAOYSA-K [Ir](Cl)(Cl)Cl.C1=CCCCCCC1.C1=CCCCCCC1 Chemical class [Ir](Cl)(Cl)Cl.C1=CCCCCCC1.C1=CCCCCCC1 OLIWQDQTJVIVPA-UHFFFAOYSA-K 0.000 description 1
- DVWQPFSIOVXZKT-UHFFFAOYSA-K [Ir](Cl)(Cl)Cl.COC1=CC=CCCCC1 Chemical class [Ir](Cl)(Cl)Cl.COC1=CC=CCCCC1 DVWQPFSIOVXZKT-UHFFFAOYSA-K 0.000 description 1
- JQBANSUVXLEDBI-UHFFFAOYSA-N [Ir].C1=CCCC=CCC1.CC1=CC=CC1 Chemical compound [Ir].C1=CCCC=CCC1.CC1=CC=CC1 JQBANSUVXLEDBI-UHFFFAOYSA-N 0.000 description 1
- ZLBYGFRHXDKHED-UHFFFAOYSA-N [Ir].C1CCCC=CCC1 Chemical class [Ir].C1CCCC=CCC1 ZLBYGFRHXDKHED-UHFFFAOYSA-N 0.000 description 1
- FGWGEOYSHPQXPR-UHFFFAOYSA-N [Ir].N1=CC=CC2=CC=C3C=CC=NC3=C12.ClC1=CCCC=CCC1 Chemical compound [Ir].N1=CC=CC2=CC=C3C=CC=NC3=C12.ClC1=CCCC=CCC1 FGWGEOYSHPQXPR-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 125000005595 acetylacetonate group Chemical group 0.000 description 1
- CECABOMBVQNBEC-UHFFFAOYSA-K aluminium iodide Chemical compound I[Al](I)I CECABOMBVQNBEC-UHFFFAOYSA-K 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- NKQIMNKPSDEDMO-UHFFFAOYSA-L barium bromide Chemical compound [Br-].[Br-].[Ba+2] NKQIMNKPSDEDMO-UHFFFAOYSA-L 0.000 description 1
- 229910001620 barium bromide Inorganic materials 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- SGUXGJPBTNFBAD-UHFFFAOYSA-L barium iodide Chemical compound [I-].[I-].[Ba+2] SGUXGJPBTNFBAD-UHFFFAOYSA-L 0.000 description 1
- 229910001638 barium iodide Inorganic materials 0.000 description 1
- 229940075444 barium iodide Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- LYQFWZFBNBDLEO-UHFFFAOYSA-M caesium bromide Chemical compound [Br-].[Cs+] LYQFWZFBNBDLEO-UHFFFAOYSA-M 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 1
- 229910001622 calcium bromide Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 description 1
- 229910001640 calcium iodide Inorganic materials 0.000 description 1
- 229940046413 calcium iodide Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- ASURECOXOZVQDX-UHFFFAOYSA-N dimethyl 4-ethyl-4-formylheptanedioate Chemical compound COC(=O)CCC(CC)(CCC(=O)OC)C=O ASURECOXOZVQDX-UHFFFAOYSA-N 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940117360 ethyl pyruvate Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- ORUIBWPALBXDOA-UHFFFAOYSA-L magnesium fluoride Chemical compound [F-].[F-].[Mg+2] ORUIBWPALBXDOA-UHFFFAOYSA-L 0.000 description 1
- 229910001635 magnesium fluoride Inorganic materials 0.000 description 1
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 description 1
- 229910001641 magnesium iodide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229940102127 rubidium chloride Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- RXPRRQLKFXBCSJ-DQVLVPHSSA-N vincachron Chemical class C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)C[C@@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-DQVLVPHSSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- 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
Description
技术领域
本发明属于有机合成领域,具体的涉及一种(1S,12bS)内酰胺酯化合物(I)的合成方法。
背景技术
长春胺类生物碱对细胞增殖、心血管系统和大脑功能有不同的药理作用,具有抗氧化、抗癌、改善循环、提高认知能力、神经元保护以及益智等活性,特别是在脑血管扩张和神经保护等方面作用显著。(1S,12bS)内酰胺酯化合物(I)是合成长春胺类生物碱的关键中间体。
Kuehne等(J.Am.Chem.Soc.1964,86,2946)首次报道以色胺与4-乙基-4-甲酰基庚二酸二甲酯发生Pictet-Spengler反应并内酰胺化即得外消旋(I)(未说明顺反式比例,R1=R3=H,R2=Me);Ho等(Helv.Chim.Acta.2006,89,249)采用1-(1-叔丁基)-1-(1-乙基环庚-4-烯-1-基)-3,4-二氢-1H-吡啶并[3,4-b]吲哚-2,9-二羧酸酯在相转移条件下高锰酸钾氧化,继而以对甲苯磺酸脱叔丁氧羰基,并内酰胺化生成外消旋(I)(cis/trans=1:1.3,R1=R3=H,R2=H,Et,Bn,SePh);Nemes等(ARKIVOC,2008,3,154)先采用上述Kuehne报道的方法制备得到外消旋体(I)(cis/trans=2:3,R1=R3=H,R2=Me),然后在氢氧化钠甲醇溶液中水解、浓盐酸酸化,并应用(–)-麻黄素为拆分剂进行拆分,继而甲酯化得到3-[(1S,12bR)-1-乙基-1,2,3,4,6,7,12,12b-八氢-4-氧代吲哚骈[2,3-a]喹嗪-1-基]丙酸甲酯,但此拆分剂为管控易制毒化合物,不易获得,且拆分率仅为26%。
上述这些方法中均得到以反式构型为主的产物,其中两篇报道为外消旋体制备,另外一篇则存在着单次拆分率低、操作繁琐、成本偏高的缺点,不利于相关药物的研发与生产。目前,高效制备此类顺式长春胺生物碱中间体仍是未解决的技术难题。
因此,开发一种工艺简单、成本低廉、环境友好的顺式(1S,12bS)内酰胺酯化合物(I)的制备方法具有重要的意义。
发明内容
本发明的目的在于克服现有技术的不足,提供一种工艺简单、高效、成本低廉、环境友好的不对称合成长春胺生物碱中间体(1S,12bS)内酰胺酯化合物(I)的方法。
具体的,本发明提供了一种式(I)的(1S,12bS)内酰胺酯化合物的合成方法,
所述方法如以下反应路线所示,通过在铱金属催化剂前体、手性双膦配体和一种或多于一种含卤添加剂的存在下,使式(II)的二氢咔啉双酯化合物在氢气气氛下,在有机溶剂中进行不对称氢化和内酰胺化反应,制得式(I)的(1S,12bS)内酰胺酯化合物,
其中:
R1为氢、直链或支链C1~C5烷基醚基、烯丙基醚基、苄基醚基、甲基硅烷基醚基、异丙基硅烷基醚基、叔丁基硅烷基醚基或苯基硅烷基醚基,优选R1为氢或直链或支链C1~C5烷基醚基;
R2为直链或支链C1~C5烷基、芳烷基或芳基,优选R2为直链或支链C1~C5烷基;
R3位于其所在苯环上的任何可取代的位置上,例如1位、2位、3位、4位等位置上,并且为氢、直链或支链C1~C5烷基、直链或支链C1~C3烷氧基或卤素,优选R3为氢、直链或支链C1~C5烷基。
在反应完成后,可经后处理得到所需化合物,例如在慢慢释放氢气后,除去溶剂,然后用硅胶柱分离得到所需化合物。
本发明方法可以>90%的收率制备(1S,12bS)内酰胺酯化合物,且dr(cis/trans)>1.8:1(最高至17:1),cis异构体ee>88%(重结晶后ee>99%),trans异构体ee>78%(重结晶后ee>99%)。
优选,本发明的方法所采用的铱金属催化剂前体选自甲氧基(环辛二烯)合铱二聚体、1,5-环辛二烯氯化铱二聚体、双(环辛烯)氯化铱二聚体、双(1,5-环辛二烯)铱四[3,5-双(三氟甲基)苯基]硼酸、(1,5-环辛二烯)(嘧啶)(三环己基膦)铱六氟磷酸盐、双(1,5-环辛二烯)四氟硼酸铱、二氯(五甲基环戊二烯基)合铱二聚体、1,5-环辛二烯(六氟乙酰丙酮)铱、氯二(环辛烯)铱二聚体、氯(1,5-环辛二烯)(1,10-菲咯啉)铱、二(1,5-环辛二烯)二-M-甲氧基二铱、(甲基环戊二炔)(1,5-环辛二烯)铱、六氟磷酸(三环已基膦)(1,5-环辛二烯)(吡啶)合铱、碳双(三苯基膦)氯化铱、1,5-环辛二烯(乙酰乙酸)铱、1,5-环辛二烯(六氟乙酰丙酮)铱、1,5-环辛二烯(H5-茚)铱、1-乙基环戊二烯基-1,3-环己二烯基铱、1,5-环辛二烯双(甲基联苯基磷化氢)铱六氟磷酸盐、三(降冰片二烯)(乙酰基丙酮酸)铱及其组合,最优选铱金属催化剂前体为1,5-环辛二烯氯化铱二聚体。
优选,本发明的方法所采用的手性双膦配体为二茂铁基双膦配体或其对映异构体、联芳基双膦配体或其对映异构体,最优选1,1'-双{(S)-4,5-二氢-3H-联萘并[1,2-C:2',1'-E]膦基}二茂铁,在本文中其用(S,S)-f-Binaphane表示。
在本发明中,所述含卤添加剂为卤素单质、卤化氢水溶液、含卤素阴离子盐或它们的组合,优选所述卤素单质为溴或碘,更优选为碘;优选所述卤化氢水溶液为溴化氢水溶液或碘化氢水溶液,更优选为碘化氢水溶液,卤化氢水溶液的摩尔浓度优选为2.0~10.0mol/L,更优选3.0~6.0mol/L,例如5.3mol/L;优选所述含卤素阴离子盐为溴化钾、碘化钾、溴化钠、碘化钠,更优选为碘化钾或碘化钠。
优选,在本发明的方法中所采用的式(II)的二氢咔啉双酯化合物、铱金属催化剂前体、手性双膦配体、全部含卤添加剂中所含卤素阴离子的摩尔比为1:0.01~0.05:0.02~0.1:0.1~0.5,更优选为1:0.01~0.03:0.02~0.06:0.1~0.5。
在本发明的方法中,在不对称氢化和内酰胺化反应中采用的氢气压力为20~100大气压,优选为40~80大气压,反应温度为–40~40℃,优选为–40~0℃,更优选为–20~0℃,反应时间为48~200h,优选为100~150h。
在本发明的方法中,所用的有机溶剂可以为非质子极性有机溶剂,如二甲亚砜、N,N-二甲基甲酰胺、乙酸乙酯、丙酮、DMI等,优选N,N-二甲基甲酰胺、乙酸乙酯;也可以为两种或多种非质子极性有机溶剂的组合,优选N,N-二甲基甲酰胺和乙酸乙酯的组合,更优选体积比为1:1的N,N-二甲基甲酰胺和乙酸乙酯混合溶剂;也可以为非质子非极性有机溶剂,如正己烷、环己烷、石油醚、甲苯、四氯化碳和二硫化碳等,优选甲苯。更优选,本发明的方法中所用的有机溶剂为体积比为1:1的N,N-二甲基甲酰胺和乙酸乙酯混合溶剂、甲苯或它们的组合。
在本发明中,有机溶剂的用量没有特别限制,技术人员可以根据具体情况确定合适的用量。优选,有机溶剂在使用前进行脱气处理。
在一个优选的实施方案中,所述含卤添加剂为一种含卤添加剂,并且所述方法包括步骤:
1)首先,将铱金属催化剂前体与手性双膦配体分散在有机溶剂中,在室温下静置或搅拌10~30min,得到溶液;
2)然后,向步骤1)所得溶液中加入式(II)的二氢咔啉双酯化合物和含卤添加剂,得到总溶液;
3)将步骤2)所得总溶液转移到高压反应釜中,并在氢气气氛下进行不对称氢化和内酰胺化反应。
在另一个优选的实施方案中,所述含卤添加剂为一种含卤添加剂,并且所述方法包括步骤:
1)首先,将铱金属催化剂前体与手性双膦配体分散在一部分有机溶剂中,在室温下静置或搅拌10~30min,得到溶液,
2)然后,向步骤1)所得溶液中加入式(II)的二氢咔啉双酯化合物、含卤添加剂和其余有机溶剂的溶液,得到总溶液;
3)将步骤2)得到的总溶液转移到高压反应釜中,并且在氢气气氛下进行不对称氢化和内酰胺化反应。
在还另一个优选的实施方案中,所述含卤添加剂为分别表示为第1含卤添加剂和第2含卤添加剂的2种不同的含卤添加剂,并且所述方法包括步骤:
1)首先,将铱金属催化剂前体与手性双膦配体分散在有机溶剂中,然后加入第1含卤添加剂,并在搅拌下,室温下反应5~20h,得到卤素桥联的铱络合物溶液;
2)然后,向步骤1)得到的卤素桥联的铱络合物溶液中加入式(II)的二氢咔啉双酯化合物和第2含卤添加剂,得到总溶液;
3)将步骤2)所得总溶液转移到高压反应釜中,并在氢气气氛下进行不对称氢化和内酰胺化反应,
其中,第1含卤添加剂中所含卤素阴离子与第2含卤添加剂中所含卤素阴离子的摩尔比为0.2~2:1,优选0.40~1.50:1。
在还另一个优选的实施方案中,其中所述含卤添加剂为分别表示为第1含卤添加剂和第2含卤添加剂的2种不同的含卤添加剂,并且所述方法包括步骤:
1)首先,在惰性气体气氛下,将铱金属催化剂前体与手性双膦配体分散在有机溶剂中,然后加入第1含卤添加剂,并在搅拌下,室温下反应5~20h,得到卤素桥联的铱络合物溶液;
2)将步骤1)所得卤素桥联的铱络合物从溶液中分离并纯化,将所得纯化的固体干燥;
3)然后,将步骤2)得到的干燥固体溶于与步骤1)的有机溶剂相同或不同的有机溶剂中,并加入式(II)的二氢咔啉双酯化合物和第2含卤添加剂,得到总溶液;
4)将步骤3)所得总溶液转移到高压反应釜中,并且在氢气气氛下进行不对称氢化和内酰胺化反应,
其中,第1含卤添加剂中所含卤素阴离子与第2含卤添加剂中所含卤素阴离子的摩尔比为0.2~2:1,优选0.40~1.50:1。
在添加2种含卤添加剂,即第1含卤添加剂和第2含卤添加剂的情况下,优选第1含卤添加剂为卤化氢水溶液,例如溴化氢水溶液或碘化氢水溶液,更优选为碘化氢水溶液,卤化氢水溶液的摩尔浓度优选为2.0~10.0mol/L,更优选3.0~6.0mol/L,例如5.3mol/L;优选第2含卤添加剂为含卤素阴离子盐,例如溴化钾、碘化钾、溴化钠、碘化钠,更优选为碘化钾或碘化钠。
本发明的方法具有反应条件温和、操作简便、化学收率和光学纯度高、非对映选择性好等优点,适合放大应用。
具体实施方式
在本发明中,术语“含卤添加剂”是指含卤素添加剂,当本发明方法中仅添加一种含卤添加剂的时候,全部含卤添加剂中所含卤素阴离子的摩尔数就是该含卤添加剂中所含卤素阴离子的摩尔数,当添加两种或多种含卤添加剂的时候,全部含卤添加剂中所含卤素阴离子的摩尔数就是该两种或多种含卤添加剂中所含卤素阴离子的摩尔数的总和。
在本发明中,烷基可表示碳数1~50、优选碳数1~10、更优选碳数1~5的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等;烷基还可表示碳数1~10、优选碳数1~5的卤代直链或支链烷基,例如三氟甲基、三氟乙基、六氟异丙基等;烷基还可表示碳数3~30、优选碳数3~10的单环、多环或稠环环烷基,例如环丙基、环丁基、环戊基、环己基等。
在本发明中,芳基是指碳数6~36、优选碳数6~14的单环、多环或稠环芳基,例如苯基、萘基、蒽基、菲基、联苯基、联萘基等。
在本发明中,芳烷基是指烷基中至少一个氢原子被芳基取代的基团,优选碳数7~15的芳烷基,例如苄基、1-苯乙基、2-苯乙基、1-苯丙基、3-萘丙基等。
在本发明中,烷氧基可表示无保护的羟基,也可表示碳数1~20,优选碳数1~10,更优选碳数1~5的直链或直链烷基形成的烷氧基,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
在本发明中,芳氧基是指碳数6~36,优选碳数6~14的单环、多环或稠环芳基形成的芳氧基,例如苯氧基,甲苯氧基、二甲苯氧基、萘氧基等。
在本发明中,卤素是指氟、氯、溴或碘。
在本发明中,杂环基包括脂肪族杂环基和芳香族杂环基。脂肪族杂环基是指具有2~14个碳原子的3~8元、优选4~6元的单环、多环或稠环脂肪族杂环基,这些基团含有至少1个、优选1~3个例如氮原子、氧原子和/或硫原子的杂原子,例如,脂肪族杂环基可为氮杂环丁烷基、氮杂环戊基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、四氢噻吩基等;芳香族杂环基是指具有2~15个碳原子的5元或6元的单环、多环或稠环芳杂环基,这些基团含有至少1个、优选1~3个例如氮原子、氧原子和/或硫原子等的杂原子,例如呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡唑基、咪唑基、噁唑基、噻唑基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基、喹喔啉基等。
在本发明中,取代的胺基是指氨基的2个氢原子被相同或不同的烷基、芳基、芳烷基、烷氧基、芳氧基、芳氧烷基取代的基团,例如:N,N-二甲基胺基、N,N-二乙基胺基、N,N-二异丙基胺基等的二烷基胺基;N,N-二环己基胺基等的二环烷基胺基;N,N-二苯基胺基、N-萘基-N-苯基胺基等的二芳基胺基;N,N-二苄基胺基等的二芳烷基胺基。
本发明可使用为二茂铁基双膦配体或其对映异构体的手性双膦配体,所述二茂铁基双膦配体可为如下通式(1)、(2)、(3)或(4)所示的二茂铁基双膦配体,
其中:
通式(1)中:
R4和R5各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基、取代的胺基;或者
R4和R5连接在一起形成环;或者
-PR4R5连接在一起形成如通式(5)、(6)、(7)所示的基团,
其中,在通式(5)和(6)中,每个X独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基,每个Y独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基,每个Z独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基;
在通式(7)中,α和β为任意取代的芳环;
R6和R7各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基、取代的胺基;或者
R6和R7连接在一起形成环;或者
-PR6R7连接在一起形成如通式(5)、(6)、(7)所示的基团;
其中,在通式(5)和(6)中,每个X独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基,每个Y独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基,每个Z独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基;
在通式(7)中,α和β为任意取代的芳环;
R8为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基或取代的胺基;
上述基团为手性基团或非手性基团。
在通式(2)中:
R4为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基或取代的胺基;
R5为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基或取代的胺基;
R6和R7各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基、取代的胺基;或者
R6和R7连接在一起形成环;或者
-PR6R7连接在一起形成如通式(5)、(6)、(7)所示的基团,
在通式(5)和(6)中,每个X独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基,每个Y独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基,每个Z独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基;
在通式(7)中,α和β为任意取代的芳环;
上述基团为手性基团或非手性基团。
在通式(3)、(4)中:
每个X独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基或酰胺基,每个Y独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基,每个Z独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基;
上述基团为手性基团或非手性基团。
本发明还可使用为联芳基双膦配体或其对映异构体的手性双膦配体,所述联芳基双膦配体可为如通式(8)、(9)所示的联芳基双膦配体,
其中:
在通式(8)中:
R11和R12各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基、取代的胺基;或者
R11和R12连接在一起形成环;
R13和R14各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基、取代的胺基;或者
R13和R14连接在一起形成环;或者
-PR13R14连接在一起形成如通式(5)、(6)、(7)所示的基团,
其中,在通式(5)和(6)中,每个X独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基,每个Y独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基,每个Z独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基;
在通式(7)中,α和β为任意取代的芳环,
上述基团为手性基团或非手性基团。
在通式(9)中:
R11和R12各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基或取代的胺基;
R13和R14各自独立为烷基、芳基、芳烷基、烷氧基、芳氧基、芳基烷氧基、杂环基或取代的胺基;或者
R13和R14连接在一起形成环;或者
-PR13R14连接在一起形成如通式(5)、(6)、(7)所示的基团,
在通式(5)和(6)中,每个X独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基,每个Y独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基,每个Z独立为氢、卤素、烷基、芳基、烷基芳基、芳烷基、烷氧基、甲硅烷基、羧酸基、酯基、酰胺基或杂环基;
在通式(7)中,α和β为任意取代的芳环;
每个W独立为碳原子或氮原子。
更优选,本发明使用如下所示的二茂铁基手性双膦配体:
其中还更优选的是(S,S)-f-Binaphane,在本发明的不对称氢化/内酰胺化反应中,(S,S)-f-Binaphane具有出色的对映选择性。
更优选,本发明使用如下所示的手性联芳基双膦配体:
作为含卤添加剂,本发明可使用卤素单质、卤化氢水溶液、含卤素阴离子盐或它们的组合,所述卤素单质可为溴或碘,更优选为碘;所述卤化氢水溶液可为溴化氢水溶液或碘化氢水溶液,更优选为碘化氢水溶液,摩尔浓度优选为2.0~10.0mol/L,例如5.3mol/L;含卤素阴离子盐可为氟化锂、氟化钠、氟化钾、氟化铷、氟化铯、氟化镁、氯化锂、氯化钠、氯化钾、氯化铷、氯化铯、氯化镁、氯化钙、氯化钡、氯化铝、溴化锂、溴化钠、溴化钾、溴化铷、溴化铯、溴化镁、溴化钙、溴化钡、溴化铝、碘化锂、碘化钠、碘化钾、碘化铷、碘化铯、碘化镁、碘化钙、碘化钡或碘化铝,优选所述含卤素阴离子盐为溴化钾、碘化钾、溴化钠或碘化钠,更优选为碘化钾或碘化钠。
作为有机溶剂,本发明可使用非质子极性有机溶剂、两种或多种非质子极性有机溶剂的组合、非质子非极性有机溶剂或质子有机溶剂,非质子极性有机溶剂可包括但不限于甲酸甲酯、甲酸乙酯、甲酸正丙酯、甲酸异丙酯、甲酸叔丁酯、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸叔丁酯、乙酰乙酸乙酯、丙酸甲酯、丙酸乙酯、苯甲酸甲酯、苯甲酸乙酯、碳酸二甲酯、丙酮酸乙酯、丙二酸二乙酯、溴乙酸叔丁酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,3-二甲基-2-咪唑啉酮、二甲基亚砜、丙酮、DMI、乙腈等,更优选N,N-二甲基甲酰胺、乙酸乙酯;两种或多种非质子极性有机溶剂的组合包括但不限于两种或多种前述非质子极性有机溶剂的组合,例如N,N-二甲基甲酰胺和乙酸乙酯的组合等,更优选体积比为1:1的N,N-二甲基甲酰胺和乙酸乙酯混合溶剂;非质子非极性溶剂可包括但不限于苯、甲苯、二甲苯、邻二甲苯、间二甲苯、对二甲苯、均三甲苯,氯苯、氟苯、正己烷、环己烷、正庚烷、正戊烷、乙醚、石油醚、四氢呋喃、甲基四氢呋喃、二氧六环、甲基叔丁基醚、异丙醚、乙二醇二甲醚、邻苯二甲醚、二氯甲烷、1,2-二氯乙烷、四氯化碳、二硫化碳等,更优选甲苯;质子有机溶剂可包括但不限于甲醇、乙醇、异丙醇、丁醇、环戊醇、三氟乙醇、1,2-丙二醇、1,3-丙二醇、苯甲醇、苯乙醇、1-苯丙醇、2-苯丙醇、3-苯丙醇、甲酸、乙酸、丙酸、苯甲酸、3-苯丙酸、苯胺、三乙醇胺、1,2-丙二胺、二乙胺、三乙胺、乙二胺等。
下面通过实施例来进一步详细描述本发明,但本发明的保护范围不局限于此。
实施例1
3-[(1S,12bS)-1-乙基-1,2,3,4,6,7,12,12b-八氢-4-氧代吲哚骈[2,3-a]喹嗪-1-基]丙酸甲酯(Ia)的制备
以N,N-二甲基甲酰胺/乙酸乙酯(v/v 1:1)为溶剂。将1,5-环辛二烯氯化铱二聚体(0.020g,0.030mmol)、(S,S)-f-Binaphane(0.050g,0.063mmol)和脱气N,N-二甲基甲酰胺/乙酸乙酯(v/v 1:1)(50mL)溶于干燥的反应瓶中,静置15min,然后向反应瓶中加入4-(4,9-二氢-3H-吡啶骈[3,4-b]吲哚-1-基)-4-乙基庚二酸二甲酯(IIa)(1.150g,3.000mmol)和碘化钾(0.050g,0.300mmol)的脱气N,N-二甲基甲酰胺/乙酸乙酯(v/v 1:1)(50mL)溶液,将其置于高压反应釜中,氢气置换3次,继而通入氢气至60个大气压,–20℃搅拌100h。慢慢释放氢气,除去溶剂后用硅胶柱分离得到白色粉末(Ia)(0.960g,90%收率,dr(cis/trans)=1.8:1,cis:91%ee,重结晶后ee>99%,trans:91%ee,重结晶后ee>99%),
以甲苯为溶剂。将1,5-环辛二烯氯化铱二聚体(0.020g,0.030mmol)、(S,S)-f-Binaphane(0.050g,0.063mmol)和甲苯(50mL)溶于干燥的反应瓶中,静置15min,然后向反应瓶中加入4-(4,9-二氢-3H-吡啶骈[3,4-b]吲哚-1-基)-4-乙基庚二酸二甲酯(IIa)(1.150g,3.000mmol)和碘化钾(0.050g,0.300mmol)的脱气甲苯(50mL)溶液,将其置于高压反应釜中,氢气置换3次,继而通入氢气至60个大气压,–20℃搅拌100h。慢慢释放氢气,除去溶剂后用硅胶柱分离得到白色粉末(Ia)[1.009g,95%收率,dr(cis/trans)=1:5,cis:94%ee,重结晶后ee>99%,trans:94%ee,重结晶后ee>99%)]。
1H NMR(600MHz,氯仿-d)δ8.05(s,1H),7.51(d,J=5.2Hz,1H),7.36(d,J=5.2Hz,1H),7.19(t,J=5.2Hz,1H),7.13(t,J=5.2Hz,1H),5.20–5.10(m,1H),4.83(s,1H),3.57(s,3H),2.88–2.70(m,3H),2.60–2.42(m,2H),2.16–2.12(m,2H),2.00–1.86(m,2H),1.80–1.74(m,2H),1.59–1.55(m,1H),1.49–1.39(m,1H),1.17(t,J=5.2Hz,3H)ppm.HRMS(ESI)m/z C21H26NaN2O3[M+Na]+的理论值:377.1836,实测值:377.1838。
实施例2
3-[(1S,12bS)-1-乙基-1,2,3,4,6,7,12,12b-八氢-4-氧代吲哚骈[2,3-a]喹嗪-1-基]丙酸异丙酯(Ib)的制备
氩气氛围下,将1,5-环辛二烯氯化铱二聚体(0.008g,0.012mmol)、(S,S)-f-Binaphane(0.021g,0.026mmol)溶于甲苯(2mL)中,再通过注射器加入5.3mmol/mL碘化氢水溶液(0.013mL),室温搅拌10h后,浓缩除去溶剂,并将所得固体溶于二氯甲烷(0.5mL),然后加入正己烷(0.5mL),继而将析出固体抽滤、干燥后再溶于脱气N,N-二甲基甲酰胺/乙酸乙酯(v/v 1:1)(24mL)中,然后一次加入4-(4,9-二氢-3H-吡啶骈[3,4-b]吲哚-1-基)-4-乙基庚二酸二异丙酯(IIb)(0.211g,0.480mmol)和碘化钠(0.007g,0.048mmol),将其置于高压反应釜中,氢气置换3次,继而通入氢气至60个大气压,–20℃搅拌150h。慢慢释放氢气,除去溶剂后用硅胶柱分离得到白色泡末(Ib)[0.165g,90%收率,dr(cis/trans)=1.9:1,cis:89%ee,trans:88%ee)],
1H NMR(400MHz,氯仿-d)δ8.13(s,1H),7.51(d,J=7.6Hz,1H),7.36(d,J=8.0Hz,1H),7.22–7.07(m,2H),5.18–5.10(m,1H),4.94–4.86(m,1H),4.81(s,1H),2.91–2.69(m,3H),2.59–2.43(m,2H),2.20–2.06(m,2H),1.98–1.84(m,2H),1.83–1.69(m,2H),1.62–1.52(m,1H),1.50–1.42(m,1H),1.18–1.14(m,9H)ppm.HRMS(ESI)C23H30NaN2O3[M+Na]+m/z的理论值:405.2149,实测值:405.2147。
实施例3
3-[(1S,12bS)-1-乙基甲醚基-1,2,3,4,6,7,12,12b-八氢-4-氧代吲哚骈[2,3-a]喹嗪-1-基]丙酸甲酯(Ic)的制备
将1,5-环辛二烯氯化铱二聚体(0.002g,0.003mmol)、(S,S)-f-Binaphane(0.005g,0.006mmol)和脱气甲苯(2mL)溶于干燥的反应瓶中,静置15min,然后向反应瓶中加入4-(4,9-二氢-3H-吡啶骈[3,4-b]吲哚-1-基)-4-乙基甲醚基庚二酸二甲酯(IIc)(0.040g,0.100mmol)和碘化钾(0.002g,0.010mmol)的脱气甲苯(3mL)溶液,将其置于高压反应釜中,氢气置换3次,继而通入氢气至60个大气压,–20℃搅拌120h。慢慢释放氢气,除去溶剂后用硅胶柱分离得到白色泡末(Ic)[0.033g,85%收率,dr(cis/trans)=4.2:1,cis:90%ee,trans:89%ee]。
1H NMR(400MHz,氯仿-d)δ9.42(s,1H),7.51(d,J=6.8Hz,1H),7.36(d,J=8.0Hz,1H),7.21–7.14(td,J=6.8,1.2Hz,1H),7.10(td,J=8.0,1.2Hz,1H),5.18–5.09(m,1H),5.03(s,1H),3.80–3.70(m,2H),3.56(s,3H),3.45(s,3H),2.81–2.67(m,3H),2.65–2.45(m,2H),2.36–2.29(m,1H),2.14–2.00(m,3H),1.83–1.75(m,1H),1.72–1.62(m,1H),1.55–1.48(m,1H),1.35–1.27(m,1H)ppm.HRMS(ESI)m/z C22H28NaN2O4[M+Na]+的理论值:407.1941,实测值:407.1945。
实施例4
3-[(1S,12bS)-1-乙基叔丁醚基-1,2,3,4,6,7,12,12b-八氢-4-氧代吲哚骈[2,3-a]喹嗪-1-基]丙酸甲酯(Id)的制备
氩气氛围下,将1,5-环辛二烯氯化铱二聚体(0.008g,0.012mmol)、(S,S)-f-Binaphane(0.021g,0.026mmol)溶于甲苯(2mL)中,再通过注射器加入5.3mmol/mL碘化氢水溶液(0.013mL),室温搅拌10h后,浓缩除去溶剂,并将所得固体溶于二氯甲烷(0.5mL),然后加入正己烷(0.5mL),继而将析出固体抽滤、干燥后再溶于脱气甲苯(22mL)中,然后一次加入4-(4,9-二氢-3H-吡啶骈[3,4-b]吲哚-1-基)-4-乙基叔丁醚基庚二酸二甲酯(IId)(0.228g,0.500mmol)和碘化钾(0.025g,0.150mmol),将其置于高压反应釜中,氢气置换3次,继而通入氢气至60个大气压,–20℃搅拌150h。慢慢释放氢气,除去溶剂后用硅胶柱分离得到黄色粉末(Id)[0.206g,92%收率,dr(cis/trans)=17:1,cis:88%ee,重结晶后ee>99%,trans:78%ee],
1H NMR(400MHz,氯仿-d)δ10.04(s,1H),7.52(d,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H),7.21–7.13(t,J=8.0Hz,1H),7.10(t,J=7.6Hz,1H),5.20–5.10(m,1H),5.07(s,1H),3.87–3.64(m,2H),3.56(s,3H),2.85–2.66(m,3H),2.62–2.48(m,2H),2.28–2.21(m,1H),2.14–1.96(m,3H),1.87–1.66(m,2H),1.55–1.49(m,1H),1.37–1.26(m,10H)ppm.HRMS(ESI)m/z C25H34NaN2O4[M+Na]+的理论值:449.2411,实测值:449.2411。
以上所述仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到许多变化或替换,它们都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求的保护范围为准。
Claims (7)
1.一种式(I)的(1S,12bS)内酰胺酯化合物的合成方法,
所述方法如以下反应路线所示,通过在铱金属催化剂前体、手性双膦配体和一种或多于一种含卤添加剂的存在下,使式(II)的二氢咔啉双酯化合物在氢气气氛下,在有机溶剂中进行不对称氢化和内酰胺化反应,制得式(I)的(1S,12bS)内酰胺酯化合物,
其中:
R1为氢、直链或支链C1~C5烷基醚基、烯丙基醚基、苄基醚基、甲基硅烷基醚基、异丙基硅烷基醚基、叔丁基硅烷基醚基或苯基硅烷基醚基;
R2为直链或支链C1~C5烷基、芳烷基或芳基;
R3位于其所在苯环上的任何可取代的位置上,并且为氢、直链或支链C1-C5烷基、直链或支链C1~C3烷氧基或卤素;
所述手性双膦配体为(S,S)-f-Binaphane;
所述铱金属催化剂前体为1,5-环辛二烯氯化铱二聚体;
所述含卤添加剂为碘化钾和氢碘酸的混合物、碘化钠和氢碘酸的混合物、碘化钾及碘化钠中的任意一种。
2.如权利要求1所述的方法,其中:
R1为氢或直链或支链C1~C5烷基醚基;
R2为直链或支链C1~C5烷基;
R3为氢、直链或支链C1~C5烷基。
3.如权利要求1所述的方法,其中所述方法中使用的式(II)的二氢咔啉双酯化合物、铱金属催化剂前体、手性双膦配体、全部含卤添加剂中所含卤素阴离子的摩尔比为1:0.01~0.05:0.02~0.1:0.1~0.5。
4.如权利要求1所述的方法,其中在不对称氢化和内酰胺化反应中采用的氢气压力为20~100大气压,反应温度为–40~40℃,反应时间为48~200h。
5.如权利要求1所述的方法,其中所述有机溶剂为非质子极性有机溶剂、两种或多种非质子极性有机溶剂的组合或非质子非极性有机溶剂。
6.如权利要求1或2所述的方法,其中所述含卤添加剂为一种含卤添加剂,并且所述方法包括步骤:
1)首先,将铱金属催化剂前体与手性双膦配体分散在一部分有机溶剂中,在室温下静置或搅拌10~30min,得到溶液,
2)然后,向步骤1)所得溶液中加入式(II)的二氢咔啉双酯化合物、含卤添加剂和其余有机溶剂的溶液,得到总溶液;
3)将步骤2)得到的总溶液转移到高压反应釜中,并且在氢气气氛下进行不对称氢化和内酰胺化反应。
7.如权利要求1或2所述的方法,其中所述含卤添加剂为分别表示为第1含卤添加剂和第2含卤添加剂的2种不同的含卤添加剂,并且所述方法包括步骤:
1)首先,在惰性气体气氛下,将铱金属催化剂前体与手性双膦配体分散在有机溶剂中,然后加入第1含卤添加剂,并在搅拌下,室温下反应5~20h,得到卤素桥联的铱络合物溶液;
2)将步骤1)所得卤素桥联的铱络合物从溶液中分离并纯化,将所得纯化的固体干燥;
3)然后,将步骤2)得到的干燥固体溶于与步骤1)的有机溶剂相同或不同的有机溶剂中,并加入式(II)的二氢咔啉双酯化合物和第2含卤添加剂,得到总溶液;
4)将步骤3)所得总溶液转移到高压反应釜中,并且在氢气气氛下进行不对称氢化和内酰胺化反应,
其中,所述第1含卤添加剂中所含卤素阴离子与第2含卤添加剂中所含卤素阴离子的摩尔比为0.2~2:1。
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