CN114478378B - 一种异喹啉类化合物的合成方法 - Google Patents
一种异喹啉类化合物的合成方法 Download PDFInfo
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- CN114478378B CN114478378B CN202210192363.4A CN202210192363A CN114478378B CN 114478378 B CN114478378 B CN 114478378B CN 202210192363 A CN202210192363 A CN 202210192363A CN 114478378 B CN114478378 B CN 114478378B
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- Prior art keywords
- ethyl acetate
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- isoquinoline
- water
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title claims abstract description 152
- -1 isoquinoline compound Chemical class 0.000 title claims abstract description 82
- 238000010189 synthetic method Methods 0.000 title claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 78
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 58
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims abstract description 52
- 125000003118 aryl group Chemical group 0.000 claims abstract description 51
- 239000001257 hydrogen Substances 0.000 claims abstract description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 229910052802 copper Inorganic materials 0.000 claims abstract description 17
- 239000010949 copper Substances 0.000 claims abstract description 17
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000001308 synthesis method Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 387
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 78
- 239000003480 eluent Substances 0.000 claims description 72
- 238000000926 separation method Methods 0.000 claims description 40
- 239000003208 petroleum Substances 0.000 claims description 39
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 36
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 150000002537 isoquinolines Chemical class 0.000 abstract description 27
- 229910052723 transition metal Inorganic materials 0.000 abstract description 5
- 150000003624 transition metals Chemical class 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- 125000004430 oxygen atom Chemical group O* 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 97
- 238000006243 chemical reaction Methods 0.000 description 55
- 239000007788 liquid Substances 0.000 description 52
- 239000012043 crude product Substances 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 238000000605 extraction Methods 0.000 description 30
- 238000001228 spectrum Methods 0.000 description 30
- 238000001819 mass spectrum Methods 0.000 description 29
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 29
- 239000012071 phase Substances 0.000 description 29
- 239000000047 product Substances 0.000 description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 28
- 239000011259 mixed solution Substances 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 4
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- MYCMTMIGRXJNSO-UHFFFAOYSA-N moxaverine Chemical compound N=1C(CC)=CC2=CC(OC)=C(OC)C=C2C=1CC1=CC=CC=C1 MYCMTMIGRXJNSO-UHFFFAOYSA-N 0.000 description 4
- 229960002902 moxaverine Drugs 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 description 3
- HTFNVAVTYILUCF-UHFFFAOYSA-N 2-[2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]anilino]-5-methyl-11-methylsulfonylpyrimido[4,5-b][1,4]benzodiazepin-6-one Chemical compound CCOc1cc(ccc1Nc1ncc2N(C)C(=O)c3ccccc3N(c2n1)S(C)(=O)=O)C(=O)N1CCC(CC1)N1CCN(C)CC1 HTFNVAVTYILUCF-UHFFFAOYSA-N 0.000 description 3
- UQQROBHFUDBOOK-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzaldehyde Chemical compound COC1=CC(Br)=C(C=O)C=C1OC UQQROBHFUDBOOK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- KAVCPAPEQJQJKH-UHFFFAOYSA-N 1,4-diphenylbut-3-yn-1-one Chemical compound C=1C=CC=CC=1C(=O)CC#CC1=CC=CC=C1 KAVCPAPEQJQJKH-UHFFFAOYSA-N 0.000 description 1
- CREOHKRPSSUXCW-UHFFFAOYSA-N 2-iodo-1-phenylethanone Chemical compound ICC(=O)C1=CC=CC=C1 CREOHKRPSSUXCW-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 238000005590 Gabriel-Colman reaction Methods 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000006796 Pomeranz-Fritsch reaction Methods 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 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
- 239000002274 desiccant Substances 0.000 description 1
- 238000010981 drying operation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- SCEZYJKGDJPHQO-UHFFFAOYSA-M magnesium;methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=CC=C1 SCEZYJKGDJPHQO-UHFFFAOYSA-M 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 229960005181 morphine Drugs 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
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/06—Halogens; Compounds thereof
- B01J27/08—Halides
- B01J27/122—Halides of copper
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及过渡金属催化合成技术领域,具体涉及一种异喹啉类化合物的合成方法。本发明提供的异喹啉类化合物的合成方法,包括以下步骤:将具有式I结构的反式2‑炔基芳香肟醚、铜基催化剂和水混合,进行环化反应,得到具有式II所示结构的异喹啉类化合物。本发明以反式2‑炔基芳香肟醚为原料,以铜基催化剂作为催化剂,水作为介质,利用反式2‑炔基芳香肟醚含有氮原子和氧原子,易和水介质形成氢键,增强反式2‑炔基芳香肟醚在水中的溶解度,同时利用铜基催化剂催化,促成成环反应的发生,进而得到异喹啉类化合物。
Description
技术领域
本发明涉及过渡金属催化合成技术领域,具体涉及一种异喹啉类化合物的合成方法。
背景技术
天然产物中小檗碱、吗啡、可待因和罂粟碱等生物碱化学结构中都含有异喹啉骨架结构。异喹啉类化合物是一类非常重要的药物中间体,具有显著的止痛、抑菌、抗疟疾、抗肿瘤、抗艾滋等生物活性。异喹啉及其衍生物的全合成和部分结构修饰构效关系和药物活性的研究日趋活跃,特别是异喹啉的高效绿色合成方法已经成为研究的热点领域。传统合成异喹啉及其衍生物的方法主要有Gabriel-Colman法、Pomeranz-Fritsch法和Bischler-Napieralski法等,但是大部分合成方法存在使用强酸强碱、剧毒试剂、合成过程繁琐、反应条件苛刻、收率低、合成工艺对环境污染大等现象。近年来,过渡金属催化、微波技术、点击化学、光催化等新技术新方法应用于异喹啉及其衍生物的合成研究被不断报道,尤其是过渡金属催化反应展现了无穷的魅力和高效性。
过渡金属(钯、铑、铱、银和钴)催化反应大多数都是使用有机溶剂作为反应介质,例如苯、甲苯、四氢呋喃、二氯甲烷、乙腈、N,N-二甲基甲酰胺和二甲基亚砜等,对环境污染严重,不符合绿色化学的进程及概念。
发明内容
鉴于此,本发明的目的在于提供一种异喹啉类化合物的合成方法,本发明提供的异喹啉类化合物的合成方法以水作为反应介质,绿色环保,对环境无污染。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种异喹啉类化合物的合成方法,包括以下步骤:
将具有式I结构的反式2-炔基芳香肟醚、铜基催化剂和水混合,进行环化反应,得到具有式II所示结构的异喹啉类化合物;
所述式I和式II中,Ar为吡啶基、噻吩、苯基、取代苯基或萘基;
所述式I和式II中,R1为氢基、烷基或苯基;
所述式I和式II中,R2为氢基、噻吩基、烷基、苯基、取代苯基或联苯基。
优选地,所述铜基催化剂包括卤化亚铜或卤化铜。
优选地,所述铜基催化剂与反式2-炔基芳香肟醚的摩尔比为1~10:100。
优选地,所述环化反应的温度为80~120℃;时间为15~24h。
优选地,所述反式2-炔基芳香肟醚和水的用量比为0.5mmol:2mL。
优选地,所述环化反应后,还包括进行后处理;所述后处理包括将得到的反应液依次进行萃取,所得有机相依次进行干燥、过滤、浓缩和纯化。
优选地,所述纯化包括色谱柱分离。
优选地,所述纯化包括色谱柱分离的洗脱剂为石油醚和乙酸乙酯的混合液。
优选地,所述洗脱剂中石油醚和乙酸乙酯的体积比为10~50:1。
本发明提供了一种异喹啉类化合物的合成方法,包括以下步骤:将具有式I结构的反式2-炔基芳香肟醚、铜基催化剂和水混合,进行环化反应,得到具有式II结构的异喹啉类化合物。本发明以简单易得的反式2-炔基芳香肟醚为反应底物,以铜基催化剂作为催化剂,水作为介质,利用反式2-炔基芳香肟醚含有氮原子和氧原子,易和水介质形成氢键,增强反式2-炔基芳香肟醚在水中的溶解度,同时利用铜基催化剂催化,促成成环反应的发生,进而得到所述异喹啉类化合物。本发明以水为介质,并未使用有机污染试剂,方法绿色环保。
附图说明
图1为实施例1所得产物异喹啉A1的核磁氢谱图;
图2为实施例1所得产物异喹啉A1的核磁碳谱图;
图3为实施例1所得产物异喹啉A1的高分辨质谱。
具体实施方式
本发明提供了一种异喹啉类化合物的合成方法,包括以下步骤:
将具有式I结构的反式2-炔基芳香肟醚、铜基催化剂和水混合,进行环化反应,得到具有式II所示结构的异喹啉类化合物;
本发明中,所述式I和式II中,Ar为吡啶基、噻吩基、苯基、取代苯基或萘基;
本发明中,所述Ar中,所述取代苯基的取代基优选包括卤基、卤代烷基、烷氧基或羟基;所述卤基优选包括氯基、溴基或氟基;所述卤代烷基优选包括三氟甲基;所述烷氧基优选包括甲氧基。
本发明中,所述式I和式II中,R1为氢基、烷基或苯基。本发明中,所述R1中烷基优选包括C1~C5的烷基,所述C1~C5的烷基优选包括C1~C5的链烷基;所述C1~C5的链烷基优选包括甲基或乙基。
本发明中,所述式I和式II中,R2为氢基、噻吩基、烷基、苯基、取代苯基或联苯基。
本发明中,所述R2中烷基优选包括C1~C5的烷基;所述C1~C5的烷基优选包括C1~C5的链烷基或C1~C5的环烷基;所述C1~C5的链烷基优选包括甲基、乙基或戊基;所述戊基优选包括正戊基或新戊基;所述C1~C5的环烷基优选包括环丙烷基或环戊基。本发明中,所述R2中取代苯基的取代基优选包括四甲硅烷基、氨基或卤基;所述卤基优选包括氯基、溴基或氟基。
本发明实施例中,具有式II所示结构的异喹啉类化合物具体优选为:
本发明中,所述具有式I所示结构的反式2-炔基芳香肟醚优选自制得到,所述具有式I所示结构的反式2-炔基芳香肟醚的制备,优选包括以下步骤:
将具有式a结构的化合物a和具有式b结构的炔类化合物b在催化剂的条件下进行偶联反应,得到具有式c结构的化合物c,然后将所述化合物c、MeONH·HCl和吡啶混合,进行取代反应,得到所述反式2-炔基芳香肟醚。
本发明中,所述Ar、R1或R2优选同式I或式II中Ar的结构相同,此处不再赘述。
本发明中,所述偶联反应的温度优选为50~70℃,进一步优选为60~70℃。本发明中,所述化合物c的制备过程中,所述催化剂优选为碘化亚铜和二(三苯基膦)二氯化钯的混合物;所述碘化亚铜和二(三苯基膦)二氯化钯的摩尔比优选为1~5:1~10,进一步优选为1:2。本发明中,所述偶联反应优选在三乙胺介质中进行。
本发明中,所述取代反应的温度优选为20~35℃,进一步优选为25~30℃,时间优选为8~12h,进一步优选为12h。本发明中,所述取代反应优选在乙醇介质中进行。
在本发明中,所述反式2-炔基芳香肟醚的反应流程为:
得到反式2-炔基芳香肟醚后,本发明将所述反式2-炔基芳香肟醚、铜基催化剂和水混合,进行环化反应,得到具有式II所示结构的异喹啉类化合物。
本发明中,所述铜基催化剂优选包括卤化亚铜或卤化铜,所述卤化亚铜优选包括碘化亚铜、溴化亚铜或氯化亚铜,进一步优选为碘化亚铜;所述卤化铜优选包括溴化铜。本发明中,所述铜基催化剂与反式2-炔基芳香肟醚的摩尔比优选为1~10:100,进一步优选为5~10:100。本发明中,所述反式2-炔基芳香肟醚和水的用量比优选为0.2~1mmol:1~5mL,进一步优选为0.5mmol:2mL。
本发明中,所述环化反应的温度优选为80~120℃,进一步优选为90~100℃,具体优选为80℃、90℃、100℃或120℃;时间优选为15~24h,进一步优选为15h或24h。
本发明中,所述环化反应的反应流程如下所示:
所述环化反应后,本发明优选还包括进行后处理;所述后处理包括将得到的反应液依次进行萃取,所得有机相依次进行干燥、过滤、浓缩和纯化。本发明中,所述萃取的萃取剂优选为乙酸乙酯和去离子水的混合液;所述萃取剂中乙酸乙酯和去离子水的体积比优选为1~3:1,进一步优选为2~3:1;本发明中,所述环化反应料液和乙酸乙酯的体积比优选为1:5~10,进一步优选为1:5。所述萃取的次数优选为2~3次,进一步优选为3次。本发明中,所述干燥的干燥剂优选包括无水硫酸钠,本发明对干燥的操作和参数不做具体限定,能够去除反应体系中的水分即可。本发明对过滤的操作不作具体限定,采用本领域技术人员熟知的操作即可。本发明对所述浓缩的操作和参数不作具体限定个,采用本领域技术人员熟知的操作将过滤所得料液浓缩至粘稠状即可。
本发明中,所述纯化优选包括色谱柱分离;所述色谱柱分离优选包括以下步骤:将浓缩所得的粗品进行色谱柱分离,所得洗脱液进行减压蒸馏,得到异喹啉类化合物。本发明中,所述色谱柱分离的洗脱液优选为石油醚和乙酸乙酯的混合液,所述洗脱液中石油醚和乙酸乙酯的体积优选为10~50:1,进一步优选为10:1、30:1或50:1。本发明对所述洗脱液进行减压蒸馏的操作不作具体限定,采用本领域技术人员熟知的操作能够将溶剂去除即可。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
在氩气氛围下,在100mL的schlenk茄形反应瓶中依次加入2-碘苯乙酮4.92g(20mmol)、苯乙炔2.25g(22mmol)、三乙胺50mL、二(三苯基膦)二氯化钯421mg(0.6mmol)和碘化亚铜228mg(1.2mmol)。然后将反应体系移至油浴锅中,加热至50℃搅拌反应12h后,静置至室温。然后将反应后所得料液依次进行萃取、干燥、过滤和蒸干,所得粗品进行色谱柱分离,洗脱剂为石油醚和乙酸乙酯(体积比100:1),所得产物为淡黄色液体4.18g(19mmol),收率95%。
所得产物2-(苯乙炔基)苯乙酮化合物的核磁数据如下:1H NMR(400MHz,CDCl3):δ7.77-7.79(m,1H),7.65-7.67(m,1H),7.56-7.59(m,2H),7.50(td,J=1.6,7.6Hz,2H),7.43(dd,J=1.2,7.6Hz,1H),7.38-7.41(m,3H),2.82(s,3H)ppm;13C NMR(100MHz,CDCl3):δ200.4,133.9,131.5,131.3,128.8,128.7,128.5,128.3,122.9,121.7,95.1,88.5,30.0ppm。
在50mL的圆底烧瓶中,依次加入2-(苯乙炔基)苯乙酮4.18g(19mmol),乙醇30mL,吡啶3.0g(38mmol),甲氧基胺盐酸盐1.95g(28.5mmol)。室温下搅拌12h后,将反应后所得料液依次进行萃取、干燥、过滤和蒸干,所得粗品进行色谱柱分离,洗脱剂为石油醚和乙酸乙酯(体积比200:1),所得产物为反式2-炔基芳香肟醚化合物(淡黄色液体)4.0g(16.1mmol),收率85%。
所得产物反式2-炔基芳香肟醚化合物的核磁数据如下:1H NMR(400MHz,CDCl3):δ7.59-7.62(m,1H),7.52-7.56(m,2H),7.43-7.46(m,1H),7.35-7.40(m,5H),4.05(s,3H),2.40(s,3H)ppm;13C NMR(100MHz,CDCl3):δ156.8,140.0,133.0,131.4,128.48,128.46,128.42,123.3,121.7,93.6,88.2,61.9,16.0ppm。
将反式2-炔基芳香肟醚125mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水2mL和乙酸乙酯10mL,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤、浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体105mg,收率为95%,记为异喹啉类化合物A1,反应流程如下:
图1为实施例1所得产物异喹啉类化合物A1的核磁氢谱图,图谱信息为:
1H NMR(400MHz,CDCl3):δ8.17-8.19(m,2H),8.13-8.16(m,1H),7.95(s,1H),7.86-7.89(m,1H),7.67-7.71(m,1H),7.57-7.61(m,1H),7.52-7.56(m,2H),7.42-7.46(m,1H),3.08(s,3H)ppm。
图2为实施例1所得产物异喹啉类化合物A1的核磁碳谱图,图谱信息为:
13C NMR(100MHz,CDCl3):δ158.6,150.0,139.9,136.8,130.0,128.8,128.3,127.7,127.0,126.8,126.6,125.7,115.3,22.7ppm。
图3为实施例1所得产物异喹啉类化合物A1的高分辨质谱,图谱信息为HRMS(ESI)m/z:calcd for C16H14N[M+H]+220.1121;found 220.1119。
实施例2
将反式2-炔基芳香肟醚132mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体114mg,收率为98%,记为异喹啉类化合物A2,反应流程如下:
实施例2所得产物异喹啉类化合物A2的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.13-8.15(m,1H),8.05-8.09(m,2H),7.92(s,1H),7.85-7.87(m,1H),7.66-7.70(m,1H),7.55-7.59(m,1H),7.32-7.35(m,2H),3.06(s,3H),2.46(s,3H)ppm。
实施例2所得产物异喹啉类化合物A2的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.5,150.1,138.2,137.1,136.8,130.0,129.5,127.6,126.9,126.6,126.5,125.6,114.7,22.7,21.3ppm。
实施例2所得产物异喹啉类化合物A2的高分辨质谱图图谱信息为:HRMS(ESI)m/z:calcd forC17H16N[M+H]+234.1277;found 234.1276。
实施例3
将反式2-炔基芳香肟醚140mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体116mg,收率为93%,记为异喹啉类化合物A3,反应流程如下:
实施例3所得产物异喹啉类化合物A3的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.10-8.14(m,3H),7.83-7.86(m,2H),7.65-7.69(m,1H),7.53-7.58(m,1H),7.04-7.07(m,2H),3.90(s,3H),3.05(s,3H)ppm。
实施例3所得产物异喹啉类化合物A3的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ160.0,158.4,149.8,136.9,132.6,130.0,128.2,127.5,126.4,126.3,125.7,114.1,55.4,22.7ppm。
实施例3所得产物异喹啉类化合物A3的高分辨质谱图图谱信息为:HRMS(ESI)m/z:calcd for C17H16NO[M+H]+250.1226;found 250.1225。
实施例4
将反式2-炔基芳香肟醚153mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体126mg,收率为91%,记为异喹啉类化合物A4,反应流程如下:
实施例4所得产物异喹啉类化合物A4的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.13-8.16(m,1H),8.06-8.10(m,2H),7.92(s,1H),7.86-7.89(m,1H),7.66-7.70(m,1H),7.53-7.60(m,3H),3.06(s,3H),1.41(s,9H)ppm。
实施例4所得产物异喹啉类化合物A4的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.5,151.4,150.2,137.1,136.8,129.9,127.6,126.7,126.6,126.5,125.69,125.66,114.9,34.7,31.4,22.7ppm。
实施例4所得产物异喹啉类化合物A4的高分辨质谱图图谱信息为:HRMS(ESI)m/z:calcd for C20H22N[M+H]+276.1747;found 276.1744。
实施例5
将反式2-炔基芳香肟醚134mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体106mg,收率为89%,记为异喹啉类化合物A5,反应流程如下:
实施例5所得产物异喹啉类化合物A5的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.12-8.16(m,3H),7.85-7.88(m,2H),7.67-7.71(m,1H),7.57-7.61(m,1H),7.17-7.23(m,2H),3.05(s,3H)ppm。
实施例5所得产物异喹啉类化合物A5的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ163.2(d,J=245.8Hz),158.7,149.0,136.8,136.0(d,J=3.0Hz),130.1,128.7(m,J=8.1Hz)127.6,126.9,126.5,125.7,115.6(d,J=21.4Hz),114.9,22.7ppm;
实施例5所得产物异喹啉类化合物A5的核磁氟谱图图谱信息为19F NMR(CDCl3):δ-114.2ppm;
实施例5所得产物异喹啉类化合物A5的高分辨质谱图图谱信息为:HRMS(ESI)m/z:calcd for C16H13FN[M+H]+238.1027;found 238.1024。
实施例6
将反式2-炔基芳香肟醚134mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体94mg,收率为74%,记为异喹啉类化合物A6,反应流程如下:
实施例6所得产物异喹啉类化合物A6的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.09-8.14(m,3H),7.89(s,1H),7.84-7.87(m,1H),7.67-7.71(m,1H),7.57-7.62(m,1H),7.46-7.50(m,2H),3.05(s,3H)ppm。
实施例6所得产物异喹啉类化合物A6的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.7,148.7,138.3,136.7,134.3,130.2,128.9,128.2,127.6,127.0,126.7,125.7,115.1,22.7ppm。
实施例6所得产物异喹啉类化合物A6的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C16H13ClN[M+H]+254.0731;found 254.0728。
实施例7
将反式2-炔基芳香肟醚164mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体112mg,收率为75%,记为异喹啉类化合物A7,反应流程如下:
实施例7所得产物异喹啉类化合物A7的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.19-8.21(m,1H),7.88-7.90(m,1H),7.81(s,1H),7.71-7.75(m,2H),7.63-7.67(m,2H),7.45(td,J=1.2,7.6Hz,1H),7.25-7.29(m,1H),3.06(s,3H)ppm。
实施例7所得产物异喹啉类化合物A7的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.4,150.7,141.6,135.9,133.3,131.8,130.2,129.3,127.7,127.5,127.3,126.5,125.7,122.4,119.8,22.5ppm。
实施例7所得产物异喹啉类化合物A7的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C16H13BrN[M+H]+298.0226;found 298.0223。
实施例8
将反式2-炔基芳香肟醚159mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体89mg,收率为62%,记为异喹啉类化合物A8,反应流程如下:
实施例8所得产物异喹啉类化合物A8的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.26-8.28(m,2H),8.14-8.17(m,1H),7.97(s,1H),7.87-7.90(m,1H),7.75-7.78(m,2H),7.70-7.74(m,1H),7.61-7.65(m,1H),3.06(s,3H)ppm。
实施例8所得产物异喹啉类化合物A8的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ159.0,148.3,143.2(q,J=1.8Hz),136.6,130.3,130.1(q,J=32.1Hz),127.8,127.4,127.2,127.0,125.7,125.6(q,J=3.7Hz),124.4(q,J=270.3Hz),116.0,22.6ppm。
实施例8所得产物异喹啉类化合物A8的核磁氟谱图图谱信息为19F NMR(CDCl3):δ-62.4ppm。
实施例8所得产物异喹啉类化合物A8的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C17H13F3N[M+H]+288.0995;found 288.0992。
实施例9
将反式2-炔基芳香肟醚161mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到黄色液体118mg,收率为81%,记为异喹啉类化合物A9,反应流程如下:
实施例9所得产物异喹啉类化合物A9的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.18-8.21(m,1H),7.86-7.89(m,1H),7.70-7.78(m,3H),7.61-7.65(m,1H),7.56-7.59(m,1H),7.41-7.50(m,2H),3.06(s,3H),0.11(s,9H)ppm。
实施例9所得产物异喹啉类化合物A9的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ157.6,154.4,147.7,139.3,136.5,135.4,130.1,129.4,128.8,127.5,127.1,126.8,126.3,125.6,118.0,22.0,0.9ppm。
实施例9所得产物异喹啉类化合物A9的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C19H22NSi[M+H]+292.1516;found 292.1513。
实施例10
将反式2-炔基芳香肟醚132mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为10:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体118mg,收率为47%,记为异喹啉类化合物A10,反应流程如下:
实施例10所得产物异喹啉类化合物A10的核磁氢谱图图谱信息为:1H NMR(400MHz,DMSO-d6):δ8.20-8.23(m,1H),7.98-8.01(m,2H),7.74-7.78(m,1H),7.62-7.66(m,1H),7.55-7.58(m,1H),7.08-7.12(m,1H),6.79(d,J=8.0Hz,1H),6.65-6.89(m,1H),6.37(s,2H,NH2),2.95(s,3H)ppm。
实施例10所得产物异喹啉类化合物A10的核磁碳谱图图谱信息为:13C NMR(100MHz,DMSO-d6):δ157.3,152.1,147.9,137.1,130.8,129.8,129.7,128.0,127.4,126.1,125.5,122.1,116.94,116.87,1116.7,22.7ppm。
实施例10所得产物异喹啉类化合物A10的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C16H15N2[M+H]+235.1230;found 235.1227。
实施例11
将反式2-炔基芳香肟醚150mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体121mg,收率为90%,记为异喹啉类化合物A11,反应流程如下:
实施例11所得产物异喹啉类化合物A11的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.71-8.72(m,1H),8.29-8.32(m,1H),8.15-8.18(m,1H),8.08(s,1H),7.99-8.04(m,2H),7.88-7.93(m,2H),7.68-7.72(m,1H),7.51-7.63(m,3H),3.12(s,3H)ppm。
实施例11所得产物异喹啉类化合物A11的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.7,149.8,137.1,136.8,133.8,133.5,130.1,128.8,128.4,127.7,126.9,126.7,126.22,126.20,125.7,124.8,115.6,22.8ppm。
实施例11所得产物异喹啉类化合物A11的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C20H16N[M+H]+270.1277;found。
实施例12
将反式2-炔基芳香肟醚163mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至120℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体126mg,收率为85%,记为异喹啉类化合物A12,反应流程如下:
实施例12所得产物异喹啉类化合物A12的核磁氢谱图图谱信息为:1H NMR(400MHz,CDCl3):δ8.24-8.27(m,2H),8.15-8.18(m,1H),8.00(s,1H),7.89-7.91(s,1H),7.75-7.78(m,2H),7.69-7.73(m,3H),7.58-7.63(m,1H),7.48-7.52(m,2H),7.38-7.42(m,1H),3.09(s,3H)ppm。
实施例12所得产物异喹啉类化合物A12的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.7,149.6,141.1,140.9,138.8,136.8,130.1,128.8,127.7,127.5,127.38,127.36,127.1,126.8,126.7,125.7,115.1,22.7ppm。
实施例12所得产物异喹啉类化合物A12的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C22H18N[M+H]+296.1434;found 296.1432。
实施例13
将反式2-炔基芳香肟醚128mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体80mg,收率为71%,记为异喹啉类化合物A13,反应流程如下:
实施例13所得产物异喹啉类化合物A13的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.08-8.12(s,1H),7.85(s,1H),7.80-7.83(m,1H),7.71(dd,J=1.2,3.6Hz,1H),7.64-7.69(m,1H),7.53-7.57(m,1H),7.40-7.41(m,1H),7.17(dd,J=3.6,5.2Hz,1H),3.02(s,3H)ppm。
实施例13所得产物异喹啉类化合物A13的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.8,145.5,145.4,136.6,130.2,128.1,127.4,126.7,126.6,125.8,123.8,113.1,22.5ppm。
实施例13所得产物异喹啉类化合物A13的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd forC14H12NS[M+H]+226.0685;found 226.0683。
实施例14
将反式2-炔基芳香肟醚107mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体71mg,收率为81%,记为异喹啉类化合物A14,反应流程如下:
实施例14所得产物异喹啉类化合物A14的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.03-8.06(s,1H),7.69-7.71(m,1H),7.58-7.62(m,1H),7.45-7.50(m,1H),7.28(s,1H),2.93(s,3H),2.16-2.22(m,1H),1.00-1.11(m,4H)ppm。
实施例14所得产物异喹啉类化合物A14的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.1,154.9,136.6,129.7,126.5,125.9,125.59,125.55,114.3,22.4,17.1,8.9ppm。
实施例14所得产物异喹啉类化合物A14的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C13H14N[M+H]+184.1121;found 184.1120。
实施例15
将反式2-炔基芳香肟醚121mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至90℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体90mg,收率为85%,记为异喹啉类化合物A15,反应流程如下:
实施例15所得产物异喹啉类化合物A15的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.00-8.03(m,1H),7.67-7.70(m,1H),7.54-7.58(m,1H),7.43-7.48(m,1H),7.32(s,1H),3.24-3.32(m,1H),2.92(m,3H),2.10-2.17(m,2H),1.70-1.89(m,6H)ppm。
实施例15所得产物异喹啉类化合物A15的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ157.9,157.8,136.7,129.6,126.9,126.0,125.9,125.5,114.9,47.9,33.6,25.7,22.4ppm。
实施例15所得产物异喹啉类化合物A15的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C15H18N[M+H]+212.1434;found 212.1432。
实施例16
将反式2-炔基芳香肟醚122mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体82mg,收率为77%,记为异喹啉类化合物A16,反应流程如下:
实施例16所得产物异喹啉类化合物A16的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.06-8.09(m,1H),7.72-7.74(m,1H),7.60-7.64(m,1H),7.49-7.53(m,1H),7.33(s,1H),2.96(s,3H),2.89-2.93(m,2H),1.79-1.86(m,2H),1.39-1.43(m,4H),0.91-0.95(m,3H)ppm。
实施例16所得产物异喹啉类化合物A16的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ158.0,154.6,136.7,129.7,126.8,126.0,125.8,125.5,116.5,38.2,31.7,29.7,22.6,22.4,14.1ppm。
实施例16所得产物异喹啉类化合物A16的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C15H20N[M+H]+214.1590;found 214.1588。
实施例17
将反式2-炔基芳香肟醚128mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到无色液体98mg,收率为87%,记为异喹啉类化合物A17,反应流程如下:
实施例17所得产物异喹啉类化合物A17的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.08-8.11(m,2H),7.98(s,1H),7.67(d,J=5.2Hz,1H),7.50-7.55(m,2H),7.41-7.45(m,2H),2.91(s,3H)ppm。
实施例17所得产物异喹啉类化合物A17的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ152.6,151.9,146.0,140.1,134.3,131.3,128.8,128.3,127.1,124.1,112.5,23.8ppm。
实施例17所得产物异喹啉类化合物A17的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C14H12NS[M+H]+226.0685;found 226.0683。
实施例18
将反式2-炔基芳香肟醚125mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体60mg,收率为54%,记为异喹啉类化合物A18,反应流程如下:
实施例18所得产物异喹啉类化合物A18的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.05-9.07(m,1H),8.41-8.44(m,1H),8.19-8.21(m,3H),7.51-7.55(m,2H),7.43-7.49(m,2H),3.04(s,3H)ppm。
实施例18所得产物异喹啉类化合物A18的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ159.4,154.4,153.8,151.7,139.1,133.9,129.0,128.8,127.2,121.7,121.6,116.3,22.1ppm。
实施例18所得产物异喹啉类化合物A18的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C15H13N2[M+H]+221.1073;found 221.1072。
实施例19
将反式2-炔基芳香肟醚118mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体92mg,收率为90%,记为异喹啉类化合物A19,反应流程如下:
实施例19所得产物异喹啉类化合物A19的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.37(s,1H),8.15-8.18(m,2H),8.09(s,1H),8.01(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.69-7.73(m,1H),7.53-7.63(m,3H),7.43-7.47(m,1H)ppm。
实施例19所得产物异喹啉类化合物A19的核磁碳谱图图谱信息为:13C NMR(100MHz,CDCl3):δ152.4,151.3,139.6,136.7,130.5,128.8,128.5,127.8,127.6,127.1,127.0,126.9,116.5ppm。
实施例19所得产物异喹啉类化合物A19的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C15H12N[M+H]+206.0964;found 206.0963。
实施例20
将反式2-炔基芳香肟醚125mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体104mg,收率为95%,记为异喹啉类化合物A20,反应流程如下:
实施例20所得产物异喹啉类化合物A20的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.30(s,1H),8.13-8.16(m,2H),8.00(s,1H),7.90(d,J=8.0Hz,1H),7.65(s,1H),7.52-7.56(m,2H),7.42-7.46(m,2H),2.58(s,3H)ppm。
实施例20所得产物异喹啉类化合物A20的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ152.0,151.3,140.9,139.8,137.0,129.4,128.8,128.4,127.3,127.0,126.3,125.8,116.1,22.1ppm。
实施例20所得产物异喹啉类化合物A20的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C16H14N[M+H]+220.1121;found 220.1119。
实施例21
将反式2-炔基芳香肟醚131mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色液体90mg,收率为78%,记为异喹啉类化合物A21,反应流程如下:
实施例21所得产物异喹啉类化合物A21的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ8.09-8.11(m,2H),7.82(s,1H),7.68-7.71(m,1H),7.61-7.63(m,1H),7.50-7.54(m,2H),7.40-7.45(m,2H),3.55-3.58(m,2H),3.46-3.50(m,2H)ppm。
实施例21所得产物异喹啉类化合物A21的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ171.4,154.2,147.5,140.8,134.5,132.9,131.9,128.7,128.2,127.4,121.4,121.3,112.5,32.9,28.7ppm。
实施例21所得产物异喹啉类化合物A21的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C17H14N[M+H]+232.1121;found 232.1119。
实施例22
将反式2-炔基芳香肟醚143mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至120℃,环化反应24h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体78mg,收率为61%,记为异喹啉类化合物A22,反应流程如下:
实施例22所得产物异喹啉类化合物A22的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.34(s,1H),8.86-8.87(m,1H),8.78-8.81(m,1H),8.22-8.24(m,2H),7.95-7.98(m,1H),7.85-7.86(m,2H),7.74-7.77(m,2H),7.59(t,J=7.6Hz,2H),7.49(t,J=7.6Hz,1H)ppm。
实施例22所得产物异喹啉类化合物A22的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ153.4,151.6,140.0,135.6,133.8,128.9,128.78,128.76,128.7,128.2,127.3,127.2,125.9,124.7,123.2,112.6ppm。
实施例22所得产物异喹啉类化合物A22的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd forC19H14N[M+H]+256.1121;found 256.1118。
实施例23
将反式2-炔基芳香肟醚126mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体81mg,收率为73%,记为异喹啉类化合物A23,反应流程如下:
实施例23所得产物异喹啉类化合物A23的核磁氢谱图图谱信息为1H NMR(400MHz,DMSO-d6):δ11.36(br,1H,OH),9.99(s,1H),7.75-7.77(m,2H),7.59(d,J=8.8Hz,1H),7.55(d,J=2.8Hz,1H),7.40-7.50(m,3H),7.21(dd,J=2.8,8.8Hz,1H),6.85(s,1H)ppm。
实施例23所得产物异喹啉类化合物A23的核磁碳谱图图谱信息为13C NMR(100MHz,DMSO-d6):δ162.9,156.8,137.1,134.6,131.0,129.2,129.1,129.0,126.83,126.77,122.9,110.6,103.8ppm。
实施例23所得产物异喹啉类化合物A23的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C15H12NO[M+H]+222.0913;found 222.0910。
实施例24
将反式2-炔基芳香肟醚133mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体91mg,收率为77%,记为异喹啉类化合物A24,反应流程如下:
实施例24所得产物异喹啉类化合物A24的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.26(s,1H),8.11-8.13(m,2H),8.03(s,1H),7.80(dd,J=2.0,8.8Hz,1H),7.53(t,J=7.2Hz,2H),7.36-7.44(m,2H),7.26-7.28(m,1H),3.99(s,3H)ppm。
实施例24所得产物异喹啉类化合物A24的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ158.4,150.9,149.7,139.7,132.3,128.9,128.8,128.5,128.2,126.8,123.8,116.5,104.7,55.5ppm。
实施例24所得产物异喹啉类化合物A24的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C16H14NO[M+H]+236.1070;found 236.1069。
实施例25
将反式2-炔基芳香肟醚148mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至100℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体104mg,收率为78%,记为异喹啉类化合物A25,反应流程如下:
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实施例25所得产物异喹啉类化合物A25的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.14(s,1H),8.09-8.11(m,2H),7.95(s,1H),7.50-7.53(m,2H),7.40-7.44(m,1H),7.23(s,1H),7.13(s,1H),4.06(s,6H)ppm。
实施例25所得产物异喹啉类化合物A25的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ153.2,150.3,150.27,149.8,139.9,133.4,128.8,128.2,126.8,123.8,115.6,105.3,105.0,56.1,56.09ppm。
实施例25所得产物异喹啉类化合物A25的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C17H16NO2[M+H]+266.1176;found 266.1174。
实施例26
将反式2-炔基芳香肟醚135mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至120℃,环化反应24h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体115mg,收率为96%,记为异喹啉类化合物A26,反应流程如下:
实施例26所得产物异喹啉类化合物A26的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.29(s,1H),8.12-8.15(m,2H),8.06(s,1H),7.99(d,J=2.0Hz,1H),7.84(d,J=8.4Hz,1H),7.65(dd,J=2.4,8.8Hz,1H),7.52-7.56(m,2H),7.43-7.48(m,1H)ppm。
实施例26所得产物异喹啉类化合物A26的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ151.7,151.4,139.2,134.9,132.6,131.6,128.9,128.8,128.6,128.1,127.0,126.4,116.2ppm。
实施例26所得产物异喹啉类化合物A26的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd for C15H11ClN[M+H]+240.0575;found 240.0573.
实施例27
将反式2-炔基芳香肟醚127mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至120℃,环化反应24h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体106mg,收率为95%,记为异喹啉类化合物A27,反应流程如下:
实施例27所得产物异喹啉类化合物A27的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.34(s,1H),8.13-8.16(m,2H),8.01-8.05(m,2H),7.44-7.57(m,4H),7.35-7.40(m,1H)ppm。
实施例27所得产物异喹啉类化合物A27的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ163.5(d,J=51.1Hz),152.1,152.0,139.1,138.2(d,J=10.5Hz),130.6(d,J=9.5Hz),128.9,127.1,124.9,117.7(d,J=26.0Hz),116.2,116.1,110.3(d,J=20.9Hz)ppm。
实施例27所得产物异喹啉类化合物A27的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd forC15H11FN[M+H]+224.0870;found 224.0869。
实施例28
将反式2-炔基芳香肟醚152mg(0.5mmol),碘化亚铜9.5mg和水2mL置于25mL密闭管中,加热至120℃,环化反应24h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为30:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体116mg,收率85%,记为异喹啉类化合物A28,反应流程如下:
实施例28所得产物异喹啉类化合物A28的核磁氢谱图图谱信息为1H NMR(400MHz,CDCl3):δ9.45(s,1H),8.32(s,1H),8.14-8.18(m,3H),8.00-8.02(m,1H),7.86-7.89(m,1H),7.53-7.58(m,2H),7.46-7.50(m,1H)ppm。
实施例28所得产物异喹啉类化合物A28的核磁碳谱图图谱信息为13C NMR(100MHz,CDCl3):δ153.4,153.1,138.9,138.0,129.2,128.9,128.8(d,J=32.5Hz),128.2,127.2,126.4,126.1(q,J=3.2Hz),125.5(q,J=4.5Hz),123.9(q,J=270.4Hz),116.1ppm。
实施例28所得产物异喹啉类化合物A28的高分辨质谱图图谱信息为HRMS(ESI)m/z:calcd forC16H11F3N[M+H]+274.0838;found 274.0836。
实施例29
将反式2-炔基芳香肟醚8.1g,碘化亚铜618mg和水20mL置于密闭管中,加热至80℃,环化反应15h后,冷却至室温,然后将环化反应料液加入水和乙酸乙酯,萃取3次,所得乙酸乙酯相用无水硫酸钠干燥,过滤,浓缩,所得粗品进行色谱柱分离,洗脱剂为体积比为50:1的石油醚和乙酸乙酯的混合液,所得洗脱液进行浓缩去除乙酸乙酯,得到淡黄色固体6.2g,得到异喹啉类化合物A1,收率为87%,反应流程为:
实施例30
以2-溴-4,5-二甲氧基苯甲醛为起始底物合成Moxaverine(莫沙维林)
中间体B1的合成
在100mL的带支管耐压瓶中,依次加入2-溴-4,5-二甲氧基苯甲醛2.7g(11mmol),2-炔戊酸1.3g(13mmol),二(三苯基膦)二氯化钯77mg(0.11mmol),1,4-双(二苯基膦)丁烷(dppb)94mg(0.22mmol),四丁基氟化铵的四氢呋喃溶液(1mmol/mL)22mL,无水二甲基亚砜15mL。抽真空换氮气循环三次,然后将耐压瓶置于油浴中,加热至110℃,反应12h后,静置至室温。然后将反应后所得料液依次进行萃取、干燥、过滤和蒸干,所得粗品进行色谱柱分离,洗脱剂为石油醚和乙酸乙酯(体积比10:1),所得产物为淡黄色液体1.66g(7.6mmol),收率69%。
中间体B1的核磁数据如下:1HNMR(400MHz,CDCl3):δ10.39(s,1H),7.38(s,1H),6.94(s.1H),3.97(s,3H),3.95(s,3H),2.47-2.53(q,J=7.6Hz,2H),1.29(t,J=7.6Hz,3H)ppm;13C NMR(100MHz,CDCl3):δ190.9,153.6,149.2,130.2,122.7,114.4,108.0,97.7,75.4,56.2,56.1,13.7,13.3ppm。
中间体B2的合成
在100mL的schlenk茄形反应瓶中,依次加入中间体B11.1 g(5mmol)和无水四氢呋喃10mL。抽真空换氮气循环三次后,将反应瓶置于-78℃的低温槽中。搅拌10min后,逐滴滴加苄基氯化镁的四氢呋喃溶液(1mmol/mL)6mL。滴加完成后,在-78℃下反应10min,然后室温搅拌3h。将反应后所得料液依次进行萃取、干燥、过滤和蒸干,得到粗产品;
在100mL的圆底烧瓶中,依次加入上述所得粗产品、二甲基亚砜15mL,2-碘酰基苯甲酸1.68g(6mmol)。在室温下搅拌12h后,将反应后所得料液依次进行萃取、干燥、过滤和蒸干,所得粗品进行色谱柱分离,洗脱剂为石油醚和乙酸乙酯(体积比5:1),所得产物为白色固体1.08g(3.5mmol),收率70%。
中间体B2的核磁数据如下:1HNMR(400MHz,CDCl3):δ7.32-7.36(m,2H),7.25-7.29(m,4H),6.96(s,1H),4.58(s,2H),3.94(s,3H),3.89(s,3H),2.51(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H)ppm;13C NMR(100MHz,CDCl3):δ199.4,151.3,148.6,135.2,133.4,129.7,129.6,128.5,126.7,116.3,115.7,111.6,97.3,79.6,56.1,55.9,48.3,13.6,13.5ppm。
中间体B3的合成
在50mL的圆底烧瓶中,依次加入中间体B2 1.08g(3.5mmol),乙醇15mL,吡啶0.55g(7mmol),甲氧基胺盐酸盐0.36g(5.25mmol)。室温下搅拌12h后,将反应后所得料液依次进行萃取、干燥、过滤和蒸干,所得粗品进行色谱柱分离,洗脱剂为石油醚和乙酸乙酯(体积比10:1),所得产物为淡黄色液体1.18g(3.5mmol),反式和顺式(3:1)的异构体混合物,收率100%。
中间体B3核磁数据如下:1HNMR(400MHz,CDCl3):δ7.14-7.26(m,5H),6.91(s,1H),6.61(s,0.75H),6.10(s,0.25H),4.27(s,1.5H),4.03(s,2.25H),3.90(s,0.75H),3.88(s,0.5H),3.87(s,2.25H),3.85(s,0.75H),3.77(s,2.25H),3.60(s,0.75H),2.38-2.47(m,2H),1.23-1.29(m,3H)ppm;13C NMR(100MHz,CDCl3):δ158.6,157.1,148.7,148.4,148.1,147.9,136.8,136.6,131.7,130.0,129.5,129.2,126.5,126.1,115.1,115.0,114.3,113.8,112.3,110.8,94.7,93.4,78.6,78.1,61.9,61.8,55.9,55.8,55.7,55.6,41.5,35.0,13.9,13.7,13.3,13.2ppm。
药物Moxaverine(莫沙维林)B4的合成
在25ml耐压管中,依次加入中间体B3(1mmol)307mg,碘化亚铜(10mol%)19mg和水4ml。密闭后,加热至100℃,反应15小时后,恢复室温,常规方法后处理和柱色谱分离提纯即可,洗脱剂为石油醚和乙酸乙酯(体积比20:1),所得产物为淡黄色液体143mg,收率62%。
药物Moxaverine(莫沙维林)B4数据表征如下:1H NMR(400MHz,CDCl3):δ7.21-7.28(m,6H),7.13-7.17(m,1H),6.99(s,1H),4.60(s,2H),3.98(s,3H),3.83(s,3H),2.94-3.00(m,2H),1.40(t,J=7.6Hz,3H)ppm;
13C NMR(100MHz,CDCl3):δ157.0,154.7,149.1,139.8,134.3,128.5,128.4,121.1,115.5,104.9,104.3,55.9,55.8,42.8,31.0,14.3ppm;HRMS(ESI)m/z:calcd forC20H22NO2[M+H]+308.1645;found 308.1643。
以2-溴-4,5-二甲氧基苯甲醛合成药物Moxaverine(莫沙维林)B4的反应流程为:
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (7)
1.一种异喹啉类化合物的合成方法,其特征在于,包括以下步骤:
将具有式I所示结构的反式2-炔基芳香肟醚、铜基催化剂和水混合,进行环化反应,得到具有式II所示结构的异喹啉类化合物;
式I;/>式II;
所述式I和式II中,Ar为吡啶基、噻吩基、苯基、萘基或取代苯基;所述取代苯基中的取代基为氯基、溴基、氟基、三氟甲基、甲氧基或羟基;
所述式I和式II中,R1为氢基、C1~C5的烷基或苯基;
所述式I和式II中,R2为氢基、噻吩基、C1~C5的烷基、苯基、联苯基或取代苯基;所述取代苯基的取代基为氯基、溴基或氟基;
所述环化反应的温度为80~120℃;时间为15~24h;所述铜基催化剂为碘化亚铜。
2.根据权利要求1所述的合成方法,其特征在于,所述铜基催化剂与反式2-炔基芳香肟醚的摩尔比为1~10:100。
3.根据权利要求1所述的合成方法,其特征在于,所述反式2-炔基芳香肟醚和水的用量比为0.2~1 mmol:1~5 mL。
4.根据权利要求1所述的合成方法,其特征在于,所述环化反应后,还包括进行后处理;所述后处理包括将得到的反应液依次进行萃取,所得有机相依次进行干燥、过滤、浓缩和纯化。
5.根据权利要求4所述的合成方法,其特征在于,所述纯化包括色谱柱分离。
6.根据权利要求5所述的合成方法,其特征在于,所述色谱柱分离的洗脱剂为石油醚和乙酸乙酯的混合液。
7.根据权利要求6所述的合成方法,其特征在于,所述洗脱剂中石油醚和乙酸乙酯的体积比为10~50:1。
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