CN111777553B - 一种异喹啉类化合物的制备方法 - Google Patents
一种异喹啉类化合物的制备方法 Download PDFInfo
- Publication number
- CN111777553B CN111777553B CN202010659891.7A CN202010659891A CN111777553B CN 111777553 B CN111777553 B CN 111777553B CN 202010659891 A CN202010659891 A CN 202010659891A CN 111777553 B CN111777553 B CN 111777553B
- Authority
- CN
- China
- Prior art keywords
- reaction
- arh
- formula
- compounds according
- isoquinoline compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 claims abstract description 45
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- 239000002904 solvent Substances 0.000 claims description 24
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 20
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 238000010499 C–H functionalization reaction Methods 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- JYFHYPJRHGVZDY-UHFFFAOYSA-N Dibutyl phosphate Chemical compound CCCCOP(O)(=O)OCCCC JYFHYPJRHGVZDY-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims description 2
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 claims description 2
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 abstract description 23
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract description 14
- 238000007306 functionalization reaction Methods 0.000 abstract description 6
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 150000002537 isoquinolines Chemical class 0.000 description 28
- RZTXNSJRJVCZEM-UHFFFAOYSA-N n,n'-di(propan-2-yl)oxamide Chemical compound CC(C)NC(=O)C(=O)NC(C)C RZTXNSJRJVCZEM-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 16
- 239000011521 glass Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 238000010791 quenching Methods 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 16
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 13
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 11
- -1 oxamide-protected benzylamine Chemical class 0.000 description 10
- 239000011734 sodium Substances 0.000 description 8
- 229910052770 Uranium Inorganic materials 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MNVWIPMVXQUFFV-UHFFFAOYSA-N 3,5,8-trimethylisoquinoline Chemical compound C1=CC(C)=C2C=C(C)N=CC2=C1C MNVWIPMVXQUFFV-UHFFFAOYSA-N 0.000 description 2
- MOVNDRMAMYLYSY-UHFFFAOYSA-N 3,6,7-trimethylisoquinoline Chemical compound CC1=C(C)C=C2C=NC(C)=CC2=C1 MOVNDRMAMYLYSY-UHFFFAOYSA-N 0.000 description 2
- UZEFQPZFOPMNMQ-UHFFFAOYSA-N 3,7,8-trimethylisoquinoline Chemical compound CC=1N=CC2=C(C(=CC=C2C1)C)C UZEFQPZFOPMNMQ-UHFFFAOYSA-N 0.000 description 2
- FVVXWRGARUACNW-UHFFFAOYSA-N 3-methylisoquinoline Chemical compound C1=CC=C2C=NC(C)=CC2=C1 FVVXWRGARUACNW-UHFFFAOYSA-N 0.000 description 2
- BARMGYTVXFHZAW-UHFFFAOYSA-N 8-methoxy-3-methylisoquinoline Chemical compound CC1=NC=C2C(OC)=CC=CC2=C1 BARMGYTVXFHZAW-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- BZKUYNBAFQJRDM-UHFFFAOYSA-N aporphine Chemical compound C12=CC=CC=C2CC2N(C)CCC3=CC=CC1=C32 BZKUYNBAFQJRDM-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- FVRABHGHBLRNNR-UHFFFAOYSA-N liriodenine Natural products O=C1C=CC=c2c1cc3nccc4cc5OCOc5c2c34 FVRABHGHBLRNNR-UHFFFAOYSA-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
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- UKLRWOHZBISUMI-UHFFFAOYSA-N (2,3-dimethylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1C UKLRWOHZBISUMI-UHFFFAOYSA-N 0.000 description 1
- LUJNPFWZXIGIPS-UHFFFAOYSA-N (2,5-dimethylphenyl)methanamine Chemical compound CC1=CC=C(C)C(CN)=C1 LUJNPFWZXIGIPS-UHFFFAOYSA-N 0.000 description 1
- NOYASZMZIBFFNZ-UHFFFAOYSA-N (2-bromophenyl)methanamine Chemical compound NCC1=CC=CC=C1Br NOYASZMZIBFFNZ-UHFFFAOYSA-N 0.000 description 1
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- LAUPTNYHVCVPFH-UHFFFAOYSA-N (2-ethoxyphenyl)methanamine Chemical compound CCOC1=CC=CC=C1CN LAUPTNYHVCVPFH-UHFFFAOYSA-N 0.000 description 1
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 description 1
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 description 1
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 1
- PXNRCZQMDSDSHJ-UHFFFAOYSA-N (3,4-dimethylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1C PXNRCZQMDSDSHJ-UHFFFAOYSA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 description 1
- IZGDXVLRMHXOJV-SFHVURJKSA-N (3s)-4-[2-[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]ethyl-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1CCP(O)(=O)C[C@@H](O)CC(O)=O IZGDXVLRMHXOJV-SFHVURJKSA-N 0.000 description 1
- WHQUHTXULUACFD-KRWDZBQOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4-methyl-6-propan-2-ylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC(C)C1=CC(C)=CC(C=2C=C(C)C(F)=CC=2)=C1COP(O)(=O)C[C@@H](O)CC(O)=O WHQUHTXULUACFD-KRWDZBQOSA-N 0.000 description 1
- USTCFIRCUNVNNM-UHFFFAOYSA-N (4-ethoxyphenyl)methanamine Chemical compound CCOC1=CC=C(CN)C=C1 USTCFIRCUNVNNM-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- MPWSRGAWRAYBJK-UHFFFAOYSA-N (4-tert-butylphenyl)methanamine Chemical compound CC(C)(C)C1=CC=C(CN)C=C1 MPWSRGAWRAYBJK-UHFFFAOYSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 1
- 125000006184 2,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C(=C1[H])C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000006185 3,4-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C(=C1[H])C([H])([H])[H])C([H])([H])[H])C([H])([H])* 0.000 description 1
- OUSUBDOSELFGLT-UHFFFAOYSA-N 3,6-dimethylisoquinoline Chemical compound C1=NC(C)=CC2=CC(C)=CC=C21 OUSUBDOSELFGLT-UHFFFAOYSA-N 0.000 description 1
- UGDBAADRKHLXQS-UHFFFAOYSA-N 3,7-dimethylisoquinoline Chemical compound C1=C(C)N=CC2=CC(C)=CC=C21 UGDBAADRKHLXQS-UHFFFAOYSA-N 0.000 description 1
- WUUDEJJHMBBKHD-UHFFFAOYSA-N 3,8-dimethylisoquinoline Chemical compound C1=CC(C)=C2C=NC(C)=CC2=C1 WUUDEJJHMBBKHD-UHFFFAOYSA-N 0.000 description 1
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 description 1
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 1
- VWGLYYFNIUKSAH-UHFFFAOYSA-N 3-methyl-6-propan-2-ylisoquinoline Chemical compound C1=NC(C)=CC2=CC(C(C)C)=CC=C21 VWGLYYFNIUKSAH-UHFFFAOYSA-N 0.000 description 1
- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003352 4-tert-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UICBHOXXGLYZJH-UHFFFAOYSA-N 5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium Chemical compound C1=CC=C2CC[N+]3=CC4=CC=CC=C4C=C3C2=C1 UICBHOXXGLYZJH-UHFFFAOYSA-N 0.000 description 1
- BZKVKVNLNRBYEE-UHFFFAOYSA-N 6-ethoxy-3-methylisoquinoline Chemical compound CC=1N=CC2=CC=C(C=C2C1)OCC BZKVKVNLNRBYEE-UHFFFAOYSA-N 0.000 description 1
- IRFSFYPWBSAISE-UHFFFAOYSA-N 6-methoxy-3-methylisoquinoline Chemical compound C1=NC(C)=CC2=CC(OC)=CC=C21 IRFSFYPWBSAISE-UHFFFAOYSA-N 0.000 description 1
- DMOCRXGJWWDLPE-UHFFFAOYSA-N 6-tert-butyl-3-methylisoquinoline Chemical compound CC(C)(C)C1=CC=C2C=NC(C)=CC2=C1 DMOCRXGJWWDLPE-UHFFFAOYSA-N 0.000 description 1
- UIBRIYQVQCXESP-UHFFFAOYSA-N 7-methoxy-3-methylisoquinoline Chemical compound C1=C(C)N=CC2=CC(OC)=CC=C21 UIBRIYQVQCXESP-UHFFFAOYSA-N 0.000 description 1
- CPSOASVAUHHEBI-UHFFFAOYSA-N 8-bromo-3-methylisoquinoline Chemical compound Cc1cc2cccc(Br)c2cn1 CPSOASVAUHHEBI-UHFFFAOYSA-N 0.000 description 1
- SFPYXLRJQYXSTP-UHFFFAOYSA-N 8-chloro-3-methylisoquinoline Chemical compound Cc1cc2cccc(Cl)c2cn1 SFPYXLRJQYXSTP-UHFFFAOYSA-N 0.000 description 1
- LUKMFZSMPNWRFY-UHFFFAOYSA-N 8-ethoxy-3-methylisoquinoline Chemical compound CC=1N=CC2=C(C=CC=C2C1)OCC LUKMFZSMPNWRFY-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 241001598984 Bromius obscurus Species 0.000 description 1
- FABUBSGIRKPNDO-UHFFFAOYSA-N C1(=C(C=C(C=C1)C)NCC1=CC=CC=C1)C(C)C Chemical compound C1(=C(C=C(C=C1)C)NCC1=CC=CC=C1)C(C)C FABUBSGIRKPNDO-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 208000025174 PANDAS Diseases 0.000 description 1
- 208000021155 Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Diseases 0.000 description 1
- 240000000220 Panda oleosa Species 0.000 description 1
- 235000016496 Panda oleosa Nutrition 0.000 description 1
- 101150034459 Parpbp gene Proteins 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- QCMQEZNBBPGFKQ-UHFFFAOYSA-N Thalisopynine Natural products CN1CCC2=C(OC)C(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 QCMQEZNBBPGFKQ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- MUMCCPUVOAUBAN-UHFFFAOYSA-N liriodenine Chemical compound C1=NC(C(=O)C=2C3=CC=CC=2)=C2C3=C(OCO3)C3=CC2=C1 MUMCCPUVOAUBAN-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种异喹啉类化合物的制备方法,以草酰胺保护的苄胺和醋酸烯丙酯为原料,通过C‑H键官能团化和水解的串联反应,两步“一锅”合成得到一系列异喹啉类化合物,其所用的原料简单、易得,反应条件温和、后处理简单。
Description
技术领域
本发明属于有机化合成领域,涉及一种异喹啉类化合物的制备方法。
背景技术
异喹啉作为杂环化合物的一种,广泛存在于天然产物、生物活性分子和药物中(Joule,J.A.;Mills,K.Heterocyclic Chemistry.John Wiley&Sons,2008.),并且在近年来也被广泛应用于有机功能分子和光电材料等领域(Eicher,T.;Hauptmann,S.;Speicher,A.The Chemistry of Heterocycles:Structures,Reactions,Synthesis,andApplications,3rd.John Wiley&Sons,2013.)。异喹啉骨架广泛存在于生物碱中,该类生物碱是已知的生物碱中最大的一类,如罂粟碱、鹅掌楸碱、吗啡烷类、原小檗碱类和阿朴菲类等,它们的生源合成也都是由异喹啉衍生出来的(Chrzanowska,M.;Rozwadowska,M.D.Chem.Rev.,2004,104,3341.Delcey,M.C.;Croisy,A.;Carrez,D.;Huel,C.;Chiaroni,A.;Ducrot,P.;Bisagni,E.;Jin,L.;Leclercq,G.Bioorg.Med.Chem.,2000,8,2629.)。异喹啉衍生物显示出卓越的生物活性,例如钾离子通道抑制剂(Trotter,B.W.;Nanda,K.K.;Kett,N.R.;Dinsmore,C.J.J.Med.Chem.,2006,49,6954.)、抗癌活性(Zaman,K.;Rahima,F.;Tahab,M.;Wadoodc,A.;Shah,S.A.A.;Gollapallif,M.;Ullahg,F.;Ahmedh,A.Bioorg.Chem.,2019,89,102999.Khadka,D.B.;Woo,H.;Yang,S.H.;Zhao,C.;Jin,Y.;Le,T.N.;Kwon,Y.;Cho,W.J.Eur.J.Med.Chem.,2015,92,583.Elsayed,M.S.A.;Su,Y.;Wang,P.;Sethi,T.;Agama,K.;Ravji,A.;Redon,C.E.;Kiselev,E.;Horzmann,K.A.;Freeman,J.L.;Pommier,Y.;Cushman,M.J.Med.Chem.,2017,60,5364.)、降血糖(Takada,K.;Uehara,T.;Nakao,Y.;Matsunaga,S.;van Soest,R.W.;Fusetani,N.J.;Schulzeines,A.C.J.Am.Chem.Soc.,2004,126,187.Taha,M.;Ismail,N.H.;Imran,S.;Wadood,A.;Rahim,F.;Ali,M.;Rehman,U.A.Med.Chem.Commun.,2015,6,1826)、抗凝血(Rewinkel,J.B.M.;Lucas,H.;van Galen,P.J.M.;Noach,A.B.J.;van Dinther,T.G.;Rood,A.M.M.;Jenneboer,A.J.S.M.;van Boeckel,C.A.A.Bioorg.Med.Chem.Lett.,1999,9,685.)、抗疟疾(Parai,M.K.;Panda,G.;Srivastava,K.;Puri,S.K.Bioorg.Med.Chem.Lett.,2008,18,776.)、拓扑异构酶I催化抑制剂(Khadka,D.B.;Park,S.;Jin,Y.;Han,J.;Kwon,Y.;Cho,W.J.Eur.J.Med.Chem.,2018,143,200.)。另外,异喹啉由于其具有优良的配位能力而广泛用作配体(Chen,C.;Li,X.D.;Schreiber,S.L.J.Am.Chem.Soc.,2003,125,10174.Chen,Z.F.;Liu,Y.C.;Liu,L.M.;Wang,H.S.;Qin,S.H.;Wang,B.L.;Bian,H.D.;Yang,B.;Fun,H.K.;Liu,H.G.;Liang,H.;Orvig,C.Dalton Trans.,2009,262.),异喹啉配合物也可用于制备OLED(Su,Y.J.;Huang,H.L.;Li,C.L.;Chen,C.H.;Tao,Y.T.;Chou,P.T.;Datta,S.;Liu,R.S.Adv.Mater.,2003,15,884.)。
异喹啉衍生物的经典合成方法有:Pomeranz-Fritsch反应、Bischler-Napieralski反应和Pictet-Gams改进法.这些传统合成方法大多反应条件不温和,且一般需要活性较高的底物进行反应,能合成的杂环往往只能在少数位点带来某些特定的取代基。因此,寻找简单便捷的合成异喹啉的方法成为人们关注的重点。
C-H键官能团化是有机合成中重要的研究内容,它是通过C-H键构建C-C、C-O、C-N等多种化学键的方法。过渡金属催化剂的出现很大的促进了C-H键官能团化的研究。近年来,利用过渡金属催化的C-H键活化反应已经取得了许多重要的研究进展(Ackerman,L.Chem.Rev.,2011,111,1315.He,J.;Wasa,M.;Chan,K.S.L.;Shao,Q.;Yu,J.Q.Chem.Rev.,2017,117,8754.)。随着C-H键官能团化研究的不断深入,越来越多的有机合成工作者使用C-H键官能团化反应来构建异喹啉骨架,发展了一些新的合成异喹啉衍生物的方法。
发明内容
本发明目的是基于异喹啉衍生物具有广泛的生物和药理活性提供一种以草酰胺保护的苄胺和醋酸烯丙酯为原料,利用醋酸钯催化的C-H键官能团化反应及水解的串联反应,两步“一锅”法合成了异喹啉衍生物。
本发明的技术方案是:
一种异喹啉类化合物的制备方法,一种异喹啉类化合物的制备方法,其特征在于,该方法包括:以草酰胺保护的苄胺(式Ⅰ)及醋酸烯丙酯(式Ⅱ)为原料,醋酸钯作为催化剂,碳酸银作为氧化剂,磷酸二丁酯、磷酸二苯酯、磷酸二乙酯或磷酸二苄酯中的任意一种作为添加剂,1,2-二氯乙烷、1,4-二氧六环、氯苯、甲苯、乙醇、叔丁醇或特戊醇中的任意一种作为溶剂,进行C-H官能团化反应,接着用氢氧化钠进行水解,合成获得异喹啉衍生物(式Ⅲ),
其反应式如(式Ⅳ):
进一步的,所述苄胺选自苄胺、邻甲基苄胺、邻甲氧基苄胺、邻氯苄胺、邻溴苄胺、邻乙氧基苄胺、间甲基苄胺、间甲氧基苄胺、对甲基苄胺、对甲氧基苄胺、对异丙基苄胺、对叔丁基苄胺、对乙氧基苄胺、2,3-二甲基苄胺、2,5-二甲基苄胺或3,4-二甲基苄胺中的任意一种。
进一步的,所述草酰胺保护的苄胺和醋酸烯丙酯的摩尔比为1:1-1:2,所述催化剂的用量为所述草酰胺保护的苄胺的用量的5mol%,所述氧化剂与所述草酰胺保护的苄胺的摩尔比为2:1。
进一步的,所述添加剂与所述草酰胺保护的苄胺的摩尔比为1.5:1。
进一步的,每mmol原料所需的溶剂的量是3mL。
进一步的,所述氢氧化钠的用量为25当量。
进一步的,所述C-H官能团化反应的反应时间为36小时,反应温度为120℃。
进一步的,所述水解的反应时间为24小时,反应温度为80℃。
进一步的,以草酰胺保护的苄胺及醋酸烯丙酯为原料,所述草酰胺保护的苄胺和醋酸烯丙酯的摩尔比为1:2,以5mol%醋酸钯作为催化剂,2当量的碳酸银作为氧化剂,1.5当量的磷酸二丁酯作为添加剂,以1,2-二氯乙烷作为溶剂,在120℃的温度条件下进行C-H官能团化反应,反应36小时,接着在80℃的温度条件下用氢氧化钠进行水解24小时,合成获得异喹啉衍生物。
本发明提供了一种异喹啉类化合物的制备方法,以草酰胺保护的苄胺和醋酸烯丙酯为原料,通过C-H键官能团化和水解的串联反应,两步“一锅”合成得到一系列异喹啉类化合物,优点为:所用的原料简单、易得,反应条件温和、后处理简单。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合具体实施例进一步说明本发明的技术方案。但是本发明不限于所列出的实施例,还应包括在本发明所要求的权利范围内其他任何公知的改变。
此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例,也不是单独的或选择性的与其他实施例互相排斥的实施例。
实施例1
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-苄基-N2,N2-二异丙基草酰胺(1a)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基异喹啉(化合物3a)。收率63%;1H NMR(400MHz,CDCl3)δ9.18(s,1H,ArH),7.92(d,J=8.2Hz,1H,ArH),7.72(d,J=8.2Hz,1H,ArH),7.66-7.61(m,1H,ArH),7.54-7.49(m,1H,ArH),7.48(s,1H,ArH),2.70(s,3H,CH3).13C NMR(100MHz,CDCl3)δ151.7,130.5,129.9,127.6,126.8,126.4,125.9,118.7,29.7;HRMScalcd for C10H10N[M+H]+:144.0813,found:144.0829.
实施例2
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2-甲基苄基)-N2,N2-二异丙基草酰胺(1b)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3,8-二甲基异喹啉(化合物3b)。收率61%;1H NMR(400MHz,CDCl3)δ9.36(s,1H,ArH),7.56(d,J=8.2Hz,1H,ArH),7.53-7.48(m,1H,ArH),7.46(s,1H,ArH),7.29(d,J=6.8Hz,1H,ArH),2.76(s,3H,CH3),2.70(s,3H,CH3).13C NMR(100MHz,CDCl3)δ151.5,148.9,137.0,135.4,130.2,127.2,126.0,124.4,119.0,24.2,18.5.HRMScalcd for C11H12N[M+H]+:158.0970,found:158.0967.
实施例3
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2-甲氧基苄基)-N2,N2-二异丙基草酰胺(1c)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-8-甲氧基异喹啉(化合物3c)。收率57%;1H NMR(400MHz,CDCl3)δ9.52(s,1H,ArH),7.52(t,J=8.0Hz,1H,ArH),7.40(s,1H,ArH),7.28-7.24(m,1H,ArH),6.79(d,J=7.7Hz,1H,ArH),4.01(s,3H,CH3O),2.68(s,3H,CH3).13C NMR(100MHz,CDCl3)δ156.7,152.3,147.2,137.9,131.0,119.1,118.1,118.1,104.3,55.6,24.3.HRMS calcd for C11H12NO[M+H]+:174.0919,found:174.0921.
实施例4
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2-氯苄基)-N2,N2-二异丙基草酰胺(1d)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-8-氯异喹啉(化合物3d)。收率51%;1H NMR(400MHz,CDCl3)δ9.18(s,1H,ArH),7.93(d,J=8.2Hz,1H,ArH),7.73(d,J=8.3Hz,1H,ArH),7.67-7.62(m,1H,ArH),7.52(t,J=7.5Hz,1H,ArH),7.49(s,1H,ArH),2.71(s,3H,CH3).13C NMR(101MHz,CDCl3)δ152.0,151.7,136.7,130.4,127.6,127.0,126.4,126.0,118.6,24.3.HRMS calcd for C10H9ClN[M+H]+:178.0424,found:178.0420.
实施例5
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2-溴苄基)-N2,N2-二异丙基草酰胺(1e)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-8-溴异喹啉(化合物3e)。收率47%;1H NMR(400MHz,CDCl3)δ9.18(s,1H,ArH),7.93(d,J=8.2Hz,1H,ArH),7.73(d,J=8.3Hz,1H,ArH),7.66-7.61(m,1H,ArH),7.54-7.50(m,1H,ArH),7.48(s,1H,ArH),2.70(s,3H,CH3).13CNMR(100MHz,CDCl3)δ152.0,151.7,136.7,130.4,127.6,126.9,126.4,126.0,118.6,24.3.HRMS calcd for C10H8BrNNa[M+Na]+:243.9738,found:243.9733.
实施例6
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2-乙氧基苄基)-N2,N2-二异丙基草酰胺(1f)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-8-乙氧基异喹啉(化合物3f)。收率60%;1H NMR(400MHz,CDCl3)δ9.54(s,1H,ArH),7.50(t,J=8.0Hz,1H,ArH),7.39(s,1H,ArH),7.24(d,J=8.3Hz,1H,ArH),6.77(d,J=7.7Hz,1H,ArH),4.22(q,J=7.0Hz,2H,CH2O),2.68(s,3H,CH3),1.55(t,J=7.0Hz,3H,CH3).13C NMR(100MHz,CDCl3)δ156.0,152.2,147.4,137.9,131.0,119.2,118.0,117.8,105.0,64.0,24.3,14.8.HRMS calcd for C12H13NNaO[M+Na]+:210.0895,found:210.0891.
实施例7
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(3-甲基苄基)-N2,N2-二异丙基草酰胺(1g)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3,7-二甲基异喹啉(化合物3g)。收率63%;1H NMR(400MHz,CDCl3)δ9.10(s,1H,ArH),7.60(d,J=8.2Hz,1H,ArH),7.52-7.50(m,1H,ArH),7.48(s,1H,ArH),7.30(d,J=6.8Hz,1H,ArH),2.71(s,3H,CH3),2.66(s,3H,CH3).13C NMR(100MHz,CDCl3)δ150.8,150.1,136.6,135.2,133.2,127.1,126.5,125.9,118.8,23.7,21.8.HRMScalcd for C11H12N[M+H]+:158.0970,found:158.0967.
实施例8
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(3-甲氧基苄基)-N2,N2-二异丙基草酰胺(1h)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-7-甲氧基异喹啉(化合物3h)。收率59%;1H NMR(400MHz,CDCl3)δ9.07(s,1H,ArH),7.62(d,J=9.0Hz,1H,ArH),7.40(s,1H,ArH),7.29(dd,J=9.0,2.5Hz,1H,ArH),7.17(d,J=2.4Hz,1H,ArH),3.92(s,3H,CH3O),2.66(s,3H,CH3).13C NMR(100MHz,CDCl3)δ157.8,150.5,149.8,132.4,127.9,127.6,123.7,118.5,104.6,55.5,24.0.HRMS calcd for C11H12NO[M+H]+:174.0919,found:174.0922.
实施例9
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(4-甲基苄基)-N2,N2-二异丙基草酰胺(1i)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3,6-二甲基异喹啉(化合物3i)。收率58%;1H NMR(400MHz,CDCl3)δ9.10(s,1H,ArH),7.81(d,J=8.4Hz,1H,ArH),7.48(s,1H,ArH),7.38(s,1H,ArH),7.34(dd,J=8.4,1.4Hz,1H,ArH),2.67(s,3H,CH3),2.52(s,3H,CH3).13C NMR(100MHz,CDCl3)δ151.7,151.6,140.7,137.0,128.7,127.4,125.4,124.9,118.1,24.3,22.2.HRMScalcd for C11H12N[M+H]+:158.0970,found:158.0974.
实施例10
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(4-甲氧基苄基)-N2,N2-二异丙基草酰胺(1j)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-6-甲氧基异喹啉(化合物3j)。收率57%;1H NMR(400MHz,CDCl3)δ9.02(s,1H,ArH),7.80(d,J=8.9Hz,1H,ArH),7.38(s,1H,ArH),7.14(dd,J=8.9,2.3Hz,1H,ArH),6.96(d,J=2.1Hz,1H,ArH),3.93(s,3H,CH3O),2.66(s,3H,CH3).HRMS calcd for C11H12NO[M+H]+:174.0919,found:174.0915.
实施例11
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(4-异丙基苄基)-N2,N2-二异丙基草酰胺(1k)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-6-异丙基异喹啉(化合物3k)。收率50%;1H NMR(400MHz,CDCl3)δ9.10(s,1H,ArH),7.84(d,J=8.5Hz,1H,ArH),7.51(s,1H,ArH),7.43-7.39(m,2H,ArH),3.16-2.99(m,1H,ArH),2.68(s,3H,CH3),1.33(d,J=6.9Hz,6H,2×CH3).13C NMR(100MHz,CDCl3)δ151.7,151.2,137.2,127.6,126.6,125.7,122.2,118.7,34.6,24.0,23.7.HRMS calcd for C13H15NNa[M+Na]+:208.1102,found:208.1099.
实施例12
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(4-叔丁基苄基)-N2,N2-二异丙基草酰胺(1l)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-6-叔丁基异喹啉(化合物3l)。收率41%;1H NMR(400MHz,CDCl3)δ9.10(s,1H,ArH),7.86(d,J=8.6Hz,1H,ArH),7.64(s,1H,ArH),7.61(dd,J=8.6,1.8Hz,1H,ArH),7.45(s,1H,ArH),2.68(s,3H,CH3),1.41(s,9H,3×CH3).13C NMR(100MHz,CDCl3)δ154.4,150.6,150.6,137.2,127.4,125.9,125.2,121.1,119.4,35.5,31.1,23.7).HRMS calcd for C14H17NNa[M+Na]+:222.1259,found:222.1260.
实施例13
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(4-乙氧基苄基)-N2,N2-二异丙基草酰胺(1m)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3-甲基-6-乙氧基异喹啉(化合物3m)。收率54%;1H NMR(400MHz,CDCl3)δ9.01(s,1H,ArH),7.80(d,J=8.9Hz,1H,ArH),7.35(s,1H,ArH),7.13(dd,J=8.9,2.4Hz,1H,ArH),6.94(d,J=2.3Hz,1H,ArH),4.15(q,J=7.0Hz,2H,CH2O),2.65(s,3H,CH3),1.49(t,J=7.0Hz,3H.CH3).13C NMR(100MHz,CDCl3)δ160.4,152.1,151.1,138.7,129.3,122.8,119.7,117.9,104.2,63.8,24.3,14.8.HRMS calcd for C12H13NNaO[M+Na]+:210.0895,found:210.0887.
实施例14
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2,3-二甲基苄基)-N2,N2-二异丙基草酰胺(1n)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3,7,8-三甲基异喹啉(化合物3n)。收率53%;1H NMR(400MHz,CDCl3)δ9.39(s,1H,ArH),7.47(d,J=8.4Hz,1H,ArH),7.44-7.39(m,2H,ArH),2.67(s,3H,CH3),2.65(s,3H,CH3),2.46(s,3H,CH3).13C NMR(100MHz,CDCl3)δ150.2,148.5,135.6,133.8,133.5,132.2,126.2,123.7,118.8,24.0,20.4,13.9.HRMS calcd forC12H13NNa[M+Na]+:194.0946,found:194.0955.
实施例15
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(2,5-二甲基苄基)-N2,N2-二异丙基草酰胺(1o)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3,5,8-三甲基异喹啉(化合物3o)。收率50%;1H NMR(400MHz,CDCl3)δ9.33(s,1H,ArH),7.57(s,1H,ArH),7.33(d,J=7.1Hz,1H,ArH),7.17(d,J=7.1Hz,1H,ArH),2.73(s,3H,CH3),2.72(s,3H,CH3),2.59(s,3H,CH3).13C NMR(100MHz,CDCl3)δ151.4,149.3,136.3,133.1,130.9,130.4,126.7,125.9,115.6,24.4,18.5,18.4.HRMS calcd for C12H13NNa[M+Na]+:194.0946,found:194.0951.
实施例16
本实施案例按如下步骤展示一种异喹啉类化合物的制备方法:将草酰胺保护的N1-(3,4-二甲基苄基)-N2,N2-二异丙基草酰胺(1p)(0.2mmol),醋酸烯丙酯(2)(0.4mmol),Pd(OAc)2(2.25mg,5mol%),Ag2CO3(110mg,0.4mmol),(n-BuO)2PO2H(12.6mg,0.06mmol)分别加入15mL玻璃反应管中,最后加入0.6mL的1,2-二氯乙烷,并密封在120℃的空气氛围中反应36h。反应结束后,直接加入NaOH(25equiv.)和乙醇溶剂(2mL),80℃下继续反应24h。结束后加入水淬灭,用乙酸乙酯萃取3次,合并有机相,旋蒸浓缩,通过柱层析分离(石油醚:乙酸乙酯=5:1)得到无色油状液体,为3,6,7-三甲基异喹啉(化合物3p)。收率49%;1H NMR(400MHz,CDCl3)δ9.04(s,1H,ArH),7.65(s,1H,ArH),7.47(s,1H,ArH),7.35(s,1H,ArH),2.66(s,3H,CH3),2.43(s,6H,2×CH3).HRMS calcd for C12H13NNa[M+Na]+:194.0946,found:194.0953.
综上所述,本发明所述的一种异喹啉类化合物的制备方法,以草酰胺保护的苄胺和醋酸烯丙酯为原料,通过C-H键官能团化和水解的串联反应,两步“一锅”合成得到一系列异喹啉类化合物,其所用的原料简单、易得,反应条件温和、后处理简单。
应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (8)
2.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:所述式Ⅰ和醋酸烯丙酯的摩尔比为1:1-1:2,所述催化剂的用量为所述式Ⅰ的用量的5mol%,所述氧化剂与所述式Ⅰ的摩尔比为2:1。
3.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:所述添加剂与所述式Ⅰ的摩尔比为1.5:1。
4.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:每mmol原料所需的溶剂的量是3mL。
5.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:所述氢氧化钠的用量为25当量。
6.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:所述C-H官能团化反应的反应时间为36小时,反应温度为120℃。
7.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:所述水解的反应时间为24小时,反应温度为80℃。
8.根据权利要求1所述的一种异喹啉类化合物的制备方法,其特征在于:以式Ⅰ及醋酸烯丙酯为原料,所述式Ⅰ和醋酸烯丙酯的摩尔比为1:2,以5mol%醋酸钯作为催化剂,2当量的碳酸银作为氧化剂,1.5当量的磷酸二丁酯作为添加剂,以1,2-二氯乙烷作为溶剂,在120℃的温度条件下进行C-H官能团化反应,反应36小时,接着在80℃的温度条件下用氢氧化钠和乙醇溶剂进行水解24小时,合成获得异喹啉衍生物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010659891.7A CN111777553B (zh) | 2020-07-10 | 2020-07-10 | 一种异喹啉类化合物的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010659891.7A CN111777553B (zh) | 2020-07-10 | 2020-07-10 | 一种异喹啉类化合物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111777553A CN111777553A (zh) | 2020-10-16 |
CN111777553B true CN111777553B (zh) | 2022-03-18 |
Family
ID=72767016
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010659891.7A Active CN111777553B (zh) | 2020-07-10 | 2020-07-10 | 一种异喹啉类化合物的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111777553B (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107382856B (zh) * | 2017-07-04 | 2020-07-28 | 江苏理工学院 | 新型多取代异喹啉衍生物及其合成方法 |
-
2020
- 2020-07-10 CN CN202010659891.7A patent/CN111777553B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN111777553A (zh) | 2020-10-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1105721C (zh) | 麻醉性镇痛剂的制备 | |
CN110590820B (zh) | 手性有机硼化合物的制备方法 | |
CN110590819A (zh) | 有机硼化合物的制备方法以及β-羟基有机硼化合物的制备方法 | |
CN108892601B (zh) | 一种苯并芴结构的稠环芳烃的制备方法 | |
CN111777553B (zh) | 一种异喹啉类化合物的制备方法 | |
CN103467300A (zh) | 一种邻硝基苯甲醛类化合物的合成方法 | |
CN111138465B (zh) | 1-硼烷基甲基-6-芳基-3-苯磺酰基-3-氮杂双环己烷衍生物的合成方法 | |
CN116925093A (zh) | 一种盐酸伊立替康的合成方法 | |
CN113861228B (zh) | 一种烷基硼烷衍生物及其合成方法 | |
CN116082111A (zh) | 一种合成1,1,2-三芳基乙烷的方法 | |
CN102477019A (zh) | 制备s-3-羟基四氢呋喃的新方法 | |
CN111807977B (zh) | 9-苯胺芴-9-羧酸酯类化合物及其制备方法 | |
CN112300184B (zh) | 一种三元环化合物的制备方法 | |
CN108659028B (zh) | 一种(z)式氟烷基化烯基硼酸酯及其制备方法和应用 | |
CN115894365B (zh) | 一种四氢异喹啉类化合物及其中间体的合成方法 | |
CN111217847A (zh) | 一种硫代硅烷配体及其制备方法和在芳基硼化催化反应中的应用 | |
CN113735799A (zh) | 一种盐酸达克罗宁的合成方法 | |
CN101215292B (zh) | 双苄生物素及其衍生物的合成方法 | |
Wang et al. | Dehydrogenative Fluorination of gem‐Difluoroalkenes to Access Multi‐Substituted Trifluoromethylalkenes | |
CN116239529B (zh) | 一种二氧化碳参与的n-甲基四氢喹啉类生物碱的制备方法 | |
CN113563355B (zh) | 一种靛红骨架上c-h活化产物及其制备方法与应用 | |
CN104098481A (zh) | 一种沙格列汀中间体的制备方法 | |
CN116283772B (zh) | 一种具有环丁烯结构的化合物及其制备方法与应用 | |
CN116969987A (zh) | 一种利用壳聚糖席夫碱铜功能材料制备1,2,3,4-二甲硅烷基四氢喹啉化合物的方法 | |
CN107445879B (zh) | 拉曲替尼中间体的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |