CN114874139A - 一种1-苄或烯丙基3,4-二氢异喹啉的合成方法 - Google Patents
一种1-苄或烯丙基3,4-二氢异喹啉的合成方法 Download PDFInfo
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- CN114874139A CN114874139A CN202210591912.5A CN202210591912A CN114874139A CN 114874139 A CN114874139 A CN 114874139A CN 202210591912 A CN202210591912 A CN 202210591912A CN 114874139 A CN114874139 A CN 114874139A
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- China
- Prior art keywords
- reaction
- benzyl
- compound
- allyl
- dihydroisoquinoline
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Links
- -1 allyl 3, 4-dihydroisoquinoline Chemical compound 0.000 title claims abstract description 49
- 238000001308 synthesis method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000000758 substrate Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 15
- 238000005937 allylation reaction Methods 0.000 claims abstract description 7
- 238000010189 synthetic method Methods 0.000 claims abstract 2
- 239000000047 product Substances 0.000 claims description 36
- 238000003786 synthesis reaction Methods 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 16
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 14
- 239000010453 quartz Substances 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical group BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000003990 18-crown-6 derivatives Chemical group 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 6
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000011261 inert gas Substances 0.000 claims 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- 238000001819 mass spectrum Methods 0.000 description 17
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 241000973497 Siphonognathus argyrophanes Species 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 238000007872 degassing Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 238000001514 detection method Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 235000010288 sodium nitrite Nutrition 0.000 description 8
- LWYMLCYZEMSNBK-UHFFFAOYSA-N 4-methylbenzenediazonium Chemical class CC1=CC=C([N+]#N)C=C1 LWYMLCYZEMSNBK-UHFFFAOYSA-N 0.000 description 6
- 125000005394 methallyl group Chemical group 0.000 description 6
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- JQKBUTDZZRGQDR-UHFFFAOYSA-N hydron;4-methylaniline;chloride Chemical compound Cl.CC1=CC=C(N)C=C1 JQKBUTDZZRGQDR-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- BQNOIPNXSHVKPI-UHFFFAOYSA-N 1-(1-phenylethyl)-3,4-dihydroisoquinoline Chemical compound N=1CCC2=CC=CC=C2C=1C(C)C1=CC=CC=C1 BQNOIPNXSHVKPI-UHFFFAOYSA-N 0.000 description 2
- DOZZQXFFCKJCNM-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]-3,4-dihydroisoquinoline Chemical compound CC1=CC=C(CC2=NCCC3=CC=CC=C23)C=C1 DOZZQXFFCKJCNM-UHFFFAOYSA-N 0.000 description 2
- BQIIGTSQOCWPDH-UHFFFAOYSA-N 1-benzyl-3,4-dihydroisoquinoline Chemical compound N=1CCC2=CC=CC=C2C=1CC1=CC=CC=C1 BQIIGTSQOCWPDH-UHFFFAOYSA-N 0.000 description 2
- PRTRSEDVLBBFJZ-UHFFFAOYSA-N 1-phenyl-1,2,3,4-tetrahydroisoquinoline Chemical compound N1CCC2=CC=CC=C2C1C1=CC=CC=C1 PRTRSEDVLBBFJZ-UHFFFAOYSA-N 0.000 description 2
- CETXVHPHDDJNJH-UHFFFAOYSA-N ClC1=CC=C(CC2=NCCC3=CC=CC=C23)C=C1 Chemical compound ClC1=CC=C(CC2=NCCC3=CC=CC=C23)C=C1 CETXVHPHDDJNJH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-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
- 238000005574 benzylation reaction Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 description 2
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- BJWWOUUGCAPHOV-UHFFFAOYSA-N 1,3-dibenzylisoquinoline Chemical class C=1C2=CC=CC=C2C(CC=2C=CC=CC=2)=NC=1CC1=CC=CC=C1 BJWWOUUGCAPHOV-UHFFFAOYSA-N 0.000 description 1
- YCOHEPDJLXZVBZ-UHFFFAOYSA-N 2-benzylsulfonyl-1-(1h-indol-3-yl)-1h-isoquinoline Chemical compound C1=CC2=CC=CC=C2C(C=2C3=CC=CC=C3NC=2)N1S(=O)(=O)CC1=CC=CC=C1 YCOHEPDJLXZVBZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical compound C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 1
- URDGCPQHZSDBRG-UHFFFAOYSA-N 6-bromo-1,2,3,4-tetrahydroisoquinoline Chemical compound C1NCCC2=CC(Br)=CC=C21 URDGCPQHZSDBRG-UHFFFAOYSA-N 0.000 description 1
- 241000133570 Berberidaceae Species 0.000 description 1
- 241001436672 Bhatia Species 0.000 description 1
- YLSSZXBNWOCLJM-ISLYRVAYSA-N CC(C=C1)=CC=C1/N=N/N1CC2=CC=CC=C2CC1 Chemical compound CC(C=C1)=CC=C1/N=N/N1CC2=CC=CC=C2CC1 YLSSZXBNWOCLJM-ISLYRVAYSA-N 0.000 description 1
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- 206010017533 Fungal infection Diseases 0.000 description 1
- CEIXWJHURKEBMQ-UHFFFAOYSA-N Heliamine Chemical compound C1CNCC2=C1C=C(OC)C(OC)=C2 CEIXWJHURKEBMQ-UHFFFAOYSA-N 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 241000218180 Papaveraceae Species 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 102000001195 RAD51 Human genes 0.000 description 1
- 108010068097 Rad51 Recombinase Proteins 0.000 description 1
- 241000218201 Ranunculaceae Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N Tetrahydropalmatine Natural products C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- TVRHDFJMHSSQCP-UHFFFAOYSA-M [Ir]Cl.C1CC=CCCC=C1 Chemical class [Ir]Cl.C1CC=CCCC=C1 TVRHDFJMHSSQCP-UHFFFAOYSA-M 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical compound [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 1
- 229960003855 solifenacin Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- AEQDJSLRWYMAQI-KRWDZBQOSA-N tetrahydropalmatine Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3C[C@H]2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-KRWDZBQOSA-N 0.000 description 1
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Images
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
- C07D217/08—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 a hetero atom directly attached to the ring nitrogen atom
-
- 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
- C07D217/18—Aralkyl radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种在常温条件下以偶氮芳基作为保护基光诱导四氢异喹啉与苄或烯丙基溴化物的α‑烯丙基化反应,其收率可达63%。这种转化为一种1‑苄或烯丙基3,4‑二氢异喹啉的合成方法提供了一条方便的途径,具有广泛的底物。本发明的优点包括:反应绿色、操作简单;原料便宜易得、来源广泛、制备简单、结构稳定。
Description
技术领域
本发明涉及有机合成领域,具体涉及一种在常温条件下以紫光作为光源,使用偶氮芳基保护的四氢异喹啉化合物(I)与苄或烯丙基溴化物(II)作为底物,实现了可见光诱导偶氮芳基保护的四氢异喹啉化合物的α-烯丙或苄基化反应,去合成1-苄或烯丙基3,4-二氢异喹啉类产物(III)。
背景技术
异喹啉是包含有苯并吡咯的双环结构,氮原子位于吡啶环的2位,根据不饱和度可以分为异喹啉、二氢异喹啉、四氢异喹啉三种形式。在种类繁多的天然氮杂环生物碱家族中,四氢异喹啉类化合物,尤其是C1官能团化的四氢异喹啉生物碱分布十分广泛在罂粟科、小檗科、防已科、毛莨科、海洋动植物等众多生物中都能发现这类化合物的身影(E.M.Shamma,2012;Vol.25.)。这些四氢异喹啉生物碱往往具有显著而且多样的生物活性,例如从粉防已中提取的双苄基异喹啉生物碱粉防已碱,几十年来一直被用于***、高血压、真菌感染等疾病(a)W.A.Creasey,Biochem.Pharmacol.1976,25,1887-1891;b)Y-J,Chen,Acta.Pharmacol.Sin.2002,23,1102-1106;c)L.X.Zhao,L.De-Dong,H.Dan-Dan,H.Gan-Hai,Y.Lan,W.Yan,J.Yuan-Ying,C.Tom,Plos one,8,e79671;d)B.C.Liu,Y.X.He,Q.Miao,H.H.Wang,B.R.You,Biomed.Environ.Sci.1994,7,199-204.)。莲花叶片中分离得到的(R)-乌药碱能够抑制人T淋巴细胞H9中HIV病毒复制(Y.Kashiwada,A.Aoshima,Y.Ikeshiro,Y.P.Chem,H.Furukawa,M.Itoigawa,T.Fujioka,K.Mihashi,L.M.Cosentino,S.L.Morris-Natschke,K.H.Lee,Biorg.Med.Chem.2005,13,443-448)。延胡索乙素作为多巴胺受体拮抗剂(H.Chu,G.Jin,E.Friedman,X.Zhen,Cell.Mol.Neurobiol.2008,28,491-499)。
四氢异喹啉是众多生理活性天然产物的核心骨架,对四氢异喹啉骨架进行修饰和改造已经成为新药研发的热门领域。一些人工合成的异喹啉类化合物也表现出了良好的生物活性。C1-吲哚取代的四氢异喹啉化合物索利那新是竞争性毒覃碱抑制剂,临床上用于缓解膀胱过度活动症(A.Ohtake,M.Ukai,T.Hatanaka,S.Kobayashi,K.Ikeda,S.Sato,K.Miyata,M.Sasamata,Eur.J.Pharmacol.2004,492,243-250.)。α-吲哚异喹啉类似物IBR2是RAD51的小分子抑制剂(a)J.Zhu,L.Zhou,G.Wu,H.Konig,X.Lin,G.Li,X.-L.Qiu,C.-F.Chen,C.-M.Hu,E.Goldblatt,R.Bhatia,A.R.Chamberlin,P.-L.Chen,W.-H.Lee,EMBOMol.Med.2013,5,353-365;b)T.-W.Chung,Y.-T.Hung,T.Thikekar,V.V.Paike,F.Y.Lo,P.-H.Tsai,M.-C.Liang,C.-M.Sun,ACS Comb.Sci.2015,17,442-451;c)J.Zhu,H.Chen,X.E.Guo.X.-L.Qiu,C.-M.Hu,A.R.Chamberlin,W.-H.Lee,Eur,J.Med.Chem.2015,96,196-208.)。
叔胺的α-烯丙基烷基化反应是制备高烯丙基胺特别有用和具有挑战性的反应,而高烯丙基胺常被用作合成药物和天然产物的中间体(a)S.A.Lawrence,Amines:Synthesis,Properties and Applications.Cambridge University Press,Cambridge,2004;b)T.C.Nugent,Chiral Amine Synthesis:Methods,Developments and Applications,Wiley-VCH,Weinheim,2010;c)C.O.Puentes,V.Kouznetsov,J.Heterocycl.Chem.2002,39,595-614.)。传统的叔胺直接α-烯丙基化方法主要是基于交叉脱氢偶联(CDC)策略(a)Z.Liand C.-J.Li,J.Am.Chem.Soc.2004,126,11810-11811;b)C.-J.Li,Acc.Chem.Res.2009,42,335-344.For applications of CDC inα-allylation of tertiary amines,see:c)G.Kumaraswamy,A.Murthyand A.Pitchaiah,J.Org.Chem.2010,75,3916-3919;d)E.Boessand M.Klussmann,J.Am.Chem.Soc.2011,133,8106-8109;e)J.W.Tucker,Y.Zhang,T.F.Jamison and C.R.J.Stephenson,Angew.Chem.Int.Ed.2012,51,4144-4147;f)W.-J.Yoo,A.Tanoue and S.Kobayashi,Asian J.Org.Chem.2014,3,1066-1069;g)J.P.Barham,M.P.John and J.A.Murphy,Beilstein J.Org.Chem.2014,10,2981-2988;h)L.and S.Blechert,Adv.Synth.Catal.2014,356,2825-2829;(i)T.-T.Wang,M.Schrempp,A.O.Schiemann and D.Menche,Org.Lett.2015,17,3982-3985;j)J.Wang and S.Yang,Tetrahedron Lett.2016,57,3444-3448;k)T.T.Chen and C.Cai,Synlett.2017,28,1368-1372.)。相比之下,我们利用可见光诱导芳基偶氮基保护的四氢异喹啉与烯丙基/苄溴的烯丙基和苄基化反应,不需要水敏亲核试剂或化学计量学氧化剂,在温和条件下合成了1-苄/烯丙基3,4-二氢异喹啉类产物。
发明内容
本发明克服了芳基三氮烯Csp3-H键活化的诸多缺点(如需当量的氧化剂氧化),本发明在仅需当量的碱,无促进剂,氮气氛围下,绿色高效地实现了交叉偶联反应去合成1-苄或烯丙基3,4-二氢异喹啉类产物。
本发明使用环境友好、可见光催化底物分子从而得到EDA复合物,然后再自由基和自由基偶联。以制备简单、来源广泛的偶氮芳基保护的四氢异喹啉作为原料,实现可见光诱导偶氮芳基保护的四氢异喹啉化合物的α-烯丙或苄基化反应。
通过这种方法制备得到了如下反应式中1-(2-甲烯丙基)-3,4-二氢异喹啉(III);
其中,所述反应过程如下反应式所示;
其中
苄或烯丙基溴化物(II)中虚线表示此处为无苯环或有苯环二种情形的溴化物,无苯环时溴化物为烯丙基溴化物,有苯环时溴化物为苄基溴化物;而1-苄或烯丙基3,4-二氢异喹啉类化合物(III)中虚线表示此处为无苯环或有苯环二种情形的化合物,无苯环时其为1-烯丙基3,4-二氢异喹啉类化合物,有苯环时其为1-苄基3,4-二氢异喹啉类化合物;
R、R1分别独立地表示在苯环邻位、间位、对位等中的一种或二种以上不同位置的取代基或为氢的无取代基,取代基的个数分别为1-5个,优选1-2个,其具体可分别独立地为甲基、异丙基、氯、溴、碘、甲氧基中的一种或二种以上;R2表示为氢、甲基中的一种或二种;
优选:R为氢、溴、甲氧基中的一种或二种以上,取代基的个数为1-5个,优选1-2个;R1为氢、2-甲基、3-甲基、4-甲基、4-异丙基、4-氯、4-溴中的一种或二种以上,取代基的个数为1-5个,优选1-2个;R2为氢、甲基中的一种或二种。
如以上反应式,本发明一种在常温条件下以紫光作为光源,使用偶氮芳基保护的四氢异喹啉化合物(I)与苄或烯丙基溴化物(II)作为底物,实现了可见光诱导偶氮芳基保护的四氢异喹啉化合物的α-烯丙或苄基化反应,去合成1-苄或烯丙基3,4-二氢异喹啉类产物(III)。
本发明中,所述反应中,反应光源为390-395nm紫光。
本发明中,所述反应中,反应碱为K2CO3。
本发明中,所述反应中,反应添加剂为18-Crown-6。
本发明中,所述反应中,反应温度为25℃。
本发明中,所述反应溶剂为CH3CN。
本发明中,所述反应反应时间为36-48h。优选地,反应时间为36h。
本发明合成反应包括以下步骤:
偶氮芳基保护的四氢异喹啉的合成:
根据先前制备文献报道(L.G.Margaret,H.B.David,M.W.Willard.J.Org.Chem.1993,58,2104-2109.),在100mL的三口烧瓶中,加入芳基苯胺(10mmol),然后在0℃下将2mL的质量浓度12.0mol/L浓盐酸入三口烧瓶中。在50mL的烧杯中加入亚硝酸钠0.76g(11mmol),再加入5mL的蒸馏水使其溶解,然后用恒压滴液漏斗将亚硝酸钠水溶液逐滴加入到对甲基苯胺的盐酸溶液中,在0℃下继续搅拌10min,得芳基重氮盐溶液;在50mL烧杯中加入四氢异喹啉(10mmol)和1.2mol/L的碳酸钾溶液(1.6585g溶于10mL水),搅拌均匀后一次性将上述芳基重氮盐溶液加入其中,在0℃搅拌反应半小时后出现大量黄色固体,用布氏漏斗抽滤并用冰水洗涤固体,得粗产品,将无水乙醇加热到60℃,将粗产品转移至圆底烧瓶中,滴加60℃无水乙醇重结晶,得到淡黄色固体产物,真空干燥称重并计算产率。
1-(2-甲烯丙基)-3,4-二氢异喹啉(III)的合成:
在石英管中依次加入(E)-2-(对甲苯基二氮烯)-1,2,3,4-四氢异喹啉(I)(Xmmol)、2-甲基-3-溴丙烯(Y mmol)、K2CO3(Z mmol)、18-Crown-6(M mmol)以及溶剂DMA(NmL),在N2氛围以及紫光(390-395nm)照射条件下搅拌36h,得到上述反应产物1-(2-甲烯丙基)-3,4-二氢异喹啉。
本发明克服了偶氮芳基保护的四氢异喹啉Csp3-H键活化的诸多缺点(如需当量的氧化剂氧化),本发明在仅需光诱导催化,无促进剂,氮气氛围下,绿色高效地实现了偶氮芳基保护的四氢异喹啉与苄/烯丙基溴化物去合成1-苄或烯丙基3,4-二氢异喹啉类化合物。本发明使用的各原料均为工业化商品,原料便宜易得、来源广泛、简单易得,来源广泛;制备简单、价格便宜、结构稳定、污染小、绿色环保;反应绿色、操作简单。
附图说明
图1是实施例2产物(E)-6,7-二甲氧基-2-(对甲苯基二氮烯基)-1,2,3,4-四氢异喹啉的核磁氢碳谱图;
图2是实施例3产物(E)-6溴-2-(对甲苯基二氮烯基)-1,2,3,4-四氢异喹啉的核磁氢碳谱图;
图3是实施例4产物1-(2-甲烯丙基)-3,4-二氢异喹啉的核磁氢碳谱图;
图4是实施例5产物1-苄基-3,4-二氢异喹啉的核磁氢碳谱图;
图5是实施例6产物1-(4-甲基苄基)-3,4-二氢异喹啉的核磁氢碳谱图;
图6是实施例7产物1-(3-甲基苄基)-3,4-二氢异喹啉的核磁氢碳谱图;
图7是实施例8产物1-(2-甲基苄基)-3,4-二氢异喹啉的核磁氢碳谱图;
图8是实施例9产物1-(4-异丙基苄基)-3,4-二氢异喹啉的核磁氢碳谱图;
图9是实施例10产物1-(4-氯苄基)-3,4-二氢异喹啉的核磁氢碳谱图;
图10是实施例11产物1-(4-溴苄基)-3,4-二氢异喹啉的核磁氢碳谱图;
图11是实施例12产物1-(1-苯乙基)-3,4-二氢异喹啉的核磁氢碳谱图;
图12是实施例13产物1-烯丙基-3,4-二氢异喹啉的核磁氢碳谱图;
图13是实施例14产物6,7-二甲氧基-1-(2-甲基烯丙基)-3,4-二氢异喹啉的核磁氢碳谱图;
图14是实施例15产物6-溴-1-(2-甲基烯丙基)-3,4-二氢异喹啉的核磁氢碳谱图。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁、高分辨质谱鉴定。
实施例1
(E)-2-(对甲苯基二氮烯基)-1,2,3,4-四氢异喹啉的合成
在100mL的三口烧瓶中,加入对甲基苯胺(10mmol),然后在0℃下将2mL的质量浓度12.0mol/L浓盐酸入三口烧瓶中。在50mL的烧杯中加入亚硝酸钠0.76g(11mmol),再加入5mL的蒸馏水使其溶解,然后用恒压滴液漏斗将亚硝酸钠水溶液逐滴加入到对甲基苯胺的盐酸溶液中,在0℃下继续搅拌10min,得对甲基苯基重氮盐溶液;
在50mL烧杯中加入四氢异喹啉(10mmol)和1.2mol/L的碳酸钾溶液(1.6585g溶于10mL水),搅拌均匀后一次性将上述对甲基苯基重氮盐溶液加入其中,在0℃搅拌反应半小时后出现大量黄色固体,用布氏漏斗抽滤并用冰水洗涤固体,得粗产品,将无水乙醇加热到60℃,将粗产品转移至圆底烧瓶中,滴加60℃无水乙醇重结晶,得到淡黄色固体产物,产率(2.26g,90%)。该化合物经核磁、高分辨质谱表征,该化合物核磁、高分辨质谱数据与文献报道的数据一致(N.Jung,S.Brase.Sci.Synth.2010,41,613-640.)。
实施例2
(E)-6,7-二甲氧基-2-(对甲苯基二氮烯基)-1,2,3,4-四氢异喹啉的合成
在100mL的三口烧瓶中,加入对甲基苯胺(10mmol),然后在0℃下将2mL的质量浓度12.0mol/L浓盐酸入三口烧瓶中。在50mL的烧杯中加入亚硝酸钠0.76g(11mmol),再加入5mL的蒸馏水使其溶解,然后用恒压滴液漏斗将亚硝酸钠水溶液逐滴加入到对甲基苯胺的盐酸溶液中,在0℃下继续搅拌10min,得对甲基苯基重氮盐溶液;
在50mL烧杯中加入6,7-二甲氧基四氢异喹啉(10mmol)和1.2mol/L的碳酸钾溶液(1.6585g溶于10ml水),搅拌均匀后一次性将上述对甲基苯基重氮盐溶液加入其中,在0℃搅拌反应半小时后出现大量黄色固体,用布氏漏斗抽滤并用冰水洗涤固体,得粗产品,将无水乙醇加热到60℃,将粗产品转移至圆底烧瓶中,滴加60℃无水乙醇重结晶,得到淡黄色固体产物,产率(2.12g,88%),熔点为:137-138℃。该化合物经核磁、高分辨质谱表征,所得产品的参数为1H NMR(400MHz,CDCl3)δ7.29(d,J=8.2Hz,2H),7.08(d,J=8.2Hz,2H),6.62(d,J=14.7Hz,2H),4.78(s,2H),3.99(t,J=5.9Hz,2H),3.80(s,3H),3.79(s,3H),2.91(t,J=5.9Hz,2H),2.27(s,3H)ppm.13C NMR(100MHz,CDCl3)δ148.68,148.05,147.92,135.56,129.62,128.27,126.69,120.56,111.46,109.81,56.11,48.33,47.67,29.18,21.17ppm.HRMS(ESI)m/z Calcd for 2.C18H21N3O2[M+H]+:312.17065;Found:312.16977.
实施例3
(E)-6-溴-2-(对甲苯基二氮烯基)-1,2,3,4-四氢异喹啉的合成
在100mL的三口烧瓶中,加入对甲基苯胺(10mmol),然后在0℃下将2mL的质量浓度12.0mol/L浓盐酸入三口烧瓶中。在50mL的烧杯中加入亚硝酸钠0.76g(11mmol),再加入5mL的蒸馏水使其溶解,然后用恒压滴液漏斗将亚硝酸钠水溶液逐滴加入到对甲基苯胺的盐酸溶液中,在0℃下继续搅拌10min,得对甲基苯基重氮盐溶液;
在50mL烧杯中加入6-溴四氢异喹啉(10mmol)和1.2mol/L的碳酸钾溶液(1.6585g溶于10mL水),搅拌均匀后一次性将上述对甲基苯基重氮盐溶液加入其中,在0℃搅拌反应半小时后出现大量黄色固体,用布氏漏斗抽滤并用冰水洗涤固体,得粗产品,将无水乙醇加热到60℃,将粗产品转移至圆底烧瓶中,滴加60℃无水乙醇重结晶,得到淡黄色固体产物,产率(2.12g,88%),熔点为:108-109℃。该化合物经核磁、高分辨质谱表征,所得产品的参数为1H NMR(400MHz,CDCl3)δ7.36(d,J=8.3Hz,3H),7.31(d,J=8.1Hz,1H),7.15(d,J=8.4Hz,2H),7.04(d,J=8.1Hz,1H),4.88(s,2H),4.05(t,J=5.9Hz,2H),2.98(t,J=5.9Hz,2H),2.34(s,3H)ppm.13C NMR(100MHz,CDCl3)δ148.43,135.87,133.90,132.40,130.28,129.95,129.89,129.66,129.18,128.26,120.64,120.28,49.03,47.82,29.14,21.20ppm.HRMS(ESI)m/z Calcd for 3.C16H16BrN3[M+H]+:330.06004;Found:330.05939.
实施例4
1-(2-甲烯丙基)-3,4-二氢异喹啉的合成
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,54ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(23.32mg,收率63%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.10(dd,J=7.7,1.2Hz,1H),7.41(td,J=7.4,1.5Hz,1H),7.34(t,J=6.9Hz,1H),7.18(d,J=7.5Hz,1H),4.91(d,J=11.9Hz,2H),4.16(s,2H),3.48(t,J=6.6Hz,2H),2.98(t,J=6.6Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ164.50,141.08,138.20,131.74,129.58,128.55,127.16,126.99,52.70,45.11,28.23,20.19ppm.HRMS(ESI)m/z Calcd for C13H15N[M+H]+:186.12773;Found:186.12746.说明在上述条件作用下时,可获得最高产率的目标产物。
实施例5
1-苄基-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,48ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(23.44mg,收率55%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.15(d,J=7.4Hz,1H),7.44-7.39(m,1H),7.38-7.27(m,6H),7.16(d,J=7.1Hz,1H),7.28(d,J=3.9Hz,1H),7.16(d,J=7.1Hz,1H),4.80(s,2H),3.48(t,J=6.4Hz,2H),2.93(t,J=6.4Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ164.69,138.17,137.57,131.81,129.50,129.50,128.75,128.57,128.17,127.56,127.18,127.02,50.56,45.47,28.21ppm.HRMS(ESI)m/z Calcd forC16H15N[M+H]+:222.12773;Found:222.12685.
化合物III(0.2mmol,44.2mg)经过在(1,5-环辛二烯)氯化铱(I)二聚体(0.5mol%,0.7mg)和(Ra,SS)-3a(2.2mol%,2.2mg)催化下,碘化钾(10mol%,3.3mg),氢气(1atm)作为还原剂,以叔丁基甲基醚(2mL)作为溶剂,常温反应顺利转化为1-苯基-1,2,3,4-四氢异喹啉(收率:96%,42.8mg)(采用核磁共振仪、高分辨质谱检测),因具有药理活性而被作为合成药物分子的核心骨架(J.-H.Xie,P.-C.Yan,Q.-Q.Zhang,K.-X.Yuan,Q.-L.Zhou.ACS Catal.2012,2,561-564.)。
实施例6
1-(4-甲基苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,74.1mg),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(24.92mg,收率53%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.14(d,J=7.4Hz,1H),7.40(dt,J=7.4,3.7Hz,1H),7.35(t,J=7.3Hz,1H),7.22(d,J=7.9Hz,2H),7.14(t,J=6.9Hz,3H),4.75(s,2H),3.46(t,J=6.6Hz,2H),2.91(t,J=6.6Hz,2H),2.33(s,3H)ppm.13C NMR(100MHz,CDCl3)δ164.64,138.17,137.21,134.50,131.76,129.55,129.41,128.55,128.19,127.15,126.99,50.24,45.32,28.21,21.22ppm.HRMS(ESI)m/z Calcd for C17H11N[M+H]+:236.14338;Found:236.14314.
实施例7
1-(3-甲基苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,54ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(24.92mg,收率53%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.15(d,J=7.4Hz,1H),7.42(td,J=7.3,1.0Hz,1H),7.35(t,J=7.3Hz,1H),7.21(t,J=7.5Hz,1H),7.12(dt,J=15.8,7.3Hz,4H),4.76(s,2H),3.48(t,J=6.6Hz,2H),2.93(t,J=6.6Hz,2H),2.33(s,3H)ppm.13CNMR(100MHz,CDCl3)δ164.64,138.45,138.19,137.48,131.78,129.54,128.87,128.60,128.56,128.32,127.16,127.01,125.23,50.46,45.39,28.20,21.50ppm.HRMS(ESI)m/zCalcd for C17H17N[M+H]+:236.14338;Found:236.14311.
实施例8
1-(2-甲基苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,54ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(25.39mg,收率54%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.15(d,J=7.7Hz,1H),7.43(td,J=7.4,1.4Hz,1H),7.36(t,J=7.2Hz,1H),7.24-7.20(m,2H),7.20-7.15(m,3H),4.82(s,2H),3.44(t,J=6.6Hz,2H),2.93(t,J=6.6Hz,2H),2.33(s,3H)ppm.13C NMR(100MHz,CDCl3)δ164.58,138.15,136.93,135.01,131.83,130.71,129.51,128.62,127.65,127.21,127.02,126.18,48.32,44.98,28.17,19.41ppm.HRMS(ESI)m/z Calcd for C17H17N[M+H]+:236.14338;Found:236.14305.
实施例9
1-(4-异丙基苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,67ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(22.11mg,收率42%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.14(dd,J=7.6,1.0Hz,1H),7.41(td,J=7.4,1.4Hz,1H),7.35(t,J=7.3Hz,1H),7.25(d,J=2.1Hz,2H),7.18(d,J=8.1Hz,2H),7.15(d,J=7.4Hz,1H),4.76(s,2H),3.48(t,J=6.6Hz,2H),2.93(t,J=6.6Hz,2H),2.88(dd,J=13.8,6.9Hz,1H),1.23(d,J=6.9Hz,6H)ppm.13C NMR(100MHz,CDCl3)δ164.64,148.21,138.19,134.85,131.75,129.58,128.55,128.18,127.14,126.99,126.78,50.32,45.45,33.90,28.22,24.10ppm.HRMS(ESI)m/z Calcd for C19H21N[M+H]+:264.17468;Found:264.17435.
实施例10
1-(4-氯苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,54ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(21.43mg,收率42%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.14(d,J=7.5Hz,1H),7.43(t,J=7.0Hz,1H),7.36(t,J=7.4Hz,1H),7.29(d,J=2.2Hz,4H),7.16(d,J=7.3Hz,1H),4.75(s,2H),3.48(t,J=6.6Hz,2H),2.94(t,J=6.6Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ164.73,138.11,136.15,133.41,131.96,129.56,129.32,128.92,128.58,127.25,127.08,50.03,45.59,28.20ppm.HRMS(ESI)m/z Calcd for C16H14NCl[M+H]+:256.08875;Found:256.08829.
实施例11
1-(4-溴苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.25mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,99.97mg),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(29.31mg,收率49%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.13(dd,J=7.6,0.9Hz,1H),7.45(d,J=8.3Hz,2H),7.42(dd,J=7.5,1.4Hz,1H),7.36(t,J=7.3Hz,1H),7.21(d,J=8.3Hz,2H),7.16(d,J=7.4Hz,1H),4.73(s,2H),3.47(t,J=6.6Hz,2H),2.94(t,J=6.6Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ164.75,138.10,136.65,131.97,131.87,129.90,129.27,128.57,127.25,127.08,121.49,50.08,45.59,28.18ppm.HRMS(ESI)m/z Calcd forC16H14NBr[M+H]+:300.03824;Found:300.03827.
化合物III(0.2mmol,59.8mg)经过在(1,5-环辛二烯)氯化铱(I)二聚体(0.5mol%,0.7mg)和(Ra,SS)-3a(2.2mol%,2.2mg)催化下,碘化钾(10mol%,3.3mg),氢气(1atm)作为还原剂,以叔丁基甲基醚(2mL)作为溶剂,常温反应顺利转化为1-苯基-1,2,3,4-四氢异喹啉(收率:94%,56.6mg)(采用核磁共振仪、高分辨质谱检测),因具有药理活性而被作为合成药物分子的核心骨架(J.-H.Xie,P.-C.Yan,Q.-Q.Zhang,K.-X.Yuan,Q.-L.Zhou.ACS Catal.2012,2,561-564.)。
实施例12
1-(1-苯乙基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,55ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(23.51mg,收率50%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.14(dt,J=20.4,10.2Hz,1H),7.39(dt,J=6.8,2.5Hz,3H),7.37-7.32(m,3H),7.28(dt,J=5.1,2.0Hz,1H),7.13(dd,J=7.3,0.6Hz,1H),6.25(q,J=7.1Hz,1H),3.39(ddd,J=12.4,8.0,6.4Hz,1H),3.23-3.01(m,1H),2.82(t,J=6.5Hz,1H),1.59(d,J=7.1Hz,3H)ppm.13C NMR(100MHz,CDCl3)δ164.36,140.93,138.14,131.75,129.87,128.67,128.59,127.46,127.44,127.18,126.93,50.35,40.24,28.46,15.81ppm.HRMS(ESI)m/z Calcd for C17H17N[M+H]+:236.14338;Found:236.14304.
实施例13
1-烯丙基-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例1制备的反应底物(I)(0.2mmol,50.2mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.6mmol,3.0equiv.,72ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(15.55mg,收率42%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.03(d,J=7.5Hz,1H),7.34(td,J=7.5,1.1Hz,1H),7.27(t,J=7.4Hz,1H),7.10(d,J=7.4Hz,1H),5.79(ddt,J=16.1,10.2,5.9Hz,1H),5.27-5.01(m,2H),4.14(d,J=5.9Hz,2H),3.45(t,J=6.6Hz,2H),2.92(t,J=6.6Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ164.39,138.20,133.30,131.75,129.58,128.48,127.16,127.01,117.57,49.73,45.46,28.23ppm.HRMS(ESI)m/z Calcd forC12H13N[M+H]+:172.11208;Found:172.11187.
实施例14
在干燥清洁的石英管中加入实施例2制备的反应底物(I)(0.2mmol,62.23mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,54ul),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(19.62mg,收率40%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ7.55(s,1H),6.57(s,1H),4.83(d,J=11.2Hz,2H),4.06(s,2H),3.85(s,2H),3.84(s,2H),3.40(t,J=6.7Hz,2H),2.84(t,J=6.7Hz,2H),1.67(s,3H)ppm.13C NMR(100MHz,CDCl3)δ164.63,151.97,148.17,141.36,131.88,122.20,112.81,110.91,109.45,56.27,56.23,52.78,45.44,27.92,20.26ppm.HRMS(ESI)m/z Calcd for C15H19NO2[M+H]+:246.14886;Found:246.14926.
实施例15
6-溴-1-(4-甲基苄基)-3,4-二氢异喹啉的合成反应
在干燥清洁的石英管中加入实施例3制备的反应底物(I)(0.2mmol,65.81mg)、K2CO3(0.5mmol,2.5equiv.,69.1mg)和18-Crown-6(0.3mmol,1.5equiv.,79.3mg),然后,密闭封管管口在脱气充入N2(1atm),在氮气氛围下加入溶剂CH3CN(2mL)和化合物(II)(0.4mmol,2.0equiv.,74.1mg),最后在紫光(390-395nm)照射下反应36h。反应完成后,向反应体系中加入5mL的水淬灭反应,用乙酸乙酯萃取(3×5mL,共进行3次,每次5mL)含水混合物。萃取完后有机相用无水硫酸镁干燥,过滤并减压浓缩,通过柱色谱(洗脱剂:石油醚/乙酸乙酯15:1-5:1,v/v,(在此为5:1))分离纯化得到黄色固体(26.30mg,收率42%)。采用核磁共振仪、高分辨质谱检测,所得产品的参数为1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.44(d,J=7.9Hz,1H),7.13(d,J=7.5Hz,2H),7.05(d,J=7.3Hz,2H),6.95(d,J=7.9Hz,1H),4.65(s,2H),3.37(t,J=6.1Hz,2H),2.78(t,J=6.1Hz,2H),2.25(s,3H).13C NMR(100MHz,CDCl3)δ163.33,137.41,136.92,134.61,134.17,131.52,129.49,128.76,128.22,50.38,45.14,27.72,21.24.HRMS(ESI)m/z Calcd for C17H16BrN[M+H]+:314.05389;Found:314.05469.
以上所述仅为本发明的实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书及附图内容所作的等效结构或等效流程变换,或直接或间接运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (10)
1.一种1-苄或烯丙基3,4-二氢异喹啉的合成方法,其特征在于:以偶氮芳基保护的四氢异喹啉化合物和苄或烯丙基溴化物作为底物,可见光诱导偶氮芳基保护的四氢异喹啉与苄或烯丙基溴化物的α-烯丙基化反应,合成1-苄或烯丙基3,4-二氢异喹啉类化合物。
2.如权利要求1所述的合成方法,其特征在于:以紫光作为光源,使用偶氮芳基-1,2,3,4-四氢异喹啉化合物(I)与苄或烯丙基溴化物(II)作为底物,可见光诱导偶氮芳基-1,2,3,4-四氢异喹啉化合物的α-烯丙基化反应,合成1-苄或烯丙基3,4-二氢异喹啉类化合物(III);所述反应过程如下反应式所示;
苄或烯丙基溴化物(II)中虚线表示此处为无苯环或有苯环二种情形的溴化物,无苯环时溴化物为烯丙基溴化物,有苯环时溴化物为苄基溴化物;而1-苄或烯丙基3,4-二氢异喹啉类化合物(III)中虚线表示此处为无苯环或有苯环二种情形的化合物,无苯环时其为1-烯丙基3,4-二氢异喹啉类化合物,有苯环时其为1-苄基3,4-二氢异喹啉类化合物;
R、R1分别独立地表示在苯环邻位、间位、对位等中的一种或二种以上不同位置的取代基或为氢的无取代基,取代基的个数分别为1-5个,优选1-2个,其具体可分别独立地为甲基、异丙基、氯、溴、碘、甲氧基中的一种或二种以上;R2表示为氢、甲基中的一种或二种;
优选:R为氢、溴、甲氧基中的一种或二种以上,取代基的个数为1-5个,优选1-2个;R1为氢、2-甲基、3-甲基、4-甲基、4-异丙基、4-氯、4-溴中的一种或二种以上,取代基的个数为1-5个,优选1-2个;R2为氢、甲基中的一种或二种。
4.如权利要求1或2或3所述的合成方法,其特征在于:所述反应中可见光为紫光,紫光的波长390nm-435nm,优选390nm-395nm的紫光。
5.如权利要求1所述的合成方法,其特征在于:所述反应在溶剂中进行,溶剂为乙腈、DMF之任意一种或二种,优选的溶剂为乙腈;偶氮芳基保护的四氢异喹啉化合物的浓度为0.1-0.3M,较优为0.15-0.25M,最优选偶氮芳基保护的四氢异喹啉化合物于溶剂中的浓度为0.2-0.21M。
6.如权利要求1或2或3所述的合成方法,其特征在于:所述反应中的碱存在下进行,添加剂为K2CO3、Cs2CO3、KOAc、Na2CO3、Et3N、DBU(1,8-二氮杂环[5,4,0]十一烯-7)之任意一种或二种,优选的碱为K2CO3;碱对溶剂中的浓度为0.1-0.3M,较优为0.2-0.3M,最优为0.25-0.275,最优0.25M。
7.如权利要求1或2或3所述的合成方法,其特征在于:所述反应中的添加剂存在下进行,添加剂为18-Crown-6、Benzo-18-Crown-6之任意一种或二种,优选的添加剂为18-Crown-6;添加剂对溶剂中的浓度为0.1-0.2M,较优为0.15-0.2M,最优为0.15-0.175,最优0.15M。
8.如权利要求1或2或3所述的合成方法,其特征在于:所述反应中偶氮芳基保护的四氢异喹啉化合物(I)与苄或烯丙基溴化物(II)或2-甲基-3-溴丙烯(II)用量的摩尔比例为0.5:1-1:3,优选偶氮芳基保护的四氢异喹啉化合物(I)与苄或烯丙基溴化物(II)或2-甲基-3-溴丙烯(II)用量的摩尔比例为1:2-3,最优选偶氮芳基保护的四氢异喹啉化合物(I)与苄或烯丙基溴化物(II)或2-甲基-3-溴丙烯(II)用量的摩尔比例为1:2-2.5。
9.如权利要求1-8任一所述的合成方法,其特征在于:所述反应包括以下步骤:
在密闭容器(如:石英管)中加入偶氮芳基保护的四氢异喹啉、苄或烯丙基溴化物(II)或3-溴甲基丙烯、碱、添加剂、惰性气氛(如:N2)以及溶剂,在常温条件下紫光照射搅拌反应,得到上述反应1-苄或烯丙基3,4-二氢异喹啉类产物。
10.如权利要求1或2或3或9所述的合成方法,其特征在于:
反应在惰性气氛(如:氮气)氛围下进行,反应时间为24-48h,优选反应时间为30-36h。
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