CN113549020B - Quinazoline derivatives, their preparation and use - Google Patents
Quinazoline derivatives, their preparation and use Download PDFInfo
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- CN113549020B CN113549020B CN202110839056.6A CN202110839056A CN113549020B CN 113549020 B CN113549020 B CN 113549020B CN 202110839056 A CN202110839056 A CN 202110839056A CN 113549020 B CN113549020 B CN 113549020B
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- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 49
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 157
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 111
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 229910052736 halogen Chemical group 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 3
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 3
- MULYSYXKGICWJF-UHFFFAOYSA-L cobalt(2+);oxalate Chemical compound [Co+2].[O-]C(=O)C([O-])=O MULYSYXKGICWJF-UHFFFAOYSA-L 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 140
- 150000002527 isonitriles Chemical class 0.000 abstract description 36
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 7
- 150000001540 azides Chemical class 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 238000010276 construction Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 238000010667 large scale reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 239000007795 chemical reaction product Substances 0.000 description 105
- 239000000047 product Substances 0.000 description 78
- 238000004440 column chromatography Methods 0.000 description 70
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 48
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 35
- 230000005526 G1 to G0 transition Effects 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
- 238000012512 characterization method Methods 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000003208 petroleum Substances 0.000 description 35
- 239000000843 powder Substances 0.000 description 35
- 238000000926 separation method Methods 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 35
- 229910002027 silica gel Inorganic materials 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 27
- HTMWQSKIYNDFNU-UHFFFAOYSA-N 2-isocyanobenzonitrile Chemical compound [C-]#[N+]C1=CC=CC=C1C#N HTMWQSKIYNDFNU-UHFFFAOYSA-N 0.000 description 24
- 150000003246 quinazolines Chemical class 0.000 description 21
- -1 class of nitrogen-containing heterocyclic compounds Chemical class 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 14
- 125000001544 thienyl group Chemical group 0.000 description 7
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical group C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 4
- QFHYNRYGVDLHDY-UHFFFAOYSA-N N#[C-].C(C1=CC=CC=C1)#N Chemical compound N#[C-].C(C1=CC=CC=C1)#N QFHYNRYGVDLHDY-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- MMHFQKUQSDMGSY-UHFFFAOYSA-N 1-isocyano-2-phenylbenzene Chemical compound [C-]#[N+]C1=CC=CC=C1C1=CC=CC=C1 MMHFQKUQSDMGSY-UHFFFAOYSA-N 0.000 description 3
- 241000194032 Enterococcus faecalis Species 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- KPJASRYNNMEKPY-UHFFFAOYSA-N n-diazocyclohexanesulfonamide Chemical compound [N-]=[N+]=NS(=O)(=O)C1CCCCC1 KPJASRYNNMEKPY-UHFFFAOYSA-N 0.000 description 3
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 3
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 2
- HQNSWBRZIOYGAW-UHFFFAOYSA-N 2-chloro-n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC(Cl)=C1 HQNSWBRZIOYGAW-UHFFFAOYSA-N 0.000 description 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 2
- GXMBSYQFGJYUBQ-UHFFFAOYSA-N 4-bromo-n-diazobenzenesulfonamide Chemical compound BrC1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 GXMBSYQFGJYUBQ-UHFFFAOYSA-N 0.000 description 2
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 2
- WQBQDHDUGLLGHT-UHFFFAOYSA-N 4-chloro-n-diazobenzenesulfonamide Chemical compound ClC1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 WQBQDHDUGLLGHT-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 2
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940052810 complex b Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- NTMHWRHEGDRTPD-UHFFFAOYSA-N n-(4-azidosulfonylphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 NTMHWRHEGDRTPD-UHFFFAOYSA-N 0.000 description 2
- XUUDFFJLFDUNPT-UHFFFAOYSA-N n-diazo-4-(trifluoromethyl)benzenesulfonamide Chemical compound FC(F)(F)C1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 XUUDFFJLFDUNPT-UHFFFAOYSA-N 0.000 description 2
- LWFLTKAQFZYQEJ-UHFFFAOYSA-N n-diazo-4-fluorobenzenesulfonamide Chemical compound FC1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 LWFLTKAQFZYQEJ-UHFFFAOYSA-N 0.000 description 2
- WGMMTPWFPUPFKG-UHFFFAOYSA-N n-diazo-4-methoxybenzenesulfonamide Chemical compound COC1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 WGMMTPWFPUPFKG-UHFFFAOYSA-N 0.000 description 2
- PKOMWXNFNKIIDP-UHFFFAOYSA-N n-diazopropane-1-sulfonamide Chemical compound CCCS(=O)(=O)N=[N+]=[N-] PKOMWXNFNKIIDP-UHFFFAOYSA-N 0.000 description 2
- UTIPTKYYZQIJLI-UHFFFAOYSA-N n-methyl-1h-indol-5-amine Chemical compound CNC1=CC=C2NC=CC2=C1 UTIPTKYYZQIJLI-UHFFFAOYSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 238000007867 post-reaction treatment Methods 0.000 description 2
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- ASQOQJYHIYYTEJ-GBESFXJTSA-N (1r,7s,9as)-7-decyl-2,3,4,6,7,8,9,9a-octahydro-1h-quinolizin-1-ol Chemical compound O[C@@H]1CCCN2C[C@@H](CCCCCCCCCC)CC[C@H]21 ASQOQJYHIYYTEJ-GBESFXJTSA-N 0.000 description 1
- GIQHRQOXGOFHRV-UHFFFAOYSA-N 2-isocyano-6-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=CC([N+]#[C-])=C1C#N GIQHRQOXGOFHRV-UHFFFAOYSA-N 0.000 description 1
- 229940123786 Adenosine A3 receptor antagonist Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101000783645 Homo sapiens Adenosine receptor A3 Proteins 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- XZTOUFLBTSKLKT-UHFFFAOYSA-N N-diazooxolane-2-sulfonamide Chemical compound O1C(CCC1)S(=O)(=O)N=[N+]=[N-] XZTOUFLBTSKLKT-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002580 adenosine A3 receptor antagonist Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 150000004700 cobalt complex Chemical class 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 102000046278 human ADORA3 Human genes 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MNNCYDMLAZRMQX-UHFFFAOYSA-N n-diazothiophene-2-sulfonamide Chemical compound [N-]=[N+]=NS(=O)(=O)C1=CC=CS1 MNNCYDMLAZRMQX-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- RCIBIGQXGCBBCT-UHFFFAOYSA-N phenyl isocyanide Chemical compound [C-]#[N+]C1=CC=CC=C1 RCIBIGQXGCBBCT-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
本发明属于有机合成领域，具体涉及一种喹唑啉衍生物及其制备和应用，所述喹唑啉衍生物由异腈、叠氮化物和胺类衍生物作为反应原料，一锅法制备而得。本发明提供了一种更为步骤经济性、原子经济性高、后处理方便、高效的喹唑啉衍生物的合成方法，原料廉价易得，条件简单温和，原子经济性高，产率优异，同时还具有底物范围宽等优点，放大量反应中可以实现催化剂的回收和利用，未发现催化活性出现明显降低，为喹唑啉骨架的高效构筑提供了非常绿色的合成方法；该喹唑啉衍生物具有潜在的抗菌活性的特性。The invention belongs to the field of organic synthesis, and specifically relates to a quinazoline derivative and its preparation and application. The quinazoline derivative is prepared from isonitrile, azide and amine derivatives as reaction raw materials in a one-pot method. have to. The present invention provides a method for synthesizing quinazoline derivatives with more step economy, high atom economy, convenient post-treatment and high efficiency. The raw materials are cheap and easy to obtain, the conditions are simple and mild, the atom economy is high, and the yield is excellent. At the same time, it also has the advantages of a wide range of substrates, and the recovery and utilization of the catalyst can be realized in large-scale reactions. No significant reduction in catalytic activity has been found, which provides a very green synthetic method for the efficient construction of quinazoline skeletons; the quinazoline Derivatives are characterized by potential antibacterial activity.
Description
技术领域technical field
本发明属于有机合成领域，具体涉及一种喹唑啉衍生物及其制备和应用。The invention belongs to the field of organic synthesis, and in particular relates to a quinazoline derivative and its preparation and application.
背景技术Background technique
喹唑啉衍生物是一类具有重要生物活性的含氮杂环化合物，广泛存在于天然产物和生物活性分子中，例如含有喹唑啉骨架的抗癌药物Gefitinib和Erlotinib已经被批准用于治疗非小细胞肺癌(NSCLC)，(Angew.Chem.Int.Ed.2012,51,8960)还有人腺苷A3受体拮抗剂I已经成功用于治疗剂。(Acc.Chem.Res.2015,48,1832)因此，构建喹唑啉类化合物的策略报道屡见不鲜。Quinazoline derivatives are a class of nitrogen-containing heterocyclic compounds with important biological activities, which widely exist in natural products and bioactive molecules. For example, the anticancer drugs Gefitinib and Erlotinib containing quinazoline skeletons have been approved for the treatment of non- Small cell lung cancer (NSCLC), (Angew. Chem. Int. Ed. 2012, 51, 8960) also the human adenosine A3 receptor antagonist I has been successfully used as a therapeutic agent. (Acc. Chem. Res. 2015, 48, 1832) Therefore, reports on strategies for constructing quinazoline compounds are not uncommon.
尽管已经有数例有效合成上述化合物的相关报道，但这些方法需要多种添加剂、使用昂贵金属催化剂、反应后处理复杂、催化剂无法回收利用等缺陷，在步骤经济性、原子经济性方面十分低效。在此类化合物，合成效率是最重要的部分，此外，操作简单、安全、经济、环保等方面也需要统筹兼顾，从而达到“绿色有机合成理念”的要求。Although there have been several reports on the effective synthesis of the above compounds, these methods require a variety of additives, use expensive metal catalysts, complex post-reaction treatment, and catalysts cannot be recycled, and are very inefficient in terms of step economy and atom economy. In this type of compound, the synthesis efficiency is the most important part. In addition, the simple operation, safety, economy, and environmental protection also need to be taken into consideration, so as to meet the requirements of the "green organic synthesis concept".
因此，在温和条件下，从简单易得的底物出发，一锅法高效构建新型的喹唑啉类化合物的方法是极具吸引力的，其合成过程不使用昂贵金属催化剂、反应后处理简单、催化剂可以回收利用，具有十分重要的意义。Therefore, starting from simple and easy-to-obtain substrates under mild conditions, a one-pot method for efficiently constructing novel quinazoline compounds is very attractive. The synthesis process does not use expensive metal catalysts and the post-reaction treatment is simple. , The catalyst can be recycled, which is of great significance.
发明内容Contents of the invention
为解决上述技术问题，本发明的目的是提供一种喹唑啉衍生物及其制备和应用，本发明的喹唑啉衍生物利用简单原料一步构建而成，反应条件温和，环境友好，操作简单，且该反应在放大量中，催化剂可以回收利用，未发现催化活性出现明显降低，为喹唑啉骨架的高效构筑提供了绿色的合成方法，该喹唑啉衍生物具有抗菌活性的特性。In order to solve the above technical problems, the object of the present invention is to provide a quinazoline derivative and its preparation and application. The quinazoline derivative of the present invention is constructed in one step using simple raw materials, with mild reaction conditions, friendly environment and simple operation , and the reaction is in a large amount, the catalyst can be recycled, and the catalytic activity is not found to be significantly reduced, which provides a green synthesis method for the efficient construction of quinazoline skeletons, and the quinazoline derivatives have antibacterial properties.
本发明的第一方面提供了一种喹唑啉衍生物，结构式如式(IV)所示：The first aspect of the present invention provides a kind of quinazoline derivative, structural formula is as shown in formula (IV):
其中，R1选自C1-C6烷基或C6-C18芳基；Wherein, R1 is selected from C1-C6 alkyl or C6-C18 aryl;
R2选自C1-C6烷基或C6-C18芳基；R2 is selected from C1-C6 alkyl or C6-C18 aryl;
R3选自氢、甲基、烷氧基、硝基或卤素。R3 is selected from hydrogen, methyl, alkoxy, nitro or halogen.
优选地，R3选自氢、甲基、甲氧基、硝基、氟、氯或溴。Preferably, R3 is selected from hydrogen, methyl, methoxy, nitro, fluoro, chloro or bromo.
进一步的，R1为C6-C18芳基时，所述C6-C18芳基选自苯基、噻吩基、苯并四氢呋喃基、取代苯基、取代噻吩基或取代苯并四氢呋喃基，所述取代苯基、取代噻吩基和取代苯并四氢呋喃基的取代基分别独立地选自C1-C5烷基、C1-C5烷氧基、C1-C5氟代烷基、卤素或乙酰氨基。Further, when R1 is a C6-C18 aryl group, the C6-C18 aryl group is selected from phenyl, thienyl, benzotetrahydrofuryl, substituted phenyl, substituted thienyl or substituted benzotetrahydrofuryl, and the substituted benzene The substituents of the radical, substituted thienyl and substituted benzotetrahydrofuryl are independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 fluoroalkyl, halogen or acetamido.
进一步的，C6烷基为直链烷基或环烷基。Further, C6 alkyl is straight chain alkyl or cycloalkyl.
优选地，R1选自环己基、噻吩基、苯并四氢呋喃基或取代苯基，其中取代苯基上的取代基选自氢、正丙基、甲氧基、甲基、乙酰氨基、三氟甲基、苯基、硝基、氰基、氟、氯或溴。Preferably, R1 is selected from cyclohexyl, thienyl, benzotetrahydrofuryl or substituted phenyl, wherein the substituent on the substituted phenyl is selected from hydrogen, n-propyl, methoxy, methyl, acetamido, trifluoromethane phenyl, nitro, cyano, fluoro, chloro or bromo.
进一步的，R2为C6-C18芳基时，所述C6-C18芳基选自苯基、苯并吡咯基、取代苯基或取代苯并吡咯基，所述取代苯基和取代苯并吡咯基的取代基分别独立地选自C1-C5烷基、C1-C5烷氧基、卤素或C1-C5氟代烷基。Further, when R2 is a C6-C18 aryl group, the C6-C18 aryl group is selected from phenyl, benzopyrrolyl, substituted phenyl or substituted benzopyrrolyl, and the substituted phenyl and substituted benzopyrrolyl The substituents of are independently selected from C1-C5 alkyl, C1-C5 alkoxy, halogen or C1-C5 fluoroalkyl.
优选地，R2选正丁基、色胺基或取代苯基，其中取代苯基上的取代基选自氢、甲基、甲氧基、酯基、硝基、三氟甲基、氟、氯或溴。Preferably, R2 is selected from n-butyl, tryptamine or substituted phenyl, wherein the substituent on the substituted phenyl is selected from hydrogen, methyl, methoxy, ester, nitro, trifluoromethyl, fluorine, chlorine or bromine.
本发明的第二方面提供了上述喹唑啉衍生物的制备方法，包括以下步骤：将式(I)、式(II)和式(III)化合物在金属盐催化剂的作用下，在有机溶剂中反应，得到所述喹唑啉衍生物；其中，式(I)、式(II)和式(III)化合物的通式分别如下所示：The second aspect of the present invention provides the preparation method of the above-mentioned quinazoline derivatives, comprising the following steps: formula (I), formula (II) and formula (III) compound under the effect of metal salt catalyst, in an organic solvent Reaction, obtains described quinazoline derivative; Wherein, the general formula of formula (I), formula (II) and formula (III) compound is as follows respectively:
反应路线如下：The reaction scheme is as follows:
其中，R1选自C1-C6烷基或C6-C18芳基；Wherein, R1 is selected from C1-C6 alkyl or C6-C18 aryl;
R2选自C1-C6烷基或C6-C18芳基；R2 is selected from C1-C6 alkyl or C6-C18 aryl;
R3选自氢、甲基、烷氧基、硝基或卤素。R3 is selected from hydrogen, methyl, alkoxy, nitro or halogen.
进一步的，R1为C6-C18芳基时，所述C6-C18芳基选自苯基、噻吩基、苯并四氢呋喃基、取代苯基、取代噻吩基或取代苯并四氢呋喃基，所述取代苯基、取代噻吩基和取代苯并四氢呋喃基的取代基分别独立地选自C1-C5烷基、C1-C5烷氧基、C1-C5氟代烷基、卤素或乙酰氨基。Further, when R1 is a C6-C18 aryl group, the C6-C18 aryl group is selected from phenyl, thienyl, benzotetrahydrofuryl, substituted phenyl, substituted thienyl or substituted benzotetrahydrofuryl, and the substituted benzene The substituents of the radical, substituted thienyl and substituted benzotetrahydrofuryl are independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 fluoroalkyl, halogen or acetamido.
优选地，式(I)化合物选自4-甲基苯磺酰叠氮(I-1)、苯磺酰叠氮(I-2)、4-甲氧基苯磺酰叠氮(I-3)、4-氟苯磺酰叠氮(I-4)、4-氯苯磺酰叠氮(I-5)、4-溴苯磺酰叠氮(I-6)、4-三氟甲基苯磺酰叠氮(I-7)、4-乙酰氨基苯磺酰叠氮(I-8)、5-四氢呋喃基磺酰叠氮(I-9)、2-噻吩基磺酰叠氮(I-10)、环己基磺酰叠氮(I-11)或正丙基磺酰叠氮(I-12)。以上各编号对应的式(I)化合物的具体结构式如下：Preferably, the compound of formula (I) is selected from 4-methylbenzenesulfonyl azide (I-1), benzenesulfonyl azide (I-2), 4-methoxybenzenesulfonyl azide (I-3 ), 4-fluorobenzenesulfonyl azide (I-4), 4-chlorobenzenesulfonyl azide (I-5), 4-bromobenzenesulfonyl azide (I-6), 4-trifluoromethyl Benzenesulfonyl azide (I-7), 4-acetylaminobenzenesulfonyl azide (I-8), 5-tetrahydrofurylsulfonyl azide (I-9), 2-thienylsulfonyl azide (I -10), cyclohexylsulfonyl azide (I-11) or n-propylsulfonyl azide (I-12). The concrete structural formula of the corresponding formula (I) compound above each numbering is as follows:
进一步的，R2为C6-C18芳基时，所述C6-C18芳基选自苯基、苯并吡咯基、取代苯基或取代苯并吡咯基，所述取代苯基和取代苯并吡咯基的取代基分别独立地选自C1-C5烷基、C1-C5烷氧基、卤素或C1-C5氟代烷基。Further, when R2 is a C6-C18 aryl group, the C6-C18 aryl group is selected from phenyl, benzopyrrolyl, substituted phenyl or substituted benzopyrrolyl, and the substituted phenyl and substituted benzopyrrolyl The substituents of are independently selected from C1-C5 alkyl, C1-C5 alkoxy, halogen or C1-C5 fluoroalkyl.
优选地，式(II)化合物选自苯胺(II-1)、4-甲基苯胺(II-2)、4-甲氧基苯胺(II-3)、4-氟苯胺(II-4)、4-氯苯胺(II-5)、4-溴苯胺(II-6)、4-三氟甲基苯胺(II-7)、4-酯基苯胺(II-8)、4-硝基苯胺(II-9)、2-甲基苯胺(II-10)、2-甲氧基苯胺(II-11)、2-氯苯胺(II-12)、2-溴苯胺(II-13)、2,6-二甲基苯胺(II-14),N-甲基吲哚-5-胺(II-15)、色胺(II-16)或正丁胺(II-17)。以上各编号对应的式(II)化合物的具体结构式如下：Preferably, the compound of formula (II) is selected from the group consisting of aniline (II-1), 4-methylaniline (II-2), 4-methoxyaniline (II-3), 4-fluoroaniline (II-4), 4-chloroaniline (II-5), 4-bromoaniline (II-6), 4-trifluoromethylaniline (II-7), 4-ester aniline (II-8), 4-nitroaniline ( II-9), 2-methylaniline (II-10), 2-methoxyaniline (II-11), 2-chloroaniline (II-12), 2-bromoaniline (II-13), 2, 6-Dimethylaniline (II-14), N-methylindole-5-amine (II-15), tryptamine (II-16) or n-butylamine (II-17). The specific structural formula of the corresponding formula (II) compound above each numbering is as follows:
优选地，式(III)化合物选自邻氰基苯基异腈(III-1)、3-甲基邻氰基苯基异腈(III-2)、3-甲氧基邻氰基苯基异腈(III-3)、3,4-二甲氧基邻氰基苯基异腈(III-4)、3-氟邻氰基苯基异腈(III-5)、3-氯邻氰基苯基异腈(III-6)、3-溴邻氰基苯基异腈(III-7)或3-硝基邻氰基苯基异腈(III-8)。以上各编号对应的式(III)化合物的具体结构式如下：Preferably, the compound of formula (III) is selected from o-cyanophenyl isonitrile (III-1), 3-methyl o-cyanophenyl isonitrile (III-2), 3-methoxy o-cyanophenyl Isonitrile (III-3), 3,4-dimethoxy-o-cyanophenylisonitrile (III-4), 3-fluoro-o-cyanophenylisonitrile (III-5), 3-chloro-o-cyanocyanide phenylisonitrile (III-6), 3-bromo-o-cyanophenylisonitrile (III-7) or 3-nitro-o-cyanophenylisonitrile (III-8). The specific structural formula of the formula (III) compound corresponding to each of the above numbers is as follows:
优选地，式(IV)所示的喹唑啉衍生物的结构式如式(IV-1)至式(IV-35)任一所示：Preferably, the structural formula of the quinazoline derivative shown in formula (IV) is as shown in any one of formula (IV-1) to formula (IV-35):
以上结构式中，Ts代表对甲苯磺酰基。In the above structural formula, Ts represents p-toluenesulfonyl.
进一步的，所述金属盐催化剂为乙酰丙酮钴(Co(acac)3)、氯化钴和草酸亚钴中的一种或几种，优选为Co(acac)3。Further, the metal salt catalyst is one or more of cobalt acetylacetonate (Co(acac) 3 ), cobalt chloride and cobaltous oxalate, preferably Co(acac) 3 .
进一步的，所述式(I)、式(II)和式(III)化合物与金属盐催化剂的摩尔比为1.0-1.5：1.0：1.0-1.2：0.025-0.075，优选为1.5：1.0：1.2：0.05。Further, the molar ratio of the compound of formula (I), formula (II) and formula (III) to the metal salt catalyst is 1.0-1.5:1.0:1.0-1.2:0.025-0.075, preferably 1.5:1.0:1.2: 0.05.
进一步的，所述有机溶剂选自乙腈、1,4-二氧六环、N,N-二甲基甲酰胺和甲苯中的一种或几种。Further, the organic solvent is selected from one or more of acetonitrile, 1,4-dioxane, N,N-dimethylformamide and toluene.
进一步的，所述反应温度为40-100℃，优选为80℃。Further, the reaction temperature is 40-100°C, preferably 80°C.
进一步的，所述反应时间为6-12h，优选为12h。Further, the reaction time is 6-12h, preferably 12h.
进一步地，反应在空气气氛中进行。Further, the reaction is carried out in an air atmosphere.
具体的，以原料为磺酰叠氮、苯胺和邻氰基苯基异腈、催化剂为Co(acac)3的反应为例，本发明的式(IV)所示的喹唑啉衍生物在制备过程中，反应原理如下：Concrete, take raw material as sulfonyl azide, aniline and o-cyanophenyl isocyanide, catalyzer is the reaction of Co(acac) 3 is example, the quinazoline derivative shown in formula (IV) of the present invention is in preparation In the process, the reaction principle is as follows:
首先，Co(acac)3和异腈发生快速的配体交换得到金属钴配合物A。金属配合物A与磺酰叠氮反应得到配合物B。配合物B脱去N2后得到碳二亚胺中间体C。接着苯胺对C亲核进攻得到E，分子内氨基对氰基亲核进攻环化得到喹唑啉类化合物4a。First, Co(acac) 3 undergoes rapid ligand exchange with isocyanide to obtain metal cobalt complex A. Metal complex A reacts with sulfonyl azide to give complex B. The carbodiimide intermediate C is obtained after the removal of N2 from the complex B. Then aniline attacks C nucleophilically to obtain E, and the intramolecular amino group nucleophilically attacks cyano to obtain quinazoline compound 4a.
本发明的第三方面提供了上述喹唑啉衍生物在制备抗菌活性药物中的应用。The third aspect of the present invention provides the use of the above-mentioned quinazoline derivatives in the preparation of antibacterial active drugs.
借由上述方案，本发明至少具有以下优点：By means of the above solution, the present invention has at least the following advantages:
本发明以异腈、叠氮化物和胺类衍生物作为反应原料，一锅法制备得到喹唑啉衍生物。与现有技术相比，本发明提供了一种更为步骤经济性、原子经济性高、后处理方便、高效的喹唑啉衍生物的合成方法。该方法利用简单原料一步构建而成，具有原料廉价易得，条件简单温和，原子经济性高，产率优异，其产率最高可达98％，同时还具有底物范围宽等优点，放大量反应中可以实现催化剂的回收和利用，未发现催化活性出现明显降低，为喹唑啉骨架的高效构筑提供了非常绿色的合成方法。The invention uses isonitrile, azide and amine derivatives as reaction raw materials to prepare quinazoline derivatives in one pot. Compared with the prior art, the present invention provides a method for synthesizing quinazoline derivatives with more step economy, high atom economy, convenient post-treatment and high efficiency. The method is constructed by using simple raw materials in one step. It has the advantages of cheap and easy-to-obtain raw materials, simple and mild conditions, high atom economy, and excellent yield. The yield can reach up to 98%. The recovery and utilization of the catalyst can be realized in the reaction, and no significant decrease in catalytic activity is found, which provides a very green synthetic method for the efficient construction of the quinazoline skeleton.
本发明提供了一系列有潜在生物活性的喹唑啉衍生物，该喹唑啉衍生物具有潜在的抗菌活性的特性。The invention provides a series of quinazoline derivatives with potential biological activity, and the quinazoline derivatives have the property of potential antibacterial activity.
具体实施方式Detailed ways
下面结合具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。The present invention will be further described below in conjunction with specific examples, so that those skilled in the art can better understand the present invention and implement it, but the given examples are not intended to limit the present invention.
本发明以下实施例提供了上文中式(III-1)至式(III-35)之一所示的喹唑啉衍生物的制备方法。以下原料中的编号与上文中的编号相对应。The following examples of the present invention provide the preparation method of the quinazoline derivatives represented by one of the above formulas (III-1) to (III-35). The numbers in the following materials correspond to the numbers above.
实施例1：合成(IV-1)所示的化合物Embodiment 1: the compound shown in synthetic (IV-1)
1.1、称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0760g反应产物。1.1. Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to number (I-1), 0.056g), 0.2mmol aniline (compound corresponding to number (II-1), 0.019g), 0.24mmol ortho Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0760 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ8.2(d,J＝8.0Hz,1H),7.7–7.5(m,6H),7.3–7.3(m,1H),7.2–7.1(m,5H),2.4(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.2 (d, J=8.0Hz, 1H), 7.7-7.5(m, 6H), 7.3-7.3(m, 1H), 7.2-7.1(m, 5H), 2.4(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为98％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 98%.
1.2、在1.1的基础上将称取对甲基苯磺酰叠氮的量改为0.2mmol，0.0373g，产品产率为89％。1.2. On the basis of 1.1, change the amount of p-toluenesulfonyl azide to 0.2mmol, 0.0373g, and the product yield is 89%.
1.3、在1.1的基础上将称取对甲基苯磺酰叠氮的量改为0.24mmol，0.0448g，产品产率为91％。1.3. On the basis of 1.1, change the amount of p-toluenesulfonyl azide to 0.24mmol, 0.0448g, and the product yield is 91%.
1.4、在1.2的基础上将称取邻氰基苯基异腈的量改为0.2mmol，0.0258g，产品产率为62％。1.4. On the basis of 1.2, change the amount of o-cyanophenylisonitrile to 0.2mmol, 0.0258g, and the product yield is 62%.
1.5、在1.2的基础上将称取邻氰基苯基异腈的量改为0.3mmol，0.0388g，产品产率为89％。1.5. On the basis of 1.2, change the amount of o-cyanophenylisonitrile to 0.3mmol, 0.0388g, and the product yield is 89%.
1.6、在1.1的基础上将称取Co(acac)3的量分别改为0.005mmol和0.015mmol，产品产率分别为75％和80％。1.6. On the basis of 1.1, change the amount of Co(acac) 3 by weighing to 0.005mmol and 0.015mmol respectively, and the product yields are 75% and 80% respectively.
1.7、在1.4的基础上将Co(acac)3分别替换成氯化钴和草酸亚钴，产品产率分别为50％和49％。1.7. On the basis of 1.4, replace Co(acac) 3 with cobalt chloride and cobaltous oxalate, and the product yields are 50% and 49% respectively.
1.8、在2.0的基础上反应温度分别改为40℃和100℃，产品产率分别为23％和62％。1.8. On the basis of 2.0, the reaction temperature was changed to 40°C and 100°C respectively, and the product yields were 23% and 62% respectively.
1.9、在1.1的基础上反应时间分别改为6h和12h，产品产率分别为96％和98％。1.9. On the basis of 1.1, the reaction time was changed to 6h and 12h respectively, and the product yields were 96% and 98% respectively.
实施例2：合成(IV-2)所示的化合物Embodiment 2: the compound shown in synthetic (IV-2)
称取0.3mmol苯磺酰叠氮(编号(I-2)对应的化合物，0.055g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0740g反应产物。Weigh 0.3mmol benzenesulfonyl azide (compound corresponding to numbering (I-2), 0.055g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanophenyliso Nitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, and stir at 80°C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0740 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.12(s,1H),8.20(d,J＝8.0Hz,1H),7.69(d,J＝7.8Hz,2H),7.65–7.43(m,5H),7.39(t,J＝7.7Hz,2H),7.26(t,J＝7.7Hz,1H),7.23–7.01(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.12(s, 1H), 8.20(d, J=8.0Hz, 1H), 7.69(d, J=7.8Hz, 2H), 7.65–7.43(m, 5H) ,7.39(t,J=7.7Hz,2H),7.26(t,J=7.7Hz,1H),7.23–7.01(m,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为98％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 98%.
实施例3：合成(IV-3)所示的化合物Embodiment 3: the compound shown in synthetic (IV-3)
称取0.3mmol对甲氧基苯磺酰叠氮(编号(I-3)对应的化合物，0.064g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0800g反应产物。Weigh 0.3mmol p-methoxybenzenesulfonyl azide (compound corresponding to numbering (I-3), 0.064g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanogen Phenyl phenyl isocyanide (compound corresponding to code (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0800 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.41(s,1H),8.20(d,J＝8.0Hz,1H),7.62(d,J＝8.9Hz,2H),7.59–7.45(m,4H),7.29–7.23(m,1H),7.15(d,J＝6.9Hz,2H),7.10(d,J＝8.1Hz,1H),6.86(d,J＝8.9Hz,2H),3.82(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.41(s, 1H), 8.20(d, J=8.0Hz, 1H), 7.62(d, J=8.9Hz, 2H), 7.59–7.45(m, 4H) ,7.29–7.23(m,1H),7.15(d,J=6.9Hz,2H),7.10(d,J=8.1Hz,1H),6.86(d,J=8.9Hz,2H),3.82(s, 3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为95％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 95%.
实施例4：合成(IV-4)所示的化合物Embodiment 4: the compound shown in synthetic (IV-4)
称取0.3mmol对氟苯磺酰叠氮(编号(I-4)对应的化合物，0.060g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0760g反应产物。Weigh 0.3mmol p-fluorobenzenesulfonyl azide (compound corresponding to number (I-4), 0.060g), 0.2mmol aniline (compound corresponding to number (II-1), 0.019g), 0.24mmol o-cyanobenzene Isocyanide (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C for 12 hours . After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0760 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.39(s,1H),8.21(d,J＝7.7Hz,1H),7.75–7.64(m,2H),7.62–7.47(m,4H),7.29(d,J＝7.7Hz,1H),7.22–7.10(m,3H),7.06(t,J＝8.6Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ10.39(s, 1H), 8.21(d, J=7.7Hz, 1H), 7.75–7.64(m, 2H), 7.62–7.47(m, 4H), 7.29( d, J=7.7Hz, 1H), 7.22–7.10(m, 3H), 7.06(t, J=8.6Hz, 2H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为97％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 97%.
实施例5：合成(IV-5)所示的化合物Embodiment 5: the compound shown in synthetic (IV-5)
称取0.3mmol对氯苯磺酰叠氮(编号(I-5)对应的化合物，0.065g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0800g反应产物。Weigh 0.3mmol p-chlorobenzenesulfonyl azide (compound corresponding to numbering (I-5), 0.065g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanobenzene Isocyanide (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C for 12 hours . After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0800 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.37(s,1H),8.21(d,J＝8.0Hz,1H),7.65–7.57(m,3H),7.57–7.48(m,3H),7.35(d,J＝8.6Hz,2H),7.29(d,J＝7.7Hz,1H),7.19–7.06(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.37(s, 1H), 8.21(d, J=8.0Hz, 1H), 7.65–7.57(m, 3H), 7.57–7.48(m, 3H), 7.35( d,J=8.6Hz,2H),7.29(d,J=7.7Hz,1H),7.19–7.06(m,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为98％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 98%.
实施例6：合成(IV-6)所示的化合物Embodiment 6: the compound shown in synthetic (IV-6)
称取0.3mmol对溴苯磺酰叠氮(编号(I-6)对应的化合物，0.078g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0890g反应产物。Weigh 0.3mmol p-bromobenzenesulfonyl azide (compound corresponding to numbering (I-6), 0.078g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanobenzene Isocyanide (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C for 12 hours . After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0890 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.43(s,1H),8.20(d,J＝8.0Hz,1H),7.61–7.48(m,8H),7.34–7.26(m,1H),7.19–7.07(m,3H). 1 H NMR (400MHz, CDCl 3 )δ10.43(s,1H),8.20(d,J=8.0Hz,1H),7.61–7.48(m,8H),7.34–7.26(m,1H),7.19– 7.07(m,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为98％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 98%.
实施例7：合成(IV-7)所示的化合物Embodiment 7: the compound shown in synthetic (IV-7)
称取0.3mmol对三氟甲基苯磺酰叠氮(编号(I-7)对应的化合物，0.075g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0850g反应产物。Weigh 0.3mmol p-trifluoromethylbenzenesulfonyl azide (compound corresponding to numbering (I-7), 0.075g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol ortho Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0850 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.22(d,J＝8.3Hz,1H),8.00(d,J＝8.0Hz,2H),7.76–7.52(m,7H)one-NH-is contained,7.38(d,J＝7.6Hz,2H),7.22(d,J＝8.4Hz,1H),7.15(t,J＝7.7Hz,1H). 1 H NMR (400MHz, DMSO-d 6 )δ9.43(s, 1H), 8.22(d, J=8.3Hz, 1H), 8.00(d, J=8.0Hz, 2H), 7.76–7.52(m, 7H) one-NH-is contained, 7.38(d, J=7.6Hz, 2H), 7.22(d, J=8.4Hz, 1H), 7.15(t, J=7.7Hz, 1H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为96％。According to the characterization data, it can be known that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 96%.
实施例8：合成(IV-8)所示的化合物Embodiment 8: the compound shown in synthetic (IV-8)
称取0.3mmol对乙酰胺基苯磺酰叠氮(编号(I-8)对应的化合物，0.072g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0650g反应产物。Weigh 0.3mmol p-acetamidobenzenesulfonyl azide (compound corresponding to numbering (I-8), 0.072g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanogen Phenyl phenyl isocyanide (compound corresponding to code (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0650 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.37(s,1H),8.21(d,J＝8.3Hz,1H),7.80–7.46(m,9H),one-NH-is contained,7.35(d,J＝7.7Hz,2H),7.24(d,J＝8.5Hz,1H),7.14(t,J＝7.7Hz,1H),2.01(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.04(s, 1H), 9.37(s, 1H), 8.21(d, J=8.3Hz, 1H), 7.80–7.46(m, 9H), one- NH-is contained, 7.35(d, J=7.7Hz, 2H), 7.24(d, J=8.5Hz, 1H), 7.14(t, J=7.7Hz, 1H), 2.01(s, 3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为75％。According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 75%.
实施例9：合成(IV-9)所示的化合物Embodiment 9: the compound shown in synthetic (IV-9)
称取0.3mmol苯并四氢呋喃基磺酰叠氮(编号(I-9)对应的化合物，0.068g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0800g反应产物。Weigh 0.3mmol benzotetrahydrofuranylsulfonyl azide (compound corresponding to numbering (I-9), 0.068g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyano Phenyl isonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, and stir the reaction at 80°C for 12 Hour. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0800 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ8.19(d,J＝8.0Hz,1H),7.66–7.40(m,6H),7.25(t,J＝7.4Hz,1H),7.21–7.13(m,2H),7.10(d,J＝8.1Hz,1H),6.72(d,J＝8.4Hz,1H),4.61(t,J＝8.8Hz,2H),3.17(t,J＝8.8Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.19(d, J=8.0Hz, 1H), 7.66–7.40(m, 6H), 7.25(t, J=7.4Hz, 1H), 7.21–7.13(m, 2H), 7.10(d, J=8.1Hz, 1H), 6.72(d, J=8.4Hz, 1H), 4.61(t, J=8.8Hz, 2H), 3.17(t, J=8.8Hz, 2H) .
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为96％。According to the characterization data, it can be known that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 96%.
实施例10：合成(IV-10)所示的化合物Embodiment 10: the compound shown in synthetic (IV-10)
称取0.3mmol噻吩基磺酰叠氮(编号(I-10)对应的化合物，0.057g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0730g反应产物。Weigh 0.3mmol thienylsulfonyl azide (compound corresponding to numbering (I-10), 0.057g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanophenyl Isonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, and stir at 80°C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0730 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.25(d,J＝8.3Hz,1H),7.72(t,J＝7.7Hz,1H),7.67–7.46(m,6H)one-NH-is contained,7.42–7.30(m,3H),7.18(t,J＝7.6Hz,1H),6.91(t,J＝4.3Hz,1H). 1 H NMR (400MHz, DMSO-d 6 )δ9.43(s, 1H), 8.25(d, J=8.3Hz, 1H), 7.72(t, J=7.7Hz, 1H), 7.67–7.46(m, 6H) one-NH-is contained, 7.42–7.30(m, 3H), 7.18(t, J=7.6Hz, 1H), 6.91(t, J=4.3Hz, 1H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为96％。According to the characterization data, it can be known that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 96%.
实施例11：合成(IV-11)所示的化合物Embodiment 11: Synthetic compound shown in (IV-11)
称取0.3mmol环己基磺酰叠氮(编号(I-11)对应的化合物，0.057g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0670g反应产物。Weigh 0.3mmol cyclohexylsulfonyl azide (compound corresponding to numbering (I-11), 0.057g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanophenyl Isonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, and stir at 80°C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0670 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.0Hz,1H),7.66–7.44(m,4H),7.30–7.21(m,3H),7.05(d,J＝8.1Hz,1H),2.88–2.58(m,1H),2.07–1.99(m,2H),1.88–1.70(m,2H),1.64(d,J＝12.7Hz,1H),1.28–1.12(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.21(d, J=8.0Hz, 1H), 7.66–7.44(m, 4H), 7.30–7.21(m, 3H), 7.05(d, J=8.1Hz, 1H),2.88–2.58(m,1H),2.07–1.99(m,2H),1.88–1.70(m,2H),1.64(d,J＝12.7Hz,1H),1.28–1.12(m,4H) .
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为88％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 88%.
实施例12：合成(IV-12)所示的化合物Embodiment 12: Synthetic compound shown in (IV-12)
称取0.3mmol正丙基磺酰叠氮(编号(I-12)对应的化合物，0.045g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0480g反应产物。Weigh 0.3mmol n-propylsulfonyl azide (compound corresponding to numbering (I-12), 0.045g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol o-cyanobenzene Isocyanide (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C for 12 hours . After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0480 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.26(d,J＝8.2Hz,1H),7.71(t,J＝7.6Hz,1H),7.61(t,J＝7.5Hz,2H),7.54(d,J＝7.2Hz,1H),7.34(t,J＝8.6Hz,3H),7.18(t,J＝7.5Hz,1H),3.16–2.99(m,2H),1.57–1.43(m,2H),0.85(t,J＝7.4Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.40(s, 1H), 8.26(d, J=8.2Hz, 1H), 7.71(t, J=7.6Hz, 1H), 7.61(t, J= 7.5Hz, 2H), 7.54(d, J=7.2Hz, 1H), 7.34(t, J=8.6Hz, 3H), 7.18(t, J=7.5Hz, 1H), 3.16–2.99(m, 2H) ,1.57–1.43(m,2H),0.85(t,J＝7.4Hz,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为70％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 70%.
实施例13：合成(IV-13)所示的化合物Embodiment 13: Synthetic compound shown in (IV-13)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对甲基苯胺(编号(II-2)对应的化合物，0.021g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0780g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol p-methylaniline (compound corresponding to numbering (II-2), 0.021g), 0.24mmol o-cyanophenylisonitrile (the compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0780 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.57(s,1H),8.18(d,J＝8.1Hz,1H),7.60(d,J＝8.1Hz,2H),7.57–7.49(m,J＝7.8,1.5Hz,1H),7.31(d,J＝7.9Hz,2H),7.26–7.16(m,3H),7.08(d,J＝8.1Hz,1H),7.01(d,J＝8.1Hz,2H),2.42(s,3H),2.36(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.57(s, 1H), 8.18(d, J=8.1Hz, 1H), 7.60(d, J=8.1Hz, 2H), 7.57–7.49(m, J= 7.8,1.5Hz,1H),7.31(d,J=7.9Hz,2H),7.26–7.16(m,3H),7.08(d,J=8.1Hz,1H),7.01(d,J=8.1Hz, 2H), 2.42(s,3H), 2.36(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为97％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 97%.
实施例14：合成(IV-14)所示的化合物Embodiment 14: Synthetic compound shown in (IV-14)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对甲氧基苯胺(编号(II-3)对应的化合物，0.025g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物,0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0790g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol p-methoxyaniline (compound corresponding to numbering (II-3), 0.025g), 0.24 Mmol o-cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0790 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.0Hz,1H),7.68–7.55(m,3H),7.33–7.26(m,1H),7.23(d,J＝8.0Hz,2H),7.12(d,J＝8.1Hz,1H),7.10–7.03(m,4H),3.90(s,3H),2.40(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.23(d, J=8.0Hz, 1H), 7.68–7.55(m, 3H), 7.33–7.26(m, 1H), 7.23(d, J=8.0Hz, 2H), 7.12(d, J＝8.1Hz, 1H), 7.10–7.03(m, 4H), 3.90(s, 3H), 2.40(s, 3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为94％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 94%.
实施例15：合成(IV-15)所示的化合物Embodiment 15: Synthetic compound shown in (IV-15)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对氟苯胺(编号(II-4)对应的化合物，0.022g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0730g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol p-fluoroaniline (compound corresponding to numbering (II-4), 0.022g), 0.24mmol o Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0730 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ8.16(d,J＝8.0Hz,1H),7.65–7.52(m,3H),7.31–7.26(m,1H),7.25–7.18(m,4H),7.18–7.03(m,3H),2.38(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.16 (d, J=8.0Hz, 1H), 7.65–7.52 (m, 3H), 7.31–7.26 (m, 1H), 7.25–7.18 (m, 4H), 7.18–7.03(m,3H),2.38(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为90％。According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 90%.
实施例16：合成(IV-16)所示的化合物Embodiment 16: Synthetic compound shown in (IV-16)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对氯苯胺(编号(II-5)对应的化合物，0.025g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0730g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol p-chloroaniline (compound corresponding to numbering (II-5), 0.025g), 0.24mmol o Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0730 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.22(d,J＝8.3Hz,1H),7.91–7.62(m,6H)one-NH-is contained,7.48–7.39(m,2H),7.25(d,J＝8.4Hz,1H),7.18(d,J＝7.8Hz,3H),2.29(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.42(s,1H),8.22(d,J＝8.3Hz,1H),7.91–7.62(m,6H)one-NH-is contained,7.48–7.39 (m,2H),7.25(d,J=8.4Hz,1H),7.18(d,J=7.8Hz,3H),2.29(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为86％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 86%.
实施例17：合成(IV-17)所示的化合物Embodiment 17: Synthetic compound shown in (IV-17)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对溴苯胺(编号(II-6)对应的化合物，0.034g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0820g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol p-bromoaniline (compound corresponding to numbering (II-6), 0.034g), 0.24mmol o Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0820 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.22(d,J＝8.3Hz,1H),8.02–7.57(m,6H)one-NH-is contained,7.37(d,J＝8.2Hz,2H),7.25(d,J＝8.4Hz,1H),7.18(d,J＝7.8Hz,3H),2.29(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.43(s,1H),8.22(d,J＝8.3Hz,1H),8.02–7.57(m,6H)one-NH-is contained,7.37(d ,J=8.2Hz,2H),7.25(d,J=8.4Hz,1H),7.18(d,J=7.8Hz,3H),2.29(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为88％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 88%.
实施例18：合成(IV-18)所示的化合物Embodiment 18: Synthetic compound shown in (IV-18)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对三氟甲基苯胺(编号(II-7)对应的化合物，0.032g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0550g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to number (I-1), 0.056g), 0.2mmol p-trifluoromethylaniline (compound corresponding to number (II-7), 0.032g), 0.24mmol o-cyanophenylisonitrile (the compound corresponding to numbering (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, 80 The reaction was stirred at °C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0550 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.25(d,J＝8.3Hz,1H),8.02(d,J＝8.1Hz,2H),7.88(s,1H),7.79–7.59(m,5H),7.29(d,J＝8.5Hz,1H),7.24–7.06(m,3H),2.29(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.45(s,1H),8.25(d,J＝8.3Hz,1H),8.02(d,J＝8.1Hz,2H),7.88(s,1H) ,7.79–7.59(m,5H),7.29(d,J＝8.5Hz,1H),7.24–7.06(m,3H),2.29(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为60％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 60%.
实施例19：合成(IV-19)所示的化合物Embodiment 19: Synthetic compound shown in (IV-19)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对酯基苯胺(编号(II-8)对应的化合物，0.033g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0670g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol para-ester aniline (compound corresponding to numbering (II-8), 0.033g), 0.24mmol o-cyanophenylisonitrile (the compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0670 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.28–8.14(m,3H),7.91–7.62(m,4H)one-NH-is contained,7.56(d,J＝8.1Hz,2H),7.26(d,J＝8.5Hz,1H),7.17(d,J＝7.9Hz,3H),4.41(q,J＝7.1Hz,2H),2.29(s,3H),1.37(t,J＝7.1Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.44(s,1H),8.28–8.14(m,3H),7.91–7.62(m,4H)one-NH-is contained,7.56(d,J＝ 8.1Hz, 2H), 7.26(d, J=8.5Hz, 1H), 7.17(d, J=7.9Hz, 3H), 4.41(q, J=7.1Hz, 2H), 2.29(s, 3H), 1.37 (t,J=7.1Hz,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为73％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 73%.
实施例20：合成(IV-20)所示的化合物Embodiment 20: Synthetic compound shown in (IV-20)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol对硝基苯胺(编号(II-9)对应的化合物，0.028g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0450g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol p-nitroaniline (compound corresponding to numbering (II-9), 0.028g), 0.24mmol o-cyanophenylisonitrile (the compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0450 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.49(d,J＝8.5Hz,2H),8.23(d,J＝8.3Hz,1H),8.12–7.80(m,1H),7.80–7.64(m,5H),7.29(d,J＝8.4Hz,1H),7.24–7.07(m,3H),2.28(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.49(s, 1H), 8.49(d, J=8.5Hz, 2H), 8.23(d, J=8.3Hz, 1H), 8.12–7.80(m, 1H),7.80–7.64(m,5H),7.29(d,J＝8.4Hz,1H),7.24–7.07(m,3H),2.28(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为52％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 52%.
实施例21：合成(IV-21)所示的化合物Embodiment 21: Synthesis of compounds shown in (IV-21)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol邻甲基苯胺(编号(II-10)对应的化合物，0.021g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0660g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol o-methylaniline (compound corresponding to numbering (II-10), 0.021g), 0.24mmol o-cyanophenylisonitrile (the compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0660 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.67(s,1H),8.22(d,J＝7.8Hz,1H),7.62–7.54(m,3H),7.43–7.32(m,3H),7.30–7.25(m,1H),7.18(d,J＝8.1Hz,2H),7.14–7.10(m,1H),7.08–7.03(m,1H),2.37(s,3H),1.97(s,3H). 1 H NMR (400MHz, CDCl 3 )δ10.67(s,1H),8.22(d,J=7.8Hz,1H),7.62–7.54(m,3H),7.43–7.32(m,3H),7.30– 7.25(m,1H),7.18(d,J＝8.1Hz,2H),7.14–7.10(m,1H),7.08–7.03(m,1H),2.37(s,3H),1.97(s,3H) .
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为82％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 82%.
实施例22：合成(IV-22)所示的化合物Embodiment 22: Synthetic compound shown in (IV-22)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol邻甲氧基苯胺(编号(II-11)对应的化合物，0.025g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0800g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol o-methoxyaniline (compound corresponding to numbering (II-11), 0.025g), 0.24 Mmol o-cyanophenylisonitrile (the compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, 80°C The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0800 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.71(s,1H),8.23(d,J＝8.0Hz,1H),7.70–7.54(m,3H),7.52–7.45(m,1H),7.34–7.27(m,1H),7.22(d,J＝8.0Hz,2H),7.18–7.05(m,3H),7.01(d,J＝8.3Hz,1H),3.54(s,3H),2.39(s,3H). 1 H NMR (400MHz, CDCl 3 )δ10.71(s,1H),8.23(d,J=8.0Hz,1H),7.70–7.54(m,3H),7.52–7.45(m,1H),7.34– 7.27(m,1H),7.22(d,J=8.0Hz,2H),7.18–7.05(m,3H),7.01(d,J=8.3Hz,1H),3.54(s,3H),2.39(s ,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为95％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 95%.
实施例23：合成(IV-23)所示的化合物Embodiment 23: Synthetic compound shown in (IV-23)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol邻氯苯胺(编号(II-12)对应的化合物，0.026g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物,0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0700g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol o-chloroaniline (compound corresponding to numbering (II-12), 0.026g), 0.24mmol o-chloroaniline Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0700 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.24(d,J＝8.3Hz,1H),8.01(s,1H),7.77(dd,J＝5.8,3.5Hz,1H),7.74–7.65(m,3H),7.65–7.62(m,3H),7.24(d,J＝8.4Hz,1H),7.18(d,J＝7.9Hz,3H),2.29(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.51(s, 1H), 8.24(d, J=8.3Hz, 1H), 8.01(s, 1H), 7.77(dd, J=5.8, 3.5Hz, 1H),7.74–7.65(m,3H),7.65–7.62(m,3H),7.24(d,J=8.4Hz,1H),7.18(d,J=7.9Hz,3H),2.29(s,3H ).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为82％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 82%.
实施例24：合成(IV-24)所示的化合物Embodiment 24: Synthetic compound shown in (IV-24)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol邻溴苯胺(编号(II-13)对应的化合物，0.034g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0720g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol o-bromoaniline (compound corresponding to numbering (II-13), 0.034g), 0.24mmol o- Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0720 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),8.24(d,J＝8.3Hz,1H),7.97(s,1H),7.91(d,J＝8.0Hz,1H),7.79–7.61(m,4H),7.61–7.49(m,2H),7.33–7.06(m,4H),2.29(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.50(s,1H),8.24(d,J＝8.3Hz,1H),7.97(s,1H),7.91(d,J＝8.0Hz,1H) ,7.79–7.61(m,4H),7.61–7.49(m,2H),7.33–7.06(m,4H),2.29(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为72％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 72%.
实施例25：合成(IV-25)所示的化合物Embodiment 25: Synthetic compound shown in (IV-25)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol2,6-二甲基苯胺(编号(II-14)对应的化合物，0.024g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0700g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to number (I-1), 0.056g), 0.2mmol 2,6-dimethylaniline (compound corresponding to number (II-14), 0.024g) , 0.24mmol o-cyanophenyl isonitrile (the compound corresponding to numbering (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, The reaction was stirred at 80°C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0700 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.71(s,1H),8.24(d,J＝7.7Hz,1H),7.59(d,J＝7.9Hz,3H),7.28(dd,J＝7.7,4.8Hz,2H),7.22–7.12(m,5H),2.37(s,3H),1.95(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ10.71(s, 1H), 8.24(d, J=7.7Hz, 1H), 7.59(d, J=7.9Hz, 3H), 7.28(dd, J=7.7, 4.8Hz, 2H), 7.22–7.12(m, 5H), 2.37(s, 3H), 1.95(s, 6H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为83％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 83%.
实施例26：合成(IV-26)所示的化合物Embodiment 26: Synthesis of compounds shown in (IV-26)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol N-甲基吲哚-5-胺(编号(II-15)对应的化合物，0.030g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0640g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol N-methylindole-5-amine (compound corresponding to numbering (II-15), 0.030g), 0.24mmol o-cyanophenylisonitrile (the compound corresponding to numbering (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene As a solvent, the reaction was stirred at 80°C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) was 1:3), yielding 0.0640 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.21(d,J＝8.3Hz,1H),7.67(dd,J＝15.0,8.0Hz,4H),7.58–7.40(m,3H)one-NH-is contained,7.22(d,J＝8.4Hz,1H),7.13(d,J＝7.9Hz,3H),7.02(d,J＝8.6Hz,1H),6.56(d,J＝3.3Hz,1H),3.86(s,3H),2.26(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.37(s, 1H), 8.21(d, J=8.3Hz, 1H), 7.67(dd, J=15.0, 8.0Hz, 4H), 7.58–7.40( m,3H)one-NH-is contained,7.22(d,J=8.4Hz,1H),7.13(d,J=7.9Hz,3H),7.02(d,J=8.6Hz,1H),6.56(d ,J＝3.3Hz,1H),3.86(s,3H),2.26(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为72％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 72%.
实施例27：合成(IV-27)所示的化合物Embodiment 27: Synthesis of compounds shown in (IV-27)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol色胺(编号(II-16)对应的化合物，0.032g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0740g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol tryptamine (compound corresponding to numbering (II-16), 0.032g), 0.24mmol o-cyanogen Phenyl phenyl isocyanide (compound corresponding to code (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as a solvent, and stir the reaction at 80°C 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0740 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.09(s,1H),8.97(s,1H),8.09(d,J＝8.3Hz,1H),7.94–7.81(m,3H),7.59(t,J＝7.7Hz,1H),7.30(d,J＝8.1Hz,1H),7.26–7.13(m,4H),7.10(t,J＝7.7Hz,1H),7.03(t,J＝7.5Hz,1H),6.90(t,J＝7.4Hz,1H),4.50(s,2H),3.02(t,J＝8.2Hz,2H),2.25(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.82(s, 1H), 9.09(s, 1H), 8.97(s, 1H), 8.09(d, J=8.3Hz, 1H), 7.94–7.81( m,3H),7.59(t,J=7.7Hz,1H),7.30(d,J=8.1Hz,1H),7.26–7.13(m,4H),7.10(t,J=7.7Hz,1H), 7.03(t, J=7.5Hz, 1H), 6.90(t, J=7.4Hz, 1H), 4.50(s, 2H), 3.02(t, J=8.2Hz, 2H), 2.25(s, 3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为81％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 81%.
实施例28：合成(IV-28)所示的化合物Embodiment 28: Synthesis of compounds shown in (IV-28)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol正丁胺(编号(II-17)对应的化合物，0.015g)，0.24mmol邻氰基苯基异腈(编号(III-1)对应的化合物，0.031g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0740g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol n-butylamine (compound corresponding to numbering (II-17), 0.015g), 0.24mmol ortho Cyanophenylisonitrile (compound corresponding to number (III-1), 0.031g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, stir at 80°C React for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0740 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ10.67(s,1H),8.29(s,1H),7.84(d,J＝8.0Hz,2H),7.81–7.65(m,1H),7.53(t,J＝7.7Hz,1H),7.27(t,J＝8.2Hz,3H),7.07(d,J＝8.1Hz,1H),4.20(t,J＝7.6Hz,2H),2.41(s,3H),1.57(p,J＝7.7Hz,2H),1.31(h,J＝7.5Hz,2H),0.86(t,J＝7.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ10.67(s, 1H), 8.29(s, 1H), 7.84(d, J=8.0Hz, 2H), 7.81–7.65(m, 1H), 7.53(t, J＝7.7Hz, 1H), 7.27(t, J＝8.2Hz, 3H), 7.07(d, J＝8.1Hz, 1H), 4.20(t, J＝7.6Hz, 2H), 2.41(s, 3H) , 1.57(p, J=7.7Hz, 2H), 1.31(h, J=7.5Hz, 2H), 0.86(t, J=7.3Hz, 3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为77％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 77%.
实施例29：合成(IV-29)所示的化合物Embodiment 29: Synthesis of compounds shown in (IV-29)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3-甲基邻氰基苯基异腈(编号(III-2)对应的化合物，0.034g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0710g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol 3-methyl O-cyanophenylisocyanide (compound corresponding to code (III-2), 0.034g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0710 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.1Hz,1H),7.61–7.45(m,5H),7.16(dd,J＝16.9,7.6Hz,4H),7.07(d,J＝8.2Hz,1H),6.91(s,1H),2.43(s,3H),2.37(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.05(d, J=8.1Hz, 1H), 7.61–7.45(m, 5H), 7.16(dd, J=16.9, 7.6Hz, 4H), 7.07(d, J＝8.2Hz,1H),6.91(s,1H),2.43(s,3H),2.37(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为88％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 88%.
实施例30：合成(IV-30)所示的化合物Example 30: Synthesis of compounds shown in (IV-30)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3-甲氧基邻氰基苯基异腈(编号(III-3)对应的化合物，0.038g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0710g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol 3-methyl Oxygen-o-cyanophenylisonitrile (compound corresponding to code (III-3), 0.038g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, 80 The reaction was stirred at °C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0710 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.14(d,J＝9.1Hz,1H),7.62(dd,J＝15.8,7.7Hz,4H),7.54(t,J＝7.3Hz,1H),7.32(d,J＝7.8Hz,3H)one-NH-is contained,7.14(d,J＝7.8Hz,2H),6.77(dd,J＝9.1,2.6Hz,1H),6.63(s,1H),3.86(s,3H),2.26(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.13(s, 1H), 8.14(d, J=9.1Hz, 1H), 7.62(dd, J=15.8, 7.7Hz, 4H), 7.54(t, J＝7.3Hz, 1H), 7.32(d, J＝7.8Hz, 3H) one-NH-is contained, 7.14(d, J＝7.8Hz, 2H), 6.77(dd, J＝9.1, 2.6Hz, 1H ),6.63(s,1H),3.86(s,3H),2.26(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为84％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated, and the result is 84%.
实施例31：合成(IV-31)所示的化合物Example 31: Synthesis of compounds shown in (IV-31)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3,4-二甲氧基邻氰基苯基异腈(编号(III-4)对应的化合物，0.045g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0720g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to number (I-1), 0.056g), 0.2mmol aniline (compound corresponding to number (II-1), 0.019g), 0.24mmol 3,4 -dimethoxy-o-cyanophenylisonitrile (compound corresponding to numbering (III-4), 0.045g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene for solvent, stirred at 80°C for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0720 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.68–7.48(m,5H),7.33(d,J＝7.6Hz,2H),7.15(d,J＝7.9Hz,2H),6.68(s,1H),3.90(s,3H),3.80(s,3H),2.28(s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.69(s, 1H), 7.68–7.48(m, 5H), 7.33(d, J=7.6Hz, 2H), 7.15(d, J=7.9Hz, 2H), 6.68(s,1H), 3.90(s,3H), 3.80(s,3H), 2.28(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为80％。According to the characterization data, the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 80%.
实施例32：合成(IV-32)所示的化合物Example 32: Synthesis of compounds shown in (IV-32)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3-氟邻氰基苯基异腈(编号(III-5)对应的化合物，0.035g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0580g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to number (I-1), 0.056g), 0.2mmol aniline (compound corresponding to number (II-1), 0.019g), 0.24mmol 3-fluoro o-cyanophenylisonitrile (the compound corresponding to number (III-5), 0.035g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80°C The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0580 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.29(dd,J＝9.2,6.0Hz,1H),7.81–7.43(m,6H)one-NH-is contained,7.33(d,J＝7.6Hz,2H),7.13(d,J＝7.9Hz,2H),7.02(td,J＝8.8,2.7Hz,1H),6.92(d,J＝10.0Hz,1H),2.24(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.37(s,1H),8.29(dd,J＝9.2,6.0Hz,1H),7.81–7.43(m,6H)one-NH-is contained,7.33 (d,J=7.6Hz,2H),7.13(d,J=7.9Hz,2H),7.02(td,J=8.8,2.7Hz,1H),6.92(d,J=10.0Hz,1H),2.24 (s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为71％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 71%.
实施例33：合成(IV-33)所示的化合物Example 33: Synthesis of compounds shown in (IV-33)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3-氯邻氰基苯基异腈(编号(III-6)对应的化合物，0.039g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0660g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol 3-chloro o-cyanophenylisonitrile (compound corresponding to number (III-6), 0.039g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80°C The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0660 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.26(d,J＝8.8Hz,1H),7.96–7.44(m,6H)one-NH-is contained,7.38(d,J＝7.4Hz,2H),7.25(s,1H),7.23–7.11(m,3H),2.30(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.47(s,1H),8.26(d,J＝8.8Hz,1H),7.96–7.44(m,6H)one-NH-is contained,7.38(d ,J＝7.4Hz,2H),7.25(s,1H),7.23–7.11(m,3H),2.30(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为78％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 78%.
实施例34：合成(IV-34)所示的化合物Example 34: Synthesis of compounds shown in (IV-34)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3-溴邻氰基苯基异腈(编号(III-7)对应的化合物，0.049g)，0.01mmol Co(acac)3(0.00360g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0620g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to numbering (I-1), 0.056g), 0.2mmol aniline (compound corresponding to numbering (II-1), 0.019g), 0.24mmol 3-bromo o-cyanophenylisonitrile (the compound corresponding to number (III-7), 0.049g), 0.01mmol Co(acac) 3 (0.00360g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, at 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes The procedure (A:B) was 1:3), yielding 0.0620 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.18(d,J＝8.8Hz,1H),7.92–7.50(m,6H)one-NH-is contained,7.47–7.35(m,3H),7.32(dd,J＝8.8,2.0Hz,1H),7.19(d,J＝7.9Hz,2H),2.30(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.49(s,1H),8.18(d,J＝8.8Hz,1H),7.92–7.50(m,6H)one-NH-is contained,7.47–7.35 (m,3H),7.32(dd,J=8.8,2.0Hz,1H),7.19(d,J=7.9Hz,2H),2.30(s,3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为70％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 70%.
实施例35：合成(IV-35)所示的化合物Example 35: Synthesis of compounds shown in (IV-35)
称取0.3mmol对甲基苯磺酰叠氮(编号(I-1)对应的化合物，0.056g)，0.2mmol苯胺(编号(II-1)对应的化合物，0.019g)，0.24mmol 3-硝基邻氰基苯基异腈(编号(III-8)对应的化合物，0.049g)，0.01mmol Co(acac)3(0.00420g)于20mL的试管反应管中，加2mL甲苯作溶剂，80℃下搅拌反应12小时。反应结束后，反应液经过真空蒸发和柱层析分离(柱层析分离条件：固定相为200～300目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:3)，得到0.0390g反应产物。Weigh 0.3mmol p-toluenesulfonyl azide (compound corresponding to number (I-1), 0.056g), 0.2mmol aniline (compound corresponding to number (II-1), 0.019g), 0.24mmol 3-nitrate O-cyanophenylisocyanide (compound corresponding to code (III-8), 0.049g), 0.01mmol Co(acac) 3 (0.00420g) in a 20mL test tube reaction tube, add 2mL toluene as solvent, 80℃ The reaction was stirred for 12 hours. After the reaction, the reaction solution was vacuum evaporated and separated by column chromatography (column chromatography separation conditions: the stationary phase is 200-300 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase changes Procedure (A:B) is 1:3), yielding 0.0390 g of reaction product.
对上述反应产物进行表征，结果为：The above-mentioned reaction product is characterized, and the result is:
1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.52(s,1H),7.94–7.52(m,7H)one-NH-iscontained,7.37(d,J＝7.6Hz,2H),7.16(d,J＝7.8Hz,3H),2.29(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.44(s,1H),8.52(s,1H),7.94–7.52(m,7H)one-NH-iscontained,7.37(d,J＝7.6Hz, 2H), 7.16(d, J=7.8Hz, 3H), 2.29(s, 3H).
根据表征数据可知，制得的反应产物为纯品(纯度＞95％)；对产品产率进行计算，结果为42％。According to the characterization data, it can be seen that the obtained reaction product is a pure product (purity>95%); the product yield is calculated and the result is 42%.
检测实施例1：生物活性测试Detection example 1: biological activity test
根据相关参考文献(Bioorg.Med.Chem.Lett.2013,23,4968；)，本发明选取以上实施例所制备的9种化合物，采用MIC方法对四种菌类进行了抗菌活性测试，这些不同的喹唑啉衍生物对金黄色葡萄球菌(MSSA)、金黄色葡萄球菌(MRSA)、粪肠球菌(VSE)和粪肠球菌(VRE)的相对抗菌活性结果如表1所示，抗菌活性结果和苯唑西林、万古霉素、红霉素、四环素和克林霉素做为对比。结果表明，式IV-1、IV-6对S.aureus或E.faecalis没有表现出显着的抗菌活性。式IV-9、IV-16、IV-18、IV-20所示的化合物抗菌活性显着增加。值得注意的是，喹唑啉化合物IV-26、IV-27、IV-30由于取代基的变化确实导致抗菌活性显着增加。According to relevant references (Bioorg.Med.Chem.Lett.2013,23,4968;), the present invention selects 9 compounds prepared in the above examples, and uses the MIC method to test the antibacterial activity of four kinds of fungi. The relative antibacterial activity results of quinazoline derivatives to Staphylococcus aureus (MSSA), Staphylococcus aureus (MRSA), Enterococcus faecalis (VSE) and Enterococcus faecalis (VRE) are as shown in table 1, antibacterial activity result Compared with oxacillin, vancomycin, erythromycin, tetracycline, and clindamycin. The results showed that the formulas IV-1 and IV-6 did not exhibit significant antibacterial activity against S.aureus or E.faecalis. The antibacterial activity of the compounds represented by the formulas IV-9, IV-16, IV-18 and IV-20 is significantly increased. It is worth noting that quinazoline compounds IV-26, IV-27, and IV-30 did lead to a significant increase in antibacterial activity due to changes in substituents.
表1不同化合物的抗菌活性(MIC,μg/mL)测试结果Antibacterial activity (MIC, μg/mL) test results of different compounds in table 1
以上结果表明，本发明合成的喹唑啉衍生物具有抗菌活性的特性，可被制备成抗菌药物。The above results show that the quinazoline derivatives synthesized by the present invention have the characteristics of antibacterial activity and can be prepared as antibacterial drugs.
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。Apparently, the above-mentioned embodiments are only examples for clear description, and are not intended to limit the implementation. For those of ordinary skill in the art, on the basis of the above description, other changes or changes in various forms can also be made. It is not necessary and impossible to exhaustively list all the implementation manners here. However, the obvious changes or changes derived therefrom are still within the scope of protection of the present invention.
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