CN108117516B - 一种多取代吡啶衍生物的制备方法及其应用 - Google Patents
一种多取代吡啶衍生物的制备方法及其应用 Download PDFInfo
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- CN108117516B CN108117516B CN201711494476.5A CN201711494476A CN108117516B CN 108117516 B CN108117516 B CN 108117516B CN 201711494476 A CN201711494476 A CN 201711494476A CN 108117516 B CN108117516 B CN 108117516B
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- polysubstituted pyridine
- pyridine derivative
- polysubstituted
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- 150000003222 pyridines Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- -1 enamine ester compounds Chemical class 0.000 abstract description 38
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 238000000034 method Methods 0.000 abstract description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 6
- 201000005202 lung cancer Diseases 0.000 abstract description 6
- 208000020816 lung neoplasm Diseases 0.000 abstract description 6
- 239000007800 oxidant agent Substances 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 238000001212 derivatisation Methods 0.000 abstract description 2
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract 1
- 238000007243 oxidative cyclization reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 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 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000002609 medium Substances 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical class C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- LRAPCACWJYSICH-UHFFFAOYSA-N methyl 6-(4-bromophenyl)-2-methylpyridine-3-carboxylate Chemical compound N1=C(C)C(C(=O)OC)=CC=C1C1=CC=C(Br)C=C1 LRAPCACWJYSICH-UHFFFAOYSA-N 0.000 description 4
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- LFABNOYDEODDFX-UHFFFAOYSA-N bis(4-bromophenyl)methanone Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=C(Br)C=C1 LFABNOYDEODDFX-UHFFFAOYSA-N 0.000 description 3
- 229940117389 dichlorobenzene Drugs 0.000 description 3
- CGULTTSJZGXDBD-UHFFFAOYSA-N ethyl 3-amino-3-phenylprop-2-enoate Chemical compound CCOC(=O)C=C(N)C1=CC=CC=C1 CGULTTSJZGXDBD-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical class C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000003445 Hantzsch reaction Methods 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229930192474 thiophene Chemical class 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical group CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CFMMTXJMIJRUSH-UHFFFAOYSA-N 1-(4-bromophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C(Br)C=C1 CFMMTXJMIJRUSH-UHFFFAOYSA-N 0.000 description 1
- ZUEKIIWSVFBTCM-UHFFFAOYSA-N 1-(4-fluorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C(F)C=C1 ZUEKIIWSVFBTCM-UHFFFAOYSA-N 0.000 description 1
- QFKOWENRSZZLPK-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]propan-1-one Chemical compound CCC(=O)C1=CC=C(C(F)(F)F)C=C1 QFKOWENRSZZLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- AHZAKFLOHIRCDU-UHFFFAOYSA-N 4-aminochromen-2-one Chemical compound C1=CC=CC2=C1OC(=O)C=C2N AHZAKFLOHIRCDU-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- PATYHUUYADUHQS-UHFFFAOYSA-N 4-methylpropiophenone Chemical compound CCC(=O)C1=CC=C(C)C=C1 PATYHUUYADUHQS-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XKORCTIIRYKLLG-ONEGZZNKSA-N methyl (e)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(/C)N XKORCTIIRYKLLG-ONEGZZNKSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 125000000627 niacin group Chemical group 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- ZJVAWPKTWVFKHG-UHFFFAOYSA-N p-Methoxypropiophenone Chemical compound CCC(=O)C1=CC=C(OC)C=C1 ZJVAWPKTWVFKHG-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- TYYCBAISLMKLMT-UHFFFAOYSA-N tert-butyl 3-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)CC(N)C1=CC=CC=C1 TYYCBAISLMKLMT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Abstract
本发明公开了一种多取代吡啶衍生物的制备方法及其应用。本方法将烯胺酯类化合物、酮类化合物、催化剂和氧化剂溶于有机溶剂,在催化剂和氧化剂的作用下,烯胺酯类化合物和酮类化合物经氧化环合生成多取代吡啶衍生物。本发明的制备方法反应原料简单易得,实验操作简单,反应条件相对温和;反应活性高,通过高度的化学选择性和区域选择性构建不同取代基的多取代吡啶衍生物,有利于进行下一步的衍生化研究。且所获得的多取代吡啶衍生物对人肺癌细胞A‑549和人肝癌细胞HepG‑2具有潜在的抑制活性。本发明提供的吡啶衍生物(Ⅰ)和(Ⅱ)具有潜在的体外抗肿瘤细胞活性,具有开发成抗肿瘤药的前景。
Description
技术领域
本发明属于医药化工中间体合成技术领域,具体涉及一种多取代吡啶衍生物的制备方法及其应用。
背景技术
多取代吡啶衍生物是一类重要的杂环化合物,在医药、农业、化工、纺染等领域均有应用。特别是其中一类吡啶衍生物-烟酸酯,其水解产物烟酸属于维生素B族化合物,具有扩张周围血管的作用。该类多取代吡啶衍生物经结构修饰可制备多种药物,例如目前默沙东研发的MK-1064,主治失眠症,正处于临床一期实验阶段。MK-1064可由2,5位含吡啶基取代的烟酸酯经胺解得到。其结构式如下:
由于多取代吡啶衍生物具有特殊的生物和药理活性,因此众多学者专注于该类化合物的合成方法研究。其中最经典的方法为Hantzsch反应(Justus Liebigs Ann.Chem.,1882,215(1),1-82.),两分子β-羰基酸酯与一分子醛及一分子氨发生缩合反应,再用氧化剂氧化得到对称的3,5-二羧酸酯吡啶衍生物。Hantzsch反应存在着反应时间长、操作复杂、收率低且产物结构单一等缺点。
另一类方法是以烯胺酯类化合物为基本底物,与1,3-二酮化合物(Chem.Pharm.Bull.1975,23,2239-2250.)、α,β-不饱和酮(Chem.Commun.2017,53,2390-2393)、炔酮(Synlett 2001,1149-1151)、烯丙醇(Chem.Commun.2013,49,7926-7928)等反应合成吡啶衍生物。该类方法存在反应条件苛刻(高温、微波、使用有爆炸风险的强氧化剂2-碘酰基苯甲酸(IBX)等)、起始原料不易得、实验操作复杂等缺点。因此,设计一种操作简单、原料易得、选择性高的多取代吡啶衍生物的合成方法值得探究。
发明内容
针对现有技术中存在的上述问题,本发明的目的在于提供一种多取代吡啶衍生物的制备方法及其应用,使用简单易得的原料制备一系列多取代吡啶衍生物。
所述的一种多取代吡啶衍生物的制备方法,其特征在于所述的制备方法为:将式(Ⅲ)或式(Ⅴ)所示的烯胺酯类化合物、式(Ⅳ)所示的酮类化合物、催化剂和氧化剂溶于有机溶剂中,在110~150℃温度下反应15~30小时,反应结束后,反应液萃取、浓缩后经柱层析分离,得到式(Ⅰ)或(Ⅱ)所示的多取代吡啶衍生物;
多取代吡啶衍生物的结构式下所示:
烯胺酯类化合物结构式如下所示:
酮类化合物结构式如Ⅳ所示:
其中,R1为烷基、芳基或杂芳基,R2为烷基,R3为烷基、芳基或氢,R4为烷基、芳基或杂芳基;R5为氢、烷基或卤素。
所述的多取代吡啶衍生物的制备方法,其特征在于R1、R2、R3、R4选自甲基、乙基、叔丁基、苯、取代苯、萘、噻吩、吡啶、呋喃,取代苯的取代基选自H、CH3O-、CH3-、F、Cl、Br、CF3-、NO2-,R1优选为苯基或噻吩,R2优选为甲基、乙基或叔丁基,R3优选为氢或萘,R4优选为苯基、对溴苯基、对氟苯基、对甲基苯基、对氧甲基苯基或对三氟甲基苯基,R5优选为氢。
所述的多取代吡啶衍生物的制备方法,其特征在于催化剂为醋酸铜、醋酸亚铜、三氟甲烷磺酸铜、氯化铜、溴化铜、碘化铜、氯化亚铜、溴化亚铜、碘化亚铜、醋酸钯、氯化铁中的一种;催化剂的用量为5~20mol%,优选为8~15mol%。
所述的多取代吡啶衍生物的制备方法,其特征在于氧化剂为四甲基哌啶(TEMPO)或氮氧自由基哌啶醇(4-OH-TEMPO)。
所述的多取代吡啶衍生物的制备方法,其特征在于烯胺酯类化合物和酮类化合物的物质的量比为1:1~4,优选为1:1~2。
所述的多取代吡啶衍生物的制备方法,其特征在于有机溶剂为氯苯、甲苯、乙腈、二甲基亚砜、1,2-二氯苯、N,N-二甲基甲酰胺、异丙基苯、二氧六环、1,2-二氯乙烷中的一种。
所述的多取代吡啶衍生物的制备方法,其特征在于催化剂的配体为2,2'-联吡啶(bpy)、四甲基乙二胺(TMEDA)、邻二氮菲(1,10-Phen)中的一种。
本发明的反应方程式如下所示:
本发明的另一目的是提供所述的多取代吡啶衍生物的制备方法在制备抗肿瘤药物中的应用。
进一步,所述的多取代吡啶衍生物应用于制备抗肺癌或肝癌药物。
初步的药理实验发现,本发明提供的化合物对A549、HepG-2等肿瘤细胞株均有很好的体外抑制增殖作用,可应用于制备抗肺癌或肝癌药物,所述的吡啶衍生物为下列式Ⅰa、Ⅰb、Ⅰc、Ⅰd、Ⅰe、Ⅰf、Ⅱa、Ⅱb、Ⅱc、Ⅱd之一。
其中化合物Ⅱc、Ⅱd对人肝癌细胞的抑制率较突出,其IC50值达到4.11μM和3.47μM。
与现有技术相比,本发明的有益效果主要体现在:
本发明的制备方法所用的反应原料简单易得,实验操作简单,反应条件相对温和;反应活性高,通过高度的化学选择性和区域选择性构建不同取代基的多取代吡啶衍生物,有利于进行下一步的衍生化研究。所合成的吡啶衍生物(Ⅰ)和(Ⅱ)结构新颖,初步的药理活性实验表明该类化合物对人肺癌细胞A-549和人肝癌细胞HepG-2具有潜在的抑制活性。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但不仅限于本发明所列出的具体实施例描述的实施方案。
实施例1:6-(4-溴苯基)-2-苯基烟酸乙酯(Ⅰa)的制备
将3-氨基-3-苯基丙烯酸乙酯(0.96g,5mmol)、对溴苯丙酮(1.28g,6mmol)、醋酸铜(0.18g,1mmol)、bpy(0.31g,2mmol)和4-OH-TEMPO(0.86g,5mmol)的甲苯(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=50/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体6-(4-溴苯基)-2-苯基烟酸乙酯(Ⅰa)1.59g,收率:83%,熔点:59~60℃。
Ⅰa结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.18(d,J=7.8Hz,1H),8.01(d,J=8.4Hz,2H),7.75(d,J=7.8Hz,1H),7.63-7.60(m,4H),7.46(m,3H),4.17(q,J=7.2Hz,2H),1.07(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3,ppm)δ168.2,158.9,157.2,140.3,1391,137.14,132.0,129.0,128.8,128.7,128.1,125.7,124.4,117.6,61.5,13.7.HRMS(ESI-TOF)calcd forC20H16BrNNaO2[M+Na]+:404.0237;Found:404.0257.
实施例2:6-(4-溴苯基)-2-(2-噻吩基)烟酸乙酯(Ⅰb)的制备
将3-氨基-3-(2-噻吩基)烯酸乙酯(0.91g,5mmol)、对溴苯丙酮(1.07g,5mmol)、醋酸铜(0.18g,1mmol)、bpy(0.16g,1mmol)和4-OH-TEMPO(1.29g,7.5mmol)的甲苯(10mL)溶液在110℃下搅拌反应30小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=50/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体6-(4-溴苯基)-2-(2-噻吩基)烟酸乙酯(Ⅰb)1.30g,收率:70%。熔点:65.5~66.2℃。
Ⅰb结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.03-8.01(m,3H),7.66-7.63(m,3H),7.50-7.48(m,2H),7.13-7.11(m,1H),4.40(q,J=7.2Hz,2H),1.34(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3,ppm)δ168.3,156.7,150.5,143.2,138.7,136.7,132.0,128.7,128.7,128.0,127.7,124.5,124.3,117.0,61.9,14.0.HRMS(ESI-TOF)calcd for C18H14BrNNaO2S[M+Na]+:409.9814;Found:409.9821.
实施例3:6-(4-溴苯基)-2-苯甲基烟酸叔丁酯(Ⅰc)的制备
将3-氨基-3-苯基丙烯酸叔丁酯(1.10g,5mmol)、对溴苯丙酮(3.20g,15mmol)、醋酸铜(0.18g,1mmol)、1,10-Phen(0.20g,1mmol)和TEMPO(5mmol,0.78g)的甲苯(10mL)溶液在130℃下搅拌反应20小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=50/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体6-(4-溴苯基)-2-苯甲基烟酸叔丁酯(Ⅰc)1.01g,收率:49%。
Ⅰc结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.19(d,J=7.8Hz,1H),8.02(d,J=9.0Hz,2H),7.75(d,J=8.4Hz,1H),7.53(dd,J=7.8,1.8Hz,2H)7.63(d,J=9.0Hz,2H),7.51-7.46(m,3H),1.35(s,9H).13C NMR(150MHz,CDCl3,ppm)δ167.3,158.7,156.8,140.8,139.0,137.3,131.9,129.0,128.8,128.6,128.0,127.3,124.2,117.6,82.2,27.6.HRMS(ESI-TOF)calcdfor C22H20BrNNaO2[M+Na]+:432.0549;Found:432.0570.
实施例4:2,6-二苯基4-萘基烟酸乙酯(Ⅰd)的制备
将3-氨基-3-苯基丙烯酸乙酯(0.56g,5mmol)、对1-苯基-3-萘基丙酮(1.56g,6mmol)、醋酸铜(0.18g,1mmol)、1,10-Phen(0.20g,1mmol)和4-OH-TEMPO(0.86g,5mmol)的氯苯(10mL)溶液在150℃下搅拌反应18小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=50/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体2,6-二苯基4-萘基烟酸乙酯(Ⅰd)1.42g,收率:33%,熔点:53~55℃。
Ⅰd结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.21-8.19(m,2H),7.98(m,2H),7.89(m,2H),7.82(s,1H),7.76(d,J=8.5Hz,1H),7.59-7.47(m,10H),3.77(q,J=7.0Hz,2H),0.58(t,J=7.0Hz,3H).13C NMR(150MHz,CDCl3,ppm)δ168.2,156.8,156.8,148.8,140.1,138.4,136.0,133.5,131.4,129.6,128.9,128.8,128.8,128.3,128.3,128.1,127.3,126.5,126.5,126.2,125.9,125.0,120.4,61.1,13.1.HRMS(ESI-TOF)calcd for C30H23NNaO2[M+Na]+:452.1599;Found:452.1621.
实施例5:6-(4-溴苯基)-2-甲基烟酸甲酯(Ⅰe)的制备
将3-氨基-2-丁烯酸甲酯(0.58g,5mmol)、对溴苯丙酮(1.28g,6mmol)、醋酸铜(0.18g,1mmol)、bpy(0.16g,1mmol)和4-OH-TEMPO(0.86g,5mmol)的二甲基亚砜(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=50/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体6-(4-溴苯基)-2-甲基烟酸甲酯(Ⅰe)0.76g,收率:52%,熔点:106~107℃。
Ⅰe结构式为:
1HNMR(600MHz,CDCl3,ppm)δ8.30(d,J=7.8Hz,1H),7.98(d,J=8.4Hz,2H),7.64(d,J=7.8Hz,3H),3.96(s,3H),2.93(s,3H).13C NMR(150MHz,CDCl3,ppm)δ166.9,160.2,157.9,139.6,137.2,132.0,128.9,124.4,123.7,117.2,52.3,25.3.HRMS(ESI-TOF)calcdfor C14H13BrNO2[M+H]+:306.0117;Found:306.0124.
实施例6:6-(4-氟苯基)-2-苯基烟酸乙酯(Ⅰf)的制备
将3-氨基-3-苯基丙烯酸乙酯(9.56g,5mmol)、对氟苯丙酮(9.13g,6mmol)、醋酸铜(0.05g,0.25mmol)、TMEDA(0.06g,0.5mmol)和4-OH-TEMPO(0.86g,5mmol)的甲苯(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=50/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到油状液体6-(4-氟苯基)-2-苯基烟酸乙酯(Ⅰf)1.19g,收率:74%。
Ⅰf结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.21(d,J=7.8Hz,1H),8.16-8.14(m,2H),7.75(d,J=7.8Hz,1H),7.66-7.65(m,2H),7.50-7.46(m,3H),7.19(m,2H),4.20(q,J=7.2Hz,2H),1.10(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3,ppm))δ168.2,164.4(JC-F=248.3Hz),158.8,157.3,140.5,139.0,134.4(JC-F=3.1Hz),129,2(JC-F=8.6Hz),128.8,128.7,128.0,125.3,117.5,115.8(JC-F=21.5Hz),61.4,13.7.HRMS(ESI-TOF)calcd forC20H16FNNaO2[M+Na]+:344.1040;Found:305.1057.
实施例7:2-(对甲苯基)-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱa)的制备
将4-氨基香豆素(0.81g,5mmol)、对甲基苯丙酮(0.89g,6mmol)、醋酸铜(0.18g,1mmol)、TMEDA(0.23g,2mmol)和4-OH-TEMPO(0.86g,5mmol)的甲苯(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=5/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体2-(对甲苯基)-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱa)1.15g,收率:80%,熔点:201~202℃。
Ⅱa结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.77(d,J=7.8Hz,1H),8.63(d,J=8.4Hz,1H),8.17(d,J=7.8Hz,2H),7.94(d,J=8.4Hz,1H),7.62-7.59(m,1H),7.46-7.43(m,1H),7,42-7,03(s,1H)7,38(d,J=7.8Hz,2H),2.48(s,3H).13C NMR(150MHz,CDCl3,ppm)δ162.4,161.4,152.9,151.6,141.27,138.8,135.0,132.1,129.8,127.7,124.9,124.7,120.0,119.7,117.2,115.3,21.5.HRMS(ESI-TOF)calcd for C19H14NO2[M+H]+:288.1029;Found:288.1019.
实施例8:2-(4-甲氧基苯基)-9-叔丁基-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱb)的制备
于反应瓶中加入3-氨基-6-叔丁基-3-苯基丙烯酸乙酯(1.09g,5mmol)、对甲氧基苯丙酮(0.98g,6mmol)、醋酸铜(0.18g,1mmol)、bpy(0.16g,1mmol)和4-OH-TEMPO(0.86g,5mmol)的二氯苯(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=5/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体2-(4-甲氧基苯基)-9-叔丁基-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱb)1.37g,收率:76%,熔点:195~196℃。
Ⅱb结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.78-8.76(m,1H),8.62(d,J=8.4Hz,1H),8.28-8.25(m,2H),7.93(d,J=8.4Hz,1H),7.62-7.60(m,1H),7.46-7.43(m,1H),7.43(d,J=8.4Hz,1H)7.12-7.07(m,2H),3.94(s,3H).13C NMR(150MHz,CDCl3,ppm)δ162.1,162.0,161.4,152.9,151.7,138.7,132.0,130.3,129.3,124.9,124.7,119.7,119.5,117.2,114.9,114.4,55.5.HRMS(ESI-TOF)calcd for C19H14NO3[M+H]+:304.0962;Found:304.0968.
实施例9:2-(4-三氟甲基苯基)-9-叔丁基-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱc)的制备
于反应瓶中加入3-氨基-6-叔丁基-3-苯基丙烯酸乙酯(1.09g,5mmol)、对三氟甲基苯丙酮(1.21g,6mmol)、醋酸铜(0.18g,1mmol)、bpy(0.16g,1mmol)和4-OH-TEMPO(0.86g,5mmol)的二氯苯(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=5/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体2-(4-三氟甲基苯基)-9-叔丁基-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱc)1.77g,收率:89%,熔点:220~222℃。
Ⅱc结构式为:
1H NMR(600MHz,CDCl3,ppm)δ8.69(dd,J=7.8,1.8Hz,1H),8.66(d,J=8.4Hz,1H),8.34(d,J=7.2Hz,2H),7.95(d,J=7.8Hz,1H),7.82(d,J=7.8Hz,2H),7.62-7.59(m,1H),7.44-7.42(m,1H),7.38(d,J=7.8Hz,1H).13C NMR(150MHz,CDCl3,ppm)δ160.9,160.8,152.8,151.8,140.9,139.3,132.4,132.5(JC-F=32.0Hz)128.0,125.9(JC-F=3.8Hz),124.9(JC-F=8.0Hz),123.9(JC-F=170.6Hz)120.5,119.3,117.3,116.3.19F NMR(376MHz,CDCl3,ppm)δ=-62.7.HRMS(ESI-TOF)calcd for C19H11F3NO2[M+H]+:342.0723;Found:342.0736.
实施例10:2-(4-溴苯)-9-叔丁基-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱd)的制备
于反应瓶中加入3-氨基-6-叔丁基-3-苯基丙烯酸乙酯(1.09g,5mmol)、对溴苯丙酮(1.28g,6mmol)、氯化铁(0.08g,0.5mmol)、bpy(0.16g,1mmol)和4-OH-TEMPO(0.86g,5mmol)的二氯苯(10mL)溶液在120℃下搅拌反应24小时,反应结束后,用水和乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,用石油醚/乙酸乙酯=5/1(V/V)混合溶剂作洗脱剂,经硅胶柱层析分离得到白色固体2-(4-溴苯)-9-叔丁基-5H-香豆素并[4,3-b]吡啶-5-酮(Ⅱd)1.67g,收率:81%,熔点:206~207℃。
Ⅱd结构式:
1H NMR(600MHz,CDCl3,ppm)δ8.74(d,J=1.8Hz,1H),8.69(d,J=8.4Hz,1H),8.15(d,J=8.4Hz,2H),7.95(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,2H),7.68-7.67(m,1H),7.38(d,J=9.0Hz,1H),1.47(s,9H).13C NMR(150MHz,CDCl3,ppm)δ161.4,161.3,152.1,150.9,148.0,139.3,136.8,132.3,129.9,129.26,125.6,120.9,119.9,118.6,116.9,115.9,34.8,31.5.HRMS(ESI-TOF)calcd for C22H18BrNO2[M+H]+:408.0544;Found:408.0594.
实施例11:抗肿瘤生物活性测试方法(MTT法)
将化合物Ⅰa、Ⅰb、Ⅰc、Ⅰd、Ⅰe、Ⅰf、Ⅱa、Ⅱb、Ⅱc、Ⅱd进行抗肿瘤活性测试,具体测试方法为将细胞用EDTA-胰酶消化液消化,并用DMEM培养基(每1000mL培养基中含80万单位青霉素,1.0g链霉素,10%灭火胎牛血清)稀释成1×106/mL培养基中,每孔100μL,置37℃,5%CO2培养箱中培养。接种24小时后,倾去培养基,加入培养基稀释的样品,每孔200μL,每个浓度加3孔,置37℃,5%CO2培养箱中培养,72小时后在细胞培养孔中加入5mg/mL的MTT,每孔10μL,置37℃孵育4小时,倾去培养基,加入DMSO,以相同条件用不含样品,含相同浓度DMSO的培养基培养的细胞作为对照,计算样品对肿瘤细胞生长的半数致死浓度(IC50),所得结果如下表1。
表1.吡啶衍生物对不同肿瘤细胞株的IC50(μM)值
从表1可以看出,本发明制备得到的此类化合物对人肺癌细胞A-549和人肝癌细胞HepG-2具有潜在的抗癌活性,从表1可以得出:
1)所有化合物对人肺癌细胞A-549具有一般的抑制活性;2)所有化合物中,化合物Ⅰb、Ⅱa、Ⅱb、Ⅱc对人肝癌细胞HepG-2具有较好的抑制活性,IC50值分别为36.92、16.92、4.112、3.47,其中化合物Ⅱc的抑制活性最好。
可见,本发明提供的吡啶衍生物(Ⅰ)和(Ⅱ)具有潜在的体外抗肿瘤细胞活性,具有开发成抗肿瘤药的前景。
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