CN113200926B - 一种修饰2-芳基喹唑啉-4(3h)-酮类化合物的方法 - Google Patents
一种修饰2-芳基喹唑啉-4(3h)-酮类化合物的方法 Download PDFInfo
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- CN113200926B CN113200926B CN202110507292.8A CN202110507292A CN113200926B CN 113200926 B CN113200926 B CN 113200926B CN 202110507292 A CN202110507292 A CN 202110507292A CN 113200926 B CN113200926 B CN 113200926B
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- aryl
- silver
- silver salt
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- 238000000034 method Methods 0.000 title claims abstract description 10
- -1 diaryl difluorocyclopropene Chemical compound 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000010898 silica gel chromatography Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical group CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- AYKOTYRPPUMHMT-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag] AYKOTYRPPUMHMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 238000003786 synthesis reaction Methods 0.000 abstract description 15
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 abstract description 9
- 230000004913 activation Effects 0.000 abstract description 5
- 239000004215 Carbon black (E152) Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 4
- 229930195733 hydrocarbon Natural products 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002430 hydrocarbons Chemical class 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 150000003624 transition metals Chemical group 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
- 239000012298 atmosphere Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000004305 biphenyl Substances 0.000 description 5
- 235000010290 biphenyl Nutrition 0.000 description 5
- 125000006267 biphenyl group Chemical group 0.000 description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 5
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- VDULOAUXSMYUMG-UHFFFAOYSA-N 2-phenyl-1h-quinazolin-4-one Chemical compound N=1C2=CC=CC=C2C(O)=NC=1C1=CC=CC=C1 VDULOAUXSMYUMG-UHFFFAOYSA-N 0.000 description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001345 alkine derivatives Chemical group 0.000 description 2
- 230000000078 anti-malarial effect Effects 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 2
- GGRQLKPIJPFWEZ-UHFFFAOYSA-N cycloprop-2-en-1-one Chemical group O=C1C=C1 GGRQLKPIJPFWEZ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 2
- 229940071536 silver acetate Drugs 0.000 description 2
- 229910001958 silver carbonate Inorganic materials 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 229940096017 silver fluoride Drugs 0.000 description 2
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 2
- 229910000367 silver sulfate Inorganic materials 0.000 description 2
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical compound [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- GPCDGGKVBPVZCT-UHFFFAOYSA-N 1,1-difluorocyclopropane Chemical compound FC1(F)CC1 GPCDGGKVBPVZCT-UHFFFAOYSA-N 0.000 description 1
- XPIFUSSSVUOPHT-UHFFFAOYSA-N 1,2-difluorocyclopropene Chemical compound FC1=C(F)C1 XPIFUSSSVUOPHT-UHFFFAOYSA-N 0.000 description 1
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
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- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- NRCCYFAMXZIJSC-UHFFFAOYSA-N 2-(4-bromophenyl)-1h-quinazolin-4-one Chemical compound C1=CC(Br)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 NRCCYFAMXZIJSC-UHFFFAOYSA-N 0.000 description 1
- UTEHUKGJDLVHIH-UHFFFAOYSA-N 2-(4-methylphenyl)-1h-quinazolin-4-one Chemical compound C1=CC(C)=CC=C1C1=NC(=O)C2=CC=CC=C2N1 UTEHUKGJDLVHIH-UHFFFAOYSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- XHKUTQNVGAHLPK-UHFFFAOYSA-N 2-fluorocyclohexa-2,5-diene-1,4-dione Chemical compound FC1=CC(=O)C=CC1=O XHKUTQNVGAHLPK-UHFFFAOYSA-N 0.000 description 1
- PWLHUQRFCZDOQK-UHFFFAOYSA-N 2-naphthalen-1-yl-1h-quinazolin-4-one Chemical compound C1=CC=C2C(C3=NC(C4=CC=CC=C4N3)=O)=CC=CC2=C1 PWLHUQRFCZDOQK-UHFFFAOYSA-N 0.000 description 1
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- PGMBDCKPRFLKLG-UHFFFAOYSA-N 6-chloro-2-phenyl-1h-quinazolin-4-one Chemical compound N=1C(=O)C2=CC(Cl)=CC=C2NC=1C1=CC=CC=C1 PGMBDCKPRFLKLG-UHFFFAOYSA-N 0.000 description 1
- UHSQXWSTFPABAF-UHFFFAOYSA-N 6-methoxy-2-phenyl-1h-quinazolin-4-one Chemical compound N=1C(=O)C2=CC(OC)=CC=C2NC=1C1=CC=CC=C1 UHSQXWSTFPABAF-UHFFFAOYSA-N 0.000 description 1
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- SAXQOYZKDFVDTH-UHFFFAOYSA-N CC1=C(C(=C(C1(C)[Rh])C)C)C Chemical compound CC1=C(C(=C(C1(C)[Rh])C)C)C SAXQOYZKDFVDTH-UHFFFAOYSA-N 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- JPZNYOGNIYAACO-UHFFFAOYSA-N FC1(C(C(C=C2)=CC=C2Cl)=C1C(C=C1)=CC=C1Cl)F Chemical compound FC1(C(C(C=C2)=CC=C2Cl)=C1C(C=C1)=CC=C1Cl)F JPZNYOGNIYAACO-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GQVCUDFXRZJEIA-UHFFFAOYSA-N N1=NC(C2=C1C=CC1=C2C=CC=2C=NC=NC1=2)=O Chemical class N1=NC(C2=C1C=CC1=C2C=CC=2C=NC=NC1=2)=O GQVCUDFXRZJEIA-UHFFFAOYSA-N 0.000 description 1
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- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
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- 230000000895 acaricidal effect Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
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- 230000002365 anti-tubercular Effects 0.000 description 1
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- AQTIRDJOWSATJB-UHFFFAOYSA-K antimonic acid Chemical compound O[Sb](O)(O)=O AQTIRDJOWSATJB-UHFFFAOYSA-K 0.000 description 1
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- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
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- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 229940125872 compound 4d Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical compound C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
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- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- YIAPLDFPUUJILH-UHFFFAOYSA-N indan-1-ol Chemical group C1=CC=C2C(O)CCC2=C1 YIAPLDFPUUJILH-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- GKLAHZJLALYDPS-UHFFFAOYSA-N isoindolo[4,5-h]quinazolin-6-one Chemical class C12=CC=C3C=NC=C3C1=CC=C1C2=NC=NC1=O GKLAHZJLALYDPS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
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- 230000007170 pathology Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
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- 125000003003 spiro group Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
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
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Abstract
本发明公开了一种利用二芳基二氟环丙烯修饰2‑芳基喹唑啉‑4(3H)‑酮类化合物的方法，用于合成两种2‑芳基喹唑啉‑4(3H)‑酮类化合物骨架。本发明以2‑芳基喹唑啉‑4(3H)‑酮类与二芳基二氟环丙烯类化合物为原料，在银盐或银盐和酸的辅助下，通过过渡金属催化的碳氢活化反应高效地构建2‑(2‑(2‑芳基茚满‑1‑醇)芳基)喹唑啉酮或环戊二烯螺吡咯并[1,2‑b]喹唑啉酮结构。与传统合成方法相比，本方法的优势如下：（1）底物适用范围广，产物收率高。（2）一锅法实现三组分高效合成各种喹唑啉酮类衍生物，操作步骤简单，无需对底物进行预活化，后处理简便。（3）二芳基二氟环丙烯类化合物作为一种新的偶联试剂，具有合成方法简单、活性高的特点。（4）反应可以进行克级放大，具有潜在的应用价值。
Description
技术领域
本发明涉及一种利用二芳基二氟环丙烯修饰2-芳基喹唑啉-4(3H)-酮类化合物的方法：以2-芳基喹唑啉-4(3H)-酮类与二芳基二氟环丙烯类化合物为原料，通过过渡金属催化的碳氢活化反应高效构建茚满-1-醇或螺环骨架，属于化学合成领域。
背景技术
喹唑啉酮以苯并嘧啶酮为骨架，是一种重要的生物碱，广泛存在于各种天然产物中，因其结构简单、易于改造，同时具有杀菌、杀虫、抗炎、抗病毒、抗高血压、抗结核、抗疟、抗肿瘤等多种活性，成为精细化工和医药合成的重要中间体1。例如，氟喹唑是市售杀菌剂的主要成分2；喹螨醚是一种有效的杀螨成分3；具有4-喹唑啉酮骨架的安眠酮、氟喹酮、地普喹酮、氯喹酮等是优秀的镇静催眠类药物4；常山碱用于抗疟5；抗叶酸剂雷替曲塞已用于晚期结、直肠癌的治疗等6。因此，喹唑啉酮具有广阔的应用前景，对其进行结构修饰，以期得到具有更好活性的衍生物引起了科学家们的持续关注。
最近几十年，过渡金属催化的碳氢键活化/转化已经成为有机化学合成强有力的工具。近几年，喹唑啉酮的碳氢活化研究也有很多报道。例如，2014年，Chen小组从2-芳基-3-芳胺基喹唑啉酮出发，通过钯催化分子内氧化胺化生成吲唑并喹唑啉酮类化合物7。2017年，Wang小组报道了2-(2-溴芳基)喹唑啉-4-酮与末端炔烃在铜催化下生成异吲哚并喹唑啉酮类化合物8；Cui等人通过钯催化2-芳基喹唑啉-4(3H)-酮与炔，在氧气作用下通过[4+2]和[3+2]环加成反应构建了四氢吡啶并二氢呋喃环9。
二氟代环丙烯可在水的参与下，脱掉两个氟原子，形成环丙烯酮结构。环丙烯酮易与亲核试剂和亲电试剂反应，其氧负离子的亲核性强，而阳离子部分为最小的Huckel芳香体系-环丙烯阳离子，极易被各种亲核试剂进攻；另一方面环丙烯酮很容易在三元环应变张力的驱动下开环，因此有具有极大的应用前景10。本发明首次通过二氟代环丙烯-水-2-芳基喹唑啉-4(3H)-酮实现三组分一锅法构建新的喹唑啉酮衍生物，跳过了合成环丙烯酮的步骤，提高了该反应的步骤经济性。
发明内容
本发明实现了以2-芳基喹唑啉-4(3H)-酮类与二芳基二氟环丙烯类化合物为原料，在银盐或银盐和酸的存在下通过过渡金属Rh或Ru催化的芳基碳氢活化/环合反应对2-芳基喹唑啉-4(3H)-酮类化合物进行结构修饰，解决了传统合成方法中反应步骤繁琐、原料难以得到等问题。同时，本发明使用了一种新型小环偶联试剂，该试剂简单易得，反应活性高，具有广阔的应用前景。
本发明化学反应式如下所示：
方案I：
方案II：
其中：
R1为氢、卤素、C1~C3烷基、C1~C3烷氧羰基、硝基中的一种；
R2为氢、卤素、C1~C3烷基、C1~C3烷氧基、硝基中的一种；
R3为氢、卤素、C1~C3烷基中的一种。
制备步骤如下：
方案I：制备化合物3
（1）在洁净的耐压瓶中加入2-芳基喹唑啉-4(3H)-酮类化合物、二芳基二氟环丙烯类化合物、催化剂、银盐、水和溶剂，于100 ℃油浴锅里加热搅拌36 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品。
方案I中的催化剂为三氯化铑、醋酸铑、双环辛烯氯化铑二聚体、二氯（五甲基环戊二烯基）合铑（III）二聚体、(二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III))中的一种或几种。
方案I中的银盐为六氟锑酸银、碳酸银、硫酸银、硝酸银、醋酸银、双三氟甲烷磺酰亚胺银、三氟甲烷磺酸银、六氟磷酸银、氟化银中的一种或几种。
方案I中的溶剂为二氯甲烷、1，2-二氯乙烷、甲苯、乙腈、氯苯、丙酮、1，4-二氧六环中的一种或几种。
方案I中的2-芳基喹唑啉-4(3H)-酮类化合物：二氟环丙烯类化合物：催化剂：银盐：水的摩尔比为1：(1.05~1.5)：(0.02~0.1)：(0.1~0.5)：(5~15)。
方案I所述2-芳基喹唑啉-4(3H)-酮类化合物的反应浓度为0.05~0.2 mol/L。
方案II：制备化合物4
（1）在洁净的耐压瓶中加入2-芳基喹唑啉-4(3H)-酮类化合物、二芳基二氟环丙烯类化合物、催化剂、银盐、添加剂、水和溶剂，于130 ℃油浴锅里加热搅拌48 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品。
方案II中的催化剂为二氯双(4-甲基异丙基苯基)钌(II)、三氯化钌、二氯二羰基双三苯基膦钌、双（2-甲基烯丙基）（1,5-环辛二烯）钌（II）中的一种或几种。
方案II中的银盐为六氟锑酸银、碳酸银、硫酸银、硝酸银、醋酸银、双三氟甲烷磺酰亚胺银、三氟甲烷磺酸银、六氟磷酸银、氟化银中的一种或几种。
方案II中的酸添加剂为金刚烷甲酸、冰乙酸、特戊酸、甲酸中的一种或几种。
方案II中的溶剂为二氯甲烷、1，2-二氯乙烷、甲苯、乙腈、氯苯、丙酮、1，4-二氧六环中的一种或几种。
方案II所述2-芳基喹唑啉-4(3H)-酮类化合物：二氟环丙烯类化合物：催化剂：银盐：有机酸：水的摩尔比为1：(1.05~1.5)：(0.02~0.1)：(0.1~0.5)：(1.5~2.5)：(5~15)。
方案II所述2-芳基喹唑啉-4(3H)-酮类化合物的反应浓度为0.05~0.2 mol/L。
用核磁共振氢谱（1H NMR）、碳谱（13C NMR）以及高分辨质谱证实了在芳环上形成C-C键以及2-（2-（2-芳基茚满-1-醇）芳基）喹唑啉酮或环戊二烯螺吡咯并[1,2-b]喹唑啉酮的结构。其中核磁共振图采用Varian INOVA-400 型核磁共振仪测定，以四甲基硅烷（TMS）为内标（δ 0 ppm），氘代氯仿为溶剂；高分辨质谱用 Agilent 1946B 质谱仪测定。
具体实施方式
下面结合具体实施方式对本发明作进一步描述，有助于对本发明的理解。但并不能以此来限制本发明的权利范围，而本发明的权利范围应以权利要求书阐述的为准。
实施实例1：化合物3a的合成
（1）在洁净的耐压瓶中依次加入，2-(4-甲基苯基)喹唑啉-4(3H)-酮（23.6 mg,0.10 mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（27.4 mg, 0.12 mmol），二氯（五甲基环戊二烯基）合铑（III）二聚体（3.0 mg, 0.005 mmol），六氟锑酸银（6.9 mg, 0.02 mmol），二氯甲烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于100 ℃油浴锅里搅拌36 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品34.5 mg，白色固体，收率78%；1H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 7.9 Hz, 1H), 7.83 (d, J =7.9 Hz, 1H), 7.73-7.67 (m, 1H), 7.65-7.58 (m, 2H), 7.55 (s, 1H), 7.42 (q, J =7.6 Hz, 2H), 7.14-7.06 (m, 3H), 7.01 (t, J = 7.2 Hz, 1H), 6.96-6.88 (m, 4H),6.54 (s, 1H), 5.55 (s, 1H), 2.52 (s, 3H). 13C NMR (100 MHz, Chloroform-d) δ161.4, 152.9, 149.1, 144.2, 143.9, 140.3, 135.7, 135.6, 134.5, 131.8, 131.5,129.6, 129.4, 129.3, 129.1, 128.4, 128.4, 128.0, 127.8, 127.6, 127.5, 126.5,126.3, 123.9, 122.8, 121.1, 95.9, 22.2. HRMS (ESI)：计算值C30H22N2NaO2 [M+Na]+：465.1573, 实测值：465.1571。
实施实例2：化合物3b的合成
（1）在洁净的耐压瓶中依次加入，6-氯-2-苯基喹唑啉-4(3H)-酮（25.7 mg, 0.10mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（27.4 mg, 0.12 mmol），二氯（五甲基环戊二烯基）合铑（III）二聚体（3.0 mg, 0.005 mmol），六氟锑酸银（6.9 mg, 0.02 mmol），二氯甲烷（2.0 mL）和水（18 μL, 10 mmolL），空气氛围下于100 ℃油浴锅里搅拌36 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品37.5 mg，黄色固体，收率81%；1H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 2.2 Hz, 1H), 7.93 (d, J =7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.66-7.56(m, 4H), 7.15-7.06 (m, 3H), 7.02 (t, J = 7.4 Hz, 1H), 6.95-6.90 (m, 4H), 6.51(s, 1H), 5.47 (s, 1H). 13C NMR (100 MHz, Chloroform-d) δ 160.2, 153.0, 147.6,143.6, 139.8, 135.5, 135.4, 134.9, 133.2, 132.6, 131.5, 130.8, 129.5, 129.4,129.1, 128.5, 128.1, 127.9, 127.7, 125.8, 123.7, 123.1, 122.3, 96.4. HRMS(ESI)：计算值C29H19ClN2NaO2 [M+Na]+：485.1027, 实测值：485.1035。
实施实例3：化合物3c的合成
（1）在洁净的耐压瓶中依次加入，2-苯基喹唑啉-4(3H)-酮（22.2 mg, 0.10mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（27.4 mg, 0.12 mmol），二氯（五甲基环戊二烯基）合铑（III）二聚体（3.0 mg, 0.005 mmol），六氟锑酸银（6.9 mg, 0.02 mmol），二氯甲烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于100 ℃油浴锅里搅拌36 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品33.6 mg，黄色固体，收率81%；1H NMR (400 MHz, Chloroform-d) δ 8.27 (dd, J = 7.9, 1.5 Hz, 1H), 7.95 (d,J = 7.6 Hz, 1H), 7.78-7.75 (m, 1H), 7.72 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H),7.69-7.65 (m, 2H), 7.62-7.57 (m, 2H) 7.46 (ddd, J = 8.1, 6.9, 1.4 Hz, 1H),7.13-7.05 (m, 3H), 7.03-6.98 (m, 1H), 6.95-6.88 (m, 4H), 6.53 (s, 1H), 5.58(s, 1H). 13C NMR (100 MHz, Chloroform-d) δ 161.4, 152.8, 149.1, 143.7, 140.2,135.7, 135.5, 134.5, 133.0, 131.8, 130.7, 129.5, 129.3, 128.5, 128.4, 128.4,128.0, 127.8, 127.6, 126.8, 126.4, 123.6, 123.1, 121.3, 96.2. HRMS (ESI)：计算值C29H20N2NaO2 [M+Na]+：451.1417, 实测值：451.1410。
实施实例4：化合物3d的合成
（1）在洁净的耐压瓶中依次加入，2-(4-溴苯基)喹唑啉-4(3H)-酮（30.1 mg, 0.10mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（27.4 mg, 0.12 mmol），二氯（五甲基环戊二烯基）合铑（III）二聚体（3.0 mg, 0.005 mmol），六氟锑酸银（6.9 mg, 0.02 mmol），二氯甲烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于100 ℃油浴锅里搅拌36 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品39.1 mg，黄色固体，收率77%；1H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J = 7.7 Hz, 1H), 7.91-7.86 (m,1H), 7.81 (dd, J = 14.9, 8.1 Hz, 1H), 7.75-7.69 (m, 2H), 7.64 (d, J = 8.1 Hz,1H), 7.60 (s, 1H), 7.55-7.44 (m, 1H), 7.14-7.07 (m, 3H), 7.05-7.00 (m, 1H),6.94 (t, J = 7.6 Hz, 4H), 6.57 (s, 1H), 5.63 (s, 1H). 13C NMR (100 MHz,Chloroform-d) δ 161.1, 151.9, 148.8, 145.4, 139.3, 135.4, 135.2, 134.7,134.1, 130.6, 129.7, 129.6, 128.8, 128.5, 128.4, 128.1, 128.0, 127.8, 127.6,127.5, 127.1, 127.0, 126.4, 125.6, 124.3, 121.2, 95.7. HRMS (ESI)：计算值C29H19BrN2NaO2 [M+Na]+：529.0522, 实测值：529.0521。
实施实例5：化合物3e的合成
（1）在洁净的耐压瓶中依次加入，6-甲氧基-2-苯基喹唑啉-4(3H)-酮（25.2 mg,0.10 mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（27.4 mg, 0.12 mmol），二氯（五甲基环戊二烯基）合铑（III）二聚体（3.0 mg, 0.005 mmol），六氟锑酸银（6.9 mg, 0.02 mmol），二氯甲烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于100 ℃油浴锅里搅拌36 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品33.1 mg，黄色固体，收率78%；1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 7.5 Hz, 1H), 7.74 (d, J =7.5 Hz, 1H), 7.67-7.51 (m, 5H), 7.31 (dd, J = 8.9, 2.9 Hz, 1H), 7.13-6.97 (m,4H), 6.95-6.85 (m, 4H), 6.52 (s, 1H), 5.73 (s, 1H), 3.91 (s, 3H). 13C NMR (100MHz, Chloroform-d) δ 161.1, 158.5, 151.0, 143.3, 140.1, 135.7, 135.5, 132.6,131.8, 130.7, 129.5, 129.2, 129.1, 129.0, 128.4, 128.4, 128.0, 127.8, 127.6,126.9, 125.2, 124.4, 123.6, 122.7, 122.0, 106.2, 96.2, 55.8. HRMS (ESI)：计算值 C30H22N2NaO3 [M+Na]+：481.1523, 实测值：481.1518。
实施实例6：化合物4a的合成
（1）在洁净的反应器中依次加入，2-(4-甲氧羰基苯基)喹唑啉-4(3H)-酮（28.0mg， 0.10 mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（25.1 mg, 0.11 mmol），二氯双(4-甲基异丙基苯基)钌(II)（3.0 mg, 0.005 mmol），六氟锑酸银（10.3 mg, 0.03 mmol），1，2-二氯乙烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于130 ℃油浴锅里搅拌48 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品42.2 mg，黄色固体，收率90%；1H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 8.1 Hz, 1H), 8.26 (dd, J =8.1, 1.4 Hz, 1H), 8.13 (dd, J = 8.0, 1.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H),7.79-7.67 (m, 2H), 7.57 (s, 1H), 7.53 (dd, J = 8.3, 3.6 Hz, 1H), 7.42 (t, J =7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.10-7.04 (m, 4H), 7.01-6.95 (m 2H),6.72 (d, J = 7.5 Hz, 1H), 3.85 (s, 3H). 13C NMR (100 MHz, Chloroform-d) δ184.4, 165.9, 158.7, 154.4, 148.7, 145.3, 144.2, 143.0, 134.7, 134.6, 131.8,131.0, 131.0, 129.5, 129.0, 128.9, 128.3, 127.6, 127.3, 127.2, 127.1, 125.7,124.2, 123.4, 122.5, 121.9, 121.1, 79.2, 52.7. HRMS (ESI)：计算值 C31H20N2NaO3[M+Na]+：491.1366, 实测值：491.1365。
实施实例7：化合物4b的合成
（1）在洁净的反应器中依次加入，2-苯基喹唑啉-4(3H)-酮（22.2 mg， 0.10mmol），4，4'-（3，3-二氟环丙烷-1-烯-1，2-二基）双（氯苯）（32.7 mg, 0.11 mmol），二氯双(4-甲基异丙基苯基)钌(II)（3.0 mg, 0.005 mmol），六氟锑酸银（10.3 mg, 0.03 mmol），1，2-二氯乙烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于130 ℃油浴锅里搅拌48 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品34.0 mg，黄色固体，收率71%；1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 7.7 Hz, 1H), 8.12 (dd, J =8.0, 1.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.63 (t, J =7.5 Hz, 1H), 7.51 (td, J = 7.5, 1.2 Hz, 1H), 7.47-7.40 (m, 3H), 7.30 (dt, J =8.1, 1.4 Hz, 1H), 7.07-7.01 (m, 3H), 6.89 (d, J = 8.5 Hz, 2H), 6.70 (d, J =1.8 Hz, 1H) 13C NMR (100 MHz, Chloroform-d) δ 157.8, 153.7, 147.8, 144.3,143.3, 142.6, 140.0, 133.5, 133.2, 132.5, 131.9, 131.2, 130.1, 129.5, 129.0,128.4, 128.0, 126.5, 126.0, 125.9, 125.9, 123.2, 122.0, 120.8, 120.8, 120.4,77.5. HRMS (ESI)：计算值 C29H16Cl2N2NaO [M+Na]+：501.0532, 实测值：501.0538。
实施实例8：化合物4c的合成
（1）在洁净的反应器中依次加入，2-(4-甲氧羰基苯基)喹唑啉-4(3H)-酮（26.7mg， 0.10 mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（25.1 mg, 0.11 mmol），二氯双(4-甲基异丙基苯基)钌(II)（3.0 mg, 0.005 mmol），六氟锑酸银（10.3 mg, 0.03 mmol），1，2-二氯乙烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于130 ℃油浴锅里搅拌48 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品41.0 mg，黄色固体，收率90%；1H NMR (400 MHz, Chloroform-d) δ 8.47-8.41 (m, 2H), 8.15 (d, J = 7.6 Hz,1H), 7.92-7.84 (m, 2H), 7.83-7.77 (m, 1H), 7.61 (s, 1H), 7.56 (d, J = 7.5 Hz,1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.15-7.06 (m, 4H),7.01-6.95 (m, 2H), 6.74 (d, J = 7.5 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ183.8, 158.4, 153.0, 151.0, 148.5, 146.5, 143.6, 142.7, 142.1, 137.7, 134.7,132.6, 132.1, 129.8, 128.9, 128.4, 127.8, 127.7, 127.3, 127.2, 125.5, 125.0,122.7, 121.8, 121.0, 117.8, 79.0. HRMS (ESI)：计算值 C29H17N3NaO3 [M+Na]+：478.1162, 实测值：478.1147。
实施实例9：化合物4d的合成
（1）在洁净的反应器中依次加入，2-(萘-1-基)喹唑啉-4(3H)-酮（27.2 mg， 0.10mmol），（3，3-二氟环丙烷-1-烯-1，2-二基）二苯（25.1 mg, 0.11 mmol），二氯双(4-甲基异丙基苯基)钌(II)（3.0 mg, 0.005 mmol），六氟锑酸银（10.3 mg, 0.03 mmol），1，2-二氯乙烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于130 ℃油浴锅里搅拌48 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品32.7 mg，黄色固体，收率71%；1H NMR (400 MHz, Chloroform-d) δ 9.82 (d, J = 8.4 Hz, 1H), 8.17-8.13 (m,1H), 7.99-7.84 (m, 4H), 7.80-7.75 (m, 1H), 7.71-7.65 (m, 1H), 7.59 (s, 1H),7.53 (d, J = 7.5 Hz, 1H), 7.43-7.37 (m, 1H), 7.36-7.30 (m, 1H), 7.08-6.99 (m,7H), 6.73 (d, J = 7.5 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ 159.4, 154.7,152.7, 150.9, 148.6, 141.7, 139.5, 137.8, 136.8, 133.4, 132.6, 131.8, 131.4,131.3, 131.1, 130.6, 130.3, 129.5, 128.9, 128.6, 128.5, 128.2, 127.6, 127.2,127.0, 126.9, 126.7, 126.6, 126.6, 126.4, 55.7. HRMS (ESI)：计算值 C33H20N2NaO[M+Na]+：483.1468, 实测值：483.1470。
实施实例10：化合物4e的合成
（1）在洁净的反应器中依次加入，2-苯基喹唑啉-4(3H)-酮（22.2 mg， 0.10mmol），4，4'-（3，3-二氟环丙烷-1-烯-1，2-二基）双（甲苯）（28.2 mg, 0.11 mmol），二氯双(4-甲基异丙基苯基)钌(II)（3.0 mg, 0.005 mmol），六氟锑酸银（10.3 mg, 0.03 mmol），1，2-二氯乙烷（2.0 mL）和水（18 μL, 10 mmol），空气氛围下于130 ℃油浴锅里搅拌48 h；
（2）反应完成后，直接采用硅胶柱层析分离纯化即得产品33.7 mg，黄色固体，收率77%；1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 7.8 Hz, 1H), 8.18-8.09 (m,1H), 7.85 (d, J = 8.2 Hz, 1H), 7.79-7.69 (m, 1H), 7.58 (t, J = 7.5 Hz, 1H),7.50-7.43 (m, 2H), 7.42-7.34 (m, 2H), 7.08 (dd, J = 27.0, 7.7 Hz, 2H), 6.93-6.82 (m, 4H), 6.51 (s, 1H), 2.16 (d, J = 5.9 Hz, 6H). 13C NMR (100 MHz,Chloroform-d) δ 157.8, 153.7, 147.8, 144.3, 143.3, 142.6, 140.0, 133.5,133.2, 132.5, 131.9, 131.2, 130.1, 129.5, 129.0, 128.4, 128.0, 126.5, 126.0,125.9, 125.9, 123.2, 122.0, 120.8, 120.8, 120.4, 77.5, 35.4, 26.8. HRMS(ESI)：计算值 C31H22N2NaO [M+Na]+：461.1624, 实测值：461.1624。
参考文献
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Claims (3)
1.一种2-（2-（2-芳基茚满-1-醇）芳基）喹唑啉酮类化合物（3）的合成方法，其特征在于采用如下制备步骤：
（I）在洁净的耐压瓶中加入2-芳基喹唑啉-4(3H)-酮类化合物（1）、二芳基二氟环丙烯类化合物（2）、催化剂、银盐、水和溶剂，于100 ℃油浴锅里加热搅拌36 h；
（II）反应完成后，直接采用硅胶柱层析分离纯化即得产品；
其中，催化剂为二氯（五甲基环戊二烯基）合铑（III）二聚体；
银盐为六氟锑酸银；
溶剂为二氯甲烷、1，2-二氯乙烷、甲苯、乙腈、氯苯、丙酮、1，4-二氧六环中的一种或几种；
其化学反应式为：
其中：
R1为氢、卤素、C1~C3烷基、C1~C3烷氧羰基、硝基中的一种；
R2为氢、卤素、C1~C3烷基、C1~C3烷氧基、硝基中的一种；
R3为氢、卤素、C1~C3烷基中的一种。
2.根据权利要求1所述的方法，其特征在于：所述2-芳基喹唑啉-4(3H)-酮类化合物（1）：二氟环丙烯类化合物（2）：催化剂：银盐：水的摩尔比为1：(1.05~1.5)：(0.02~0.1)：(0.1~0.5)：(5~15)。
3.根据权利要求1所述的方法，其特征在于：所述2-芳基喹唑啉-4(3H)-酮类化合物（1）的反应浓度为0.05~0.2 mol/L。
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