CN115073485B - 3-aryl-7, 8-pyranocoumarin derivative, and preparation method and application thereof - Google Patents
3-aryl-7, 8-pyranocoumarin derivative, and preparation method and application thereof Download PDFInfo
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- CN115073485B CN115073485B CN202210705698.1A CN202210705698A CN115073485B CN 115073485 B CN115073485 B CN 115073485B CN 202210705698 A CN202210705698 A CN 202210705698A CN 115073485 B CN115073485 B CN 115073485B
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- pyranocoumarin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 45
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 42
- HWDSXZLYIKESML-UHFFFAOYSA-N 3-phenylchromen-2-one Chemical class O=C1OC=2C=CC=CC=2C=C1C1=CC=CC=C1 HWDSXZLYIKESML-UHFFFAOYSA-N 0.000 claims abstract description 30
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000002156 mixing Methods 0.000 claims abstract description 28
- -1 propargyl ether compound Chemical class 0.000 claims abstract description 23
- HRDCVMSNCBAMAM-UHFFFAOYSA-N 3-prop-2-ynoxyprop-1-yne Chemical class C#CCOCC#C HRDCVMSNCBAMAM-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 15
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 15
- OTIGZTVNVNDUNV-UHFFFAOYSA-N 3-hydroxy-2,4-dimethylbenzaldehyde Chemical compound CC1=CC=C(C=O)C(C)=C1O OTIGZTVNVNDUNV-UHFFFAOYSA-N 0.000 claims abstract description 9
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical group OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims abstract description 9
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- 238000010438 heat treatment Methods 0.000 claims description 58
- 239000007787 solid Substances 0.000 claims description 46
- 238000003756 stirring Methods 0.000 claims description 39
- 238000001914 filtration Methods 0.000 claims description 35
- 238000010992 reflux Methods 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 23
- 239000000706 filtrate Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- MGKPFALCNDRSQD-UHFFFAOYSA-N 2-(4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1 MGKPFALCNDRSQD-UHFFFAOYSA-N 0.000 claims description 4
- GXXXUZIRGXYDFP-UHFFFAOYSA-N 2-(4-methylphenyl)acetic acid Chemical compound CC1=CC=C(CC(O)=O)C=C1 GXXXUZIRGXYDFP-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- ODVLMCWNGKLROU-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)acetic acid Chemical compound OC(=O)CC1=CC=C2OCOC2=C1 ODVLMCWNGKLROU-UHFFFAOYSA-N 0.000 claims description 3
- GFLQMGYDUPLXHZ-UHFFFAOYSA-N 2-(3-chloro-5-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=CC(Cl)=C1 GFLQMGYDUPLXHZ-UHFFFAOYSA-N 0.000 claims description 2
- QSILYWCNPOLKPN-UHFFFAOYSA-N 3-chloro-3-methylbut-1-yne Chemical compound CC(C)(Cl)C#C QSILYWCNPOLKPN-UHFFFAOYSA-N 0.000 claims description 2
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 229960003424 phenylacetic acid Drugs 0.000 claims description 2
- 239000003279 phenylacetic acid Substances 0.000 claims description 2
- 238000011403 purification operation Methods 0.000 claims 2
- 238000000746 purification Methods 0.000 abstract description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 15
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- ZGFASEKBKWVCGP-UHFFFAOYSA-N cyclocoumarol Chemical compound C12=CC=CC=C2OC(=O)C2=C1OC(OC)(C)CC2C1=CC=CC=C1 ZGFASEKBKWVCGP-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
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- 238000000967 suction filtration Methods 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 241000202807 Glycyrrhiza Species 0.000 description 5
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 5
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 5
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 5
- PHHAXWBLJNBVNS-UHFFFAOYSA-N Isoglycycoumarin Natural products C=1C=2C(OC)=C3CCC(C)(C)OC3=CC=2OC(=O)C=1C1=CC=C(O)C=C1O PHHAXWBLJNBVNS-UHFFFAOYSA-N 0.000 description 5
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 5
- 229940010454 licorice Drugs 0.000 description 5
- XGPBRZDOJDLKOT-UHFFFAOYSA-N praeruptorin A Natural products C1=CC(=O)OC2=C1C=CC1=C2C(OC(C)=O)C(OC(=O)C(C)=CC)C(C)(C)O1 XGPBRZDOJDLKOT-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 3
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 3
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 2
- YEAUYVGUXSZCFI-UHFFFAOYSA-N 2-(3-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(F)=C1 YEAUYVGUXSZCFI-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229960000956 coumarin Drugs 0.000 description 2
- 235000001671 coumarin Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000750718 Pterocarpus santalinus Species 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000000040 effect on leukemia Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 3-aryl-7, 8-pyranocoumarin derivative, which has a structure shown in a general formula I, and a preparation method of the 3-aryl-7, 8-pyranocoumarin derivative, comprising the following steps: mixing phenylacetic acid substituent, acetic anhydride, triethylamine and 2, 4-dimethylhydroxybenzaldehyde for reaction, and purifying to obtain a 3-phenylcoumarin derivative; mixing 3-phenylcoumarin derivative, acetonitrile, potassium tert-butoxide, potassium iodide, tetrabutylammonium bromide and acetylide for reaction, and purifying to obtain propargyl ether compounds; the propargyl ether compound and the diphenyl ether are mixed for reaction, and the target compound I is obtained through purification. The invention discloses an application of a 3-aryl-7, 8-pyranocoumarin derivative in preparing an antitumor drug.
Description
Technical Field
The invention relates to the technical field of organic synthesis. More particularly, the invention relates to a 3-aryl-7, 8-pyranocoumarin derivative, a preparation method and application thereof.
Background
Coumarin is a compound containing a benzo alpha-pyrone skeleton, and a compound formed by cyclizing isopentenyl of 6-position carbon or 8-position carbon of coumarin and ortho-phenol hydroxyl is called pyranocoumarin, and can be classified into linear pyranocoumarin, namely 6, 7-pyranocoumarin and angular pyranocoumarin (7, 8-pyranocoumarin) according to the structure, wherein the pyranocoumarin has pharmacological activities of anti-tumor, antibacterial, anti-HIV, anti-inflammatory, anti-oxidation and the like, and the anti-tumor activity of the pyranocoumarin has great attention in recent years, and has potential application prospect in the research of anti-tumor drugs.
Researches show that the linear pyranocoumarin-earth licorice A is separated and identified from the two-Yue pterocarpus santalinus stems with the functions of resisting tumor, androgen, bacteria, inflammation, oxidization and the like, and experiments show that the pyranocoumarin-earth licorice A has the activities of resisting oxidization, tumor and the like, but the extraction yield is lower, the process is complex, the further application of the pyranocoumarin-earth licorice A cannot be limited because of the requirement of the research, so that the preparation method of the pyranocoumarin derivative is designed, and the pyranocoumarin-earth licorice A is worthy of a profound effect in obtaining the antitumor activity similar to the pyranocoumarin-earth licorice A, but the pyranocoumarin derivative has a simple process and a novel structure.
Disclosure of Invention
It is an object of the present invention to solve at least the above problems and to provide at least the advantages to be described later.
To achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided a 3-aryl-7, 8-pyranocoumarin derivative having the structure of formula I:
when R is 4 、R 6 、R 1 、R 3 When hydrogen, R 2 Is any one of methoxy, methyl, fluorine and chlorine; or alternatively, the first and second heat exchangers may be,
when R is 4 、R 6 Is methyl, R 1 、R 3 When hydrogen, R 2 Is any one of methoxy, methyl and hydroxyl; or alternatively, the first and second heat exchangers may be,
when R is 4 、R 6 Is methyl, R 3 When hydrogen, R 1 、R 2 Is methylenedioxy; or alternatively, the first and second heat exchangers may be,
when R is 1 Is chlorine, R 2 Is hydrogen, R 3 When fluorine is used, R 4 、R 6 Is either methyl or hydrogen.
Provided is a method for preparing a 3-aryl-7, 8-pyranocoumarin derivative, comprising the following steps:
step one, mixing phenylacetic acid substitutes and acetic anhydride, heating to 80-100 ℃, adding triethylamine, continuously heating to 100-135 ℃, adding 2, 4-dimethylol benzaldehyde, heating to 145-160 ℃, stirring for reaction, and separating and purifying to obtain a 3-phenylcoumarin derivative after the reaction is finished;
mixing a 3-phenylcoumarin derivative with acetonitrile, heating to 45-56 ℃ for dissolution, adding potassium tert-butoxide, potassium iodide and tetrabutylammonium bromide, adding acetylide in the environment of 0-5 ℃, heating to 60-70 ℃ for reflux stirring reaction, and separating after the reaction is finished to obtain propargyl ether compounds;
and step three, mixing the propargyl ether compound with diphenyl ether, carrying out reflux stirring reaction, and after the reaction is finished, reducing the temperature to below 50 ℃, and separating and purifying to obtain the target compound I.
Preferably, the phenylacetic acid substituent in the first step is any one of 4-methoxyphenylacetic acid, 4-methylphenylacetic acid, 4-fluorophenylacetic acid, 4-chlorophenylacetic acid, 4-hydroxyphenylacetic acid, 3, 4-methylenedioxyphenylacetic acid, 3-chloro, 5-fluorophenylacetic acid.
Preferably, the acetylide in step two is bromopropyne or 3-chloro-3-methyl-butyne.
Preferably, the organic solvent in the third step is one of ethyl acetate, carbon tetrachloride, chloroform and petroleum ether.
Preferably, the molar ratio of the phenylacetic acid substituent to the acetic anhydride to the triethylamine to the 2, 4-dimethylhydroxybenzaldehyde in the first step is 1:3-5:1-2:1-2, and the specific operation of separation and purification is as follows: and standing the reacted solution until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, and recrystallizing in acetonitrile to obtain the 3-phenylcoumarin derivative.
Preferably, the molar ratio of the 3-phenylcoumarin derivative, the potassium tert-butoxide, the potassium iodide, the tetrabutylammonium bromide and the acetylide in the second step is 1:1-2:0.1-0.3:0.1-0.3:1-2, the reaction time of the reflux stirring reaction is 4-6 h, and the separation specific operation is as follows: filtering, taking filtrate and spin-drying to obtain propargyl ether compounds.
Preferably, the molar ratio of the propargyl ether compound to the diphenyl ether in the third step is 1:1-2, the reaction temperature of the reflux stirring reaction is 180-210 ℃, the reaction time is 2-3 h, and the separation and purification specific operation is as follows: extracting with organic solvent, collecting organic phase layer, drying, filtering, concentrating filtrate to obtain mixture, and separating and purifying by column chromatography to obtain target compound I.
An antitumor drug is provided, comprising the 3-aryl-7, 8-pyranocoumarin derivative.
Provides an application of 3-aryl-7, 8-pyranocoumarin derivative in preparing antitumor drugs.
The invention at least comprises the following beneficial effects:
the first, the invention provides a 3-aryl-7, 8-pyranocoumarin derivative and a preparation method thereof, wherein the 3-aryl-7, 8-pyranocoumarin derivative has novel structure, and the preparation method has high yield, wide substrate applicability, simple and convenient operation, few byproducts, convenient separation and purification, suitability for large-scale preparation and considerable application prospect.
The second, the 3-aryl-7, 8-pyranocoumarin derivative provided by the invention has excellent anti-tumor activity, wherein,
has better proliferation inhibition effect on liver cancer cell line HepG20 in vitro, and the IC50 value reaches 4.41+/-0.18 mu m; />Has better proliferation inhibition effect on leukemia cell line HL-60 in vitro, and the IC50 value reaches 13.83+/-0.60 mu m.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a synthetic scheme showing the preparation method of the 3-aryl-7, 8-pyranocoumarin derivative of the present invention.
Detailed Description
The present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
The experimental methods described in the following embodiments are conventional methods unless otherwise indicated, and the reagents and materials are commercially available.
Example 1 ]
Step one, mixing 1mmol of 4-methoxyphenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylhydroxybenzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative a:
step two, heating 4mmol of the 3-phenylcoumarin derivative a in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1a:
step three, mixing the propargyl ether compound 1a in the step 4mmol and 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain a compound 2a, namely 3- (4' -methoxyphenyl) -2"H-7, 8-pyranocoumarin:
yield: 30%, compound 2a was a white solid, and compound 2a gave a melting point of: 120.3-121.2 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+H)] + ) Calculated value C 19 H 14 O 4 : 307.0892, found 307.0893; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.62(s,1H,H-4),7.59(d,J＝7.2Hz,2H,H-2′,6′),7.28(d,J＝7.9Hz,1H,H-5),7.19 (d,J＝7.1Hz,2H,H-3′,5′),7.02(d,J＝9.9Hz,1H,4″),6.83(d,J＝8.5Hz,1H,H-6),5.89(d,J＝7.9Hz,1H,H-3″),4.94(s,2H,H-2″),3.85(s,3H,4′-OCH 3 )。
example 2 ]
Step one, mixing 1mmol of 4-methoxyphenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylhydroxybenzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative a:
step two, heating 4mmol of the 3-phenylcoumarin derivative a in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1b:
step three, mixing the propargyl ether compound 1b in the step 4mmol and 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting a silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain a compound 2b, namely 2 ', 2 ' -dimethyl-3- (4 ' -methoxyphenyl) -7, 8-pyranocoumarin:
yield: 35, compound 2b was a white solid, and compound 2b had a melting point of: 138.0-139.4 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+H)] + ) Calculated value C 21 H 18 O 4 : 335.1278, found 335.1276; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(400MHz, CDCl 3 )δ7.69(s,1H,H-4),7.69-7.64(m,2H,H-2′,6′),7.28(d,J＝6.8Hz,1H,H-5),7.02-6.91 (m,3H,H-6,3′,5′),6.76(dd,J＝8.4,0.5Hz,1H,H-4″),5.76(d,J＝10.0Hz,1H,H-3″),3.87(s, 3H,4′-OCH 3 ),1.51(s,6H,2″-2×CH 3 )。
example 3 ]
Step one, mixing 1mmol of 4-methylphenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylol benzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative c:
step two, 4mmol of the 3-phenylcoumarin derivative a and 60mL of acetonitrile in the step one, heating to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1c:
step three, mixing the propargyl ether compound 1c in the step 4mmol and 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain the compound 2c, namely 3- (4' -methylphenyl) -2"H-7, 8-pyranocoumarin:
yield: compound 2c was a white solid and compound 2c gave a melting point by melting point determination experiments of: 175.2-176.6 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+H)] + ) Calculated value C 19 H 14 O 3 :291.1016, found 291.1021; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.69(s,1H,H-4),7.58(d,J＝7.3Hz,2H,H-3′,5′),7.26(s,3H,H-2′,6′,5),7.02(d,J ＝9.9Hz,1H,H-4″),6.73(d,J＝8.4Hz,1H,H-6),5.88(d,J＝7.9Hz,1H,H-3″),4.95(s,2H, H-2″),2.40(s,3H,4′-CH 3 )。
example 4 ]
Step one, mixing 1mmol of 4-methylphenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylol benzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative c:
step two, heating 4mmol of the 3-phenylcoumarin derivative c in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1d:
step three, mixing 4mmol of propargyl ether compound 1d in the step one with 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting a silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain a compound 2d, namely 2 ', 2 ' -dimethyl-3- (4 ' -methylphenyl) -7, 8-pyranocoumarin:
yield: 35%, compound 2d was a white solid, and compound 2d had a melting point of: 132.2-133.3 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+H)] + ) Calculated value C 21 H 18 O 3 : 319.3720, found 319.3721; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3) δ7.70(s,1H,H-4),7.58(d,J＝7.5Hz,2H,H-3′,5′),7.25(d,J＝9.0Hz,3H,H-4″,2′, 6′),6.94(d,J＝10.0Hz,1H,H-6),6.74(d,J＝8.4Hz,1H,H-4″),5.74(d,J＝9.9Hz,1H,H-3″), 2.39(s,3H,4′-CH 3 ),1.49(s,6H,2″-2×CH 3 )。
example 5 ]
Step one, mixing 1mmol of 4-fluorophenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylol benzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative e:
step two, heating 4mmol of the 3-phenylcoumarin derivative e in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1e:
step three, mixing the propargyl ether compound 1e in the step 4mmol and 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain a compound 2e, namely 3- (4' -fluorophenyl) -2"H-7, 8-pyranocoumarin:
yield: compound 2e was a white solid, compound 2e had a melting point of: 196.0-197.2 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+Na)] + ) Calculated value C 18 H 11 FO 3 : 317.0584, found 317.0589; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.68(s,1H,H-4),7.60(d,J＝7.5Hz,2H,H-2′,6′),7.30(d,J＝7.9Hz,1H,H-5),7.23 (d,J＝7.3Hz,2H,H-3′,5′),7.05(d,J＝9.8Hz,1H,4″),6.86(d,J＝8.4Hz,1H,H-6),5.88(d,J＝7.8Hz,1H,H-3″),4.96(s,2H,H-2″)。
example 6 ]
Step one, mixing 1mmol of 4-fluorophenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylol benzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative f:
step two, 4mmol of the 3-phenylcoumarin derivative f and 60mL of acetonitrile in the step one are heated to 56 ℃ to be dissolved, 4mmol of potassium tert-butoxide and 0.4mmol of tetrabutylammonium bromide are added, 4mmol of bromopropyne are added in an environment of 0 ℃, then the temperature is raised to 64 ℃, the mixture is stirred and refluxed for 6 hours at 64 ℃, and the mixture is filtered, and dried by spinning to obtain propargyl ether compounds 1f:
step three, mixing the propargyl ether compound 1f in the step 4mmol and 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain the compound 2f, namely 3- (4' -chlorophenyl) -2"H-7, 8-pyranocoumarin:
yield: 33, compound 2f was a white solid, compound 2f had a melting point of: 156.1-157.2 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+Na)] + ) Calculated value C 18 H 11 ClO 3 : 349.0602, found 349.0608; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.60(s,1H,H-4),7.56(d,J＝7.6Hz,2H,H-2′,6′),7.31(d,J＝7.9Hz,1H,H-5),7.20 (d,J＝7.5Hz,2H,H-3′,5′),6.98(d,J＝9.6Hz,1H,H-4″),6.84(d,J＝8.0Hz,1H,H-6),5.86(d,J＝7.6Hz,1H,H-3″),4.93(s,2H,H-2″)。
example 7 ]
Step one, mixing 1mmol of 4-hydroxyphenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylhydroxybenzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative g:
step two, heating 4mmol of the 3-phenylcoumarin derivative g in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1g:
step three, mixing 1g of propargyl ether compound in the step two with 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting a silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain 2g of compound, namely 2 ', 2 ' -dimethyl-3- (4 ' -hydroxyphenyl) -7, 8-pyranocoumarin:
yield: 31%, compound 2g was a white solid, and compound 2g gave a melting point by melting point determination experiments: 166.0-167.3 deg.c; by high resolutionElectrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+Na)] + ) Calculated value C 20 H 16 O 4 : 343.0941, found 343.0939; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(400MHz, CDCl 3 )δ7.85-7.63(m,3H,H-4,2′,6′),7.40-7.24(m,2H,H-6,4″),7.24-7.11(m,1H,H-5), 6.95(d,J＝10.0Hz,1H,H-5′),6.77(d,J＝8.5Hz,1H,H-3′),5.77(d,J＝10.0Hz,1H,H-3″),1.51 (s,6H,2″-2×CH 3 )。
example 8 ]
Step one, mixing 1mmol of 3, 4-methylenedioxyphenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylhydroxybenzaldehyde, heating to 160 ℃, stirring to the end of the reaction, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative h:
step two, heating 4mmol of the 3-phenylcoumarin derivative h and 60mL of acetonitrile in the step one to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1h:
step three, mixing 4mmol of propargyl ether compound 1h and 4mmol of diphenyl ether in the step one, stirring and refluxing at 200 ℃ for reaction for 3h, extracting with ethyl acetate after the reaction is finished, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting a silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain a compound 2h, namely 2 ', 2' -dimethyl-3- (3 ',4' -methylenedioxyphenyl) -7, 8-pyranocoumarin:
yield: 32%, compound 2h was a white solid, and compound 2h gave a melting point by melting point determination experiments: 170.3-171.7 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+Na)] + ) Calculated value C 21 H 16 O 5 : 371.1041, found 371.0999; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.58(s,1H,H-4),7.16(d,J＝16.9Hz,2H,H-2′,5′),7.08(d,J＝8.0Hz,1H,H-5), 6.94(d,J＝10.4Hz,1H,H-6′),6.81(d,J＝8.0Hz,1H,H-6),6.66(d,J＝8.2Hz,1H,H-4),5.94(s,2H,H-7′),5.81(d,J＝7.6Hz,1H,H-3″),1.50(s,6H,2″-2×CH 3 )。
example 9 ]
Step one, mixing 1mmol of 3-chlorine, 5-fluorophenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylhydroxybenzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative i:
step two, heating 4mmol of the 3-phenylcoumarin derivative i in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1i:
step three, mixing 4mmol of propargyl ether compound 1i in the step one with 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished and the temperature is reduced to below 50 ℃, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain compound 2i, namely 3- (3 '-chloro-5' -fluorophenyl) -2"H-7, 8-pyranocoumarin:
yield: compound 2i was a white solid and compound 2i gave a melting point by a melting point determination experiment of: 150.4-151.3 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+Na)] + ) Calculated value C 20 H 15 ClFO 3 : 351.0303, found 351.0304; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.68(s,1H,H-4),7.41(t,J＝7.2Hz,1H,H-4′),7.28(dd,J＝11.0,8.7Hz,2H,H-2′, 6′),7.10(t,J＝8.4Hz,1H,H-5),6.70(d,J＝9.4Hz,1H,H-6),6.81(d,J＝8.4Hz,1H,H-4″), 5.69(d,J＝10.2Hz,1H,H-3″),4.98(s,2H,H-2″)。
example 10 ]
Step one, mixing 1mmol of 3-chlorine, 5-fluorophenylacetic acid and 5mmol of acetic anhydride, heating to 100 ℃, adding 1.2mmol of triethylamine, continuously heating to 135 ℃, adding 1mmol of 2, 4-dimethylhydroxybenzaldehyde, heating to 160 ℃, stirring until the reaction is finished, standing until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, recrystallizing in acetonitrile to obtain crystals, and carrying out suction filtration to obtain the 3-phenylcoumarin derivative i:
step two, heating 4mmol of the 3-phenylcoumarin derivative i in the step one and 60mL of acetonitrile to 56 ℃ for dissolution, adding 4mmol of potassium tert-butoxide, 0.4mmol of potassium iodide and 0.4mmol of tetrabutylammonium bromide, adding 4mmol of bromopropyne in an environment of 0 ℃, heating to 64 ℃, stirring and refluxing at 64 ℃ for reaction for 6 hours, filtering, taking filtrate and spin-drying to obtain propargyl ether compounds 1j:
step three, mixing the propargyl ether compound 1j in the step 4mmol and 4mmol of diphenyl ether, stirring and refluxing at 200 ℃ for 3 hours, extracting with ethyl acetate after the reaction is finished, taking an upper organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by reduced pressure distillation to obtain a mixture, and separating and purifying the mixture by adopting a silica gel column chromatography with the volume ratio of petroleum ether to ethyl acetate of 8:1 to obtain a compound 2j, namely 2 ', 2' -dimethyl-3- (3 '-chloro-5' -fluorophenyl) -7, 8-pyranocoumarin:
yield: compound 2j was a yellow solid and compound 2j had a melting point of: 210.5-211.8 ℃; by high resolution electrospray ionization mass spectrometry (HRMS-ESI: M/z [ M+ N a)] + ) Calculated value C 20 H 15 ClFO 3 : 357.068, found 357.0692; characterization data of hydrogen spectra measured by nuclear magnetic resonance are: 1 H NMR(500MHz, CDCl 3 )δ7.64(s,1H,H-4),7.39(t,J＝7.0Hz,1H,H-4′),7.25(dd,J＝11.4,8.9Hz,2H,H-2′, 6′),7.06(t,J＝8.2Hz,1H,H-5),6.93(d,J＝9.9Hz,1H,H-6),6.77(d,J＝8.3Hz,1H,H-4″), 5.76(d,J＝10.0Hz,1H,H-3″),1.50(s,6H,2″-2×CH 3 )。
< in vitro anti-tumor Activity experiment >
The antitumor activity of compounds 2a to 2j was studied using the MTS method:
inoculating cells: single cell suspensions were prepared with 10wt% fetal bovine serum in culture (DMEM or RMP 11640) and seeded into 96-well plates at 15000 cells per well, 100. Mu.L per well volume, and 24h in advance.
Adding solutions of compounds 2 a-2 j to be tested: the compounds 2 a-2 j are respectively dissolved by DMSO to obtain solutions of the compounds 2 a-2 j to be tested, 40 mu M of the solutions of the compounds 2 a-2 j to be tested are used for respectively carrying out preliminary screening on leukemia cells HL-60, liver cancer cells HepG2, cervical cancer cells HeLa, breast cancer cells MCF-7 and human normal liver cells LO2, the final volume of each hole is 200 mu L, and 3 compound holes are arranged in each treatment.
Color development: after 48h of culture at 37 ℃, the adherent cells pour the culture solution in the wells, and then 20 mu L of MTS solution and 100 mu L of culture solution are added into each well; 100. Mu.L of culture supernatant was removed from the suspension cells and 20. Mu.L of MTS solution was added to each well; 3 blank wells were set, i.e., 20. Mu.L MTS solution and 100. Mu.L culture medium were added to each well and incubated for 4h.
Colorimetric: after full color development, 492nm wavelength is selected, the light absorption value of each hole is read in a multifunctional enzyme-labeling instrument, the result is recorded, and the IC is obtained after calculation 50 The value results are set forth in table 1:
table 13 IC of aryl-7, 8-pyranocoumarin derivatives against different tumor cell lines 50 Value of
| Compounds of formula (I) | Leukemia HL-60 | Liver cancer HepG2 | Cervical cancer HeLa | Mammary glandCancer MCF-7 |
| 2a | ＞100 | ＞100 | 70.84±2.19 | 52.56±2.31 |
| 2b | 49.18±1.15 | 98.57±1.46 | ＞100 | 54.11±2.62 |
| 2c | ＞100 | ＞100 | 73.03±2.65 | 72.93±0.93 |
| 2d | 53.08±1.56 | 66.31±0.87 | 22.68±1.68 | ＞100 |
| 2e | ＞100 | 4.41±0.18 | 18.24±0.26 | 25.85±1.59 |
| 2f | 82.59±2.27 | ＞100 | ＞100 | 64.62±2.90 |
| 2g | 13.83±0.60 | 76.57±1.37 | 19.26±0.76 | 45.74±2.65 |
| 2h | 46.18±0.95 | 59.70±1.06 | 40.45±0.63 | ＞100 |
| 2i | ＞100 | ＞100 | 46.38±0.74 | 59.12±1.53 |
| 2j | ＞100 | ＞100 | ＞100 | ＞100 |
The 3-aryl-7, 8-pyranocoumarin derivative provided by the invention is subjected to in vitro anti-tumor experiments to obtain the data in table 1, and it can be seen that the 3-aryl-7, 8-pyranocoumarin derivative has certain anti-tumor activity on leukemia cell line HL-60, lung cancer cell line HepG2, cervical cancer cell line HeLa and breast cancer cell line MCF-7, wherein the compound 2e has good in vitro proliferation inhibition IC50 value on liver cancer cell line HepG2 reaching 4.41+/-0.18 mu m.
Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown, it is well suited to various fields of use for which the invention is suited, and further modifications may be readily made by one skilled in the art, and the invention is therefore not to be limited to the particular details and examples shown and described herein, without departing from the general concepts defined by the claims and the equivalents thereof.
Claims (10)
- The 3-aryl-7, 8-pyranocoumarin derivative is characterized by having a structure shown in a general formula I:general formula I;when R is 4 、R 6 、R 1 、R 3 When hydrogen, R 2 Is any one of methoxy, methyl, fluorine and chlorine; or alternatively, the first and second heat exchangers may be,when R is 4 、R 6 Is methyl, R 1 、R 3 When hydrogen, R 2 Is methyl; or alternatively, the first and second heat exchangers may be,when R is 1 Is chlorine, R 2 Is hydrogen, R 3 When fluorine is used, R 4 、R 6 Is either methyl or hydrogen.
- 2. The process for the preparation of 3-aryl-7, 8-pyranocoumarin derivatives according to claim 1, characterized by comprising the steps of:step one, mixing phenylacetic acid substitutes and acetic anhydride, heating to 80-100 ℃, adding triethylamine, continuously heating to 100-135 ℃, adding 2, 4-dimethylol benzaldehyde, heating to 145-160 ℃, stirring for reaction, and separating and purifying to obtain a 3-phenylcoumarin derivative after the reaction is finished;mixing a 3-phenylcoumarin derivative and acetonitrile, heating to 45-56 ℃ for dissolution, adding potassium tert-butoxide, potassium iodide and tetrabutylammonium bromide, adding acetylide in an environment of 0-5 ℃, heating to 60-70 ℃ for reflux stirring reaction, and separating after the reaction is finished to obtain propargyl ether compounds;and step three, mixing the propargyl ether compound with diphenyl ether, carrying out reflux stirring reaction, and after the reaction is finished, reducing the temperature to below 50 ℃, and separating and purifying to obtain the target compound I.
- 3. The process for producing a 3-aryl-7, 8-pyranocoumarin derivative according to claim 2, wherein said phenylacetic acid substituent in step one is any one of 4-methoxyphenylacetic acid, 4-methylphenylacetic acid, 4-fluorophenylacetic acid, 4-chlorophenylacetic acid, 4-hydroxyphenylacetic acid, 3, 4-methylenedioxyphenylacetic acid, 3-chloro, 5-fluorophenylacetic acid.
- 4. The process for the preparation of 3-aryl-7, 8-pyranocoumarin derivatives according to claim 2, wherein the acetylide in step two is bromopropyne or 3-chloro-3-methyl-butyne.
- 5. The method for preparing 3-aryl-7, 8-pyranocoumarin derivative according to claim 2, wherein the organic solvent in step three is one of ethyl acetate, carbon tetrachloride, chloroform and petroleum ether.
- 6. The method for preparing the 3-aryl-7, 8-pyranocoumarin derivative according to claim 2, wherein the molar ratio of phenylacetic acid substituent, acetic anhydride, triethylamine and 2, 4-dimethylhydroxybenzaldehyde in the first step is 1:3-5:1-2:1-2, and the specific separation and purification operations are as follows: and standing the reacted solution until the solid is completely separated out, filtering, washing the solid with water and ethyl acetate in sequence until the solid is light yellow, and recrystallizing in acetonitrile to obtain the 3-phenylcoumarin derivative.
- 7. The method for preparing the 3-aryl-7, 8-pyranocoumarin derivative according to claim 2, wherein the molar ratio of the 3-phenylcoumarin derivative, potassium tert-butoxide, potassium iodide, tetrabutylammonium bromide and acetylide in the second step is 1:1-2:0.1-0.3:0.1-0.3:1-2, the reaction time of the reflux stirring reaction is 4-6 h, and the separation specific operation is as follows: filtering, taking filtrate and spin-drying to obtain propargyl ether compounds.
- 8. The method for preparing 3-aryl-7, 8-pyranocoumarin derivative according to claim 2, wherein the molar ratio of propargyl ether compound to diphenyl ether in step three is 1:1-2, the reaction temperature of reflux stirring reaction is 180-210 ℃, the reaction time is 2-3 h, and the specific separation and purification operations are as follows: extracting with organic solvent, collecting organic phase layer, drying, filtering, concentrating filtrate to obtain mixture, and separating and purifying by column chromatography to obtain target compound I.
- 9. An antitumor agent comprising the 3-aryl-7, 8-pyranocoumarin derivative according to claim 1.
- 10. Use of a 3-aryl-7, 8-pyranocoumarin derivative according to claim 1 for the preparation of an antitumor drug.
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| Liu, JW.A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranoc -oumarin as a Selective Inibitor of Human Cytochrome P450 1A2.Journal of Medicinal Chemistry.2015,第58卷(第16期),第6481-6493页. * |
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