CN105622574B - 3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application - Google Patents
3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application Download PDFInfo
- Publication number
- CN105622574B CN105622574B CN201610078898.3A CN201610078898A CN105622574B CN 105622574 B CN105622574 B CN 105622574B CN 201610078898 A CN201610078898 A CN 201610078898A CN 105622574 B CN105622574 B CN 105622574B
- Authority
- CN
- China
- Prior art keywords
- compound
- quinolinone
- preparation
- reaction
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- -1 methoxyl group Chemical group 0.000 claims abstract description 24
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 21
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 111
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 abstract description 13
- 229960002949 fluorouracil Drugs 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 11
- 231100000419 toxicity Toxicity 0.000 abstract description 8
- 230000001988 toxicity Effects 0.000 abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 150000002431 hydrogen Chemical class 0.000 abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 abstract description 3
- 239000011737 fluorine Substances 0.000 abstract description 3
- 229910052697 platinum Inorganic materials 0.000 abstract description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 3
- 150000004987 o-phenylenediamines Chemical class 0.000 abstract description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract 1
- 210000004185 liver Anatomy 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 107
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 238000012360 testing method Methods 0.000 description 28
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- 238000001514 detection method Methods 0.000 description 24
- 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 18
- 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 15
- 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 15
- 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 15
- 239000000047 product Substances 0.000 description 11
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 10
- 229960004316 cisplatin Drugs 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 210000005229 liver cell Anatomy 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 4
- NVKJOXRVEKMMHS-UHFFFAOYSA-N 5-nitro-1,2,4-triazol-3-one Chemical compound [O-][N+](=O)C1=NC(=O)N=N1 NVKJOXRVEKMMHS-UHFFFAOYSA-N 0.000 description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- CQARNQGPINVKMX-UHFFFAOYSA-N 9h-[1,3]dioxolo[4,5-h]quinolin-8-one Chemical compound C1=C2OCOC2=C2NC(=O)C=CC2=C1 CQARNQGPINVKMX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- DLUPXHPRWLKDHH-UHFFFAOYSA-N 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound Cc1cc2nc([nH]c2cc1C)-c1cc2ccccc2[nH]c1=O DLUPXHPRWLKDHH-UHFFFAOYSA-N 0.000 description 2
- HAVFFLLRAIEYMB-UHFFFAOYSA-N 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-methoxy-1H-quinolin-2-one Chemical compound CC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)OC)=O)C=C1C HAVFFLLRAIEYMB-UHFFFAOYSA-N 0.000 description 2
- IQRAXXWTUBRQQW-UHFFFAOYSA-N 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-methyl-1H-quinolin-2-one Chemical compound CC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)C)=O)C=C1C IQRAXXWTUBRQQW-UHFFFAOYSA-N 0.000 description 2
- VOECVANYCBHRHG-UHFFFAOYSA-N 3-(6-bromo-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound BrC1=CC2=C(NC(=N2)C=2C(NC3=CC=CC=C3C=2)=O)C=C1 VOECVANYCBHRHG-UHFFFAOYSA-N 0.000 description 2
- WYEYAIOOXUQKPH-UHFFFAOYSA-N 3-(6-bromo-1H-benzimidazol-2-yl)-6-methoxy-1H-quinolin-2-one Chemical compound BrC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)OC)=O)C=C1 WYEYAIOOXUQKPH-UHFFFAOYSA-N 0.000 description 2
- NBCZLJJKAATXFF-UHFFFAOYSA-N 3-(6-bromo-1H-benzimidazol-2-yl)-6-methyl-1H-quinolin-2-one Chemical compound BrC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)C)=O)C=C1 NBCZLJJKAATXFF-UHFFFAOYSA-N 0.000 description 2
- DXOHCQPYGGDAGK-UHFFFAOYSA-N 3-(6-chloro-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound ClC1=CC2=C(NC(=N2)C=2C(NC3=CC=CC=C3C=2)=O)C=C1 DXOHCQPYGGDAGK-UHFFFAOYSA-N 0.000 description 2
- BFPGXSRKBRGGFS-UHFFFAOYSA-N 3-(6-chloro-1H-benzimidazol-2-yl)-6-methoxy-1H-quinolin-2-one Chemical compound ClC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)OC)=O)C=C1 BFPGXSRKBRGGFS-UHFFFAOYSA-N 0.000 description 2
- ZHRKACWENXXEIZ-UHFFFAOYSA-N 3-(6-chloro-1H-benzimidazol-2-yl)-6-methyl-1H-quinolin-2-one Chemical compound ClC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)C)=O)C=C1 ZHRKACWENXXEIZ-UHFFFAOYSA-N 0.000 description 2
- KFCRELHNXJIWMY-UHFFFAOYSA-N 3-(6-fluoro-1H-benzimidazol-2-yl)-6-methoxy-1H-quinolin-2-one Chemical compound FC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)OC)=O)C=C1 KFCRELHNXJIWMY-UHFFFAOYSA-N 0.000 description 2
- WRWRQCPXJPMHHX-UHFFFAOYSA-N 3-(6-fluoro-1H-benzimidazol-2-yl)-6-methyl-1H-quinolin-2-one Chemical compound FC1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)C)=O)C=C1 WRWRQCPXJPMHHX-UHFFFAOYSA-N 0.000 description 2
- KQONSQGSHCEZDQ-UHFFFAOYSA-N 3-(6-nitro-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound [N+](=O)([O-])C1=CC2=C(NC(=N2)C=2C(NC3=CC=CC=C3C=2)=O)C=C1 KQONSQGSHCEZDQ-UHFFFAOYSA-N 0.000 description 2
- RYWOXJCRZULBTL-UHFFFAOYSA-N 6-methoxy-3-(6-nitro-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound [N+](=O)([O-])C1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)OC)=O)C=C1 RYWOXJCRZULBTL-UHFFFAOYSA-N 0.000 description 2
- BIEAGGCDGUHTAM-UHFFFAOYSA-N 6-methyl-3-(6-nitro-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound [N+](=O)([O-])C1=CC2=C(NC(=N2)C=2C(NC3=CC=C(C=C3C=2)C)=O)C=C1 BIEAGGCDGUHTAM-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- NCSGPOWDKZUREZ-UHFFFAOYSA-N 1-methoxyquinolin-2-one Chemical compound C1=CC=C2C=CC(=O)N(OC)C2=C1 NCSGPOWDKZUREZ-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- KRAPWXIKIAHKAM-UHFFFAOYSA-N 3-(6-fluoro-1H-benzimidazol-2-yl)-1H-quinolin-2-one Chemical compound Fc1ccc2[nH]c(nc2c1)-c1cc2ccccc2[nH]c1=O KRAPWXIKIAHKAM-UHFFFAOYSA-N 0.000 description 1
- IWFHBRFJOHTIPU-UHFFFAOYSA-N 4,5-dichlorobenzene-1,2-diamine Chemical compound NC1=CC(Cl)=C(Cl)C=C1N IWFHBRFJOHTIPU-UHFFFAOYSA-N 0.000 description 1
- SKIUVOVOIJBJPN-UHFFFAOYSA-N 4,5-dimethoxybenzene-1,2-diamine Chemical compound COC1=CC(N)=C(N)C=C1OC SKIUVOVOIJBJPN-UHFFFAOYSA-N 0.000 description 1
- XSZYBMMYQCYIPC-UHFFFAOYSA-N 4,5-dimethyl-1,2-phenylenediamine Chemical compound CC1=CC(N)=C(N)C=C1C XSZYBMMYQCYIPC-UHFFFAOYSA-N 0.000 description 1
- RQWJHUJJBYMJMN-UHFFFAOYSA-N 4-(trifluoromethyl)benzene-1,2-diamine Chemical compound NC1=CC=C(C(F)(F)F)C=C1N RQWJHUJJBYMJMN-UHFFFAOYSA-N 0.000 description 1
- BXIXXXYDDJVHDL-UHFFFAOYSA-N 4-Chloro-ortho-phenylenediamine Chemical compound NC1=CC=C(Cl)C=C1N BXIXXXYDDJVHDL-UHFFFAOYSA-N 0.000 description 1
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 description 1
- KWEWNOOZQVJONF-UHFFFAOYSA-N 4-fluorobenzene-1,2-diamine Chemical compound NC1=CC=C(F)C=C1N KWEWNOOZQVJONF-UHFFFAOYSA-N 0.000 description 1
- RAUWPNXIALNKQM-UHFFFAOYSA-N 4-nitro-1,2-phenylenediamine Chemical compound NC1=CC=C([N+]([O-])=O)C=C1N RAUWPNXIALNKQM-UHFFFAOYSA-N 0.000 description 1
- ZDSUKNAKOLBIPX-UHFFFAOYSA-N 6-fluoro-1h-benzimidazole Chemical compound FC1=CC=C2N=CNC2=C1 ZDSUKNAKOLBIPX-UHFFFAOYSA-N 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 230000010718 Oxidation Activity Effects 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- XVAIDCNLVLTVFM-UHFFFAOYSA-N methacetin Chemical compound COC1=CC=C(NC(C)=O)C=C1 XVAIDCNLVLTVFM-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- CGLCDOZYDURWIG-UHFFFAOYSA-N n-(1,3-benzodioxol-5-yl)acetamide Chemical compound CC(=O)NC1=CC=C2OCOC2=C1 CGLCDOZYDURWIG-UHFFFAOYSA-N 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of 3- benzimidazolyl-2 radicals (1H)-qualone derivatives and its preparation method and application.The derivative the preparation method comprises the following steps: 2 (1H)-qualone derivatives and O-phenylene diamine derivatives is taken to be dissolved in organic solvent, reacted under heating condition to get.Compared with common anti-tumor drug 5-FU and cis-platinum, the activity of certain derivatives in derivative of the present invention is more efficient, lower to people's normal cell lines of human liver HL-7702 toxicity.3- benzimidazolyl-2 radicals (1H)-qualone derivative of the present invention has the structure as shown in following formula (I):Wherein, R1For hydrogen, methyl, methoxyl group or and R2Form 1,2- methylene-dioxy；R2For hydrogen or and R1Form 1,2- methylene-dioxy；R3For hydrogen, methyl, methoxyl group, fluorine-based, chloro, bromo, nitro or trifluoromethyl；R4For hydrogen, methyl, methoxyl group or chloro.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a 3-benzimidazole-2 (1H) -quinolinone derivative, and a preparation method and application thereof.
Background
Malignant tumor, also called cancer, is one of the stubborn diseases that seriously endanger people's life in the world. It is reported that about 700 million people die from cancer every year in the world, and about 150 million people die from cancer every year in China. Meanwhile, the research and development of novel antitumor drugs are highly concerned by people due to the defects of large toxic and side effects, strong drug resistance and the like of the antitumor drugs.
It has been shown that antioxidants with excellent activity are candidate compounds for antitumor drugs (Tyagi, Y.K.; Kumar, A.; Raj, H.G.; Vohra, P.; Gupta, G.; Kumar, R.; Kumar, P.; Gupta, R.K. Eur.J. Med. chem.2005,40,413.). In our earlier studies it was found that 3-schiff base-2 (1H) -quinolinone derivatives have good oxidation activity (Zhang, y.; Fang, y.l.; Liang, H.; Wang, h.s.; Hu, k.; Liu, x.x.; Yi, x.h.; Peng, y.bioorg.med.chem.2013,23,107.). In addition, studies have shown that 2(1H) -quinolinone derivatives have biological activities such as anti-cancer, anti-oxidation, anti-inflammatory, etc. (deraiter, j.brubaker, a.n.; Whitmer, w.l.; Stein, j.l.; j.med.chem.1986,29,2024.; Zhang, y.; Fang, y.l.; Liang, H.; Wang, h.s.; Hu, k.; Liu, x.x.; Yi, x.h.; pen, y.bioorg.med.chem.2013,23,107.; hewasam, p.; Fan, w.; Knipe, j.; Moon, l.s.; boisard, g.c.; gribsoff, k.v.; Starett e.j.bioorg. 12,1779). However, no published report exists for preparing 2(1H) -quinolinone derivatives by introducing functional group benzimidazole at the 3-position of 2(1H) -quinolinone.
Disclosure of Invention
The invention aims to provide a series of 3-benzimidazole-2 (1H) -quinolinone derivatives with novel structures, and a preparation method and application thereof.
The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
R1is hydrogen (H), methyl (CH)3) Methoxy (OCH)3) Or is with R2Formation of 1, 2-methylenedioxy (CH)2-O-CH2)；
R2Is hydrogen (H) or is with R1Formation of 1, 2-methylenedioxy (CH)2-O-CH2)；
R3Is hydrogen (H), methyl (CH)3) Methoxy (OCH)3) Fluorine (F), chlorine (Cl), bromine (Br), Nitro (NO)2) Or trifluoromethyl (CF)3)；
R4Is hydrogen (H), methyl (CH)3) Methoxy (OCH)3) Or a chlorine group (Cl).
The preparation method of the compound shown in the formula (I) comprises the following steps: dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent, and reacting under a heating condition to obtain a target product;
wherein,
R1is hydrogen (H), methyl (CH)3) Methoxy (OCH)3) Or is with R2Formation of 1, 2-methylenedioxy (CH)2-O-CH2)；
R2Is hydrogen (H) or is with R1Formation of 1, 2-methylenedioxy (CH)2-O-CH2)；
R3Is hydrogen (H), methyl (CH)3) Methoxy (OCH)3) Fluorine (F), chlorine (Cl), bromine (Br), Nitro (NO)2) Or trifluoromethyl (CF)3)；
R4Is hydrogen (H), methyl (CH)3) Methoxy (OCH)3) Or a chlorine group (Cl).
In the production method of the present invention, the ratio of the amounts of the substance of the compound represented by the formula (II) and the compound represented by the formula (III) is preferably 1: 0.9 to 1.1. When the amount of the compound represented by the formula (III) exceeds the above range, the reaction may also produce the desired product, but the subsequent separation may be difficult and the desired product may be reduced.
In the preparation method of the invention, the compound shown in the formula (II) can be 3-formaldehyde-2 (1H) -quinolinone, 3-formaldehyde-6-methyl-2 (1H) -quinolinone, 3-formaldehyde-6-methoxy-2 (1H) -quinolinone or 3-formaldehyde-6, 7-methylenedioxy-2 (1H) -quinolinone. The compound represented by the formula (II) can be synthesized by designing a synthetic route, and can also be prepared by referring to papers published by the inventor (Zhang, Y.; Fang, Y.L.; Liang, H.; Wang, H.S.; Hu, K.; Liu, X.X.; Yi, X.H.; Peng, Y.Bioorg.Med.Chem.2013,23,107), wherein the specific synthetic route is as follows:
wherein when R is1Is H, R2When the H is the product, the product is 3-formaldehyde-2 (1H) -quinolinone; when R is1Is methyl, R2When the H is the product, the product is 3-formaldehyde-6 methyl-2 (1H) -quinolinone; when R is1Is methoxy, R2When the H is the product, the product is 3-formaldehyde-6 methoxy-2 (1H) -quinolinone; when R is1And R2When 1, 2-methylenedioxy is formed, the product is 3-carboxaldehyde-6, 7-methylenedioxy-2 (1H) -quinolinone.
In the preparation method of the invention, the compound shown in the formula (III) can be an unsubstituted o-phenylenediamine derivative, a 4-position mono-substituted o-phenylenediamine derivative or a 4, 5-disubstituted o-phenylenediamine derivative. Specifically, it may be o-phenylenediamine, 4-fluorophenylenediamine, 4-chlorophenylenediamine, 4-bromoo-phenylenediamine, 4-nitrophenylenediamine, 4-trifluoromethyl-o-phenylenediamine, 4, 5-dimethyl-o-phenylenediamine, 4, 5-dimethoxy-o-phenylenediamine or 4, 5-dichloro-o-phenylenediamine, etc.
In the preparation method of the invention, the organic solvent can be an alcohol solvent and/or an aprotic polar solvent. Wherein, the alcohol solvent can be one or the combination of more than two of methanol with volume concentration of 80-100%, ethanol with volume concentration of 80-100%, n-propanol, n-butanol and ethylene glycol monomethyl ether; the aprotic polar solvent can be one or the combination of more than two of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and toluene. When the organic solvent is selected from a combination of two or more substances in the above alcohol solvents, or a combination of two or more substances in the above aprotic polar solvent, or a combination of one or more substances selected from the alcohol solvents and one or more substances selected from the aprotic polar solvent, the ratio of the organic solvent to the aprotic polar solvent may be any ratio.
In the preparation method of the invention, the dosage of the polar solvent can be determined according to needs, and in general, 1mmol of the compound shown in the formula (II) and 0.9-1.1 mmol of the compound shown in the formula (III) are dissolved by 5-15 mL of organic solvent. In a specific dissolving step, the compound shown in the formula (II) and the compound shown in the formula (III) can be respectively dissolved by partial solvents and then mixed together for reaction; or mixing the compound shown in the formula (II) and the compound shown in the formula (III), and then adding an organic solvent for dissolving.
In the preparation method of the invention, the reaction is usually carried out in a conventional reactor, and whether the reaction is complete or not can be detected by adopting thin layer chromatography tracking. In order to increase the reaction rate, the reaction is preferably carried out at a temperature ranging from 50 ℃ to the boiling point of the organic solvent (under such conditions, a time of 5 to 10 hours is usually required for the reaction to be completed), and more preferably at a temperature ranging from 70 ℃ to the boiling point of the organic solvent. After the reaction is completed, the obtained reactant is filtered, and the solid is collected, washed (usually by absolute ethyl alcohol, absolute methanol or water, etc.), dried (can be naturally dried or dried, and when a drying mode is adopted, the drying temperature is preferably not higher than 50 ℃), so that the final target product is obtained.
It is particularly preferred that the reaction is carried out under conditions of heat and ultrasound in order to further accelerate the speed of the reaction. The frequency of the ultrasonic wave is preferably 40-65 kHz, the power is preferably 240-600W, and more preferably 420-600W; when the reaction is carried out under the ultrasonic condition and the temperature is in the range of 50 ℃ to the boiling point of the organic solvent, the reaction takes about 1 to 1.5 hours to complete.
The invention also discloses the application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
The invention further comprises an antitumor drug prepared by taking the compound shown in the formula (I) or pharmaceutically acceptable salt thereof as an effective component.
Compared with the prior art, the invention provides a series of 3-benzimidazole-2 (1H) -quinolinone derivatives with novel structures, the preparation period is short, the post-treatment is simple, the cost is low, and the obtained derivatives have high purity and stable quality; the applicant also finds that the derivative can improve the antitumor activity of a 3-formaldehyde-2 (1H) -quinolinone skeleton, and compared with common antitumor drugs of 5-FU and cisplatin, the derivative has higher activity, lower toxicity to normal human liver cells HL-7702, better potential medicinal value and is expected to be used for preparing various antitumor drugs.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
In the following examples, the starting material 3-carboxaldehyde-2 (1H) -quinolinone was represented by compound 1a, the starting material 3-carboxaldehyde-6-methyl-2 (1H) -quinolinone was represented by compound 2a, the starting material 3-carboxaldehyde-6-methoxy-2 (1H) -quinolinone was represented by compound 3a, and the starting material 3-carboxaldehyde-6, 7-methylenedioxy-2 (1H) -quinolinone (also referred to as 3-carboxaldehyde- [1,3] dioxolano [6,7-g ] -2(1H) -quinolinone) was represented by compound 4a, and they were prepared as follows:
1.1 a preparation: 3.5mL of LDMF and 17mL of POCl3Mixing, stirring, adding 2.03g of acetanilide, heating to 90 ℃, heating and refluxing for 16h, cooling, pouring into a large amount of ice water, and filtering to obtain yellow powder. The resulting yellow powder was mixed with 200mL of 70% acetic acid solution, refluxed at 95 ℃ for 8h, and cooled to give Compound 1a as a yellow needle-like solid, 91%.
Compound 1a:1H NMR(500MHz,DMSO-d6)δ:12.22(s,1H,NH),10.23(s,1H,CHO),8.49(s,1H,C＝CH),7.91(d,J＝7.9Hz,1H,Ar–H),7.65(t,J＝7.8Hz,1H,Ar–H),7.35(d,J＝8.3Hz,1H,Ar–H),7.25(t,J＝8.0Hz,1H,Ar–H)；13C NMR(126MHz,DMSO-d6)δ:190.24,161.90,142.92,141.60,134.16,131.38,126.07,123.14,118.60,115.89.MS m/z:174[M+H]+.
2. 2a preparation: referring to the preparation procedure of compound 1a, compound 2a was prepared with 87% yield and the crystal structure shown in formula:
compound 2a:1H NMR(500MHz,DMSO)δ:12.13(s,1H,NH),10.22(s,1H,CHO),8.37(s,1H,C＝CH),7.65(s,1H,Ar–H),7.47(d,J＝8.5Hz,1H,Ar–H),7.24(d,J＝8.4Hz,1H,Ar–H),2.32(s,3H,CH3)；13CNMR(126MHz,DMSO-d6)δ:190.27,161.81,142.51,139.72,135.58,132.23,130.47,125.98,118.53,115.81,20.73.MS m/z:188[M+H]+.
3.3 a preparation: referring to the procedure for the preparation of compound 1a, compound 3a was prepared in 85% yield by substituting acetanilide with p-methoxyacetanilide.
Compound 3a:1H NMR(500MHz,DMSO)δ:12.15(s,1H,NH),10.23(s,1H,CHO),8.38(s,1H,C＝CH),7.66(s,1H,Ar–H),7.48(d,J＝8.5Hz,1H,Ar–H),7.25(d,J＝8.4Hz,1H,Ar–H),3.77(s,3H,CH3)；13CNMR(126MHz,DMSO-d6)δ:189.25,161.80,143.51,138.98,135.58,132.23,130.47,125.98,118.53,116.78,55.72.MS m/z:204[M+H]+.
4. 4a preparation: referring to the procedure for the preparation of compound 1a, compound 4a was prepared in 82% yield by substituting acetanilide with 3, 4-methylenedioxyacetanilide.
Compound 4a:1H NMR(500MHz,d6-DMSO)δ:12.13(s,1H,NH),10.22(s,1H,CHO),8.37(s,1H,C＝CH),7.65(s,1H,Ar–H),7.47(d,J＝8.5Hz,1H,Ar–H),5.98(s,2H,OCH2O)；13CNMR(126MHz,DMSO-d6)δ190.27,161.81,142.51,139.72,135.58,132.23,130.47,125.98,118.53,115.81,20.73. MS m/z:218[M+H]+.
example 1: 3- (5, 6-dimethyl-1H-benzimidazol-2-yl) -2(1H) -quinolinone (Compound 1 a)1) Preparation of
Weighing 0.1g (0.58mmol) of compound 1a, 0.09g (0.64mmol) of 4, 5-dimethyl-1, 2-phthalic acid and 6mL of anhydrous methanol, placing the mixture in a pressure-resistant test tube (sealed tube), reacting at 85 ℃,40 kHz of ultrasonic frequency and 540W of ultrasonic power till the mixture is completely reacted (TLC tracking detection for about 1h), cooling, performing suction filtration, and washing with anhydrous ethanol to obtain compound 1a10.148g, 88.3% yield.
Compound 1a1：Yields 88.3％,1H NMR(500MHz,DMSO-d6)δ12.42(s,2H,NH),9.05(s,1H,H-Ar),7.94(d,J＝7.2Hz,1H,H-Ar),7.60(s,1H,H-Ar),7.43(s,3H,H-Ar),7.28(d,J＝7.5Hz,1H,H-Ar),2.30(s,6H,2CH3-)；13C NMR(126MHz,DMSO-d6)δ161.28,147.31,138.99,138.83,131.80,129.38,123.07,120.75,119.70,115.68,20.59.MS m/z:290[M+H]+.
Thus, the above-mentioned compound 1a can be identified1Is 3- (5, 6-dimethyl-1H-benzimidazole-2-yl) -2(1H) -quinolinone, and the structural formula is shown as the following formula:
example 2: 3- (5, 6-dichloro-1H-benzimidazol-2-yl) -2(1H) -quinolinone (Compound 1 a)2) Preparation of
Weighing 0.1g (0.58mmol) of compound 1a, 0.11g (0.64mmol) of 4, 5-dichloro-1, 2-o-phenylenediamine and 6mL of anhydrous methanol, placing the mixture in a pressure-resistant test tube (sealed tube), stirring and reacting at 80 ℃ until the reaction is complete (TLC tracking detection, about 6h), cooling, performing suction filtration, and washing with anhydrous ethanol to obtain compound 1a20.136g, yield 71.4%.
Compound 1a2：Yields 71.4％,1H NMR(500MHz,DMSO-d6)δ12.89(s,1H,NH),12.53(s,1H,NH),9.12(s,1H,H-Ar),7.97(d,J＝7.1Hz,1H,H-Ar),7.93(s,2H,H-Ar),7.64(s,1H,H-Ar),7.45(s,1H,H-Ar),7.30(d,J＝7.5Hz,1H,H-Ar)；13C NMR(126MHz,DMSO-d6)δ161.26,161.10,153.43,150.77,140.59,139.42,132.54,129.75,124.91,123.23,119.61,119.48,115.81,115.31.MS m/z:330[M+H]+.
Thus, the above-mentioned compound 1a can be identified2Is 3- (5, 6-dichloro-1H-benzimidazole-2-yl) -2(1H) -quinolinone, and the structural formula is shown as the following formula:
example 3: 3- (5-fluoro-1H-benzimidazol-2-yl) -2(1H) -quinolinone (Compound 1 a)3) Preparation of
Referring to the method of example 2, 0.1g (0.58mmol) of compound 1a, 0.08g (0.64mmol) of 5-fluoro-1, 2-o-phenylenediamine and 10mL of anhydrous ethanol were weighed, placed in a pressure-resistant test tube (sealed tube), stirred at 80 ℃ until the reaction was completed (TLC follow-up detection, about 6 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound 1a30.116g, yield 71.7%.
Compound 1a3：Yields 71.7％,1H NMR(500MHz,DMSO-d6)δ12.75(s,1H,NH),12.49(s,1H,NH),9.10(s,1H,H-Ar),7.96(d,J＝7.9Hz,1H,H-Ar),7.58(s,5H,H-Ar),7.30(d,J＝7.5Hz,1H,H-Ar),7.07(s,1H,H-Ar)；13C NMR(126MHz,DMSO-d6)δ161.23,161.15,139.96,139.47,139.24,135.08,134.96,132.23,131.67,129.60,129.55,123.15,120.25,115.75,110.56,103.89.MS m/z:280[M+H]+.
Thus, the above-mentioned compound 1a can be identified3Is 3- (5-fluoro-1H-benzimidazole)Oxazol-2-yl) -2(1H) -quinolinone, having the formula:
example 4: 3- (5-chloro-1H-benzimidazol-2-yl) -2(1H) -quinolinone (Compound 1 a)4) Preparation of
Referring to the method of example 1, 0.1g (0.58mmol) of compound 1a, 0.09g (0.64mmol) of 5-chloro-1, 2-o-phenylenediamine and 6mL of n-propanol were weighed and placed in a pressure-resistant test tube (sealed tube), and the mixture was reacted at 85 ℃ with an ultrasonic frequency of 40kHz and an ultrasonic power of 540W until completion (TLC follow-up detection, about 1.5 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 1a40.150g, yield 87.7%.
Compound 1a4：Yields 87.7％,1H NMR(500MHz,DMSO-d6)δ12.80(s,1H,NH),12.50(s,1H,NH),9.12(s,1H,H-Ar),7.98(s,1H,H-Ar),7.75(d,J＝7.2Hz,1H,H-Ar),7.68(s,1H,H-Ar),7.63(s,1H,H-Ar),7.46(s,1H,H-Ar),7.30(d,J＝7.5Hz,1H,H-Ar),7.23(s,1H,H-Ar)；13C NMR(126MHz,DMSO-d6)δ161.16,142.05,140.15,140.00,139.31,135.64,133.78,132.32,129.65,126.98,126.85,122.89,120.02,119.55,118.05,115.77.MS m/z:296[M+H]+.
Thus, the above-mentioned compound 1a can be identified4Is 3- (5-chloro-1H-benzimidazole-2-yl) -2(1H) -quinolinone, and the structural formula is shown as the following formula:
example 5: 3- (5-bromo-1H-benzimidazol-2-yl) -2(1H) -quinolinone (Compound 1 a)5) Preparation of
Referring to the method of example 2, 0.1g (0.58mmol) of compound 1a, 0.12g (0.64mmol) of 5-bromo-1, 2-o-phenylenediamine and 6mL of dimethyl sulfoxide were weighed, placed in a pressure-resistant test tube (sealed tube), stirred at 80 ℃ until completion (TLC follow-up detection, about 7 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound 1a50.145g, 73.5% yield.
Compound 1a5：Yields 73.5％,1H NMR(500MHz,DMSO-d6)δ12.80(s,1H,NH),12.50(s,1H,NH),9.12(s,1H,H-Ar),7.96(d,J＝7.9Hz,1H,H-Ar),7.87(s,1H,H-Ar),7.69(d,J＝8.5Hz,1H,H-Ar),7.63(s,1H,H-Ar),7.44(d,J＝9.3Hz,1H,H-Ar),7.34(s,1H,H-Ar),7.30(t,J＝7.5Hz,1H,H-Ar)；13C NMR(126MHz,DMSO-d6)δ161.17,142.33,140.18,140.09,139.30,136.17,134.07,132.33,129.66,125.45,125.34,123.18,121.05,120.46,119.56,119.54.MS m/z:340[M+H]+.
Thus, the above-mentioned compound 1a can be identified5Is 3- (5-bromo-1H-benzimidazol-2-yl) -2(1H) -quinolinone, and the structural formula is shown as the following formula:
example 6: 3- (5-Nitro-1H-benzimidazol-2-yl) -2(1H) -quinolinone (Compound 1 a)6) Preparation of
Referring to the method of example 2, 0.1g (0.58mmol) of compound 1a, 0.1g (0.64mmol) of 5-nitro-1, 2-o-phenylenediamine and 5mL of N, N-dimethylformamide were weighed, placed in a pressure-resistant test tube (sealed tube), stirred at 70 ℃ until completion (TLC follow-up detection, about 7 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 1a60.123g, yield 69.1%.
Compound 1a6：Yields 69.1％,1H NMR(500MHz,DMSO-d6)δ13.24(s,1H,NH),12.56(s,1H,NH),9.19(s,1H,H-Ar),8.94(s,1H,H-Ar),8.15(s,1H,H-Ar),8.00(s,1H,H-Ar),7.95(d,J＝7.9Hz,1H,H-Ar),7.66(s,1H,H-Ar),7.46(s,1H,H-Ar),7.31(d,J＝7.5Hz,1H,H-Ar)；13C NMR(126MHz,DMSO-d6)δ161.06,154.37,147.17,141.38,139.63,134.78,132.82,129.92,129.28,128.06,127.35,123.28,122.37,119.44,118.27,115.86.MS m/z:307[M+H]+.
Thus, the above-mentioned compound 1a can be identified6Is 3- (5-nitro-1H-benzimidazole-2-yl) -2(1H) -quinolinone, and the structural formula is shown as the following formula:
example 7: 3- (5, 6-dimethyl-1H-benzimidazol-2-yl) -6-methyl-2 (1H) -quinolinone (Compound 2 a)1) Preparation of
Referring to the method of example 2, 0.1g (0.54mmol) of compound 2a, 0.08g (0.59mmol) of 4, 5-dimethyl-1, 2-o-phenylenediamine, and 6mL of N, N-dimethylacetamide were weighed and placed in a pressure-resistant test tube (sealed tube), and the reaction was stirred at 80 ℃ until completion (TLC follow-up detection, about 7 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 2a10.118g, yield 72.1%.
Compound 2a1：Yields 72.1％,1H NMR(500MHz,DMSO-d6)δ12.40(s,1H,NH),12.35(s,1H,NH),8.96(s,1H,H-Ar),7.71(s,1H,H-Ar),7.49(s,1H,H-Ar),7.43(d,J＝8.4Hz,2H,H-Ar),7.34(d,J＝8.4Hz,1H,H-Ar),2.35(s,9H,3CH3-)；13C NMR(126MHz,DMSO-d6)δ161.17,147.44,142.05,138.52,137.07,133.21,132.14,128.62,120.65,119.66,118.79,115.62,113.05,20.94,20.62.MS m/z:304[M+H]+.
Thus, the above-mentioned compound 2a was identified1Is 3- (5, 6-dimethyl-1H-benzimidazole-2-yl) -6-methyl-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 8: 3- (5, 6-dichloro-1H-benzimidazol-2-yl) -6-methyl-2 (1H) -quinolinone (Compound 2 a)2) Preparation of
Referring to the method of example 2, 0.1g (0.54mmol) of compound 2a, 0.1g (0.59mmol) of 4, 5-dichloro-1, 2-o-phenylenediamine and 6mL of 80 vol% methanol were weighed into a pressure-resistant test tube (sealed tube), the reaction was stirred at 50 ℃ until completion (TLC follow-up detection, about 9 hours), cooled, suction filtered, and washed with anhydrous ethanol to obtain compound 2a20.117g, yield 63.4%.
Compound 2a2：Yields 63.4％,1H NMR(500MHz,DMSO-d6)δ12.47(s,1H,NH),12.20(s,1H,NH),9.03(s,1H,H-Ar),7.93(s,1H,H-Ar),7.75(s,1H,H-Ar),7.46(s,2H,H-Ar),7.12(s,1H,H-Ar),2.36(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ161.12,142.57,140.32,137.97,134.01,133.69,132.36,128.95,128.54,128.06,125.69,123.32,118.97,118.89,20.91.MS m/z:344[M+H]+.
Thus, the above-mentioned compound 2a was identified2Is 3- (5, 6-dichloro-1H-benzimidazole-2-yl) -6-methyl-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 9: 3- (5-fluoro-1H-benzimidazol-2-yl) -6-methyl-2 (1H) -quinolinone (Compound 2 a)3) Preparation of
Referring to the procedure of example 2, 0.1g (0.54mmol) of Compound 2a, 0.07g (0.59mmol) of 5-fluoro-1, 2-o-phenylenediamine and 8mL of toluene were weighed and placed in a pressure-resistant test tube(tube sealing), stirring and reacting at 80 ℃ until the reaction is complete (TLC tracking detection, about 8h), cooling, performing suction filtration, and washing with absolute ethyl alcohol to obtain a compound 2a30.114g, yield 71.9%.
Compound 2a3：Yields 71.9％,1H NMR(500MHz,DMSO-d6)δ12.74(s,1H,NH),12.42(s,1H,NH),9.00(s,1H,H-Ar),7.75(s,1H,H-Ar),7.65(s,1H,H-Ar),7.50(s,1H,H-Ar),7.45(d,J＝8.4Hz,1H,H-Ar),7.35(d,J＝8.4Hz,1H,H-Ar),7.07(s,1H,H-Ar),2.38(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ161.03,158.24,139.97,139.56,139.14,134.93,133.64,133.55,132.24,131.64,128.80,128.76,120.13,115.68,110.51,103.89,20.91.MS m/z:294[M+H]+.
Thus, the above-mentioned compound 2a was identified3Is 3- (5-fluoro-1H-benzimidazole-2-yl) -6-methyl-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 10: 3- (5-chloro-1H-benzimidazol-2-yl) -6-methyl-2 (1H) -quinolinone (Compound 2 a)4) Preparation of
Referring to the method of example 2, 0.1g (0.54mmol) of compound 2a, 0.08g (0.59mmol) of 5-chloro-1, 2-o-phenylenediamine and 6mL of 90 vol% ethanol were weighed and placed in a pressure-resistant test tube (sealed tube), and the reaction was stirred at 45 ℃ until completion (TLC follow-up detection, about 10 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 2a40.115g, yield 68.7%.
Compound 2a4：Yields 68.7％,1H NMR(500MHz,DMSO-d6)δ12.79(s,1H,NH),12.43(s,1H,NH),9.02(s,1H,H-Ar),7.79(s,1H,H-Ar),7.73(s,1H,H-Ar),7.67(s,1H,H-Ar),7.46(d,J＝8.4Hz,1H,H-Ar),7.35(d,J＝8.4Hz,1H,H-Ar),7.22(s,1H,H-Ar),2.38(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ161.04,142.06,139.82,139.67,137.37,133.74,132.27,128.86,126.94,126.82,122.83,122.71,120.00,118.04,115.70,20.92.MS m/z:310[M+H]+.
Thus, the above-mentioned compound 2a was identified4Is 3- (5-chloro-1H-benzimidazole-2-yl) -6-methyl-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 11: 3- (5-bromo-1H-benzimidazol-2-yl) -6-methyl-2 (1H) -quinolinone (Compound 2 a)5) Preparation of
Referring to the method of example 2, 0.1g (0.54mmol) of compound 2a, 0.11g (0.59mmol) of 5-bromo-1, 2-o-phenylenediamine, and 6mL of 95 vol% methanol were weighed into a pressure-resistant test tube (sealed tube), and the reaction was stirred at 85 ℃ until completion (TLC follow-up detection, about 6 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 2a50.137g, yield 71.8%.
Compound 2a5：Yields 71.8％,1H NMR(500MHz,DMSO-d6)δ12.80(s,1H,NH),12.43(s,1H,NH),9.02(s,1H,H-Ar),7.90(s,1H,H-Ar),7.72(s,1H,H-Ar),7.70(s,1H,H-Ar),7.47(d,J＝8.4Hz,1H,H-Ar),7.36(d,J＝8.4Hz,1H,H-Ar),7.33(s,1H,H-Ar),2.38(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ161.05,142.33,139.86,139.76,137.40,134.04,133.75,132.29,128.87,128.83,125.40,125.31,121.04,119.51,115.87,115.71,20.92.MS m/z:354[M+H]+.
Thus, the above-mentioned compound 2a was identified5Is 3- (5-bromo-1H-benzimidazol-2-yl) -6 methyl-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 12: 3- (5-Nitro-1H-benzimidazol-2-yl) -6-methyl-2 (1H) -quinolinone (Compound 2 a)6) Preparation of
Referring to the method of example 2, 0.1g (0.54mmol) of compound 2a, 0.09g (0.59mmol) of 5-nitro-1, 2-o-phenylenediamine and 15mL of n-propanol were weighed and placed in a pressure-resistant test tube (sealed tube) to react completely (TLC follow-up detection, about 6 hours), cooled, suction-filtered, and washed with water to obtain compound 2a60.114g, yield 66.2%.
Compound 2a6：Yields 66.2％,1H NMR(500MHz,DMSO-d6)δ12.41(s,1H,NH),12.09(s,1H,NH),8.91(s,1H,H-Ar),7.93(s,1H,H-Ar),7.57(s,1H,H-Ar),7.42(d,J＝8.4Hz,1H,H-Ar),7.27(d,J＝8.4Hz,1H,H-Ar),6.87(s,1H,H-Ar),6.79(s,1H,H-Ar),2.38(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ161.87,154.43,151.54,138.98,138.44,136.47,134.45,133.87,131.95,129.18,126.76,124.94,119.42,115.72,113.34,113.17,20.85.MS m/z:321[M+H]+.
Thus, the above-mentioned compound 2a was identified6Is 3- (5-nitro-1H-benzimidazole-2-yl) -6 methyl-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 13: 3- (5, 6-dimethyl-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone (Compound 3 a)1) Preparation of
Referring to the procedure of example 2, 0.1g (0.49mmol) of compound 3a, 0.1g (0.73mmol) of 4, 5-dichloro-1, 2-phthalic anhydride and 6mL of anhydrous methanol were weighed and placed in a pressure-resistant test tube (sealed tube), and the reaction was stirred at 85 ℃ until completion (TLC follow-up detection,about 7h), cooling, then carrying out suction filtration, and washing with absolute ethyl alcohol to obtain a compound 3a10.141g, yield 80.3%.
Compound 3a2：Yields 80.3％,1H NMR(500MHz,DMSO-d6)δ12.31(s,1H,NH),11.74(s,1H,NH),9.08(s,1H,H-Ar),8.22(s,1H,H-Ar),7.85(s,1H,H-Ar),7.62(s,1H,H-Ar),7.38(d,J＝9.0Hz,1H,H-Ar),7.28(d,J＝8.9Hz,1H,H-Ar),3.76(s,3H,CH3-),2.36(s,6H,CH3-)；13C NMR(126MHz,DMSO-d6)δ160.61,155.22,142.63,140.07,136.07,135.82,134.14,132.96,128.54,125.72,125.10,122.31,117.16,117.08,113.32,110.44,56.04,21.90.MSm/z:321[M+H]+.
Thus, the above-mentioned compound 3a was identified1Is 3- (5, 6-dimethyl-1H-benzimidazole-2-yl) -6 methoxy-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 14: 3- (5, 6-dichloro-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone (Compound 3 a)2) Preparation of
Referring to the method of example 2, 0.1g (0.49mmol) of compound 3a, 0.1g (0.54mmol) of 4, 5-dichloro-1, 2-o-phenylenediamine, 6mL of dimethyl sulfoxide and 2mL of N, N-dimethylformamide were weighed, placed in a pressure-resistant test tube (sealed tube), reacted at 80 ℃ until completion (TLC tracing detection, about 6 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 3a20.124g, yield 70.3%.
Compound 3a2：Yields 70.3％,1H NMR(500MHz,DMSO-d6)δ12.31(s,1H,NH),11.74(s,1H,NH),9.08(s,1H,H-Ar),8.22(s,1H,H-Ar),7.85(s,1H,H-Ar),7.62(s,1H,H-Ar),7.38(d,J＝9.0Hz,1H,H-Ar),7.28(d,J＝8.9Hz,1H,H-Ar),3.76(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ160.61,155.22,142.63,140.07,136.07,135.82,134.14,132.96,128.54,125.72,125.10,122.31,117.16,117.08,113.32,110.44,56.04.MS m/z:360[M+H]+.
Thus, the above-mentioned compound 3a was identified2Is 3- (5, 6-dichloro-1H-benzimidazole-2-yl) -6 methoxy-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 15: 3- (5-fluoro-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone (Compound 3 a)3) Preparation of
Referring to the method of example 2, 0.1g (0.49mmol) of compound 3a, 0.07g (0.54mmol) of 5-fluoro-1, 2-o-phenylenediamine, 2mL of dimethyl sulfoxide, 2mL of absolute ethanol and 2mL of absolute methanol were weighed and placed in a pressure-resistant test tube (sealed tube), the reaction was stirred at 80 ℃ until completion (TLC follow-up detection, about 8 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 3a30.110g, yield 72.6%.
Compound 3a3：Yields 72.6％,1H NMR(500MHz,DMSO-d6)δ12.76(s,1H,NH),12.40(s,1H,NH),9.06(s,1H,H-Ar),7.68(s,1H,H-Ar),7.51(s,1H,H-Ar),7.45(s,1H,H-Ar),7.38(d,J＝9.0Hz,1H,H-Ar),7.26(d,J＝8.6Hz,1H,H-Ar),7.07(s,1H,H-Ar),3.83(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ160.75,155.18,143.59,139.38,138.95,133.92,131.63,121.92,121.83,120.40,120.20,117.09,110.36,103.89,56.03.MS m/z:310[M+H]+.
Thus, the above-mentioned compound 3a was identified3Is 3- (5-fluoro-1H-benzimidazole-2-yl) -6-methoxy-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 16: 3- (5-chloro-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone (Compound 3 a)4) Preparation of
Referring to the method of example 2, 0.1g (0.49mmol) of compound 3a, 0.08g (0.54mmol) of 5-chloro-1, 2-o-phenylenediamine, 5mL of 85% methanol by volume and 5mL of n-propanol were weighed and placed in a pressure-resistant test tube (sealed tube), and reacted at 75 ℃ until completion (TLC tracing, about 7 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 3a40.108g, yield 67.7%.
Compound 3a4：Yields 67.7％,1H NMR(500MHz,DMSO-d6)δ12.81(s,1H,NH),12.42(s,1H,NH),9.08(s,1H,H-Ar),7.68(s,2H,H-Ar),7.52(s,1H,H-Ar),7.36(d,J＝8.9Hz,1H,H-Ar),7.29(d,J＝9.0Hz,1H,H-Ar),7.22(s,1H,H-Ar),3.83(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ160.69,155.19,139.56,134.00,126.89,122.78,122.02,120.18,117.11,110.40,56.03.MS m/z:326[M+H]+.
Thus, the above-mentioned compound 3a was identified4Is 3- (5-chloro-1H-benzimidazole-2-yl) -6 methoxy-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 17: 3- (5-bromo-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone (Compound 3 a)5) Preparation of
Referring to the procedure of example 2, 0.1g (0.49mmol) of compound 3a, 0.1g (0.54mmol) of 5-bromo-1, 2-o-phenylenediamine, 5mL of toluene and 5mL of N, N-dimethylformamide were weighed and placed in a pressure resistant test tube (lock tube), and the reaction was stirred at 100 ℃ until completion (TLC follow-up,about 5h), cooling, then carrying out suction filtration, and washing with absolute ethyl alcohol to obtain a compound 3a50.133g, 73.3% yield.
Compound 3a5：Yields 73.3％,1H NMR(500MHz,DMSO-d6)δ12.82(s,1H,NH),12.41(s,1H,NH),9.08(s,1H,H-Ar),7.87(s,1H,H-Ar),7.65(s,1H,H-Ar),7.51(s,1H,H-Ar),7.38(d,J＝8.9Hz,1H,H-Ar),7.34(d,J＝8.5Hz,1H,H-Ar),7.27(s,1H,H-Ar),3.82(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ160.68,155.19,139.61,134.01,125.36,122.03,120.17,120.13,117.11,114.81,110.39,56.03.MS m/z:370[M+H]+.
Thus, the above-mentioned compound 3a was identified5Is 3- (5-bromo-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 18: 3- (5-Nitro-1H-benzimidazol-2-yl) -6-methoxy-2 (1H) -quinolinone (Compound 3 a)6) Preparation of
Referring to the method of example 2, 0.1g (0.49mmol) of compound 3a, 0.1g (0.54mmol) of 5-nitro-1, 2-o-phenylenediamine, 1mL of anhydrous methanol, 2mL of dimethyl sulfoxide and 3mL of toluene were weighed and placed in a pressure-resistant test tube (sealed tube), the reaction was stirred at 60 ℃ until completion (TLC tracing detection, about 7 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound 3a60.111g, yield 67.7%.
Compound 3a6：Yields 67.7％,1H NMR(500MHz,DMSO-d6)δ12.07(s,1H,NH),8.93(s,1H,NH),8.91(s,1H,H-Ar),7.93(s,1H,H-Ar),7.31(d,J＝8.9Hz,2H,H-Ar),7.25(d,J＝8.8Hz,1H,H-Ar),6.86(s,1H,H-Ar),6.79(s,1H,H-Ar),3.82(s,3H,CH3-)；13C NMR(126MHz,DMSO-d6)δ161.56,154.94,154.40,151.56,138.77,136.51,135.12,134.40,127.08,124.96,122.21,120.01,117.15,113.37,113.16,110.46,55.94.MS m/z:337[M+H]+.
Thus, the above-mentioned compound 3a was identified6Is 3- (5-nitro-1H-benzimidazole-2-yl) -6-methoxy-2 (1H) -quinolinone, and the structural formula is shown as the following formula:
example 19: 3- (5, 6-dimethyl-1H-benzimidazol-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone (Compound 4 a)1) Preparation of
Referring to the method of example 2, 0.1g (0.46mmol) of compound 4a, 0.07g (0.51mmol) of 4, 5-dimethyl-1, 2-o-phenylenediamine and 7mL of ethylene glycol monomethyl ether were weighed, placed in a pressure-resistant test tube (sealed tube), stirred at 85 ℃ until the reaction was complete (TLC follow-up detection, about 7 hours), cooled, suction-filtered, and washed with absolute ethanol to obtain compound 4a10.113g, 73.9% yield.
Compound 4a1：Yields 73.9％,1H NMR(500MHz,DMSO-d6)δ12.33(s,1H,NH),11.93(s,1H,NH),8.92(s,1H,H-Ar),7.45(s,1H,H-Ar),7.38(s,2H,H-Ar),6.92(d,J＝9.0Hz,1H,H-Ar),6.13(s,2H,-CH2-),2.30(s,6H,2CH3-)；13C NMR(126MHz,DMSO-d6)δ161.00,151.67,147.83,144.44,138.55,136.61,130.77,117.50,114.31,106.12,102.57,95.42,20.56.MSm/z:334[M+H]+.
Thus, the above-mentioned compound 4a can be identified1Is 3- (5, 6-dimethyl-1H-benzimidazole-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone, having the formula:
example 20: 3- (5, 6-dichloro-1H-benzimidazol-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone (Compound 4 a)2) Preparation of
Referring to the method of example 2, 0.1g (0.46mmol) of compound 4a, 0.09g (0.51mmol) of 4, 5-dichloro-1, 2-o-phenylenediamine and 6mL of absolute ethanol were weighed, placed in a pressure-resistant test tube (sealed tube), stirred at 65 ℃ until the reaction was complete (TLC follow-up detection, about 8 hours), cooled, suction-filtered, and washed with absolute methanol to obtain compound 4a20.119g, yield 69.1%.
Compound 4a2：Yields 69.1％,1H NMR(500MHz,DMSO-d6)δ12.44(s,1H,NH),11.71(s1H,NH),8.97(s,1H,H-Ar),7.77(s,2H,H-Ar),6.92(d,J＝9.0Hz,1H,H-Ar),6.66(s,1H,H-Ar),6.14(s,1H,-CH2-),6.05(s,1H,-CH2-)；13C NMR(126MHz,DMSO-d6)δ160.82,152.30,144.59,140.08,137.32,127.46,114.18,106.28,105.59,102.73,102.08,95.42.MS m/z:375[M+H]+.
Thus, the above-mentioned compound 4a can be identified2Is 3- (5, 6-dichloro-1H-benzimidazol-2-yl) - [1, 3%]Dioxolane [6,7-g]-2(1H) -quinolinone, having the formula:
example 21: 3- (5-fluoro-1H-benzimidazol-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone (Compound 4 a)3) Preparation of
Referring to the method of example 2, 0.1g (0.46mmol) of compound 4a, 0.06g (0.51mmol) of 5-fluoro-1, 2-o-phenylenediamine and 6mL of anhydrous methanol were weighed and placed in a pressure-resistant test tube (sealed tube), and the reaction was stirred at 85 ℃ until completion (TLC follow-up detection, about 8 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound4a30.109g, 73.1% yield.
Compound 4a3：Yields 73.1％,1H NMR(500MHz,DMSO-d6)δ12.66(s,1H,NH),12.29(s,1H,NH),8.96(s,1H,H-Ar),7.68(s,1H,H-Ar),7.46(s,1H,H-Ar),7.05(s,1H,H-Ar),6.92(d,J＝9.0Hz,1H,H-Ar),6.84(s,1H,H-Ar),6.10(s,2H,-CH2-)；13C NMR(126MHz,DMSO-d6)δ160.89,152.01,144.52,143.65,139.49,137.00,127.74,114.22,106.21,105.58,102.65,95.43.MS m/z:324[M+H]+.
Thus, the above-mentioned compound 4a can be identified3Is 3- (5-fluoro-1H-benzimidazol-2-yl) - [1, 3%]Dioxolane [6,7-g]-2(1H) -quinolinone, having the formula:
example 22: 3- (5-chloro-1H-benzimidazol-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone (Compound 4 a)4) Preparation of
Referring to the procedure of example 2, 0.1g (0.46mmol) of compound 4a, 0.07g (0.51mmol) of 5-chloro-1, 2-o-phenylenediamine and 6mL of anhydrous methanol were weighed and placed in a pressure-resistant test tube (sealed tube), reacted at 85 ℃ until completion (TLC follow-up detection, about 8 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound 4a40.107g, yield 68.3%.
Compound 4a4：Yields 68.3％,1H NMR(500MHz,DMSO-d6)δ12.70(s,1H,NH),12.41(s,1H,NH),8.98(s,1H,H-Ar),7.72(s,1H,H-Ar),7.61(s,1H,H-Ar),7.45(s,1H,H-Ar),7.20(d,J＝8.7Hz,1H,H-Ar),6.92(d,J＝8.9Hz,1H,H-Ar),6.12(s,2H,-CH2-)；13C NMR(126MHz,DMSO-d6)δ160.89,152.10,144.54,142.14,139.71,137.10,126.65,122.51,119.72,117.80,114.22,106.24,102.68,95.42.MS m/z:340[M+H]+.
Thus, the above-mentioned compound 4a can be identified4Is 3- (5-chloro-1H-benzimidazol-2-yl) - [1,3]]Dioxolane [6,7-g]-2(1H) -quinolinone, having the formula:
example 23: 3- (5-bromo-1H-benzimidazol-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone (Compound 4 a)5) Preparation of
Referring to the method of example 2, 0.1g (0.46mmol) of compound 4a, 0.09g (0.51mmol) of 5-bromo-1, 2-o-phenylenediamine, and 6mL of anhydrous methanol were weighed and placed in a pressure-resistant test tube (sealed tube), and the reaction was stirred at 80 ℃ until completion (TLC follow-up detection, about 8 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound 4a50.130g, 73.8% yield.
Compound 4a5：Yields 73.8％,1H NMR(500MHz,DMSO-d6)δ12.71(s,1H,NH),12.42(s,1H,NH),8.99(s,1H,H-Ar),7.86(s,1H,H-Ar),7.64(s,1H,H-Ar),7.46(s,1H,H-Ar),7.31(d,J＝8.5Hz,1H,H-Ar),6.93(d,J＝9.0Hz,1H,H-Ar),6.16(s,2H,-CH2-)；13C NMR(126MHz,DMSO-d6)δ160.89,152.12,144.55,139.72,137.12,125.12,116.66,114.56,114.22,106.25,102.69,95.43.MS m/z:384[M+H]+.
Thus, the above-mentioned compound 4a can be identified5Is 3- (5-bromo-1H-benzimidazol-2-yl) - [1, 3%]Dioxolane [6,7-g]-2(1H) -quinolinone, having the formula:
example 24: 3- (5-nitro-1H-benzoImidazol-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone (Compound 4 a)6) Preparation of
Referring to the method of example 2, 0.1g (0.46mmol) of compound 4a, 0.08g (0.51mmol) of 5-nitro-1, 2-o-phenylenediamine and 6mL of anhydrous methanol were weighed and placed in a pressure-resistant test tube (sealed tube), and the reaction was stirred at 60 ℃ until completion (TLC follow-up detection, about 9 hours), cooled, suction-filtered, and washed with anhydrous ethanol to obtain compound 4a60.109g, yield 67.9%.
Compound 4a6：Yields 67.9％,1H NMR(500MHz,DMSO-d6)δ12.47(s,1H,NH),11.82(s,1H,NH),9.01(s,1H,H-Ar),8.57(s,1H,H-Ar),8.10(d,J＝8.9Hz,1H,H-Ar),7.82(s,1H,H-Ar),7.47(s,1H,H-Ar),6.91(d,J＝8.9Hz,1H,H-Ar),6.15(s,2H,-CH2-)；13C NMR(126MHz,DMSO-d6)δ160.78,152.56,144.64,140.80,137.65,118.09,115.92,114.16,106.36,102.80,95.42.MS m/z:351[M+H]+.
Thus, the above-mentioned compound 4a can be identified6Is 3- (5-nitro-1H-benzimidazole-2-yl) - [1,3]Dioxolane [6,7-g]-2(1H) -quinolinone, having the formula:
to illustrate the antitumor effect of the 3-benzimidazole-2 (1H) -quinolinone derivatives of the present invention, the applicant performed antitumor activity experiments on the above compounds 1a, 2a, 3a and 4a and the compounds prepared in the above examples 1 to 24 (using common antitumor drugs 5-fluorouracil (5-FU) and cisplatin (Cis-platinum) as reference), and performed toxicity experiments on normal cells for the compounds prepared in the above examples. In-vitro antitumor activity test of compound
1. Inoculation and culture of cells
The selected cell lines were all incubated at 37 ℃ with 5% CO2Inoculating into a culture box containing 1 under sufficiently humidified conditionsCulturing in PPMI1640 culture medium containing 0% inactivated newborn calf serum. And (3) observing the growth condition of the cells by using an inverted microscope, replacing the culture medium for 2-3 times every week, carrying out passage once every 6-7 days, digesting and carrying out passage by using 0.25% trypsin during inoculation, generally taking the cells which are subjected to passage for 3-4 times and are in a logarithmic growth phase for experiment.
2. Primary screening of cellular levels of Compounds
The purity of the compound used in the experiment is more than or equal to 95 percent, all the compounds are prepared into 100 mu g/mL, the final concentration of cosolvent DMSO is not more than 1 percent, the inhibition rate of each compound to cancer cells under the concentration is tested, and if the inhibition rate is more than 50 percent and the compounds conform to the inhibited (or damaged) morphological change of cells under a light microscope (such as cell shrinkage, breakage, floating and the like) and have no great toxicity to normal cells, the compounds are preliminarily judged to be effective for preliminary screening, namely the compounds enter the next step to obtain IC50And (5) stage.
3. Cell growth inhibition assay (MTT method)
MTT colorimetric method is a method for detecting cell growth and survival. The detection principle is as follows: unlike dead cells, exogenous MTT can be reduced to water-insoluble blue-violet crystalline Formazan (Formazan) by succinate dehydrogenase in mitochondria of living cells and deposited in cells. Methanezan in cells can be solubilized by dimethyl sulfoxide (DMSO), and the number of viable cells can be indirectly reflected by measuring the light absorption at 490nm using an enzyme linked immunosorbent assay. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The method is widely used for activity detection of some bioactive factors, large-scale antitumor drug screening, cytotoxicity test, tumor radiosensitivity determination and the like, and has the characteristics of high sensitivity, economy and the like.
Cells in logarithmic growth phase were seeded in 96-well plates at 37 ℃ with 5% CO in 180. mu.L (about 4500-2Culturing for 24h under fully humidified conditions. After the cells adhere to the wall, samples are added according to the amount of 20 mu L per well, each sample is provided with 6 multiple wells, and corresponding blank control is set at the same time. Continue to useAnd after 48h of culture, adding 10 mu of LMTT reagent (the concentration is 5mg/mL) into each hole, continuing to incubate for 4h, removing the supernatant by suction, adding 150 mu of DMSO into each hole, and slightly shaking for reaction for 5-8 min to fully dissolve the crystal particles. Zeroing blank control group, and measuring absorbance value after removing background light absorption value with enzyme-labeling instrument at 490nm wavelengthCalculating cell proliferation inhibition rate, and continuously using 5 concentration gradients to continuously prepare IC of corresponding cell strains for primarily screening tested compounds with good anti-tumor effect50Values, averaged after 3 replicates for all experiments. The experimental results are detailed in table 1 below.
TABLE 1 half Inhibitory Concentration (IC) of the compounds against different tumor cell lines50，μM).
As can be seen from the data in Table 1, in the test of inhibitory activity against human hepatoma cell HepG2, Compound 1a3、1a4、1a5、2a4、4a1、4a2、4a3、4a4Shows good inhibitory activity which is obviously superior to that of the common anticancer drug 5-FU, wherein the compound 1a4、1a5、4a3、4a4The activity of the compounds is equivalent to that of cisplatin which is a clinical anticancer drug, and the toxicity of the compounds to normal human liver cells HL-7702 is obviously less than that of the cisplatin and 5-FU; in the test of the inhibitory activity of human ovarian cancer cell SKOV-3, the compound 1a3、1a4、1a5、2a4、4a1、4a2、4a4Exhibit good inhibitory activity, except for Compound 2a4In addition, the activity of the compounds is remarkably superior to that of the common anticancer drug 5-FU, wherein the compound 1a4、1a5、4a1The activity of the compound is even better than that of cisplatin which is a clinical anticancer drug, and the toxicity of the compound to normal human liver cells HL-7702 is obviously less than that of the cisplatin and 5-FU; in the human large cell lungTest of inhibitory Activity of cancer cell NCI-H460 Compound 1a3、1a4、1a5、2a4、4a1、4a2、4a4Shows good inhibitory activity which is obviously better than that of the common anticancer drug 5-FU, wherein the compound 1a4、1a5The activity of the compound is even better than that of cisplatin which is a clinical anticancer drug, and the toxicity of the compound to normal human liver cells HL-7702 is obviously less than that of the cisplatin and 5-FU; in the test of the inhibitory activity of human liver cancer cell BEL-7404, the compound 1a3、1a4、1a5、2a4、4a1、4a2、4a3、4a4Shows good inhibitory activity which is obviously superior to that of the common anticancer drug 5-FU, wherein the compound 4a2、4a3、4a4The activity of the compound is even better than that of cisplatin which is a clinical anticancer drug, and the toxicity of the compound to normal human liver cells HL-7702 is obviously lower than that of the cisplatin and 5-FU. The results show that the novel 3-o-phenylenediamine-2 (1H) -quinolinone antitumor compound prepared by introducing the benzimidazole functional group into the 2(1H) -quinolinone skeleton is feasible, and the novel high-efficiency and low-toxicity antitumor compound is expected to be screened out, compared with the common antitumor drugs of 5-FU and cis-platinum, the activity of certain 3-o-phenylenediamine-2 (1H) -quinolinone derivatives is more efficient, and the toxicity to normal human liver cells HL-7702 is lower.
Claims (9)
1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
R1is a reaction with R2Forming a 1, 2-methylenedioxy group;
R2is a reaction with R1Forming a 1, 2-methylenedioxy group;
R3is methyl, fluoro or chloro；
R4Is hydrogen, methyl or chloro.
2. A process for the preparation of a compound according to claim 1, characterized in that: dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an organic solvent, and reacting under a heating condition to obtain a target product;
wherein,
R1is a reaction with R2Forming a 1, 2-methylenedioxy group;
R2is a reaction with R1Forming a 1, 2-methylenedioxy group;
R3is methyl, fluoro or chloro;
R4is hydrogen, methyl or chloro.
3. The method of claim 2, wherein: the organic solvent is an alcohol solvent and/or an aprotic polar solvent.
4. The production method according to claim 3, characterized in that: the alcohol solvent may be one or a combination of two or more selected from methanol with a volume concentration of 80-100%, ethanol with a volume concentration of 80-100%, n-propanol, n-butanol and ethylene glycol monomethyl ether.
5. The production method according to claim 3, characterized in that: the aprotic polar solvent is one or the combination of more than two of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and toluene.
6. The production method according to any one of claims 2 to 5, characterized in that: the reaction is carried out at a temperature ranging from 50 ℃ to the boiling point of the organic solvent.
7. The production method according to any one of claims 2 to 5, characterized in that: the reaction is carried out under ultrasonic conditions.
8. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-neoplastic drug.
9. An antitumor agent comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610078898.3A CN105622574B (en) | 2016-02-04 | 2016-02-04 | 3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610078898.3A CN105622574B (en) | 2016-02-04 | 2016-02-04 | 3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105622574A CN105622574A (en) | 2016-06-01 |
| CN105622574B true CN105622574B (en) | 2018-12-25 |
Family
ID=56037957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610078898.3A Expired - Fee Related CN105622574B (en) | 2016-02-04 | 2016-02-04 | 3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105622574B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3055331B1 (en) * | 2016-08-31 | 2020-03-06 | Adpuerivitam | NMDA RECEPTOR MODULATORS, COMPOSITIONS COMPRISING SAME, AND USE OF SUCH COMPOUNDS IN THE TREATMENT OF DISEASES INVOLVING THE CENTRAL NERVOUS SYSTEM |
| CN108003150A (en) * | 2016-10-31 | 2018-05-08 | 河南工业大学 | The preparation method and applications of 4- heteroaryl qualone derivatives |
| CN109020997B (en) * | 2018-07-05 | 2021-03-02 | 桂林医学院 | 3-benzimidazole-6, 7-piperonyl-2 (1H) -quinolinone-zinc complex and preparation method and application thereof |
| CN114716346B (en) * | 2020-12-15 | 2023-07-04 | 广西师范大学 | 4-nitroaniline derivative and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6479512B1 (en) * | 1999-10-19 | 2002-11-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| CN104817535A (en) * | 2015-03-19 | 2015-08-05 | 广西师范大学 | Quinolinone derivative, and synthetic method and application thereof |
-
2016
- 2016-02-04 CN CN201610078898.3A patent/CN105622574B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6479512B1 (en) * | 1999-10-19 | 2002-11-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| CN104817535A (en) * | 2015-03-19 | 2015-08-05 | 广西师范大学 | Quinolinone derivative, and synthetic method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| A Simple One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones from the Direct Reaction of 2-Chloroquinolin-3-carbaldehyde with Aromatic o-Diamines;Rodrigo Abonia et al.;《European Journal of Organic Chemistry》;20091124(第2期);317-325 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105622574A (en) | 2016-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105622574B (en) | 3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application | |
| CN109053731B (en) | P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN105153136B (en) | Brefeldin A ester derivative and its preparation and application | |
| CN114133390A (en) | Harmine derivative and preparation method and application thereof | |
| EP3403651B1 (en) | Isocorydine derivatives, preparation method and use thereof | |
| CN104558094B (en) | Saponin(e aglycone derivative, its preparation method and the application in antineoplastic is prepared | |
| CN110437156B (en) | Paeonol dihydropyrimidinone derivative, preparation method and application thereof | |
| CN105646546B (en) | The position 20 of camptothecins ester derivant and its antitumor application thereof of acid-sensitive type | |
| CN104817535A (en) | Quinolinone derivative, and synthetic method and application thereof | |
| CN105732576B (en) | The chloro- 3- of 2- (1H- benzimidazolyl-2 radicals-yl)-quinoline preparation methods and application | |
| Reddy et al. | A short and highly convergent approach for the synthesis of rutaecarpine derivatives | |
| CN109232570B (en) | Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN110183467B (en) | P-methoxyphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN106478692A (en) | Copper-nitrate complex and its synthetic method and application with 1 (2 pyridine) 9 benzyl β carboline as part | |
| CN107857766B (en) | Synthetic method and application of spiroindole compound based on phenylalanine and polycarbonyl cyclic ketone compound | |
| CN110759920A (en) | P-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN107857765B (en) | Synthesis method and application of spiroindole compound based on sarcosine and multi-carbonyl cyclic ketone compound | |
| CN103044326A (en) | 5-bromo oxoisoaporphine, and synthesis method and application thereof | |
| CN103130803B (en) | Oxidized iso-aporphine alkaloid derivative, synthetic method and application | |
| CN109232571B (en) | P-methylmercapto-substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN109180675B (en) | P-methoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN109232572B (en) | P-methyl-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN109180676B (en) | 3,4, 5-trimethoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method thereof | |
| CN111533700B (en) | 5-substituted uracil derivative and preparation method and application thereof | |
| CN109053732B (en) | Para-fluorine substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhang Ye Inventor after: Ma Xianli Inventor after: Kuang Wenbin Inventor after: Yu Yancheng Inventor after: Huang Rizhen Inventor before: Zhang Ye Inventor before: Kuang Wenbin Inventor before: Yu Yancheng Inventor before: Huang Rizhen |
|
| CB03 | Change of inventor or designer information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20170208 Address after: 541004 the Guangxi Zhuang Autonomous Region city two Guilin Road No. 109 North Huancheng Applicant after: Guilin Medical College Address before: Xinyi Road Xiufeng District, Guilin city 541001 No. 21 the Guangxi Zhuang Autonomous Region Applicant before: Guilin Teachers Training College |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181225 Termination date: 20200204 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |