CN101041646A - Preparation method and usage for nitrogen-containing chalcone derivatives - Google Patents
Preparation method and usage for nitrogen-containing chalcone derivatives Download PDFInfo
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- CN101041646A CN101041646A CN 200710068441 CN200710068441A CN101041646A CN 101041646 A CN101041646 A CN 101041646A CN 200710068441 CN200710068441 CN 200710068441 CN 200710068441 A CN200710068441 A CN 200710068441A CN 101041646 A CN101041646 A CN 101041646A
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- 238000002360 preparation method Methods 0.000 title claims description 14
- -1 nitrogen-containing chalcone derivatives Chemical class 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 238000005821 Claisen rearrangement reaction Methods 0.000 claims abstract description 3
- 150000001788 chalcone derivatives Chemical class 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001721 carbon Chemical group 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- WRRQHEMZOCFTQP-UHFFFAOYSA-N 2,2,2-trihydroxy-1-phenylethanone Chemical compound OC(O)(O)C(=O)C1=CC=CC=C1 WRRQHEMZOCFTQP-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 238000006266 etherification reaction Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 2
- 102000004316 Oxidoreductases Human genes 0.000 claims description 2
- 108090000854 Oxidoreductases Proteins 0.000 claims description 2
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical group 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 20
- AETKQQBRKSELEL-UHFFFAOYSA-N (2E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one Natural products OC1=CC=CC=C1C(=O)C=CC1=CC=CC=C1 AETKQQBRKSELEL-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- AETKQQBRKSELEL-ZHACJKMWSA-N 2'-hydroxychalcone Chemical compound OC1=CC=CC=C1C(=O)\C=C\C1=CC=CC=C1 AETKQQBRKSELEL-ZHACJKMWSA-N 0.000 abstract 2
- 241001597008 Nomeidae Species 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 16
- 230000008569 process Effects 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 150000003053 piperidines Chemical class 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KGFYDIZALLKOLQ-UHFFFAOYSA-N 1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propan-1-on Natural products C1=CC(OC)=CC=C1CCC(=O)C1=C(O)C=C(OC)C=C1OC KGFYDIZALLKOLQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- CGIBCVBDFUTMPT-RMKNXTFCSA-N Flavokawain A Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)C1=C(O)C=C(OC)C=C1OC CGIBCVBDFUTMPT-RMKNXTFCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- CGIBCVBDFUTMPT-UHFFFAOYSA-N flavokawain A Natural products C1=CC(OC)=CC=C1C=CC(=O)C1=C(O)C=C(OC)C=C1OC CGIBCVBDFUTMPT-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- XKXLBHSNDSFICW-ZHACJKMWSA-N (e)-1-(2-aminophenyl)-3-phenylprop-2-en-1-one Chemical class NC1=CC=CC=C1C(=O)\C=C\C1=CC=CC=C1 XKXLBHSNDSFICW-ZHACJKMWSA-N 0.000 description 1
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical class ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010060766 Heteroplasia Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 235000016787 Piper methysticum Nutrition 0.000 description 1
- 240000005546 Piper methysticum Species 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 102000055102 bcl-2-Associated X Human genes 0.000 description 1
- 108700000707 bcl-2-Associated X Proteins 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a making method of 2'-hydroxy-3'-alkylamino propyl-4', 6'-disubstituted chalcone derivant, which comprises the following steps: adopting 2'-hydroxy chalcone as leading material; proceeding allyl etherifying reaction on the mother core of 2'-hydroxy chalcone; proceeding Claisen rearrangement; epoxidising; additioning; obtaining the product; fitting for industrial manufacturing; improving the receiving rate obviously.
Description
Technical field
The invention belongs to the synthetic of organic compound, relate to the preparation method of nitrogenous chalcone derivative, relate in particular to 2 '-hydroxyl-3 '-alkanamine propyl group-4 ', 6 '-two replace the preparation method of chalcone derivative, and the application in the preparation antitumor drug.
Background technology
Chalcone derivative has antitumor action.People such as X.Yi had reported a series of 2 '-amino chalcone derivatives in 2000, and wherein most compounds show very strong cytotoxic activity, especially 2 '-amido-4 ', 5 '-methylene-dioxy-3-methoxyl group phenyl styryl ketone is to kinds of tumor cells (KB, HOS, HCT-8, A-549 etc.) IC
50All less than 1 μ M.And tumour cell KB-VIN, 1A9 to multidrug resistance also show very strong inhibition activity.The nitrogenous chalcone derivative that this article provided is that structure is comparatively common, has replacements such as methoxyl group, hydroxyl, amido on the aromatic ring.The author has only carried out the discussion of preliminary activity and structure activity relationship to these compounds, and the mechanism of its antitumor action is not done further further investigation.X.L.Zi and people such as A.R.Simoneau separate Flavokawain A (the 2 '-hydroxyl-4 ' that obtains to the root extract from Kava (a kind of grow in the shrub that South Pacific island country is used for making wine), 6 '-dimethoxy-4 '-methoxyl group phenyl styryl ketone) carries out the research of anti-tumor activity, the result shows, this compound can suppress growth of tumor, mechanism is it by participating in the dependent apoptotic pathways of Bax protein dependent and plastosome, thereby has induced the apoptosis of tumour cell.Discover that further Flavokawain A has presented significant cancer suppressing action in nude mice heteroplasia model.
Summary of the invention
The chalcone derivative that contains nitrogen-atoms that the purpose of this invention is to provide a class formation novelty, mainly be meant 2 '-hydroxyl-3 '-alkanamine propyl group-4 ', 6 '-two replace chalcone derivative, the present invention is the structure that changes 2 '-hydroxy-benzalacetophenone derivative, introduce different alkanamine propyl moiety in 3 '-position, synthesized a series of 2 '-hydroxyl-3 '-alkanamine propyl group-4 ', 6 '-two replace chalcone derivative.2 '-hydroxyl-3 ' provided by the invention-alkanamine propyl group-4 ', 6 '-two replace the chalcone derivative general structure is:
Wherein
R
1Straight or branched alkane for hydrogen atom, 1 to 4 carbon atom;
Ar is for do not have replacing, singly replace, two replace or trisubstituted phenyl ring, and the substituting group on the phenyl ring is hydrogen atom, halogen atom, hydroxyl, trifluoromethyl, methylsulfonyl, contain the alkyl of the straight or branched of 1 to 10 carbon atom, contain the alkoxyl group of the straight or branched of 1 to 4 carbon atom;
R
2Tertiary amine structure NR for ring-type or open chain
3R
4, R wherein
3And R
4Identical or different, they can be methyl, ethyl, contain alkyl alcohol, alkyl oxide and the ester thereof of 1-4 carbon atom, contain the carboxylic acid and the ester thereof of 1-4 carbon atom, contain the alkylamine of 1-4 carbon atom, or R
3, R
4Be respectively carbon, oxygen, reach five yuan of nitrogen-atoms ring synthetic or six-ring.
Another object of the present invention provides 2 '-hydroxyl-3 '-alkanamine propyl group-4 ', and 6 '-two replace the preparation method of chalcone derivative, realize by following steps:
Synthetic route of the present invention:
(1) Compound I and anhydrous acetonitrile obtain intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate through Louis (Lewis) acid catalysis in inert solvent, this reaction is usually with ether, dioxane, methylene dichloride, chloroforms etc. are solvent, used Lewis acid has iron(ic) chloride, zinc chloride, tin chloride, boron trifluoride diethyl etherate etc., temperature of reaction is-15 ℃-25 ℃, reaction times 6-8 hour, intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate obtains Compound I I through acidic hydrolysis again, temperature of reaction is 80 ℃-110 ℃, reaction times 1-5 hour, normally refluxed 3 hours, products therefrom II need not purifying, can be directly used in next step reaction;
(2) Compound I I selective etherification through halohydrocarbon under alkaline condition can obtain compound III, can get pure product through recrystallization.Reaction is carried out in polar solvent such as acetone usually, and alkaline matter commonly used has sodium hydride, potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, and temperature of reaction can be carried out between 0 ℃-50 ℃, at room temperature carries out usually;
(3) compound III obtains compound IV with the aromatic aldehyde condensation under alkaline condition, reaction is carried out in the mixed solvent of protic usually, as methanol-water, alcohol-water or Virahol-water etc., alkali commonly used has potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, sodium hydride etc., temperature of reaction can be carried out between 5 ℃-30 ℃, at room temperature carries out usually, obtains crude product and can get pure product by recrystallization;
(4) compound IV allyl etherificate under alkaline condition can obtain compound V, be reflected in polar solvent such as the acetone and carry out, alkaline matter commonly used has sodium methylate, sodium ethylate, sodium hydroxide, salt of wormwood, yellow soda ash, and temperature of reaction is 30-80 ℃, and products therefrom can be directly used in next step reaction;
(5) compound V obtains compound VI through claisen (Claisen) rearrangement in high boiling solvent, high bp polar solvent commonly used has naphthane, phenyl ether, N, accelerine, N, dinethylformamide (DMF), trifluoracetic acid, temperature of reaction is 150-210 ℃, and crude product can obtain pure product through recrystallization;
(6) compound VI obtains compound VI I through the aceticanhydride acidylate, is reflected in polar solvent such as the pyridine to carry out, and catalyzer commonly used has 4-dimethylamino pyridine (DMAP), and temperature of reaction is 10-30 ℃, and crude product can obtain pure product through column chromatography;
(7) compound VI I obtains compound VIII through acid oxidase, peracid commonly used has benzoyl hydroperoxide, crosses phthalic acid, metachloroperbenzoic acid, peroxyformic acid and Peracetic Acid, be reflected in polar solvent such as methylene dichloride, the trichloromethane and carry out, temperature of reaction is 10-30 ℃, and crude product can obtain pure product through column chromatography;
(8) compound VIII and secondary amine addition obtain Compound I X, be reflected in the polar solvent and carry out, used polar solvent can in methyl alcohol, ethanol, Virahol, acetonitrile, dioxane, acetone, DMF, the dimethyl sulfoxide (DMSO) (DMSO) any, temperature of reaction is 10-80 ℃, and crude product can obtain pure product through column chromatography.
Compound I can directly be bought, and Compound I I can be by literature method (K.C.Gulai et al, Org.Synth., Coll.Vol.II, 522) make, compound III can be by literature method (I.Kazuhiko et al, JNat.Prod., 1988,51,906-914) make, compound IV can be by literature method (X.Y.Bu et al, Synthesis, 1997,11,1246-1248) make.
Another purpose of the present invention is 2 '-hydroxyl-3 '-alkanamine propyl group-4 ', and 5 ', 6 '-three replace the application of chalcone derivative in the preparation antitumor drug.Preliminary pharmacological evaluation finds that they to various tumor cell strains, comprise ECA-109, and A-549, HL-60, PC-3 etc. all have good in-vitro to suppress proliferation function, and wherein IXk shows very strong inhibition activity, IC to leukemia cell HL-60
50Value is 0.21 μ g/mL; The IXe effect is also comparatively outstanding, to ECA-109, and the IC of A-549
50Value is respectively 1.0 μ g/mL, 1.5 μ g/mL.
Characteristics of the present invention are to be guide's thing to have active 2 '-hydroxy-benzalacetophenone, on 2 '-hydroxy-benzalacetophenone parent nucleus, obtain 2 '-hydroxyl-3 '-alkanamine propyl group-4 ' by allyl etherification reaction, Claisen rearrangement, epoxidation reaction, addition reaction etc., 5 ', 6 '-three replace chalcone derivative.This is the brand-new compound of a class formation, and preliminary pharmacological activity screening experiment shows that these compounds all have better antitumor activity.
The raw materials used not only wide material sources of the present invention are easy to preparation, and the reaction conditions gentleness, and each goes on foot the yield height, and is easy and simple to handle, and production cost is lower, are fit to suitability for industrialized production.
Embodiment
The present invention is further described in conjunction with the embodiments.Following embodiment only is that explanation is of the present invention, rather than limits the present invention by any way.
Embodiment 1,2-hydroxyl-4,6-dimethoxy-methyl phenyl ketone (compound III): the reference literature method (I.Kazuhiko et al, J Nat.Prod., 1988,51,906-914) make.
M.p.77～78℃。
1H-NMR(δ，CDCl
3)：14.06(s，1H)，6.05(d，1H，J＝2.4Hz)，5.92(d，1H，J＝2.4Hz)，3.90(s，3H)，3.62(s，3H)，2.63(s，3H)。
Embodiment 2,2 '-hydroxyl-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (compound IV a): the reference literature method (X.Y.Bu et al, Synthesis, 1997,11,1246-1248) make.
M.p.123～124℃。
1H-NMR(δ，CDCl
3)：14.20(s，1H，)，8.14(d，1H，J＝15.6Hz)，7.87(d，1H，J＝15.6Hz)，7.68-7.70(m，1H)，7.42-7.44(m，1H)，7.26-7.31(m，2H)，6.11(s，1H)，5.96(s，1H)，3.90(s，3H)，3.84(s，3H)。
Embodiment 3,3 '-allyloxy-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (compound Va):
Compound IV 3.2g (10.0mmol), Anhydrous potassium carbonate 2.0g (15.0mmol) and anhydrous propanone 30mL put into reaction flask, stir to drip allyl bromide 98 10.4mL (12.0mmol) down.Finish temperature rising reflux 4 hours.Separate out small amount of solid after the reaction solution cooling, suction filtration gets light yellow liquid 3.4g, yield 95% after filtrate decompression reclaims.
1H-NMR(δ，CDCl
3)：7.79(d，1H，J＝16.0Hz)，7.66(m，1H)，7.39(m，1H)，7.28(m，2H)，6.93(d，1H，J＝16.0Hz)，6.16(d，1H，J＝2.0Hz)，6.14(d，1H，J＝2.0Hz)，5.95(m，1H)，5.33(dd，1H，J
1＝15.8Hz，J
2＝1.2Hz)，5.50(m，2H)，3.84(s，3H)，3.78(s，3H)。
Embodiment 4,2 '-hydroxyl-3 '-allyl group-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (compound VI a):
Compound Va 4.0g (12.5mmol) is dissolved among the DMF (20mL), backflow 6h under the nitrogen protection, and after reaction solution removes solvent under reduced pressure, thin up, methylene dichloride (40mL * 3) extracts, saturated nacl aqueous solution (40mL * 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and crude product gets yellow solid 3.0g through column chromatography, yield 75%.
M.p.167～168℃。
1H-NMR(δ，CDCl
3)：13.93(s，1H)，8.08(d，1H，J＝15.6Hz)，7.80(d，1H，J＝15.6Hz)，7.65(m，1H)，7.39(m，1H)，7.26(m，2H)，5.97(s，1H)，5.94(m，1H)，4.95(m，2H)，3.91(s，3H)，3.87(s，3H)，3.31(m，2H)。
Embodiment 5,2 '-acetoxy-3 '-allyl group-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (compound VI Ia):
Compound VI a 1.6g (5.0mmol) is dissolved in the anhydrous pyridine (30mL), adds aceticanhydride 0.6mL (6.3mmol), stirring at room 10 hours, and the TLC detection reaction is complete.Remove solvent under reduced pressure, thin up, with the acidifying of 2N hydrochloric acid soln, methylene dichloride (20mL * 3) extracts, saturated nacl aqueous solution (20mL * 3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and the crude product column chromatography gets yellow solid 1.7g, yield 85%.
M.p.106～109℃。
1H-NMR(δ，CDCl
3)：7.89(d，1H，J＝15.6Hz)，7.65(m，1H)，7.40(m，1H)，7.30(m，2H)，7.06(d，1H，J＝15.6Hz)，5.97(s，1H)，5.90(m，1H)，4.96(m，2H)，3.91(s，3H)，3.83(s，3H)，3.32(m，2H)，2.26(s，3H)。
Embodiment 6,2 '-acetoxy-3 '-epoxypropyl-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (compound VIII a):
Compound VI Ia 0.6g (1.5mmol) is dissolved among the methylene dichloride 20mL, adds benzoyl hydroperoxide 0.7g (4.5mmol), stirring at room 48h.The TLC detection reaction is complete.Transfer pH 7 with saturated sodium bicarbonate solution, methylene dichloride (60mL * 2) extracts, saturated nacl aqueous solution (60mL * 2) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and the crude product column chromatography gets yellow solid 0.40g, yield 65%.
M.p.115～116℃。
1H-NMR(δ，CDCl
3)：7.89(d，1H，J＝15.6Hz)，7.65(m，1H)，7.41(m，1H)，7.33(m，2H)，7.01(d，1H，J＝15.6Hz)，6.43(s，1H)，3.92(s，3H)，3.86(s，3H)，3.07(m，1H)，2.70(dd，1H，J
1＝16.0Hz，J
2＝4.0Hz)，2.67(dd，1H，J
1＝15.6Hz，J
2＝4.4Hz)，2.59(m，1H)，2.51(dd，1H，J
1＝5.2Hz，J
2＝2.4Hz)，2.25(s，3H)。
Embodiment 7,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-morpholine-4-base propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xa)
Compound VIII 150.0mg (0.36mmol), morpholine 0.2mL (1.8mmol) and ethanol 2mL drop into reaction flask.Room temperature reaction 24h, the TLC detection reaction is complete.Reclaim under reduced pressure, thin up, dichloromethane extraction (15mL * 2) extracts, saturated nacl aqueous solution (30mL * 2) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and the crude product column chromatography gets yellow solid 120.0mg, yield 72%.
M.p.141～143℃。
1H-NMR(δ，CDCl
3)：13.93(s，1H)，8.11(d，1H，J＝15.6Hz)，7.81(d，1H，J＝15.6Hz)，7.69(m，1H)，7.43(m，1H)，7.30(m，2H)，6.01(s，1H)，4.00(s，3H)，3.95(s，3H)，3.81(m，1H)，3.70(m，4H)，3.10(dd，1H，J
1＝13.6Hz，J
2＝7.2Hz)，2.91(dd，1H，J
1＝13.2Hz，J
2＝7.2Hz)，2.49(m，2H)，2.24(m，4H)。
Embodiment 8,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-piperidines-1-base propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xb)
Operating process just substitutes morpholine with piperidines referring to embodiment 7, obtains yellow solid, yield 75%.
M.p.135～136℃。
1H-NMR(δ，CDCl
3)：8.11(d，1H，J＝15.6Hz)，7.81(d，1H，J＝15.6Hz)，7.69(m，1H)，7.43(m，1H)，7.30(m，2H)，6.01(s，1H)，3.94(s，3H)，3.91(s，3H)，3.91(m，1H)，2.87(dd，1H，J
1＝13.6Hz，J
2＝6.4Hz)，2.73(dd，1H，J
1＝13.2Hz，J
2＝6.8Hz)，2.55(m，2H)，2.32(m，4H)，1.53(m，4H)，1.41(m，2H)。
Embodiment 9,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-tetramethyleneimine-1-base propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xc)
Operating process just substitutes morpholine with tetramethyleneimine referring to embodiment 7, obtains yellow solid, yield 75%.
M.p.132～135℃。
1H-NMR(δ，CDCl
3)：8.10(d，1H，J＝15.6Hz)，7.79(d，1H，J＝15.6Hz)，7.69(m，1H)，7.43(m，1H)，7.31(m，2H)，6.02(s，1H)，3.94(s，3H)，3.91(s，3H)，3.91(m，1H)，2.87(dd，1H，J
1＝13.2Hz，J
2＝5.6Hz)，2.79(dd，1H，J
1＝13.2Hz，J
2＝5.8Hz)，2.69(m，4H)，2.52(m，2H)，1.73(s，4H)。
Embodiment 10,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-(4-methylpiperazine-1-yl) propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xd)
Operating process just substitutes morpholine with the 1-methylpiperazine referring to embodiment 7, obtains yellow solid, yield 75%.
M.p.166～168℃。
1H-NMR(δ，CDCl
3)：13.94(s，1H)，8.10(d，1H，J＝15.6Hz)，7.84(d，1H，J＝15.6Hz)，7.74(m，1H)，7.43(m，1H)，7.31(m，2H)，5.98(s，1H)，3.93(s，3H)，3.90(s，3H)，3.92(m，1H)，3.07(dd，1H，J
1＝13.6Hz，J
2＝7.2Hz)，2.88(dd，1H，J
1＝13.6Hz，J
2＝6.8Hz)，2.61(s，2H)，2.37(m，8H)，2.24(s，3H)。
Embodiment 11,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-diethylin propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xe)
Operating process just substitutes morpholine with diethylamine referring to embodiment 7, obtains yellow solid, yield 75%.
M.p.114～116℃。
1H-NMR(δ，CDCl
3)：13.94(s，1H)，8.10(d，1H，J＝15.6Hz)，7.84(d，1H，J＝15.6Hz)，7.74(m，1H)，7.43(m，1H)，7.31(m，2H)，5.98(s，1H)，3.97(s，3H)，3.90(s，3H)，3.92(m，1H)，3.03(dd，1H，J
1＝13.6Hz，J
2＝7.2Hz)，2.84(dd，1H，J
1＝13.6Hz，J
2＝6.8Hz)，2.39(m，6H)，0.94(t，6H)。
Embodiment 12,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-first and second aminocarbonyl propyls) phenyl) third-2-alkene-1-ketone (Compound I Xf)
Operating process just substitutes morpholine with thyl methyl amine referring to embodiment 7, obtains yellow solid, yield 75%.
M.p.115～116℃。
1H-NMR(δ，CDCl
3)：8.12(d，1H，J＝15.6Hz)，7.82(d，1H，J＝15.6Hz)，7.70(m，1H)，7.44(m，1H)，7.30(m，2H)，6.02(s，1H)，3.95(s，3H)，3.92(s，3H)，3.92(m，1H)，2.88(dd，1H，J
1＝13.2Hz，J
2＝5.2Hz)，2.74(dd，1H，J
1＝13.6Hz，J
2＝4.8Hz)，2.41(m，4H)，2.24(s，3H)，1.04(t，3H)。
Embodiment 12,3-(2-chloro-phenyl-)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-dimethylamino-propyl) phenyl) third-2-alkene-1-ketone (Compound I Xg)
Operating process just substitutes morpholine with dimethylamine referring to embodiment 7, obtains yellow solid, yield 75%.
M.p.127～129℃。
1H-NMR(δ，CDCl
3)：14.03(s，1H)，8.12(d，1H，J＝15.6Hz)，7.82(d，1H，J＝15.6Hz)，7.69(m，1H)，7.43(m，1H)，7.30(m，2H)，6.02(s，1H)，3.95(s，3H)，3.92(s，3H)，3.92(m，1H)，2.87(dd，1H，J
1＝13.6Hz，J
2＝7.2Hz)，2.75(dd，1H，J
1＝13.6Hz，J
2＝6.8Hz)，2.44(dd，1H，J
1＝13.6Hz，J
2＝6.2Hz)，2.26(s，6H)，2.21(dd，1H，J
1＝13.6Hz，J
2＝6.8Hz)。
Embodiment 13,2 '-hydroxyl-4 ', 6 '-dimethoxy-4 '-trifluoromethyl-phenyl styryl ketone (compound IV b)
Operating process is just used trifluoromethylated benzaldehyde is substituted o-chlorobenzaldehyde referring to embodiment 2, obtains the glassy yellow solid, yield 65%.
M.p.149～152℃。
1H-NMR(δ，CDCl
3)：14.14(s，H)，7.79(d，1H，J＝15.2Hz)，7.75(d，1H，J＝15.2Hz)，7.68(m，4H)，6.11(s，1H)，5.97(s，1H)，3.92(s，3H)，3.85(s，3H)。
Embodiment 14,3 '-allyloxy-4 ', 6 '-dimethoxy-4 '-trifluoromethyl-phenyl styryl ketone (compound Vb):
Operating process just substitutes IVa with IVb referring to embodiment 3, obtains weak yellow liquid, yield 96%.
1H-NMR(δ，CDCl
3)：7.62(d，1H，J＝16.0Hz)，7.59(m，4H)，7.44(d，1H，J＝16.0Hz)，6.17(d，1H，J＝2.0Hz)，6.15(d，1H，J＝2.0Hz)，5.96(m，1H)，5.35(dd，1H，J
1＝16.8Hz，J
2＝1.2Hz)，5.30(m，2H)，3.84(s，3H)，3.78(s，3H)。
Embodiment 15,2 '-hydroxyl-3 '-allyl group-4 ', 6 '-dimethoxy-4 '-trifluoromethyl-phenyl styryl ketone (compound VI b):
Operating process just substitutes Va with Vb referring to embodiment 4, obtains yellow solid, yield 96%.
M.p.154～156℃。
1H-NMR(δ，CDCl
3)：13.95(s，1H)，7.93(d，1H，J＝15.2Hz)，7.74(d，1H，J＝15.2Hz)，7.72(m，4H)，6.03(s，1H)，6.00(m，1H)，5.00(m，2H)，3.93(s，3H)，3.78(s，3H)，3.37(m，2H)。
Embodiment 16,2 '-acetoxy-3 '-allyl group-4 ', 6 '-dimethoxy-4 '-trifluoromethyl-phenyl styryl ketone (compound VI Ib):
Operating process just substitutes VIa with VIb referring to embodiment 5, obtains yellow solid, yield 82%.
M.p.105～106℃。
1H-NMR(δ，CDCl
3)：7.89(d，1H，J＝15.2Hz)，7.40(m，4H)，7.21(d，1H，J＝15.2Hz)，6.03(s，1H)，6.00(m，1H)，5.00(m，2H)，3.93(s，3H)，3.73(s，3H)，3.47(m，2H)，2.26(s，3H)。
Embodiment 17,2 '-acetoxy-3 '-epoxypropyl-4 ', 6 '-dimethoxy-2-chloro-phenyl styryl ketone (compound VIII b):
Operating process just substitutes VIIa with VIIb referring to embodiment 6, obtains yellow solid, yield 67%.
m.p.113～114℃。
1H-NMR(δ，CDCl
3)：7.90(d，1H，J＝15.2Hz)，7.42(m，4H)，7.34(d，1H，J＝15.2Hz)，6.03(s，1H)，6.00(m，1H)，5.00(m，2H)，3.93(s，3H)，3.73(s，3H)，3.00(dd，1H，J
1＝16.0Hz，J
2＝4.0Hz)，2.97(dd，1H，J
1＝15.6Hz，J
2＝4.4Hz)，2.76(m，1H)，2.49(m，1H)，2.40(dd，1H，J
1＝5.2Hz，J
2＝2.4Hz)，2.25(s，3H)。
Embodiment 18,3-(4-trifluoromethyl)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-piperidines-1-base propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xh)
Compound VIII b 120.0mg (0.3mmol), piperidines 0.2mL (1.3mmol) and ethanol 2mL drop into reaction flask.Room temperature reaction 24h, the TLC detection reaction is complete.The reclaim under reduced pressure reaction solution, thin up, dichloromethane extraction (15mL * 2) extracts, saturated nacl aqueous solution (30mL * 2) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression reclaims, and the crude product column chromatography gets yellow solid 108.0mg, yield 72%.
M.p.114～116℃。
1H-NMR(δ，CDCl
3)：13.86(s，1H)，7.87(d，1H，J＝15.2Hz)，7.72(d，1H，J＝15.2Hz)，7.66(m，4H)，6.03(s，1H)，3.96(s，3H)，3.92(s，3H)，3.92(m，1H)，2.87(dd，1H，J
1＝13.6Hz，J
2＝7.2Hz)，2.70(dd，1H，J
1＝13.2Hz，J
2＝6.8Hz)，2.54(m，2H)，2.33(m，4H)，1.54(m，4H)，1.42(m，2H)。
Embodiment 19,3-(4-trifluoromethyl)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-diethylin propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xi)
Operating process just substitutes piperidines with diethylamine referring to embodiment 18, obtains yellow solid, yield 65%.
Mp.125～127℃。
1H-NMR(δ，CDCl
3)：13.95(s，1H)，7.86(d，1H，J＝15.2Hz)，7.74(d，1H，J＝15.2Hz)，7.66(m，4H)，6.00(s，1H)，3.96(s，3H)，3.92(s，3H)，3.92(m，1H)，2.76(dd，1H，J
1＝13.6Hz，J
2＝5.2Hz)，2.71(dd，1H，J
1＝13.2Hz，J
2＝4.8Hz)，2.54(m，2H)，2.40(m，6H)，0.94(t，6H)。
Embodiment 20,3-(4-trifluoromethyl)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-first and second aminocarbonyl propyls) phenyl) third-2-alkene-1-ketone (Compound I Xj)
Operating process just substitutes piperidines with thyl methyl amine referring to embodiment 18, obtains yellow solid, yield 76%.
M.p.113～116℃。
1H-NMR(δ，CDCl
3)：13.85(s，1H)，7.87(d，1H，J＝15.2Hz)，7.74(d，1H，J＝15.2Hz)，7.66(m，4H)，6.03(s，1H)，3.96(s，3H)，3.93(s，3H)，3.93(m，1H)，2.76(dd，1H，J
1＝13.6Hz，J
2＝5.2Hz)，2.71(dd，1H，J
1＝13.2Hz，J
2＝4.8Hz)，2.41(m，4H)，2.24(s，3H)，1.04(t，3H)。
Embodiment 21,3-(4-trifluoromethyl)-1-(2-hydroxyl-4,6-dimethoxy-3-(2-hydroxyl-3-morpholine-4-base propyl group) phenyl) third-2-alkene-1-ketone (Compound I Xk)
Operating process just substitutes piperidines with morpholine referring to embodiment 18, obtains yellow solid, yield 76%.
M.p.166～168℃。
1H-NMR(δ，CDCl
3)：14.01(s，1H)，7.90(d，1H，J＝15.2Hz)，7.74(d，1H，J＝15.2Hz)，7.68(m，4H)，6.03(s，1H)，3.98(s，3H)，3.93(s，3H)，3.92(m，1H)，3.70(m，4H)，3.10(dd，1H，J
1＝13.6Hz，J
2＝7.2Hz)，2.91(dd，1H，J
1＝13.2Hz，J
2＝7.2Hz)，2.49(m，2H)，2.24(m，4H)。
Embodiment 22, anti-tumor biological testing method:
The tumour cell isolated culture:
Choose tumour cell ECA-109, A-549, HL-60, PC-3 is in 37 ℃, 5%CO
2Hatch in the cell culture incubator, go down to posterity when treating cell density length (attached cell is gone down to posterity after using Puck ' s EDTA digestion) to 70-90%, experiment is required after being used for.
Mtt assay is measured the vitro inhibition effect of compound to tumour cell:
(HL-60 PC-3) is diluted to 4 * 10 for ECA-109, A-549 will to be in the tumour cell of logarithmic phase
4Individual cell/mL, every hole adds 0.1mL in 96 porocyte culture plates, adds the testing compound that concentration is 12.0mg/L, 6.0mg/L, 3.0mg/L, 1.5mg/L then, and 37 ℃, 5%CO are put in every group 3 multiple hole
2Hatched in the cell culture incubator 72 hours, it is the MTT solution 5 μ L of 5mg/mL that experiment stops preceding 4 hours every hole adding concentration, continues to cultivate abandoning supernatant after 4 hours, and every hole adds DMSO 200 μ L, measures the absorbance (A in each hole with the enzyme marking apparatus
570nm), the gained data are used to calculate IC
50Value.Gained the results are shown in Table 1:
11 compounds of table 1 synthetic are to the IC of different tumor cell lines
50(μ g/mL) value
| Compd. | IC 50(μg/mL) | |||
| ECA-109 | A-549 | HL-60 | PC-3 | |
| IXa IXb IXc IXd IXe IXf IXg IXh IXi IXj IXk | 6.8 1.3 4.6 4.1 1.0 2.4 2.1 2.3 6.8 2.5 11.1 | 2.8 1.6 2.4 4.8 1.5 2.6 2.5 2.2 nd 2.4 nd | - - - - - - - - 1.5 - 0.21 | - - - - - - - - 0.56 - 8.94 |
As can be seen from the above table, 11 1) all compounds all have certain inhibition activity to 2 kinds of tumor cell lines; 2) 3 '-the position substituted-amino is that the Compound I Xb and the IXe of piperidine ring and open loop analogue diethylin thereof has higher inhibition activity to tumor cell line; 3) Compound I Xk has higher inhibition activity to the HL-60 cell strain, shows that it has selectivity; 4) with respect to the Chloro-O-Phenyl substituting group, the compound that p-trifluoromethyl phenyl replaces wants weak to the inhibition of tumor cell line is active; 5) generally speaking, this compounds has certain antitumor application prospect.
Claims (7)
1. 2 '-hydroxyl-3 '-alkanamine propyl group-4 ', 6 '-two replace chalcone derivatives, and general structure is:
Wherein:
R
1Straight or branched alkane for hydrogen atom, 1 to 4 carbon atom;
Ar is for do not have replacing, singly replace, two replace or trisubstituted phenyl ring, and the substituting group on the phenyl ring is hydrogen atom, halogen atom, hydroxyl, trifluoromethyl, methylsulfonyl, contain the alkyl of the straight or branched of 1 to 10 carbon atom, contain the alkoxyl group of the straight or branched of 1 to 4 carbon atom;
R
2Tertiary amine structure NR for ring-type or open chain
3R
4, R wherein
3And R
4Identical or different, they can be methyl, ethyl, contain alkyl alcohol, alkyl oxide and the ester thereof of 1-4 carbon atom, contain the carboxylic acid and the ester thereof of 1-4 carbon atom, contain the alkylamine of 1-4 carbon atom, or R
3, R
4Be respectively carbon, oxygen, reach five yuan of nitrogen-atoms ring synthetic or six-ring.
2. 2 '-hydroxyl-3 ' according to claim 1-alkanamine propyl group-4 ', 6 '-two replace the preparation method of chalcone derivative, it is characterized in that realizing by following steps:
(1) Compound I and anhydrous acetonitrile obtain intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate through Lewis acid catalysis in inert solvent, temperature of reaction is-15 ℃-25 ℃, reaction times is 6-8 hour, intermediate trihydroxy-acetophenone inferior amine salt hydrochlorate obtains Compound I I through acidic hydrolysis again, temperature of reaction is 80 ℃-110 ℃, reacts to be time 1-5 hour;
(2) Compound I I selective etherification through halohydrocarbon under alkaline condition obtains compound III, obtains pure product through recrystallization, is reflected in the polar solvent and carries out, and temperature of reaction is 0-50 ℃;
(3) compound III obtains compound IV with the aromatic aldehyde condensation under alkaline condition, is reflected in the mixed solvent of protic to carry out, and temperature of reaction is 5-30 ℃, and crude product obtains pure product through recrystallization;
(4) compound IV allyl etherificate under alkaline condition obtains compound V, is reflected in the polar solvent and carries out, and temperature of reaction is 30-80 ℃, and products therefrom is directly used in next step reaction;
(5) compound V obtains compound VI through Claisen rearrangement in high boiling solvent, and temperature of reaction is 150-210 ℃, and crude product obtains pure product through recrystallization;
(6) compound VI and aceticanhydride acidylate obtain compound VI I, are reflected in the polar solvent and carry out, and temperature of reaction is 10-30 ℃, and crude product obtains pure product through column chromatography;
(7) compound VI I obtains compound VIII through acid oxidase, is reflected in the polar solvent and carries out, and temperature of reaction is 10-30 ℃, and crude product obtains pure product through column chromatography;
(8) compound VIII and secondary amine addition obtain Compound I X, are reflected in the polar solvent and carry out, and temperature of reaction is 10-80 ℃, and crude product obtains pure product through column chromatography;
Reaction formula is:
3. 2 '-hydroxyl-3 ' according to claim 2-substituted amido propyl group-4 ', 6 '-two replace the preparation method of chalcone derivatives, it is characterized in that: the mixed solvent of protic is selected methanol-water for use in the step (3), in alcohol-water or the Virahol-water any.
4. 2 '-hydroxyl-3 ' according to claim 2-alkanamine propyl group-4 ', 6 '-two replace the preparation method of chalcone derivative, it is characterized in that: high boiling solvent is selected naphthane, phenyl ether, N for use in the step (5), accelerine, N, in dinethylformamide or the trifluoracetic acid any.
5. 2 '-hydroxyl-3 ' according to claim 2-alkanamine propyl group-4 ', 6 '-two replace the preparation method of chalcone derivatives, it is characterized in that: peracid is selected in benzoyl hydroperoxide, peroxide phthalic acid, metachloroperbenzoic acid, peroxyformic acid or the peracetic acid any for use in the step (7).
6. 2 '-hydroxyl-3 ' according to claim 2-alkanamine propyl group-4 ', 6 '-two replace the preparation method of chalcone derivative, it is characterized in that: step (8) Semi-polarity solvent is selected methyl alcohol, ethanol, Virahol, acetonitrile, dioxane, acetone, N for use, in dinethylformamide or the dimethyl sulfoxide (DMSO) any.
7. 2 '-hydroxyl-3 ' according to claim 1-alkanamine propyl group-4 ', 6 '-two replace the application of chalcone derivative in the preparation antitumor drug.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102924249A (en) * | 2011-08-10 | 2013-02-13 | 浙江医药股份有限公司新昌制药厂 | Preparation method of lycopene intermediate 2-methyl-3,3-dimethoxy-1-propionaldehyde |
| WO2014167481A1 (en) | 2013-04-08 | 2014-10-16 | Universita' Di Pisa | Synthetic analogues of xanthohumol |
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| GB9920908D0 (en) * | 1999-09-03 | 1999-11-10 | Indena Spa | Chalcone coumarins |
| CN1188118C (en) * | 2002-07-23 | 2005-02-09 | 中国科学院昆明植物研究所 | Medicine for preventing or treating cancer and its usage |
| CN100336797C (en) * | 2005-08-19 | 2007-09-12 | 浙江大学 | Tetra substituted chalcone derivative and preparing method and use |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102924249A (en) * | 2011-08-10 | 2013-02-13 | 浙江医药股份有限公司新昌制药厂 | Preparation method of lycopene intermediate 2-methyl-3,3-dimethoxy-1-propionaldehyde |
| CN102924249B (en) * | 2011-08-10 | 2014-10-29 | 浙江医药股份有限公司新昌制药厂 | Preparation method of lycopene intermediate 2-methyl-3,3-dimethoxy-1-propionaldehyde |
| WO2014167481A1 (en) | 2013-04-08 | 2014-10-16 | Universita' Di Pisa | Synthetic analogues of xanthohumol |
| CN109293480A (en) * | 2018-10-31 | 2019-02-01 | 陕西硕博电子材料有限公司 | Diallyl bisphenol, preparation method and Bismaleimides resin pre-polymer |
| CN109608318A (en) * | 2019-01-31 | 2019-04-12 | 上海生农生化制品股份有限公司 | A kind of industrial preparative method of tebuconazole intermediate α |
| CN111995508A (en) * | 2020-03-24 | 2020-11-27 | 兰州交通大学 | Synthesis method of antitumor active compound Sanjoseolide |
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