CN107382947A - A kind of quercetin derivative and its preparation method and application - Google Patents
A kind of quercetin derivative and its preparation method and application Download PDFInfo
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- CN107382947A CN107382947A CN201710598459.XA CN201710598459A CN107382947A CN 107382947 A CN107382947 A CN 107382947A CN 201710598459 A CN201710598459 A CN 201710598459A CN 107382947 A CN107382947 A CN 107382947A
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- dihydroxy
- amoxy
- diethylamine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 150000003244 quercetin derivatives Chemical class 0.000 title claims abstract description 28
- -1 3,4 dihydroxy phenyl Chemical group 0.000 claims abstract description 55
- 235000005875 quercetin Nutrition 0.000 claims abstract description 34
- 102000012440 Acetylcholinesterase Human genes 0.000 claims abstract description 10
- 108010022752 Acetylcholinesterase Proteins 0.000 claims abstract description 10
- 229940022698 acetylcholinesterase Drugs 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 230000007131 anti Alzheimer effect Effects 0.000 claims abstract description 6
- 235000013376 functional food Nutrition 0.000 claims abstract description 6
- 150000002576 ketones Chemical class 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 45
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- JOOMLFKONHCLCJ-UHFFFAOYSA-N N-(trimethylsilyl)diethylamine Chemical compound CCN(CC)[Si](C)(C)C JOOMLFKONHCLCJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000013067 intermediate product Substances 0.000 claims description 18
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 claims description 16
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 claims description 16
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 claims description 16
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 claims description 16
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 claims description 16
- 235000005493 rutin Nutrition 0.000 claims description 16
- 229960004555 rutoside Drugs 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000001556 precipitation Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- 150000004880 oxines Chemical class 0.000 claims description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 abstract description 22
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 abstract description 12
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 abstract description 12
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 abstract description 12
- 229960001285 quercetin Drugs 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 150000008371 chromenes Chemical class 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 8
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- 229960004373 acetylcholine Drugs 0.000 description 6
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 230000001713 cholinergic effect Effects 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical class OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NTBLZMAMTZXLBP-UHFFFAOYSA-M 2-acetylsulfanylethyl(trimethyl)azanium;iodide Chemical class [I-].CC(=O)SCC[N+](C)(C)C NTBLZMAMTZXLBP-UHFFFAOYSA-M 0.000 description 1
- 150000005341 2-nitrobenzoic acids Chemical class 0.000 description 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- OWBBAPRUYLEWRR-UHFFFAOYSA-N 4-hydroxycoumarin Chemical class C1=CC=C2OC(O)=CC(=O)C2=C1 OWBBAPRUYLEWRR-UHFFFAOYSA-N 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- SZXMZDZPYADDSM-UHFFFAOYSA-N CCN(CC)CCCCCOC1=C(c(cc2O)ccc2O)Oc(cc(cc2O)O)c2C1=O Chemical compound CCN(CC)CCCCCOC1=C(c(cc2O)ccc2O)Oc(cc(cc2O)O)c2C1=O SZXMZDZPYADDSM-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical class O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- ZQPQGKQTIZYFEF-WCVJEAGWSA-N Huperzine Natural products C1([C@H]2[C@H](O)C(=O)N[C@H]2[C@@H](O)C=2C=CC=CC=2)=CC=CC=C1 ZQPQGKQTIZYFEF-WCVJEAGWSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
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- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- SCNUFWNKVSUNIP-UHFFFAOYSA-N chembl32526 Chemical class C1=CC=C2C(=O)C(O)=C(O)OC2=C1 SCNUFWNKVSUNIP-UHFFFAOYSA-N 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 150000004777 chromones Chemical class 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
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- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of quercetin derivative and its preparation method and application.A kind of quercetin derivative of the present invention, its chemical structural formula have shown in formula (I)：
Description
Technical field
The present invention relates to pharmaceutical formulating art, and in particular to a kind of quercetin derivative and preparation method thereof and its should
With.
Background technology
Alzheimer's disease is a kind of cranial nerve retrogression pathological changes being common in the elderly.The disease incidence is high, dead
Rate height is died, has become one of disease most threatening in modern society.The pathogenesis of alzheimer's disease is current still not
Clearly, in recent years for the molecular biology research of the cause of disease of alzheimer's disease, pathology and correlation, scientists are from difference
Angle proposes Different types of etiopathogenises hypothesis, wherein representative hypothesis have cholinergic theory, amyloid beta toxic action,
Free radicals injury, inflammatory disorderses, brain energy metabolism obstacle, gene defect and mutation etc..
Cholinergic theory thinks that the brain cholinergic nerve system of the patient with alzheimer's disease is compromised, causes
The decline of protuberance acetyl choline content, so as to cause the learning and remembering ability of patient to be damaged.Utilize acetylcholine ester enzyme level
Agent suppresses the hydrolysis of neurotransmitter acetylcholine, can improve the cognitive ability of patient.At present, acetylcholinesteraseinhibitors inhibitors are such as
The first-class treatment for having been used to Alzheimer disease of Tacrine, donepezil, rivastigmine, galanthamine, huperzine.So
And existing acetylcholinesteraseinhibitors inhibitors can only improve the content of acetylcholine, it is impossible to prevent cholinergic nerve of centrum unit
Progressive degeneration and death.With disease development, progressive death, acetylcholinesteraseinhibitors inhibitors occur for cholinergic nerve of centrum unit
Drug effect also can gradually reduce, while these medicines also have some toxic side effects.Therefore, less toxic, efficient acetylcholine is found
Esterase medicine becomes the Main way of current anti-Alzheimer disease drug research.
Quercetin is a kind of naturally occurring flavone compound.The compound has many physiological functions, such as anti-oxidant,
Antitumor action, the protective action to blood vessel, raising immunity and antibacterial and anti-inflammation functions etc..Because Quercetin is plane point
Son, molecular stuffing is closer, and intermolecular attraction is larger, is not easy by solvent or Dispersion of Solute Matter, so Quercetin is water-soluble poor,
Bioavilability is relatively low, and is extremely limited the clinical practice of Quercetin.By being modified Quercetin structure, being changed
Make, water-soluble enhancing can be obtained, the quercetin derivative that bioavilability improves, activity is higher, has more to develop
The medicine of clinical value.The present invention contains diethylin by being introduced in 3 hydroxyls of Quercetin, and preparation contains diethylin
Quercetin derivative.
This analog derivative has acetylcholinesteraseinhibition inhibition, and therefore, quercetin derivative is as very promising anti-
The functional food factor of Alzheimer disease or the prospect of medicine extremely merit attention.
The content of the invention
The purpose of the present invention is in view of the above-mentioned problems, having inhibiting activity of acetylcholinesterase the invention provides a kind of
Quercetin derivative and its preparation method and application.
To reach above-mentioned purpose, present invention employs following technical proposal：A kind of quercetin derivative of the present invention, its
Chemical structural formula has shown in formula (I)：
Entitled 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5, the 7- dihydroxy -4H-1- benzene of chemistry
And pyrans -4- ketone.
The preparation method of quercetin derivative of the present invention, comprises the following steps：
The preparation of (1) 7,3 ', 4 '-three benzyloxy Quercetins；
(2) 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones
Prepare；
(3) 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles
Mutter the preparation of -4- ketone.
Further, in step (1), 7,3 ', 4 ' will be obtained using sour water solution desugar after rutin and cylite reaction-
Three benzyloxy Quercetins；
In step (2), by 7,3 ', 4 '-three benzyloxy Quercetins and 1 of gained in step (1), pentamethylene bromide reaction
Intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones are made；
In step (3), the intermediate product of gained in step (2) is reacted to obtain 2- (3,4- dihydroxy benzenes with diethylamine
Base) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones.
Further, in step (1), the dry rutin for sloughing the crystallization water is dissolved in dry DMF, is then added anhydrous
Potassium carbonate is stirred at room temperature 15 minutes, cylite is then added in 50~55 DEG C of stirring reactions 3~4 hours, after reaction terminates
Second acid for adjusting pH value using 10% is 6~6.5, filtering, is precipitated, is precipitated and dissolved in absolute ethyl alcohol, add dense salt
Acid, mixture are flowed back 2~2.5 hours at 78 DEG C, filtered after being cooled to room temperature, obtained light yellow solid, and obtained solid is used
Methylene chloride/methanol is recrystallized to give 7,3 ', 4 '-three benzyloxy Quercetins.
Further, in step (2), 7,3 ', 4 '-three benzyloxy Quercetins are added in dry DMF, are then added
Anhydrous potassium carbonate, after being stirred at room temperature 15 minutes, 1 being added, pentamethylene bromide, the mixture reacts 3.5~4 hours at 35 DEG C,
After reaction terminates, reaction solution is poured into frozen water, and then with dichloromethane extraction three times, organic layer is dried with anhydrous magnesium sulfate, is obtained
Intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- bis- is made with silica gel column chromatography is used in the product arrived
Hydroxyl -4H-1- benzopyran-4-ones.
Further, in step (3), by intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7-
Dihydroxy -4H-1- benzopyran-4-ones are dissolved into dry DMF, then add diethylamine, and reaction solution reacts 3~4 in 50 DEG C
Hour, after reaction terminates, reaction solution is poured into frozen water, is filtrated to get precipitation, gained solid precipitation be dissolved into absolute ethyl alcohol with
In the mixed solution of Isosorbide-5-Nitrae-dioxane, palladium carbon is then added, is passed through hydrogen, is stirred 2~2.5 hours at room temperature, diatomite mistake
Filter, organic phase silica gel column chromatography, compound 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- is made
Dihydroxy -4H-1- benzopyran-4-ones.
Further, in step (1), the rutin, the mass ratio of Anhydrous potassium carbonate are 34:53.79, the rutin with
The mass volume ratio of cylite is 34g：46ml；The volume ratio of the dry DMF, absolute ethyl alcohol and concentrated hydrochloric acid is 26~38：75
~80:15；
In step (2), the mass ratio of described 7,3 ', 4 '-three benzyloxy Quercetins and Anhydrous potassium carbonate is 33：15.9；
The volume ratio of the dry DMF, 1, pentamethylene bromide and frozen water is 15~18：1：100~120；
In step (3), 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5, the 7- dihydroxy -4H-1- benzene
And pyrans -4- ketone and the mass volume ratio of dry DMF are 0.8g：10~12mL；The dry DMF, diethylamine, frozen water and anhydrous
The volume ratio of ethanol is 10~12：0.95：30~35：50~55；2- (3, the 4- dihydroxy phenyl) -3- (oxygen of 5- bromines penta
Base) mass ratio of -5,7- dihydroxy -4H-1- benzopyran-4-ones and palladium carbon is 4：1.
Quercetin derivative 2- (3,4- dihydroxy phenyl) -3- (5-N, N- bis- described in a kind of claim 1 of the present invention
Ethamine amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones prepare the functional food of anti-Alzheimer disease because or
Application in medicine.
Further, described quercetin derivative has inhibiting activity of acetylcholinesterase.
Beneficial effect：The present invention by being chemically modified to obtain the 2- (3,4- bis- of quercetin derivative to Quercetin
Hydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones.Conjunction of the present invention
Simple into process conditions requirement, operation is simple, and each efficiency of pcr product is higher, is advantageous to production application in the future.The compound of synthesis
2- (3,4- dihydroxy phenyls) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones have compared with
Strong inhibiting activity of acetylcholinesterase, available for the functional food or medicine for preparing anti-Alzheimer disease.
Embodiment
The present invention is further described by following examples, but the scope of the present invention is not appointed by these embodiments
What is limited.
Embodiment 1
A kind of quercetin derivative of the present invention, its chemical structural formula have shown in formula (I)：
Entitled 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5, the 7- dihydroxy -4H-1- benzene of chemistry
And pyrans -4- ketone.
The preparation method of quercetin derivative of the present invention, comprises the following steps：
The preparation of (1) 7,3 ', 4 '-three benzyloxy Quercetins；The dry rutin for sloughing the crystallization water is dissolved in dry DMF,
Then add Anhydrous potassium carbonate and be stirred at room temperature 15 minutes, then add cylite in 53 DEG C of stirring reactions 4 hours, reaction knot
The second acid for adjusting pH value that 10% is utilized after beam is 6.5, filtering, is precipitated, is precipitated and dissolved in absolute ethyl alcohol, add dense salt
Acid, mixture flow back 2 hours at 78 DEG C, filtered after being cooled to room temperature, obtained light yellow solid, obtained solid dichloromethane
Alkane/recrystallizing methanol obtains 7,3 ', 4 '-three benzyloxy Quercetins.The rutin, the mass ratio of Anhydrous potassium carbonate are 34:
53.79, the mass volume ratio of the rutin and cylite is 34g：46ml；The body of the dry DMF, absolute ethyl alcohol and concentrated hydrochloric acid
Product is than being 26：80:15.
(2) 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones
Prepare；By 7,3 ', 4 '-three benzyloxy Quercetins and 1 of gained in step (1), intermediate product 2- is made in pentamethylene bromide reaction
(3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones；7,3 ', 4 '-three benzyloxies
Base Quercetin is added in dry DMF, then adds Anhydrous potassium carbonate, after being stirred at room temperature 15 minutes, addition 1, and pentamethylene bromide,
The mixture is reacted 3.5 hours at 35 DEG C, and after reaction terminates, reaction solution is poured into frozen water, then extracts three with dichloromethane
Secondary, organic layer is dried with anhydrous magnesium sulfate, and intermediate product 2- (3,4- dihydroxies are made with silica gel column chromatography is used in obtained product
Base phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones.Described 7,3 ', 4 '-three benzyloxy quercitrins
The mass ratio of element and Anhydrous potassium carbonate is 33：15.9；The volume ratio of the dry DMF, 1, pentamethylene bromide and frozen water is 15：1：
120。
(3) 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles
Mutter the preparation of -4- ketone：By intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzene
And pyrans -4- ketone is dissolved into dry DMF, diethylamine is then added, reaction solution reacts 3 hours in 50 DEG C, after reaction terminates, instead
Answer liquid to be poured into frozen water, be filtrated to get precipitation, gained solid precipitates the mixing for being dissolved into absolute ethyl alcohol and Isosorbide-5-Nitrae-dioxane
In solution, palladium carbon is then added, is passed through hydrogen, is stirred 2 hours at room temperature, diatomite filtering, organic phase silica gel column chromatography, is made
Compound 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- chromenes -4-
Ketone.2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5, the 7- dihydroxy -4H-1- benzopyran-4-ones with it is anhydrous
DMF mass volume ratio is 0.8g：12mL；The dry DMF, diethylamine, the volume ratio of frozen water and absolute ethyl alcohol are 11：
0.95：30：53；2- (3,4- the dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- chromenes -4-
Ketone and the mass ratio of palladium carbon are 4：1.
Quercetin derivative 2- (3,4- dihydroxy phenyl) -3- (5-N, N- bis- described in a kind of claim 1 of the present invention
Ethamine amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones prepare the functional food of anti-Alzheimer disease because or
Application in medicine.
Described quercetin derivative has inhibiting activity of acetylcholinesterase.
Embodiment 2
The difference of embodiment 2 and embodiment 1 is：
The preparation method of quercetin derivative of the present invention, comprises the following steps：
The preparation of (1) 7,3 ', 4 '-three benzyloxy Quercetins；The dry rutin for sloughing the crystallization water is dissolved in dry DMF,
Then add Anhydrous potassium carbonate and be stirred at room temperature 15 minutes, then add cylite in 50 DEG C of stirring reactions 3 hours, reaction knot
The second acid for adjusting pH value that 10% is utilized after beam is 6, filtering, is precipitated, is precipitated and dissolved in absolute ethyl alcohol, add dense salt
Acid, mixture flow back 2.5 hours at 78 DEG C, filtered after being cooled to room temperature, obtained light yellow solid, obtained solid dichloro
Methane/recrystallizing methanol obtains 7,3 ', 4 '-three benzyloxy Quercetins.The rutin, the mass ratio of Anhydrous potassium carbonate are 34:
53.79, the mass volume ratio of the rutin and cylite is 34g：46ml；The body of the dry DMF, absolute ethyl alcohol and concentrated hydrochloric acid
Product is than being 28：75:15.
(2) 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones
Prepare；By 7,3 ', 4 '-three benzyloxy Quercetins and 1 of gained in step (1), intermediate product 2- is made in pentamethylene bromide reaction
(3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones；7,3 ', 4 '-three benzyloxies
Base Quercetin is added in dry DMF, then adds Anhydrous potassium carbonate, after being stirred at room temperature 15 minutes, addition 1, and pentamethylene bromide,
The mixture is reacted 4 hours at 35 DEG C, and after reaction terminates, reaction solution is poured into frozen water, then with dichloromethane extraction three times,
Organic layer is dried with anhydrous magnesium sulfate, and intermediate product 2- (3,4- dihydroxy benzenes are made with silica gel column chromatography is used in obtained product
Base) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones.Described 7,3 ', 4 '-three benzyloxy Quercetins with
The mass ratio of Anhydrous potassium carbonate is 33：15.9；The volume ratio of the dry DMF, 1, pentamethylene bromide and frozen water is 16：1：100.
(3) 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles
Mutter the preparation of -4- ketone：By intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzene
And pyrans -4- ketone is dissolved into dry DMF, diethylamine is then added, reaction solution reacts 4 hours in 50 DEG C, after reaction terminates, instead
Answer liquid to be poured into frozen water, be filtrated to get precipitation, gained solid precipitates the mixing for being dissolved into absolute ethyl alcohol and Isosorbide-5-Nitrae-dioxane
In solution, palladium carbon is then added, is passed through hydrogen, is stirred 2.5 hours at room temperature, diatomite filtering, organic phase silica gel column chromatography, system
Obtain compound 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- chromenes -4-
Ketone.2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5, the 7- dihydroxy -4H-1- benzopyran-4-ones with it is anhydrous
DMF mass volume ratio is 0.8g：10mL；The dry DMF, diethylamine, the volume ratio of frozen water and absolute ethyl alcohol are 10：
0.95：33：50.
Embodiment 3
The difference of embodiment 3 and embodiment 1 is：
The preparation method of quercetin derivative of the present invention, comprises the following steps：
The preparation of (1) 7,3 ', 4 '-three benzyloxy Quercetins；The dry rutin for sloughing the crystallization water is dissolved in dry DMF,
Then add Anhydrous potassium carbonate and be stirred at room temperature 15 minutes, then add cylite in 55 DEG C of stirring reactions 3.5 hours, reaction
The second acid for adjusting pH value that 10% is utilized after end is 6.3, filtering, is precipitated, is precipitated and dissolved in absolute ethyl alcohol, added dense
Hydrochloric acid, mixture flow back 2.3 hours at 78 DEG C, filtered after being cooled to room temperature, obtained light yellow solid, and obtained solid is with two
Chloromethanes/recrystallizing methanol obtains 7,3 ', 4 '-three benzyloxy Quercetins.The body of the dry DMF, absolute ethyl alcohol and concentrated hydrochloric acid
Product is than being 38：78:15.
(2) 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones
Prepare；By 7,3 ', 4 '-three benzyloxy Quercetins and 1 of gained in step (1), intermediate product 2- is made in pentamethylene bromide reaction
(3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones；7,3 ', 4 '-three benzyloxies
Base Quercetin is added in dry DMF, then adds Anhydrous potassium carbonate, after being stirred at room temperature 15 minutes, addition 1, and pentamethylene bromide,
The mixture is reacted 3.8 hours at 35 DEG C, and after reaction terminates, reaction solution is poured into frozen water, then extracts three with dichloromethane
Secondary, organic layer is dried with anhydrous magnesium sulfate, and intermediate product 2- (3,4- dihydroxies are made with silica gel column chromatography is used in obtained product
Base phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones.Described 7,3 ', 4 '-three benzyloxy quercitrins
The mass ratio of element and Anhydrous potassium carbonate is 33：15.9；The volume ratio of the dry DMF, 1, pentamethylene bromide and frozen water is 18：1：
110。
(3) 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles
Mutter the preparation of -4- ketone：By intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzene
And pyrans -4- ketone is dissolved into dry DMF, diethylamine is then added, reaction solution reacts 3.6 hours in 50 DEG C, after reaction terminates,
Reaction solution is poured into frozen water, is filtrated to get precipitation, and gained solid precipitation is dissolved into the mixed of absolute ethyl alcohol and Isosorbide-5-Nitrae-dioxane
Close in solution, then add palladium carbon, be passed through hydrogen, stir 2.3 hours at room temperature, diatomite filtering, organic phase silica gel column chromatography,
Obtained compound 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- chromenes -
4- ketone.2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5, the 7- dihydroxy -4H-1- benzopyran-4-ones and nothing
Water DMF mass volume ratio is 0.8g：12mL；The dry DMF, diethylamine, the volume ratio of frozen water and absolute ethyl alcohol for 10~
12：0.95：35：55.
Embodiment 4
The preparation of 7,3 ', 4 '-three benzyloxy Quercetins.
The dry rutin 34g for sloughing the crystallization water is dissolved in 260mL dry DMFs, then adds Anhydrous potassium carbonate 53.79g
It is stirred at room temperature 15 minutes.Then cylite 46mL is added in 50 DEG C of stirring reactions 3~4 hours.Reaction utilizes after terminating
10% second acid for adjusting pH value is 6, filtering, is precipitated.It is precipitated and dissolved in 800mL absolute ethyl alcohols, adds the dense salt of 150mL
Acid.Mixture flows back 2 hours at 78 DEG C.Light yellow solid is filtrated to get after being cooled to room temperature.Obtained solid with dichloromethane/
Recrystallizing methanol obtains the benzyloxy Quercetin of light yellow solid 7,3 ', 4 '-three.Yield 43%, fusing point：185-187℃；
1H NMR (400MHz, DMSO) δ 12.42 (s, 1H), 9.72 (s, 1H), 7.89 (d, J=2.0Hz, 1H), 7.84
(dd, J=8.7,2.0Hz, 1H), 7.54-7.30 (m, 15H), 7.26 (d, J=8.8Hz, 1H), 6.87 (d, J=2.1Hz,
1H), 6.45 (d, J=2.1Hz, 1H), 5.24 (s, 4H), 5.21 (s, 2H)；13C NMR (126MHz, CDCl3) δ 175.1,
164.8,160.9,156.7,150.8,148.6,145.4,137.0,136.7,135.9,135.7,128.8,128.6,
128.6,128.4,128.0,128.0,127.5,127.2,123.8,121.9,116.2,114.5,114.1,104.1,98.6,
93.2,71.6,71.0,70.5,53.4.
Embodiment 5
The system of 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones
It is standby.
7,3 ', 4 '-three benzyloxy Quercetin 3.3g are added in 15mL dry DMFs, then add 1.59g Carbon Dioxides
Potassium.After being stirred at room temperature 15 minutes, 1 is added, pentamethylene bromide 1mL.The mixture reacts 4 hours at 35 DEG C.After reaction terminates,
Reaction solution is poured into 100mL frozen water, and then with dichloromethane extraction three times, organic layer is dried with anhydrous magnesium sulfate.Obtained production
Thing with using silica gel column chromatography, obtain intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -
4H-1- benzopyran-4-ones.Yellow solid, yield 49%.Fusing point：85~86 DEG C.
1H NMR (400MHz, DMSO) δ 12.63 (s, 1H), 7.74 (s, 1H), 7.68 (d, J=8.7Hz, 1H), 7.53-
7.45 (m, 6H), 7.39 (m, 9H), 7.24 (d, J=8.7Hz, 1H), 6.78 (s, 1H), 6.43 (d, J=1.9Hz, 1H), 5.24
(s, 2H), 5.20 (s, 4H), 3.92 (t, J=6.3Hz, 2H), 3.44 (t, J=6.7Hz, 2H), 1.80-1.68 (m, 2H),
1.68-1.53 (m, 2H), 1.39-1.45 (m, 2H)；13C NMR (126MHz, CDCl3) δ 178.8,164.5,162.1,156.7,
156.0,151.4,148.4,138.1,136.9,136.6,135.8,128.7,128.6,128.6,128.4,128.1,
128.0,127.4,127.3,127.2,123.5,122.9,115.4,113.7,106.2,98.5,93.0,72.5,71.6,
70.9,70.4,33.6,32.4,29.2,24.6.
Embodiment 6
2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- chromenes -4-
The preparation of ketone (target product).
0.8g intermediate products 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles
- 4- ketone of muttering is dissolved into 10mL dry DMFs, then adds 0.95mL diethylamine.Reaction solution reacts 4 hours in 50 DEG C.Reaction knot
Shu Hou, reaction solution are poured into 30mL frozen water, are filtrated to get precipitation.Gained solid precipitation be dissolved into 50mL absolute ethyl alcohols and Isosorbide-5-Nitrae-
In the mixed solution of dioxane.Then 200mg palladium carbons are added, are passed through hydrogen, are stirred 2 hours at room temperature.Diatomite filters, and has
Machine mutually with silica gel column chromatography obtain compound 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -
4H-1- benzopyran-4-ones.Yellow solid, yield 26%.Fusing point：46-48℃.
1H NMR (400MHz, DMSO) δ 12.75 (s, 1H), 11.00 (s, 1H), 9.97 (s, 1H), 7.55 (d, J=
2.2Hz, 1H), 7.43 (dd, J=8.4,2.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.45 (d, J=2.0Hz, 1H),
6.22 (d, J=2.0Hz, 1H), 3.94 (t, J=6.2Hz, 2H), 3.13-3.01 (m, 4H), 3.00-2.90 (m, 2H), 1.76-
1.57 (m, 4H), 1.48-1.34 (m, 2H), 1.20 (t, J=7.2Hz, 6H).13C NMR (126MHz, DMSO) δ 177.9,
164.1,161.14,156.2,155.9,148.5,145.0,136.6,120.8,120.6,115.5,115.5,104.0,
98.5,93.5,71.4,54.8,50.6,46.1,28.7,22.7,22.5,8.6.
Experiment 1
2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- chromenes -4-
The inhibiting activity of acetylcholinesterase of ketone.
The present invention tests 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-
The inhibiting activity of acetylcholinesterase of 1- benzopyran-4-ones.Enzyme reaction is entered in 25 DEG C, 0.1M pH8.0 phosphate buffer
OK, total reaction volume is 200 μ L, includes 3.33mM 5, μ L, 0.35U/mL the acetyl courages of 5 '-two sulphur-connection (2- nitrobenzoic acids) 20
20 μ L and 5.3mM acetylthiocholine iodides solution of alkali esterase solution 20 μ L, the μ L of test compound solution 10, in 412nm enzymes
Mark instrument (Sunrise, Tecan, Austria) detection 5min.All samples are all in triplicate.Not add the optical density of compound well
Value is used as 100%, and the optical density in compound determination hole compares therewith, and the percentage of reduction is enzyme inhibition rate.Each compound
Inhibitory activity of 5 concentration gradients to acetylcholinesterase is at least surveyed, inhibiting rate mapping is asked by compound concentration logarithm
IC50 values (concentration for suppressing compound during 50% enzymatic activity).The compound has stronger inhibiting activity of acetylcholinesterase,
The IC of compound acetylcholine esterase inhibition50It is worth for 9.06 μM.
Specific embodiment described herein is only to spirit explanation for example of the invention.Technology belonging to the present invention is led
The technical staff in domain can be made various modifications or supplement to described specific embodiment or be replaced using similar mode
Generation, but without departing from the spiritual of the present invention or surmount scope defined in appended claims.
Claims (9)
1. a kind of quercetin derivative, its chemical structural formula has shown in formula (I)：
Entitled 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5, the 7- dihydroxy -4H-1- benzo pyrroles of chemistry
Mutter -4- ketone.
2. the preparation method of the quercetin derivative described in claim 1, it is characterised in that comprise the following steps：
The preparation of (1) 7,3 ', 4 '-three benzyloxy Quercetins；
(2) preparation of 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones；
(3) 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- chromenes -4-
The preparation of ketone.
3. the preparation method of quercetin derivative according to claim 2, it is characterised in that：
In step (1), 7,3 ', 4 '-three benzyloxy quercitrins will be obtained using sour water solution desugar after rutin and cylite reaction
Element；
In step (2), by 7,3 ', 4 '-three benzyloxy Quercetins and 1 of gained in step (1), pentamethylene bromide reaction is made
Intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones；
In step (3), by the intermediate product of gained in step (2) and diethylamine react to obtain 2- (3,4- dihydroxy phenyl)-
3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones.
4. the preparation method of quercetin derivative according to claim 3, it is characterised in that：
In step (1), the dry rutin for sloughing the crystallization water is dissolved in dry DMF, then adds Anhydrous potassium carbonate in room temperature
Lower stirring 15 minutes, cylite is then added in 50~55 DEG C of stirring reactions 3~4 hours, reaction utilizes 10% second after terminating
Acid for adjusting pH value is 6~6.5, filtering, is precipitated, is precipitated and dissolved in absolute ethyl alcohol, add concentrated hydrochloric acid, mixture is 78
DEG C backflow 2~2.5 hours, filtered after being cooled to room temperature, obtained light yellow solid, obtained solid methylene chloride/methanol
It is recrystallized to give 7,3 ', 4 '-three benzyloxy Quercetins.
5. the preparation method of quercetin derivative according to claim 4, it is characterised in that：
In step (2), 7,3 ', 4 '-three benzyloxy Quercetins are added in dry DMF, then add Anhydrous potassium carbonate, room temperature
After stirring 15 minutes, 1 is added, pentamethylene bromide, the mixture reacts 3.5~4 hours at 35 DEG C, after reaction terminates, reaction
Liquid is poured into frozen water, and then with dichloromethane extraction three times, organic layer is dried with anhydrous magnesium sulfate, and obtained product is used and uses silicon
Plastic column chromatography, intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles are made
Mutter -4- ketone.
6. the preparation method of quercetin derivative according to claim 5, it is characterised in that：
In step (3), by intermediate product 2- (3,4- dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1-
Benzopyran-4-one is dissolved into dry DMF, then adds diethylamine, and reaction solution reacts 3~4 hours in 50 DEG C, and reaction terminates
Afterwards, reaction solution is poured into frozen water, is filtrated to get precipitation, and gained solid precipitation is dissolved into absolute ethyl alcohol and Isosorbide-5-Nitrae-dioxane
In mixed solution, palladium carbon is then added, is passed through hydrogen, is stirred 2~2.5 hours at room temperature, diatomite filtering, organic phase silica gel
Chromatography, compound 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine amoxy) -5,7- dihydroxy -4H-1- benzos are made
Pyrans -4- ketone.
7. the preparation method of quercetin derivative according to claim 6, it is characterised in that：
In step (1), the rutin, the mass ratio of Anhydrous potassium carbonate are 34:53.79, the quality of the rutin and cylite
Volume ratio is 34g：46ml；The volume ratio of the dry DMF, absolute ethyl alcohol and concentrated hydrochloric acid is 26~38：75~80:15；
In step (2), the mass ratio of described 7,3 ', 4 '-three benzyloxy Quercetins and Anhydrous potassium carbonate is 33：15.9；It is described
The volume ratio of dry DMF, 1, pentamethylene bromide and frozen water is 15~18：1：100~120；
In step (3), 2- (3,4- the dihydroxy phenyl) -3- (5- bromines amoxy) -5,7- dihydroxy -4H-1- benzo pyrroles
The mass volume ratio for -4- ketone and the dry DMF of muttering is 0.8g：10~12mL；The dry DMF, diethylamine, frozen water and absolute ethyl alcohol
Volume ratio be 10~12：0.95：30~35：50~55；2- (3,4- the dihydroxy phenyl) -3- (5- bromines amoxy) -5,
7- dihydroxy -4H-1- benzopyran-4-ones and the mass ratio of palladium carbon are 4：1.
8. quercetin derivative 2- (3,4- dihydroxy phenyl) -3- (5-N, TMSDEA N diethylamine described in any one of claim 1 to 7
Amoxy) -5,7- dihydroxy -4H-1- benzopyran-4-ones prepare the functional food of anti-Alzheimer disease because or medicine
In application.
9. application according to claim 8, it is characterised in that：Described quercetin derivative has acetylcholinesterase suppression
System activity.
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