CN105622657B - Curcumin derivate, preparation method and application - Google Patents
Curcumin derivate, preparation method and application Download PDFInfo
- Publication number
- CN105622657B CN105622657B CN201610139439.1A CN201610139439A CN105622657B CN 105622657 B CN105622657 B CN 105622657B CN 201610139439 A CN201610139439 A CN 201610139439A CN 105622657 B CN105622657 B CN 105622657B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- curcumin derivate
- equation
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 45
- 229940109262 curcumin Drugs 0.000 title claims abstract description 22
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 22
- 239000004148 curcumin Substances 0.000 title claims abstract description 22
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 239000000523 sample Substances 0.000 claims abstract description 12
- 150000003384 small molecules Chemical class 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims description 31
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 19
- -1 normal-butyl Chemical group 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910003827 NRaRb Inorganic materials 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical class CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 50
- 238000003786 synthesis reaction Methods 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- OKZIUSOJQLYFSE-UHFFFAOYSA-N difluoroboron Chemical group F[B]F OKZIUSOJQLYFSE-UHFFFAOYSA-N 0.000 description 20
- 239000000178 monomer Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 239000012265 solid product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000005999 2-bromoethyl group Chemical group 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- VWZFTVUUTFRDBW-UHFFFAOYSA-N CC(C)c1cccc(C(C)C)c1[O] Chemical compound CC(C)c1cccc(C(C)C)c1[O] VWZFTVUUTFRDBW-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical class BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 150000000345 2,6-xylenols Chemical class 0.000 description 2
- DPFLEBVHBURETR-UHFFFAOYSA-N 3-[4-(2,6-dimethylphenoxy)butyl]pentane-2,4-dione Chemical class CC(=O)C(C(C)=O)CCCCOC1=C(C)C=CC=C1C DPFLEBVHBURETR-UHFFFAOYSA-N 0.000 description 2
- FZRCKLPSHGTOAU-UHFFFAOYSA-N 6-amino-1,4-dimethylcyclohexa-2,4-diene-1-carbaldehyde Chemical compound CC1=CC(N)C(C)(C=O)C=C1 FZRCKLPSHGTOAU-UHFFFAOYSA-N 0.000 description 2
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PVXQJYXODFZTBR-UHFFFAOYSA-N [4-[(2z)-2-[6-[(e)-2-[4-(dimethylamino)phenyl]ethenyl]-2,2-difluoro-1,3-dioxa-2-boranuidacyclohex-5-en-4-ylidene]ethylidene]cyclohexa-2,5-dien-1-ylidene]-dimethylazanium Chemical compound C1=CC(N(C)C)=CC=C1\C=C\C(O[B-](F)(F)O/1)=C\C\1=C\C=C1C=CC(=[N+](C)C)C=C1 PVXQJYXODFZTBR-UHFFFAOYSA-N 0.000 description 2
- VRLSUGXJBUMXRG-UHFFFAOYSA-N [O]CCBr Chemical compound [O]CCBr VRLSUGXJBUMXRG-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940125890 compound Ia Drugs 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000013399 early diagnosis Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 102100027831 14-3-3 protein theta Human genes 0.000 description 1
- DGPBVJWCIDNDPN-UHFFFAOYSA-N 2-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=CC=C1C=O DGPBVJWCIDNDPN-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 0 CC(C(C*Oc1ccccc1)=C(C)O1)=[O+][B-]1(F)F Chemical compound CC(C(C*Oc1ccccc1)=C(C)O1)=[O+][B-]1(F)F 0.000 description 1
- MENZRBGPZFGASE-UHFFFAOYSA-N CC(C(CCCOc1ccccc1)C(C)=O)=O Chemical compound CC(C(CCCOc1ccccc1)C(C)=O)=O MENZRBGPZFGASE-UHFFFAOYSA-N 0.000 description 1
- RUJKGWHPJVGPOG-NTCAYCPXSA-N CC(C(CCOc1ccccc1)=C(/C=C/C(CC1)=CC=C1N(C)C)O1)=[O][B]1(F)[F]C Chemical compound CC(C(CCOc1ccccc1)=C(/C=C/C(CC1)=CC=C1N(C)C)O1)=[O][B]1(F)[F]C RUJKGWHPJVGPOG-NTCAYCPXSA-N 0.000 description 1
- GKEYVAJOJQBXRF-FYWRMAATSA-N CCN(CC)C(CC1)=NC=C1/C=C/C(O1)=C(CCCOc2ccccc2)C(C)=[O+][B]11[F][F]1 Chemical compound CCN(CC)C(CC1)=NC=C1/C=C/C(O1)=C(CCCOc2ccccc2)C(C)=[O+][B]11[F][F]1 GKEYVAJOJQBXRF-FYWRMAATSA-N 0.000 description 1
- XVJRMWZRRVBJDN-FBMGVBCBSA-N CCN(CC)c1ccc(/C=C/C(O2)=C(CCCCOc3c(C(C)C)cccc3C(C)C)C(C)=[O+][B-]2(F)F)cn1 Chemical compound CCN(CC)c1ccc(/C=C/C(O2)=C(CCCCOc3c(C(C)C)cccc3C(C)C)C(C)=[O+][B-]2(F)F)cn1 XVJRMWZRRVBJDN-FBMGVBCBSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 102100024748 E3 ubiquitin-protein ligase UHRF2 Human genes 0.000 description 1
- 101710131422 E3 ubiquitin-protein ligase UHRF2 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 230000037308 hair color Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to medicinal chemistry arts, disclose synthetic method and its application in preparing the near-infrared Small-molecule probe for early diagnosing alzheimer's disease of a kind of curcumin derivate (I).It is demonstrated experimentally that compound according to the present invention has selectivity well to soluble A β, is combined rear fluorescence intensity to be remarkably reinforced with soluble A β, be most potential to the selective near-infrared fluorescent Small-molecule probes of soluble A β.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular, to a kind of curcumin derivate, preparation method and application.
Background technology
Alzheimer disease (Alzheimer ' s disease, AD) is a kind of progressive neurodegenerative disease, is affected
Whole world tens of millions of people is difficult diagnosis so far and can not be cured.With social senilization, AD patient is continuously increased, occurred frequently
Sick rate, high disability rate have become the great illness for influencing human health.For AD pathomechanism at present there are mainly three types of hypothesis：
Amyloid beta deposition, neurofibrillary tangles (neurofibrillary tangles) and cholinergic neuron degeneration
Lesion, wherein " amyloid cascade hypothesis " is widely recognized as by people.The hypothesis thinks：Early stage AD occurs, beta amyloid egg
(A β, mainly A β 40 and A β 42) gradually polymerize in vain, and deposition forms amyloid plaques, causes Protein tau phosphorylation and nerve is fine
Dimension is tangled, and deterioration of neurons, loss and dementia are eventually led to.40/42 monomers of A β can be assembled rapidly, shape after neurons secrete
At soluble polymer (dimer, tripolymer), it is subsequently formed soluble oligomer, last further aggregation forms insoluble
Property A betas and patch and be deposited on intracerebral.It is newest the study found that precipitation patch number had no directly with the severity of AD
The association connect.Soluble dimer, oligomer etc. has stronger neurotoxicity than insoluble precipitation patch, and leads
Cause the immediate cause of nerve retrograde affection.It is extremely successful to the imaging research of insoluble A β at present, and have several drug quilts
Approval is for clinic.But the imaging research of solable matter is rarely reported.Therefore the image probe of detection solubility A β
The exploitation of the early diagnosis and drug of AD will more effectively be pushed.Compared with other imaging methods, near-infrared fluorescent（NIRF) at
Image space method has many advantages：(1) high sensitivity, it can be achieved that small-signal detection；(2) detection safety, does not contact radioactivity
Element；(3) it is not necessarily to take, real time imagery in data acquisition；(4) moderate cost without expensive equipment and is skilled in technique
Personnel.
In the research of early period, shown after being combined with A β as the NIR fluorescence probes CRANAD-2 of skeleton framework using curcumin
Apparent fluorescence intensity increase, hair color spectrum blue shift, fluorescence lifetime extend and the optical effects such as quantum yield improves.But
CRANAD-2 does not have selectivity, can be combined with soluble A β, can be combined with insoluble A β yet, and is acted on insoluble A β
The increase of fluorescence intensity is 2.3 times after being acted on soluble A β afterwards.As it can be seen that there has been no with this curcumin in the prior art
Compound is the NIR fluorescence probes of skeleton framework, and the report optionally combined with soluble A β, therefore, this present situation is urgently
It needs to solve.
Invention content
The technical problem to be solved by the present invention is in order to overcome in the prior art using curcumin chemical compounds as skeleton frame
The NIR fluorescence probes of structure do not have selectivity, can be combined with soluble A β, and the technology that can be also combined with insoluble A β etc. is asked
Topic, and provide a kind of curcumin derivate, preparation method and application.The curcumin derivative of the present invention is optionally
It is combined with soluble A β, more effectively pushes the exploitation of the early diagnosis and drug of AD.
The present invention provides one kind curcumin derivative as shown in formula (I)：
Wherein n=2,3,4；X indicates C atoms or N atoms；R1For-NRaRb, wherein RaAnd RbIt independently is hydrogen, C1-6Alkane
Base or C3-6Naphthenic base, but RaAnd RbIt is asynchronously hydrogen；R2For hydrogen, C1-6Alkyl, C3-6Naphthenic base, C1-6Alkoxy or halogen,
Middle R2Indicate monosubstituted, two substitutions (such as 2, the positions 6- two replace) or three substitutions.
In formula (I) compound represented, Ra、RbAnd R2In, the C1-6The preferred C of alkyl1-4Alkyl.The C1-4Alkane
The preferred methyl of base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.
In formula (I) compound represented, R1And R2In, the C3-6The preferred cyclopropyl of naphthenic base, cyclobutyl, cyclopenta
Or cyclohexyl.
In formula (I) compound represented, R2In, the C1-6The preferred C of alkoxy1-4Alkoxy.The C1-4Alcoxyl
The preferred methoxyl group of base, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
In formula (I) compound represented, R2In, the halogen preferred F, Cl, Br or I.
In the present invention, in formula (I) compound represented, R1It is preferred that N, N- dimethylamino, N, N- diethylaminos, N,
N- methylethylamines.
In the present invention, in formula (I) compound represented, R2It is preferred that hydrogen, 2,6- dimethyl or 2,6- diisopropyls.
In the present invention, such as formula (I) compound represented, preferably following any compound：
The present invention also provides a kind of preparation methods of the curcumin derivate as shown in formula (I) comprising under
Row step：In organic solvent, under the catalysis of alkali, in the presence of dehydrating agent, by compound as shown in Equation 4 and as shown in Equation 5
Compound carry out condensation reaction as follows, be made the curcumin derivate as shown in formula (I)；
N, X, R in above-mentioned each compound1And R2Definition it is as previously described.
In the preparation method of curcumin derivate as shown in formula (I), the organic solvent can be this field
The conventional organic solvent of such reaction, preferably nitrile solvents.The preferred acetonitrile of the nitrile solvents.The alkali can be this field
The conventional alkali of such reaction, preferably tetrahydroisoquinoline (i.e. 1,2,3,4- tetrahydroisoquinolines).The dehydrating agent can be this field
The conventional dehydrating agent of such reaction, preferably glacial acetic acid.The dosage of the alkali can be not specifically limited, generally catalytic amount, compared with
Itself and the molar ratio of compound as shown in Equation 4 are 0.1: 1-0.9: 1 goodly, are more preferably 0.1: 1-0.3: 1.The dehydration
The dosage of agent can be the conventional dosage of the such reaction in this field, and preferably the molar ratio of itself and compound as shown in Equation 4 is 0.1
: 1-0.9: 1, it is more preferably 0.2: 1-0.5: 1.Mole of the compound as shown in Equation 4 and compound as shown in Equation 5
Than that can be not especially limited, carried out as long as not influencing reaction, preferably 1: 1.The dosage of the organic solvent can not
Make specific restriction, is carried out as long as not influencing reaction, preferably, the Molar ratio of itself and compound as shown in Equation 4 is
3mL/mmol.The temperature of the condensation reaction can be the conventional temperature of the such reaction in this field, preferably room temperature (0-30
℃).The process of the condensation reaction can be used this field organic synthesis routine detection method be monitored (such as
TLC, GC, HPLC or NMR etc.), as the terminal of reaction when usually being disappeared using compound as shown in Equation 4.The condensation is anti-
The time answered is preferably 2-6 hours (such as 3 hours).
The route of present invention preparation method of curcumin derivate as shown in formula (I) is preferably as follows：
The present invention also provides a kind of compounds as shown in formula (I) to prepare for diagnosing alzheimer's disease morning
Application in phase closely red Small-molecule probe.
In the application, the near-infrared Small-molecule probe can be combined with soluble A β and/or insoluble A β, preferably
It is combined with soluble A β.
Here is the bioactivity research of compound in the present invention.
Test target compound, targeted are distinguished under the conditions of PBS (pH 7.4) using F-4500 sepectrophotofluorometers
Close object and the fluorescence intensity level (I) after the effect of 40 monomers of A β, after target compound and the effect of A β polymer.
Experimental method：
The preparation of 40 monomers of A β：40 monomers of A β (rPeptide, catalogue No.A-1153-1 the and A- of purchase
1163-1 with HFIP treatment) it is stored in after HPLC is further purified in hexafluoroisopropanol (HFIP).Granularity passes through
It is measured by Zetasizer Nano (Malvern).40 monomers of A β (25 μM) storing solution of 10 μ L volatilizes solvent through traditional vacuum, weight
Newly it is dissolved in 1mL distilled water.Aqueous solution granule size through testing graininess 40 monomers of A β can measure minimum less than instrument
Value, i.e., without large-size particles.
The preparation of A β polymer：1.0mgA β 40 are redissolved in the ammonium hydroxide (1%) of 1.0mL, take 100 μ L of the solution dilute
It releases in the PBS buffer solutions of 900 μ L, is stirred at room temperature three days.TEM results confirm the generation of aggregation.The storing solution preserves
In 4 DEG C.
The combination active testing of 40 monomer of target compound and A β, 40 aggregations of A β：(1) PBS solution of 1.0mL is added
In silica dish, according to the fluorescent spectroscopic properties of each compound, the fluorescence signal of PBS is measured under the same conditions as blank pair
According to；(2) it is excitation wavelength to choose 610nm, collects the fluorescence of the target compound (1.0mL, 250nM) from 630nm to 900nm
Signal；(3) A β substances (a concentration of 25 μM of HFIP monomer solutions, a concentration of 25 μ of 10 μ L are added in the solution of second step
The 40 aggregation PBS solutions of A β of M), make A β ultimate density and target compound it is consistent.The fluorescence signal of the solution of third step
According to the parametric measurement of second step.Second step and the measured fluorescence signal of third step use the blank fluorescence signal of the first step to rectify
Just.
Experimental result is shown in Table 1：
The fluorescence spectrum test result of 1 target compound of table
aMaximum emission wavelength,bFluorescence intensity when target compound individually measures；cTarget compound is combined with A beta monomers
Fluorescence intensity afterwards；dTarget compound combined with A β polymer after fluorescence intensity.
As seen from Table 1, target compound has selectivity well to soluble A β, is combined rear fluorescence strong with soluble A β
Degree is remarkably reinforced.Especially compound Ia and Ib, the fluorescence intensity after being combined with A beta monomers are glimmering after being combined with A β polymer
32 times of luminous intensity and 12.5 times, and enhance 16 times and 63.1 times with the fluorescence intensity after the effect of A beta monomers.The two mesh
Mark compound is respectively less than 650nm with the launch wavelength after the effect of A beta monomers, and near infrared spectral range is not achieved.This shows the two
Increase although target compound has preferable selectivity to A beta monomers and shows significant fluorescence intensity, is conjugated aromatic ring
Reduction make it that near infrared spectral range be not achieved.It is worth noting that target compound Ie, it and the Im/ after the effect of A beta monomers
Ia is 9.5, and maximum emission wavelength shows this compound to A beta monomers near infrared spectral range in 723nm or so
With certain selectivity.To sum up it can be found that by further optimizing, the target compound in the invention, which has to become, to be selected
Selecting property combines the potentiality of the near-infrared fluorescent Small-molecule probe of solubility A β.
Specific implementation mode
Embodiment 1：The synthesis of 2- bromoethyl oxygroup benzene
Equipped with blender, reflux condensing tube, drying tube, be added in the 100ml three-necked bottles of thermometer phenol (1g,
8.2mmol), water (14mL) and 1,2- Bromofumes (1.4mL, 16.4mmol), is vigorously stirred, and is heated to flow back.NaOH is added dropwise
Aqueous solution (3mL, 3M) reacts 12h.After having reacted, it is cooled to room temperature, ethyl acetate extracts (20mL × 3), saturated common salt washing
It washs, anhydrous MgSO4It is dry.Silica gel column chromatography detaches, and eluant, eluent is petroleum ether: ethyl acetate=20, and: 1 (v/v) is obtained faint yellow
Grease 1.1g (5.47mmol), yield：52%.1H NMR (300MHz, CDCl3)δ(ppm)：7.27 (m, 2H), 6.92 (m,
3H), 4.26 (t, 2H, J=6.27Hz), 3.61 (t, 2H, J=6.27Hz)
Chemical formula is as follows：
Embodiment 2：The synthesis of 3- bromopropyl oxygroup benzene
Method is with embodiment 1, except that with 1,3- dibromopropanes replace 1,2- Bromofumes, obtain colorless oil
Object, yield：83%.1H NMR (300MHz, CDCl3)δ(ppm)：7.25 (m, 2H), 6.95 (m, 3H), 4.01 (t, 2H, J=
5.37Hz), 3.42 (t, 2H, J=6.28Hz), 1.82 (m, 2H)
Chemical formula is as follows：
Embodiment 3：The synthesis of 4- brombutyl oxygroup benzene
Method, except that replacing 1,2- Bromofumes with Isosorbide-5-Nitrae-dibromobutane, obtains colorless oil with embodiment 1
Object, yield：84%.1H NMR (300MHz, CDCl3)δ(ppm)：7.23 (m, 2H), 6.93 (m, 3H), 3.96 (t, 2H, J=
5.88Hz), 3.46 (t, 2H, J=6.63Hz), 2.05 (m, 2H), 1.95 (m, 2H)
Chemical formula is as follows：
Embodiment 4：The synthesis of 2- (3- bromopropyls oxygroup) -2,6- dimethyl benzenes
Method is with embodiment 1, except that with 2,6- xylenols replace phenol, and 1 is replaced with 1,3- dibromopropanes,
2- Bromofumes obtain colorless oil, yield：76%.1H NMR (300MHz, CDCl3)δ(ppm)：7.05 (d, 2H, J=
7.44Hz), 6.96 (m, 1H), 3.93 (t, 2H, J=5.77Hz), 3.74 (t, 2H, J=6.43Hz), 2.36 (m, 2H), 2.32
(s, 6H)
Chemical formula is as follows：
Embodiment 5：The synthesis of 2- (4- brombutyls oxygroup) -2,6- dimethyl benzenes
Method is with embodiment 1, except that with 2,6- xylenols replace phenol, and 1 is replaced with Isosorbide-5-Nitrae-dibromobutane,
2- Bromofumes obtain colorless oil, yield：80%.1H NMR (300MHz, CDCl3)δ(ppm)：7.04 (d, 2H, J=
7.2Hz), 6.97 (m, 1H), 3.83 (t, 2H, J=6.15Hz), 3.56 (t, 2H, J=6.6Hz), 2.31 (s, 6H), 2.09 (m,
2H), 1.98 (m, 2H)
Chemical formula is as follows：
Embodiment 6：The synthesis of 2- (3- bromopropyls oxygroup) -2,6- diisopropyl benzenes
Method is with embodiment 1, except that replace phenol, 1,3- dibromopropane to replace 1 with 2,6-Bis(1-methylethyl)phenol,
2- Bromofumes obtain colorless oil, yield：78%.1H NMR (300MHz, CDCl3)δ(ppm)：7.10 (m, 3H), 3.76
(t, 2H, J=5.78Hz), 3.52 (t, 2H, J=6.84Hz), 3.14 (m, 2H), 1.98 (m, 2H), 1.21 (d, 12H, J=
6.82Hz).
Chemical formula is as follows：
Embodiment 7：The synthesis of 2- (4- brombutyls oxygroup) -2,6- diisopropyl benzenes
Method is with embodiment 1, except that replacing phenol with 2,6-Bis(1-methylethyl)phenol, obtains colorless oil, receives
Rate：78%.1H NMR (300MHz, CDCl3)δ(ppm)：7.07 (m, 3H), 3.72 (t, 2H, J=6.2Hz), 3.63 (t, 2H, J
=6.6Hz), 3.23 (m, 2H), 2.03 (m, 2H), 1.88 (m, 2H), 1.17 (d, 12H, J=6.9Hz)
Chemical formula is as follows：
Embodiment 8：The synthesis of 3- (2- benzene oxygen ethyl) -2,4- pentanediones
2- bromoethyl oxygroup benzene (201mg, 1.0mmol) is dissolved in 3mL anhydrous propanones, potassium carbonate is sequentially added
(187mg, 1.45mmol), catalytic amount potassium iodide, acetylacetone,2,4-pentanedione (110 μ L, 1.04mmol), magnetic agitation is heated to reflux 20h.
TLC plates detect, and reaction finishes, and trash ice is added to stir 15min, are extracted with EA (15 × 3mL), merge organic layer, saturated salt solution (10
× 2mL) washing, after liquid separation, dried with anhydrous sodium sulfate.Revolving removes solvent, silica gel column chromatography separation, eluant, eluent PE: EA
=10: 1 (v/v) obtains faint yellow oil product 176mg, yield：80%.1H NMR (300MHz, CDCl3)δ(ppm)：16.91
(s), 7.27 (m, 2H), 6.84 (m, 3H), 3.91 (t, 2H, J=4.26Hz), 2.71 (t, 1H, J=6.96Hz), 2.27 (m,
2H), 2.17 (s, 6H)
Chemical formula is as follows：
Embodiment 9：The synthesis of 3- (3- benzene oxygen propyl group) -2,4- pentanediones
Method, except that replacing 2- bromoethyl oxygroup benzene with 3- bromopropyl oxygroup benzene, obtains faint yellow with embodiment 8
Oil product, yield：51.8%.1H NMR (300MHz, CDCl3)δ(ppm)：16.69 (s), 7.19 (m, 2H), 6.83 (m,
3H), 3.88 (t, J=7.20Hz, 2H), 3.64 (t, J=4.90Hz, 1H), 2.09 (s, 6H), 1.96 (m, 2H), 1.80 (m,
2H).
Chemical formula is as follows：
Embodiment 10：The synthesis of 3- (4- benzene oxygen-butyl) -2,4- pentanediones
Method, except that replacing 2- bromoethyl oxygroup benzene with 4- brombutyl oxygroup benzene, obtains faint yellow with embodiment 8
Oil product, yield：60%.1H NMR (300MHz, CDCl3)δ(ppm)：16.70 (s), 7.25 (m, 2H), 6.87 (m, 2H),
3.94 (t, 2H, J=6.21Hz), 3.60 (t, 1H, J=4.87Hz), 2.13 (s, 6H), 1.99 (m, 2H), 1.43 (m, 2H),
1.25 (m, 2H)
Chemical formula is as follows：
Embodiment 11：The synthesis of 3- [3- (2,6- dimethyl ethyl phenoxy group) propyl] -2,4- pentanediones
Method is with embodiment 8, except that replacing 2- bromoethyl oxygen with 2- (3- bromopropyls oxygroup) -2,6- dimethyl benzenes
Base benzene obtains faint yellow oil product, yield：63%.1H NMR (300MHz, CDCl3)δ(ppm)：17.10 (s), 7.05 (d,
2H, J=7.09Hz), 6.89 (m, 1H), 3.82 (d, 2H, J=5.21Hz), 3.28 (d, 1H, J=4.49Hz), 2.31 (s,
6H), 2.20 (s, 6H), 1.94 (m, 2H), 1.78 (m, 2H), 1.43 (m, 2H)
Chemical formula is as follows：
Embodiment 12：The synthesis of 3- [4- (2,6- dimethyl phenoxy) butyl] -2,4- pentanediones
Method is with embodiment 8, except that replacing 2- bromoethyl oxygen with 2- (4- brombutyls oxygroup) -2,6- dimethyl benzenes
Base benzene obtains faint yellow oil product, yield：78%.1H NMR (300MHz, CDCl3)δ(ppm)：16.77 (s), 7.03 (d,
2H, J=7.14Hz), 6.93 (m, 1H), 3.77 (t, 2H, J=4.59Hz), 2.32 (t, 1H, J=4.45Hz), 2.28 (s,
6H), 2.20 (s, 6H), 1.96 (m, 2H), 1.83 (m, 2H), 1.50 (m, 2H)
Chemical formula is as follows：
Embodiment 13：The synthesis of 3- [3- (2,6- diisopropyl phenyl oxygen) propyl] -2,4- pentanediones
Method is with embodiment 8, except that replacing 2- bromoethyls with 2- (3- bromopropyls oxygroup) -2,6- diisopropyl benzenes
Oxygroup benzene obtains faint yellow oil product, yield：68%.1H NMR (300MHz, CDCl3)δ(ppm)：16.81 (s), 7.10
(m, 3H), 3.65 (t, 2H, J=5.87Hz), 3.21 (t, 1H, J=6.31Hz), 2.81 (m, 2H), 2.16 (s, 6H), 1.83
(m, 2H), 1.56 (m, 2H), 1.23 (d, 12H, J=6.10Hz)
Chemical formula is as follows：
Embodiment 14：The synthesis of 3- [4- (2,6- diisopropyl phenoxy group) butyl] -2,4- pentanediones
Method is with embodiment 8, except that replacing 2- bromoethyls with 2- (4- brombutyls oxygroup) -2,6- diisopropyl benzenes
Oxygroup benzene obtains faint yellow oil product, yield：80%.1H NMR (300MHz, CDCl3)δ(ppm)：16.83 (s), 7.08
(m, 3H), 3.72 (t, 2H, J=6.3Hz), 3.66 (t, 1H, J=6.3Hz), 3.24 (m, 2H), 2.17 (s, 6H), 1.76 (m,
2H), 1.56 (m, 2H), 1.41 (m, 2H), 1.17 (m, 12H, J=5.78Hz)
Chemical formula is as follows：
Embodiment 15：The synthesis of 3- (2- benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione
3- (2- benzene oxygen ethyl) -2,4- pentanediones (220.26mg, 1mmol), butyl borate (537ul, 2mmol) are added
Enter reaction bulb, boron trifluoride ether (251ul, 2mmol) is slowly added dropwise, 2h is stirred at room temperature.TLC plates detect, and reaction finishes.Revolving
Solvent is removed, crystallization in air is put after vacuum drying.Obtain white solid 277mg, yield：91%.1H NMR (300MHz,
CDCl3)δ(ppm)：7.24 (m, 2H), 6.81 (m, 3H), 3.98 (t, 2H, J=6.33Hz), 2.82 (t, 2H, J=6.33Hz),
2.40 (s, 6H)
Chemical formula is as follows：
Embodiment 16：The synthesis of 3- (3- benzene oxygen propyl group) boron difluoride ring -2,4- pentanedione
Method is with embodiment 15, except that replacing 3- (2- benzene oxygen second with 3- (3- benzene oxygen propyl group) -2,4- pentanediones
Base) -2,4- pentanediones, obtain white solid, yield：91%.1H NMR (300MHz, CDCl3)δ(ppm)：7.30 (m, 2H),
6.97 (t, 1H, J=6Hz), 6.89 (d, 2H, J=9Hz), 3.99 (t, 2H, J=5.5Hz), 2.58 (t, 2H, J=7.5Hz),
2.36 (s, 6H), 1.92 (m, 2H)
Chemical formula is as follows：
Embodiment 17：The synthesis of 3- (4- benzene oxygen-butyl) boron difluoride ring -2,4- pentanedione
Method is with embodiment 15, except that replacing 3- (2- benzene oxygen second with 3- (4- benzene oxygen-butyl) -2,4- pentanediones
Base) -2,4- pentanediones, obtain white solid, yield：93%.1H NMR (300MHz, CDCl3)δ(ppm)：7.24 (m, 2H),
6.82 (m, 3H), 3.96 (t, 2H, J=5.97Hz), 2.35 (t, 2H, J=8.07), 2.30 (s, 6H), 1.81 (m, 2H), 1.63
(m, 2H)
Chemical formula is as follows：
Embodiment 18：The synthesis of 3- [3- (2,6- dimethyl ethyl phenoxy group) propyl] boron difluoride ring -2,4- pentanedione
Method is with embodiment 15, except that with 3- [3- (2,6- dimethyl ethyl phenoxy group) propyl] -2,4- penta 2
Ketone replaces 3- (2- benzene oxygen ethyl) -2,4- pentanediones, obtains white solid, yield：94%.1H NMR (300MHz, CDCl3)δ
(ppm)：6.98 (d, 2H, J=7.35Hz), 6.90 (m, 1H), 3.77 (t, 2H, J=5.65Hz), 2.61 (t, 2H, J=
5.42Hz), 2.37 (s, 6H), 2.23 (s, 6H), 1.87 (m, 2H)
Chemical formula is as follows：
Embodiment 19：The synthesis of 3- [4- (2,6- dimethyl phenoxy) butyl] boron difluoride ring -2,4- pentanedione
Method is with embodiment 15, except that with 3- [4- (2,6- dimethyl phenoxy) butyl] -2,4- pentanedione generations
For 3- (2- benzene oxygen ethyl) -2,4- pentanediones, white solid, yield are obtained：91%.1H NMR (300MHz, CDCl3)δ(ppm)：
7.04 (d, 2H, J=7.26Hz), 6.94 (m, 1H), 3.81 (t, 2H, J=6.00Hz), 2.45 (t, 2H, J=8.10Hz),
2.40 (s, 6H), 2.29 (s, 6H), 1.88 (m, 2H), 1.74 (m, 2H)
Chemical formula is as follows：
Embodiment 20：The synthesis of 3- [3- (2,6- diisopropyl phenyl oxygen) propyl] boron difluoride ring -2,4- pentanedione
Method is with embodiment 15, except that with 3- [3- (2,6- diisopropyl phenyl oxygen) propyl] -2,4- pentanediones
Instead of 3- (2- benzene oxygen ethyl) -2,4- pentanediones, white solid, yield are obtained：94%.1H NMR (300MHz, CDCl3)δ
(ppm)：7.10 (m, 3H), 3.71 (t, 2H, J=5.32Hz), 3.53 (t, 2H, J=6.38Hz), 2.81 (m, 2H), 2.16 (s,
6H), 1.83 (m, 2H), 1.23 (d, 12H, J=6.10Hz)
Chemical formula is as follows：
Embodiment 21：The synthesis of 3- [4- (2,6- diisopropyl phenoxy group) butyl] boron difluoride ring -2,4- pentanedione
Method is with embodiment 15, except that with 3- [3- (2,6- diisopropyl phenyl oxygen) propyl] -2,4- pentanediones
Instead of 3- (2- benzene oxygen ethyl) -2,4- pentanediones, white solid, yield are obtained：95%.1H NMR (300MHz, CDCl3)δ
(ppm)：7.10 (m, 3H), 3.76 (t, 2H, J=6.2Hz), 3.28 (t, 2H, J=6.9Hz), 2.43 (m, 2H), 2.39 (s,
6H), 1.87 (m, 2H), 1.70 (m, 2H), 1.23 (d, 12H, J=6.9Hz)
Chemical formula is as follows：
Embodiment 22：The synthesis of target compound Ia
3- (2- benzene oxygen ethyl) boron difluoride ring -2,4- pentanediones (268mg, 1mmol) and acetonitrile are added in the mono- neck bottles of 25mL
(3mL) adds paradime thylaminobenzaldehyde (149mg, 1mmol), acetic acid (20uL, 0.3mmol) and tetrahydroisoquinoline
(14uL, 0.15mmol) reacts at room temperature 3h.After having reacted, revolving removes partial solvent, silica gel column chromatography separation, and eluant, eluent is
PE: EA=5: 1 (v/v) obtains blue powder solid product 296mg, yield：58%.8.12 (d, 1H, J=12.63Hz), 4.75
(d, 2H, J=8.94Hz), 7.24 (m, 3H), 6.93 (m, 1H), 6.78 (d, 2H, J=12.63Hz), 6.70 (m, 3H), 4.01
(t, 2H, J=5.34Hz), 3.06 (s, 6H), 2.90 (t, 2H, J=5.34Hz), 2.36 (s, 3H)
Chemical formula is as follows：
Embodiment 23：The synthesis of target compound Ib
Method is with embodiment 22, except that replacing 3- (2- with 3- (3- benzene oxygen propyl group) boron difluoride ring -2,4- pentanedione
Benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, obtain dark blue powder solid product, yield：36.3%.1H NMR
(300MHz, CDCl3)δ(ppm)：8.14 (d, 1H, J=14.9Hz), 7.47 (d, 2H, J=8.9Hz), 7.30 (t, 2H, J=
7.9Hz), 6.96 (m, 3H), 6.79 (d, 1H, J=14.9Hz), 6.65 (d, 2H, J=8.9Hz), 4.03 (t, 2H, J=
5.4Hz), 3.10 (s, 6H), 2.67 (t, 2H, J=7.9Hz), 2.33 (s, 3H), 1.98 (m, 2H)
Chemical formula is as follows：
Embodiment 24：The synthesis of target compound Ic
Method is with embodiment 22, except that replacing 3- (2- with 3- (3- benzene oxygen propyl group) boron difluoride ring -2,4- pentanedione
Benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, 6- diethylin pyridine aldehydes replace paradime thylaminobenzaldehyde, obtain navy blue
Powder solid product, yield：35%.1H NMR (300MHz, CDCl3)δ(ppm)：8.33 (d, 1H, J=2.2Hz), 8.07 (d,
1H, J=15.0Hz), 7.55 (dd, 1H, J=9.2,2.2Hz), 7.30 (d, 2H, J=8.5Hz), 6.93 (m, 3H), 6.76 (d,
1H, J=15.0Hz), 6.41 (d, 1H, J=9.2Hz), 4.01 (t, 2H, J=5.4Hz), 3.59 (q, 4H, J=7.1Hz),
2.66 (t, 2H, J=7.5Hz), 2.33 (s, 3H), 1.97 (m, 2H), 1.23 (t, 6H, J=7.1Hz)
Chemical formula is as follows：
Embodiment 25：The synthesis of target compound Id
Method is with embodiment 22, except that replacing 3- (2- with 3- (4- benzene oxygen-butyl) boron difluoride ring -2,4- pentanedione
Benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, obtain dark blue powder solid product, yield：40%.1H NMR (300MHz,
CDCl3)δ(ppm)：8.08 (d, 1H, J=14.79Hz), 7.41 (d, 2H, J=8.16Hz), 7.25 (m, 3H), 6.87 (m,
3H), 6.65 (d, 1H, J=14.79Hz), 6.55 (d, 2H, J=8.16Hz), 4.01 (t, 2H, J=5.79Hz), 3.04 (s,
6H), 2.47 (t, 2H, J=7.77Hz), 2.28 (s, 3H), 1.86 (m, 2H), 1.68 (m, 2H)
Chemical formula is as follows：
Embodiment 26：The synthesis of target compound Ie
Method is with embodiment 22, except that with 3- [3- (2,6- dimethyl ethyl phenoxy group) propyl] boron difluoride ring-
2,4- pentanediones replace 3- (2- benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, obtain dark blue powder solid product, yield：
42%.1H NMR (300MHz, CDCl3)δ(ppm)：8.16 (d, 1H, J=14.85Hz), 7.53 (d, 2H, J=8.85Hz),
7.05 (d, 2H, J=7.26Hz), 6.95 (m, 2H), 6.63 (d, 2H, J=8.85Hz), 3.87 (t, 2H, J=5.28Hz),
3.07 (s, 6H), 2.77 (t, 2H, J=7.83Hz), 2.38 (s, 3H), 2.30 (s, 6H), 1.99 (m, 2H)
Chemical formula is as follows：
Embodiment 27：The synthesis of target compound If
Method is with embodiment 22, except that with 3- [4- (2,6- dimethyl phenoxy) butyl] boron difluoride ring -2,4-
Pentanedione replaces 3- (2- benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, obtains dark blue powder solid product, yield：50%
。1H NMR (300MHz, CDCl3)δ(ppm)：8.08 (d, 1H, J=14.91Hz), 7.43 (d, 2H, J=8.76Hz), 6.94 (d,
2H, J=7.14Hz), 6.88 (m, 2H), 6.51 (d, 2H, J=8.76Hz), 3.78 (t, 2H, J=5.76Hz), 2.99 (s,
6H), 2.47 (t, 2H, J=7.89Hz), 2.28 (s, 3H), 2.20 (s, 6H), 1.84 (m, 2H), 1.72 (m, 2H)
Chemical formula is as follows：
Embodiment 28：The synthesis of target compound Ig
Method is with embodiment 22, except that with 3- [3- (2,6- diisopropyl phenyl oxygen) propyl] boron difluoride ring -2,
4- pentanediones replace 3- (2- benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, obtain dark blue powder solid product, yield：
48%.1H NMR (300MHz, CDCl3)δ(ppm)：8.12 (d, 1H, J=14.94Hz), 7.47 (d, 2H, J=8.91Hz),
7.09 (m, 3H), 6.87 (d, 1H, J=14.94Hz), 6.57 (d, 2H, J=8.91Hz), 3.81 (t, 2H, J=5.37Hz),
3.27 (t, 2H, J=6.93Hz), 3.01 (s, 6H), 2.72 (m, 2H), 2.34 (s, 3H), 1.98 (m, 2H), 1.24 (d, 12H, J
=6.78Hz)
Chemical formula is as follows：
Embodiment 30：The synthesis of target compound Ih
Method is with embodiment 22, except that with 3- [4- (2,6- diisopropyl phenoxy group) butyl] boron difluoride ring -2,
4- pentanediones replace 3- (2- benzene oxygen ethyl) boron difluoride ring -2,4- pentanedione, 6- diethylin pyridine aldehydes to replace to dimethylamino
Benzaldehyde obtains dark blue powder solid product, yield：60%.1H NMR (300MHz, CDCl3)δ(ppm)：8.36 (d, 1H, J
=2.2Hz), 8.10 (d, 1H, J=15.0Hz), 7.63 (dd, 1H, J=9.2,2.2Hz), 7.11 (s, 3H), 6.77 (d, 1H, J
=15.0Hz), 6.23 (d, 1H, J=9.2Hz), 3.84 (t, 2H, J=6.0Hz), 3.55 (q, 4H, J=7.0Hz), 3.29
(dt, 2H, J=13.8,7.0Hz), 2.54 (m, 2H), 2.37 (s, 3H), 1.92 (dd, 2H, J=13.8,6.0Hz), 1.79 (d,
2H, J=7.0Hz), 1.21 (d, 18H, J=7.0Hz)
Chemical formula is as follows：
Claims (12)
1. a kind of curcumin derivate as shown in formula (I)：
Wherein n=2,3 or 4；X indicates C atoms or N atoms；R1For-NRaRb, wherein RaAnd RbIt independently is hydrogen, C1-6Alkyl
Or C3-6Naphthenic base, but RaAnd RbIt is asynchronously hydrogen；R2For hydrogen, C1-6Alkyl, C1-6Alkoxy or halogen, wherein R2Expression singly takes
Generation, two substitutions or three substitutions.
2. the curcumin derivate as shown in formula (I) in claim 1, which is characterized in that
Ra、RbAnd R2In, the C1-6Alkyl is C1-4Alkyl；
And/or R1And R2In, the C3-6Naphthenic base is cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
And/or R2In, the C1-6Alkoxy is C1-4Alkoxy；
And/or R2In, the halogen is F, Cl, Br or I.
3. the curcumin derivate as shown in formula (I) in claim 2, which is characterized in that
Ra、RbAnd R2In, the C1-4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or R2In, the C1-4Alkoxy is methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl
Oxygroup or tert-butoxy.
4. the curcumin derivate as shown in formula (I) as described in claim 1, which is characterized in that R1For N, N- dimethylaminos
Base, N, N- diethylaminos, N, N- methylethylamines.
5. the curcumin derivate as shown in formula (I) as described in claim 1, which is characterized in that R2For hydrogen, 2,6- dimethyl
Or 2,6- diisopropyls.
6. the curcumin derivate as shown in formula (I) as described in claim 1, for following any compound：
7. a kind of preparation method of the curcumin derivate as claimed in any one of claims 1 to 6 as shown in formula (I) comprising
The following steps：In organic solvent, under the catalysis of alkali, in the presence of dehydrating agent, by compound as shown in Equation 4 and such as 5 institute of formula
The compound shown carries out condensation reaction as follows, and the curcumin derivate as shown in formula (I) is made；
Wherein, n, X, R in above-mentioned each compound1And R2Definition as described in claim any one of 1-6.
8. preparation method as claimed in claim 7, which is characterized in that the curcumin derivate as shown in formula (I)
In preparation method, the organic solvent is nitrile solvents；And/or the alkali is tetrahydroisoquinoline；And/or it is described de-
Aqua is acetic acid；And/or the molar ratio of the alkali and compound as shown in Equation 4 is 0.1: 1-0.9: 1；And/or it is described
Dehydrating agent and the molar ratio of compound as shown in Equation 4 be 0.1: 1-0.9: 1；And/or the chemical combination as shown in Equation 4
The molar ratio of object and compound as shown in Equation 5 is 1: 1；And/or the temperature of the condensation reaction is 0-30 DEG C；And/or
The time of the condensation reaction is 2-6 hours.
9. preparation method as claimed in claim 8, which is characterized in that the nitrile solvents are acetonitrile.
10. a kind of curcumin derivate as claimed in any one of claims 1 to 6 as shown in formula (I) prepare for diagnose Ah
Application in the silent disease early stage near-infrared Small-molecule probe in Wurz sea.
11. application as claimed in claim 10, which is characterized in that the near-infrared Small-molecule probe and solubility A β and/
Or insoluble A β are combined.
12. application as claimed in claim 11, which is characterized in that the near-infrared Small-molecule probe is combined with solubility A β
Ability is more than the binding ability with insoluble A β.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610139439.1A CN105622657B (en) | 2016-03-09 | 2016-03-09 | Curcumin derivate, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610139439.1A CN105622657B (en) | 2016-03-09 | 2016-03-09 | Curcumin derivate, preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105622657A CN105622657A (en) | 2016-06-01 |
| CN105622657B true CN105622657B (en) | 2018-08-21 |
Family
ID=56038039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610139439.1A Expired - Fee Related CN105622657B (en) | 2016-03-09 | 2016-03-09 | Curcumin derivate, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105622657B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110615808B (en) * | 2019-05-24 | 2020-09-08 | 中国药科大学 | Fluorescent compound with affinity with Abeta oligomer as well as preparation method and application thereof |
| CN111777603B (en) * | 2020-06-15 | 2021-10-01 | 山东师范大学 | Fluorescent probe capable of simultaneously detecting beta amyloid protein deposition plaque and peroxynitrite and preparation method and application thereof |
| CN112028915B (en) * | 2020-09-11 | 2021-05-04 | 南京晓庄学院 | Fluorescent probe and synthesis and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010504332A (en) * | 2006-09-19 | 2010-02-12 | ヒューマン バイオモレキュラル リサーチ インスティテュート | Diagnostic method and genetic marker for Alzheimer's disease |
| WO2010017094A2 (en) * | 2008-07-31 | 2010-02-11 | The General Hospital Corporation | CURCUMIN DERIVATIVES FOR AMYLOID-β PLAQUE IMAGING |
| WO2011014648A2 (en) * | 2009-07-31 | 2011-02-03 | The General Hospital Corporation | METHODS AND SYSTEM FOR DETECTING SOLUBLE AMYLOID-β |
| WO2014025808A1 (en) * | 2012-08-06 | 2014-02-13 | The General Hospital Corporation | Curcumin analogs |
-
2016
- 2016-03-09 CN CN201610139439.1A patent/CN105622657B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN105622657A (en) | 2016-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104610955B (en) | A kind of Ratio-type detects the synthesis and application of fluorine ion and inferior sulfate radical fluorescent molecular probe simultaneously | |
| CN102352118B (en) | Near infrared fluorescent dye, preparation and application thereof | |
| CN105622657B (en) | Curcumin derivate, preparation method and application | |
| CN101883775B (en) | Reagents for detection of hypochlorous acid | |
| Fan et al. | 4-(8′-Hydroxyquinolin-7′-yl) methyleneimino-1-phenyl-2, 3-dimethyl-5-pyzole as a fluorescent chemosensor for aluminum ion in acid aqueous medium | |
| Zhao et al. | Two ‘turn-off’Schiff base fluorescence sensors based on phenanthro [9, 10-d] imidazole-coumarin derivatives for Fe3+ in aqueous solution | |
| Janiga et al. | Quadrupolar, emission-tunable π-expanded 1, 4-dihydropyrrolo [3, 2-b] pyrroles–synthesis and optical properties | |
| Wei et al. | A two-step responsive colorimetric probe for fast detection of formaldehyde in weakly acidic environment | |
| Sun et al. | A novel colorimetric and fluorometric probe for the detection of CN− with high selectivity in aqueous media | |
| Staneva et al. | Ultrasonic synthesis and spectral characterization of a new blue fluorescent dendrimer as highly selective chemosensor for Fe3+ cations | |
| Feng et al. | Colorimetric and “turn-on” fluorescent determination of Cu 2+ ions based on rhodamine–quinoline derivative | |
| CN112920081A (en) | Fluorescent probe for selectively identifying hypochlorous acid and preparation method and application thereof | |
| KR102401455B1 (en) | Indolizine core skeleton-Based Emissive Fluorescent Compounds and Use thereof | |
| Çelik et al. | The new water-soluble Schiff base derivative fluorometric chemosensor with highly selective and instantly sensitivity for Fe3+ ion detection in aqueous media | |
| Fuchi et al. | Characterization of Push–Pull-Type Benzo [X] quinoline Derivatives (X= g or f): Environmentally Responsive Fluorescent Dyes with Multiple Functions | |
| Safir Filho et al. | Visualization of intracellular lipid droplets using lipophilic benzothiazole-based push-pull fluorophores at ultralow concentration | |
| Gonçalves et al. | The confidence of blue: A new highly selective bio-inspired coumarin emissive probe for fluoride recognition | |
| Zhang et al. | A novel aggregation‐induced emission fluorescent probe with large Stokes shift for sensitive detection of pH changes in live cells | |
| CN102660254A (en) | Iridium complex-containing phosphorescent material, preparation method and application in mercury ion detection | |
| CN106518870B (en) | Using naphthalimide as colorimetric fluorescence probe of core and its preparation method and application | |
| CN105017040B (en) | The detection reagent and method of never poison and the like | |
| CN108410202A (en) | A kind of preparation method of seven methine cyanine dyes of quinoline | |
| CN114773305A (en) | Preparation method and application of 2-ring aropyranone pH fluorescence ratio probe | |
| CN110922338B (en) | Anthraquinone derivative and synthesis method and application thereof | |
| CN110330664B (en) | Eu/Tb-BHM-COOH complex and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180821 Termination date: 20210309 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |