CN109134540A - A kind of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- and the preparation method and application thereof - Google Patents
A kind of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- and the preparation method and application thereof Download PDFInfo
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- CN109134540A CN109134540A CN201810973682.2A CN201810973682A CN109134540A CN 109134540 A CN109134540 A CN 109134540A CN 201810973682 A CN201810973682 A CN 201810973682A CN 109134540 A CN109134540 A CN 109134540A
- Authority
- CN
- China
- Prior art keywords
- phosphine oxide
- quinoline
- diphenyl phosphine
- bis
- tetrahydroquinolinesas
- 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.)
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- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 7
- 239000012043 crude product Substances 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 6
- 229940091513 Prostaglandin E1 receptor antagonist Drugs 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- 239000003863 metallic catalyst Substances 0.000 claims abstract description 3
- 238000000746 purification Methods 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000001961 anticonvulsive agent Substances 0.000 claims description 10
- -1 secondary alcohol compounds Chemical class 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 6
- 230000003556 anti-epileptic effect Effects 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000001805 chlorine compounds Chemical class 0.000 claims description 4
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- MILUBEOXRNEUHS-UHFFFAOYSA-N iridium(3+) Chemical class [Ir+3] MILUBEOXRNEUHS-UHFFFAOYSA-N 0.000 claims description 4
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 claims description 3
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940088710 antibiotic agent Drugs 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 238000011097 chromatography purification Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical class [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims description 2
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 claims 1
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 5
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 239000011574 phosphorus Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000004679 31P NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- ASUOLLHGALPRFK-UHFFFAOYSA-N phenylphosphonoylbenzene Chemical class C=1C=CC=CC=1P(=O)C1=CC=CC=C1 ASUOLLHGALPRFK-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 3
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 2
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical group C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002082 anti-convulsion Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical group C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 1
- IFIHYLCUKYCKRH-UHFFFAOYSA-N 6-bromoquinoline Chemical compound N1=CC=CC2=CC(Br)=CC=C21 IFIHYLCUKYCKRH-UHFFFAOYSA-N 0.000 description 1
- GKJSZXGYFJBYRQ-UHFFFAOYSA-N 6-chloroquinoline Chemical compound N1=CC=CC2=CC(Cl)=CC=C21 GKJSZXGYFJBYRQ-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- YUWBVKYVJWNVLE-UHFFFAOYSA-N [N].[P] Chemical compound [N].[P] YUWBVKYVJWNVLE-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- of one kind and the preparation method and application thereof, and the general molecular formula of the compound is as shown in following formula I:Wherein, R in the Formulas I1For H, Cl or Br.The preparation method, the following steps are included: S1, in the reaction vessel, the derivative and diphenyl phosphine oxide of quinoline or quinoline is added, the molar ratio of the derivative and diphenyl phosphine oxide of the quinoline or quinoline is 1: 2~3, the metallic catalyst of the derivative quality 1~5% of quinoline or quinoline is added, alcohol is added as hydrogen donor, solvent is added, is stirred to react at 80 DEG C~160 DEG C 5~24 hours；S2, it is cooled to room temperature, filters after reaction, vacuum rotary steam, which removes solvent, can be obtained crude product, crude by column chromatography purification.The compound all has potential drug activity in the fields such as prostaglandin E1 receptor antagonist, antibacterial, tyrosine kinase inhibitory activity, antitumor.
Description
Technical field
The present invention relates to technical field of organic synthesis, and in particular to bis- (diphenyl phosphine oxide) tetrahydro chinolines of 2,4- of one kind
Close object and the preparation method and application thereof.
Background technique
Heterocyclic compound occupies very important status in nature, quantity account for organic compound nearly three/
One.Many heterocyclic compounds all have special bioactivity, are widely applied to the fields such as new medicine, novel pesticide, new material,
The heterocyclic compound for efficiently synthesizing structure diversity is all hot spot in organic synthesis all the time.Nitrogenous heterocyclic compound is
Common structure in heterocycle, many azacyclo-s containing imidazoles, pyridine, pyrimidine often all have specific physiological activity.Quinoline
Class compound is a kind of important nitrogen heterocyclic, has the bioactivity such as antitumor, antibacterial, antiviral, anti-malarial, is curing
Medicine and pesticide field are widely used.In addition to this, tetrahydro quinazoline structure is the most common skeleton in alkaloid, such compound
With tyrosine kinase inhibitory activity, antitumor, antiepileptic and anticonvulsive drug (Hennequin, L.F.；Thomas,
A.P.；Johnstone,C.；Stokes,E.S.E.；Plé,P.A.；Lohmann,J.-J.M.；Ogilvie,
D.J.；Dukes,M.；Wedge,S.R.；Curwen,J.O.；Kendrew,J.；van der Brempt,
C.L.J.Med.Chem.1999,42,5369).Therefore, the synthesis containing tetrahydro quinazoline framework compound has been a concern.
Phosphorus is the same major element of nitrogen, and in the research of organophosphorus chemistry, phosphorus hetercyclic compound is also organic phosphorus chemical combination
Hot fields in object.The synthesis of phosphorous nitrogen heterocyclic is relatively difficult, the phosphorus-nitrogen containing heterocyclic compound reported in the prior art
The synthetic method of object is limited, and existing synthetic method also all respectively has certain limitation.Therefore, develop raw material be easy to get, condition temperature
With the synthetic method of more Atom economy easy to operate, the phosphazene for further constructing various structures has weight
Want meaning.
Summary of the invention
The technical problems to be solved by the present invention are: providing, a kind of pair of tumour be inhibited and preparation process economy
Good bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- and the preparation method and application thereof.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention are as follows: bis- (diphenyl phosphine oxides) four of 2,4- of one kind
Hydrogen quinolines, the general molecular formula of the derivative is as shown in following formula I:
Wherein, R in the Formulas I1For H, Cl or Br.
The invention also includes the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- of one kind, including it is following
Step:
S1, in the reaction vessel, is added the derivative and diphenyl phosphine oxide of quinoline or quinoline, the quinoline or quinoline
The molar ratio of derivative and diphenyl phosphine oxide is 1: 2~3, and the metal that the derivative quality 1~5% of quinoline or quinoline is added is urged
Agent (Catalyst, Cat.) is added alcohol as hydrogen donor (Hydrogen donor, HD), is added solvent (Solvent),
It is stirred to react at 80 DEG C~160 DEG C 5~24 hours；
S2, it is cooled to room temperature, filters after reaction, vacuum rotary steam, which removes solvent, can be obtained crude product, crude product warp
Column Chromatographic purification obtains bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4-.
Further, in the step S1, the metallic catalyst is copper acetate, copper sulphate, iron chloride, palladium acetate, double
Triphenylphosphine palladium, iridous chloride, 1,5- cyclo-octadiene iridium chloride dimer, dichloro (pentamethylcyclopentadiene base) close iridium
(III) one or more of dimer, ten dicarbapentaborane, three ruthenium and bis- (triphenylphosphine) ruthenic chlorides (II) of cyclopentadienyl group
Mixing.
Further, in the step S1, the solvent is ethyl alcohol, tert-pentyl alcohol, isopropanol, Isosorbide-5-Nitrae-dioxane, N, N-
The mixing of one or more of dimethylformamide, dimethyl sulfoxide, toluene, paraxylene and water；The solvent
The molal volume of the derivative of additional amount and quinoline or quinoline than be preferably quinoline or quinoline derivative: solvent=0.5mmol:
1~3ml.
Further, in the step S1, the hydrogen donor is secondary alcohol compounds, and the secondary alcohol compounds include different
The mixing of one or more of propyl alcohol, isobutanol, 1- phenylethanol.
Further, in the step S1, the preferred schlenk pipe (Schlenk pipe) of reaction vessel, reaction process is excellent
It is selected as carrying out under a nitrogen atmosphere.
Further, it is (0.5~50) that eluent used in column Chromatographic purification described in the step S2, which is volume ratio: (0
~20): 1 petroleum ether: methylene chloride: ethyl acetate mixed solvent.
Wherein, part reaction equation involved in above-mentioned synthetic method is as follows:
Wherein, the R1For hydrogen or chlorine or bromine.
Preferably, the quinoline is chloroquinoline or Bromoquinoline.
As can be seen from the above description, the beneficial effects of the present invention are: if quinoline, the then production of the present invention program preparation method
Rate is up to 86%, and if chloroquinoline, then the yield of the present invention program preparation method is up to 60%, if Bromoquinoline, then originally
The yield of scheme of the invention is up to 66%.
The invention also includes bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of above-mentioned 2,4- preparation prostaglandin E1 by
Body antagonist, antibacterials, tyrosine kinase inhibitor, anti-tumor drug, antiepileptic, anticonvulsant drug or anti-tumor agent comprising salmosin
In application.
The beneficial effects of the present invention are: bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of the 2,4- of the present invention program exist
Prostaglandin E1 receptor antagonist, antibacterial, tyrosine kinase inhibitory activity, antitumor, anti-epileptic and the fields such as anticonvulsion have
There is potential pharmaceutical activity, therefore can be used for preparing prostaglandin E1 receptor antagonist, antibacterials, tyrosine kinase and inhibit
Agent, anti-tumor drug, antiepileptic or anticonvulsive drug, the derivative are alternatively arranged as anti-tumor agent comprising salmosin for anti tumor activity in vitro
In screening.The present invention is using quinoline and diphenyl phosphine oxide as bis- (diphenyl phosphine oxide) tetrahydro chinolines of raw material one-step synthesis method 2,4-
Object is closed, has synthesis step simple, safe operation, advantages of nontoxic raw materials and cheap and easy to get, synthetic method to functional group good compatibility, original
The advantages that subeconomy is high.Bis- (diphenyl phosphine oxide) the tetrahydro chinolines product structures of 2, the 4- that the present invention program obtains are novel, can
Further develop its bioactivity；Novel 2,4- of the invention bis- (diphenyl phosphine oxide) tetrahydroquinoline derivative 3a, 3b, 3c to by
Trying people's cancer K562, HL-60, HeLa, BGC-823 cell is in inhibiting effect, in 100 μ gmL-1Concentration under it is thin to above-mentioned cancer
The inhibiting rate of born of the same parents is between 1.8%~51.9%.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram of product 3a made from the embodiment of the present invention 1；
Fig. 2 is the carbon spectrogram of product 3a made from the embodiment of the present invention 1；
Fig. 3 is the phosphorus spectrogram of product 3a made from the embodiment of the present invention 1；
Fig. 4 is the hydrogen spectrogram of product 3b made from the embodiment of the present invention 2；
Fig. 5 is the carbon spectrogram of product 3b made from the embodiment of the present invention 2；
Fig. 6 is the phosphorus spectrogram of product 3b made from the embodiment of the present invention 2；
Fig. 7 is the hydrogen spectrogram of product 3c made from the embodiment of the present invention 3；
Fig. 8 is the carbon spectrogram of product 3c made from the embodiment of the present invention 3；
Fig. 9 is the phosphorus spectrogram of product 3c made from the embodiment of the present invention 3.
Specific embodiment
To explain the technical content, the achieved purpose and the effect of the present invention in detail, below in conjunction with embodiment and cooperate attached
Figure is explained.
The embodiment of the present invention one is bis- (diphenyl phosphine oxide) tetrahydroquinolines of 2,4- and preparation method thereof, the method includes with
Lower step: in the reaction vessel, 0.5 mM of quinoline and 1.0 mMs of diphenyl phosphine oxides is added, 0.01 mM of 1,5- ring is pungent
Diene iridium chloride dimer, 0.5 mM of isopropanol, 1.5ml toluene are stirred to react 16 hours at 100 DEG C, after reaction
It is cooled to room temperature, dilute reaction solution, filters, vacuum rotary steam, which removes solvent, can be obtained crude product, crude by column chromatography purification
Bis- (diphenyl phosphine oxide) tetrahydroquinolines (3a) of 2,4- are obtained, are in yellow solid and fusing point are as follows: 179.0-180.6 DEG C.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of products therefrom 3a distinguishes as shown in Figure 1, Figure 2 and Figure 3, structural characterization data
It is as follows:
1H NMR(400MHz,CDCl3)δ7.80-7.65(m,4H),7.64-7.43(m,4H),7.40-7.15(m,12H),
6.76 (d, J=6.0Hz, 1H), 6.42-6.30 (m, 1H), 6.21-6.07 (m, 1H), 5.96 (d, J=6.5Hz, 1H), 4.88
(d, J=11.8Hz, 1H), 4.08 (s, 1H), 3.66 (s, 1H), 2.43-2.21 (m, 1H), 2.12-1.94 (m, 1H)；
13C NMR(101MHz,CDCl3) δ 144.48 (d, J=4.2Hz), 144.39 (d, J=4.2Hz), 132.40,
132.00 (d, J=11.2Hz), 131.88,131.70 (d, J=8.2Hz), 131.57,131.45 (d, J=6.5Hz),
131.27 (d, J=10.5Hz), 130.98,130.62,130.17 (d, J=3.1Hz), 130.06,129.14 (d, J=
9.2Hz), 128.96 (d, J=10.7Hz), 128.85 (d, J=10.7Hz), 128.61 (d, J=11.4Hz), 128.38 (d, J
=11.5Hz), 128.10 (d, J=1.5Hz), 116.42 (d, J=116.7Hz), 113.47 (d, J=5.3Hz), 47.49 (d,
), J=81.9Hz 37.96 (d, J=67.1Hz), 22.16；
31P NMR(162MHz,CDCl3)δ32.28,30.61；
Pass through the high-resolution mass spectrometer (High of electrospray ionisation source (Electron Spray Ionization, ESI)
Resolution Mass Spectrometer, HRMS) measure the molecular weight of the compound, C33H29NO2P2Na[M+Na]+: reason
By value (Calculated value, Calcd.): 556.1566；Actually measured value (found): 556.1565.
It is shown below according to the structure of the above characterization result inferred from input data products therefrom 3a:
The embodiment of the present invention two is bis- (diphenyl phosphine oxide) -6- chlorine tetrahydroquinolines of 2,4- and preparation method thereof, the side
Method is the following steps are included: in the reaction vessel, be added 0.5 mM of 6- chloroquinoline and 1.0 mMs of diphenyl phosphine oxides, 0.05 milli
Mole dichloro (pentamethylcyclopentadiene base) closes iridium (III) dimer, 0.8 mM of isobutanol, 1ml tert-pentyl alcohol, at 160 DEG C
It is stirred to react 5 hours, is cooled to room temperature after reaction, dilute reaction solution, filter, vacuum rotary steam removes solvent and can be obtained slightly
Product, crude by column chromatography purify to obtain bis- (the diphenyl phosphine oxide) -6- chlorine 3,4-tetrahydroquinoline compounds 3b of 2,4-, which is in
Yellow solid, fusing point are 180.1-182.6 DEG C.
Hydrogen spectrogram, carbon spectrogram and the phosphorus spectrogram of products therefrom 3b distinguishes as shown in Figure 4, Figure 5 and Figure 6, structural characterization data
It is as follows:
1H NMR(400MHz,CDCl3)δ7.90-7.78(m,4H),7.72-7.63(m,2H),7.60-7.39(m,12H),
7.37-7.31 (m, 2H), 6.86 (d, J=8.6Hz, 1H), 6.41 (d, J=8.6Hz, 1H), 5.91 (s, 1H), 4.99 (d, J=
12.2Hz,1H),4.11(s,1H),3.64(s,1H),2.42-2.29(m,1H),2.21-1.98(m,1H)；
13C NMR(101MHz,CDCl3) δ 143.15 (d, J=4.2Hz), 143.06 (d, J=4.1Hz), 132.46 (d, J
=2.5Hz), 132.20 (d, J=2.7Hz), 132.07,131.63 (d, J=9.2Hz), 131.54 (d, J=9.2Hz),
131.36 (d, J=8.5Hz), 131.03,130.61,130.14,130.07 (d, J=5.8Hz), 129.86 (d, J=
3.4Hz), 129.04 (d, J=8.8Hz), 128.93 (d, J=8.5Hz), 128.65 (d, J=11.9Hz), 128.53 (d, J=
12.4Hz), 127.94 (d, J=2.8Hz), 121.40 (d, J=3.2Hz), 116.86 (d, J=2.1Hz), 114.87 (d, J=
5.4Hz), 47.38 (d, J=80.6Hz), 38.07 (d, J=67.7Hz), 21.89；
31P NMR(162MHz,CDCl3)δ32.13,30.16；
HRMS(ESI):Calcd.for C33H28ClNO2P2Na[M+Na]+:590.1176；found:590.1170.
Infer that the structure of products therefrom 3b is shown below according to above data:
The embodiment of the present invention three is bis- (diphenyl phosphine oxide) -6- bromine tetrahydroquinolines of 2,4- and preparation method thereof, the side
Method is the following steps are included: in the reaction vessel, be added 0.3 mM of 6- bromoquinoline and 0.9 mM of diphenyl phosphine oxide, 0.05 milli
Mole dichloro (pentamethylcyclopentadiene base) closes iridium (III) dimer, 0.4 mM of 1- phenylethanol, 1ml paraxylene,
It is stirred to react 12 hours, is cooled to room temperature after reaction, dilute reaction solution at 160 DEG C, filter, vacuum rotary steam removes solvent and is
Crude product can be obtained, crude by column chromatography purifies to obtain bis- (the diphenyl phosphine oxide) -6- bromine tetrahydroquinoline 3c of 2,4-, the compound
White solid-like, fusing point are 181.7-183.1 DEG C；
The hydrogen spectrum of products therefrom 3c, carbon are composed and phosphorus spectrum is as shown in Figure 7, Figure 8 and Figure 9 respectively, and structural characterization data are as follows:
1H NMR(400MHz,CDCl3)δ7.92-7.77(m,4H),7.71-7.63(m,2H),7.61-7.52(m,4H),
7.52-7.39 (m, 8H), 7.37-7.31 (m, 2H), 6.99 (d, J=8.6Hz, 1H), 6.36 (d, J=8.6Hz, 1H), 6.03
(s, 1H), 4.99 (d, J=12.2Hz, 1H), 4.13 (s, 1H), 3.62 (s, 1H), 2.42-2.30 (m, 1H), 2.19-2.02
(m,1H)；
13C NMR(101MHz,CDCl3) δ 143.58 (d, J=4.3Hz), 143.49 (d, J=4.2Hz), 132.80 (d, J
=3.3Hz), 132.48 (d, J=2.6Hz), 132.23 (d, J=2.6Hz), 132.09,131.69 (s), 131.60 (d, J=
1.1Hz), 131.51 (d, J=3.1Hz), 131.42,131.33 (d, J=1.5Hz), 130.94,130.71 (d, J=
2.7Hz), 130.56,129.99 (d, J=3.7Hz), 129.05 (d, J=9.4Hz), 128.93 (d, J=8.9Hz), 128.65
(d, J=11.8Hz), 128.53 (d, J=11.9Hz), 117.24 (d, J=1.9Hz), 115.37 (d, J=5.7Hz),
108.41 (d, J=3.5Hz), 47.34 (d, J=81.3Hz), 38.13 (dd, J=67.3,11.9Hz), 21.87；
31P NMR(162MHz,CDCl3)δ32.24,30.24；
HRMS(ESI):Calcd.for C33H28BrNO2P2Na[M+Na]+:634.0671；found:634.0668.
Infer that the structure of products therefrom 3c is shown below according to above data
Product 3a, 3b and 3c is made in embodiment 1-3 and is respectively used to anti-tumor activity test:
(1) anti-tumor activity is tested
By each compound at 100 μ gmL-1Methanol solution, positive control drug 5 FU 5 fluorouracil (5-
Fluorouracil, 5-FU) and Docetaxel (docetaxol) be made into 100 μ gmL respectively-1Dimethyl sulfoxide
(Dimethyl sulfoxide, DMSO) solution, respectively using methanol and DMSO solvent as blank control, using tetramethyl azo azoles
The test of salt (methyl thiazolyl tetrazolium method, MTT) method is thin to K562, HL-60, HeLa, BGC-823
The inhibiting effect of born of the same parents.
(2) preparation of cell culture fluid: one bag of RPMI-1640 culture medium powder (nt wt net weight 10.4g) is poured into clean
In beaker, dissolved with the ultra-clean water of 900mL, and 100mgmL is added-1Streptomysin 1mL, penicillin 0.5mL and NaHCO3
2g.After magnetic agitation is uniform, removed with autoclaved Cai Shi (Zeiss) filter through 0.22 μm of membrane filtration in super-clean bench
Bacterium, filtrate are directly stored in (450mL/ bottles) in the vial after moist heat sterilization.Culture medium is before use, take the blood of freezing
Clearly, after 56 DEG C of inactivation 30min, addition has prepared in RPMI-1640 culture solution and (50mL serum has been added in 450mL culture medium), gently
After jog is even, covers, sealed with masking foil, saved in 4 DEG C of refrigerators.
MTT solution is prepared: the MTT powder of 50mg is dissolved in the PBS solution of 10mL, with 0.22 μm of membrane filtration, in 4
It is saved in DEG C refrigerator.
The secondary culture of cell: by K562 cell be added the RPMI-1640 culture solution of 10% fetal calf serum in 37 DEG C,
5%CO2Cell incubator in secondary culture.
(3) anti-tumor activity is tested: K562, HL-60, HeLa, BGC-823 cell of growth logarithmic phase is taken respectively, in 4
DEG C, be centrifuged 3min on 3000rpm centrifuge, suck supernatant, fresh RPMI-1640 culture medium be added and is diluted to 1 × 105
The cell suspension of a/milliliter.Every 200 μ L of hole is inoculated in 96 orifice plates, in 37 DEG C, 5%CO2Cell incubator in cultivate 1h
Afterwards, every hole adds 2 μ L of sample solution, and each sample sets 3 parallel holes, separately sets the blank control in two groups of each three holes, after sample-adding with
The same terms culture is for 24 hours.After for 24 hours, cell is observed under an optical microscope whether there is or not metamorphosis, preliminary judgement sample has cell-free
Cytotoxic activity is taken pictures when necessary.5mgmL is added in every hole-1Each 20 μ L of MTT solution, continue in incubator to cultivate 4h.It takes out
96 orifice plates are centrifuged (4 DEG C, 2000rpm, 20min) and remove supernatant, and every hole adds 150 μ L DMSO, and sufficiently oscillation precipitates purple
Object is completely dissolved.Its optical density OD value is measured under 570nm in microplate reader, every group of sample is averaged and by inhibiting rate
(inhibition rate, IR) %=(ODBlank-ODSample)/ODBlank× 100% formula calculates inhibiting rate (IR%).
Mtt assay is tested bis- (diphenyl phosphine oxide) tetrahydroquinoline derivatives of 2,4- and is inhibited to the proliferation activity of four kinds of tumour cells
As a result as shown in table 1 below.
Table 1MTT method tests derivative to the result of the proliferation activity inhibiting effect of four kinds of tumour cells
The compound made from the present invention program it can be seen from upper table 1 is equal to K562, HL-60, HeLa, BGC-823 cell
With certain inhibiting effect.
In above-described embodiment 1-3, reactional equation general formula is as follows:
For embodiment 1, then R1For hydrogen, corresponding yield is 86%；If chlorine, corresponding yield is 60%, if
For bromine, corresponding yield is 66%.
In conclusion a kind of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- provided by the invention and its preparation side
Method and application, the derivative is in prostaglandin E1 receptor antagonist, antibacterial, tyrosine kinase inhibitory activity, antitumor, anti-epileptic
Potential pharmaceutical activity is all had with anticonvulsion equal fields.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalents made by bright specification and accompanying drawing content are applied directly or indirectly in relevant technical field, similarly include
In scope of patent protection of the invention.
Claims (10)
1. one kind 2, bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 4-, it is characterised in that: the general molecular formula of the compound
As shown in following formula I:
Wherein, R in the Formulas I1For H, Cl or Br.
2. one kind 2, the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 4-, it is characterised in that: including following step
It is rapid:
The derivative and diphenyl phosphine oxide of quinoline or quinoline, the derivative of the quinoline or quinoline is added in S1, in the reaction vessel
The molar ratio of object and diphenyl phosphine oxide is 1: 2~3, and the metal catalytic of the derivative quality 1~5% of quinoline or quinoline is added
Agent is added alcohol as hydrogen donor, solvent is added, is stirred to react at 80 DEG C~160 DEG C 5~24 hours；
S2, it is cooled to room temperature, filters after reaction, vacuum rotary steam, which removes solvent, can be obtained crude product, and crude product is through column layer
Analysis purification obtains bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4-.
3. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 2, feature
Be: in the step S1, the metallic catalyst is copper acetate, copper sulphate, iron chloride, palladium acetate, bi triphenyl phosphine dichloride
Change palladium, iridous chloride, 1,5- cyclo-octadiene iridium chloride dimer, dichloro (pentamethylcyclopentadiene base) close iridium (III) dimer,
The mixing of one or more of ten dicarbapentaborane, three ruthenium and bis- (triphenylphosphine) ruthenic chlorides (II) of cyclopentadienyl group.
4. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 2, feature
Be: in the step S1, the solvent be ethyl alcohol, tert-pentyl alcohol, isopropanol, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide,
The mixing of one or more of dimethyl sulfoxide, toluene, paraxylene and water.
5. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 4, feature
Be: the molal volume of the derivative of the additional amount and quinoline or quinoline of the solvent is than the derivative for quinoline or quinoline: molten
Agent=0.5mmol:1~3ml.
6. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 2, feature
Be: in the step S1, the hydrogen donor is secondary alcohol compounds.
7. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 6, feature
Be: the secondary alcohol compounds include the mixing of one or more of isopropanol, isobutanol, 1- phenylethanol.
8. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 2, feature
Be: in the step S1, the reaction vessel is schlenk pipe, and reaction process carries out under a nitrogen atmosphere.
9. the preparation method of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- according to claim 2, feature
Be: eluent used in column Chromatographic purification described in the step S2 is that volume ratio is (0.5~50): (0~20): 1 stone
Oily ether: methylene chloride: ethyl acetate mixed solvent.
10. a kind of bis- (diphenyl phosphine oxide) Tetrahydroquinolinesas of 2,4- as described in claim 1 are preparing prostaglandin
E1 receptor antagonist, antibacterials, tyrosine kinase inhibitor, anti-tumor drug, antiepileptic, anticonvulsant drug or antitumor
Application in reagent.
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| CN104876929A (en) * | 2015-05-15 | 2015-09-02 | 华南理工大学 | Synthesis method and application of 1,2,3,4-tetrahydronaphthyridine compound |
| CN107602738A (en) * | 2017-09-01 | 2018-01-19 | 谢炳 | A kind of ultrahigh-molecular ethylene polymer catalyst and preparation method and application |
| CN108264589A (en) * | 2016-12-30 | 2018-07-10 | 中国石油天然气股份有限公司 | Polypropylene catalyst component and preparation method thereof, polypropylene catalyst |
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| CN104876929A (en) * | 2015-05-15 | 2015-09-02 | 华南理工大学 | Synthesis method and application of 1,2,3,4-tetrahydronaphthyridine compound |
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