CN101712648A - Synthesis method of azepine anthraquinone - Google Patents
Synthesis method of azepine anthraquinone Download PDFInfo
- Publication number
- CN101712648A CN101712648A CN200910234521A CN200910234521A CN101712648A CN 101712648 A CN101712648 A CN 101712648A CN 200910234521 A CN200910234521 A CN 200910234521A CN 200910234521 A CN200910234521 A CN 200910234521A CN 101712648 A CN101712648 A CN 101712648A
- Authority
- CN
- China
- Prior art keywords
- reaction
- quinone
- quinoline
- naphthoquinones
- anthraquinone
- 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.)
- Granted
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- ZWMFUFUJHSFPGL-UHFFFAOYSA-N anthracene-9,10-dione 1H-azepine Chemical compound C1=CC=CC=2C(C3=CC=CC=C3C(C12)=O)=O.N1C=CC=CC=C1 ZWMFUFUJHSFPGL-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 229910052751 metal Inorganic materials 0.000 claims abstract description 17
- 239000002184 metal Substances 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 229910003771 Gold(I) chloride Inorganic materials 0.000 claims abstract description 8
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052737 gold Inorganic materials 0.000 claims abstract description 8
- 239000010931 gold Substances 0.000 claims abstract description 8
- 150000003057 platinum Chemical class 0.000 claims abstract description 6
- SDKPSXWGRWWLKR-UHFFFAOYSA-M sodium;9,10-dioxoanthracene-1-sulfonate Chemical group [Na+].O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)[O-] SDKPSXWGRWWLKR-UHFFFAOYSA-M 0.000 claims abstract description 5
- FBEIPJNQGITEBL-UHFFFAOYSA-J tetrachloroplatinum Chemical group Cl[Pt](Cl)(Cl)Cl FBEIPJNQGITEBL-UHFFFAOYSA-J 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 239000011591 potassium Substances 0.000 claims abstract description 3
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 38
- 238000000746 purification Methods 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 26
- 238000005576 amination reaction Methods 0.000 claims description 22
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 238000004440 column chromatography Methods 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 claims description 13
- 238000000926 separation method Methods 0.000 claims description 13
- 238000010189 synthetic method Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- CPYFLMXPZMBECD-UHFFFAOYSA-N 3-acetyl-1,8-dihydroxy-2-methylphenanthrene-9,10-dione Chemical compound C12=CC=CC(O)=C2C(=O)C(=O)C2=C1C=C(C(=O)C)C(C)=C2O CPYFLMXPZMBECD-UHFFFAOYSA-N 0.000 claims description 10
- 150000000191 1,4-naphthoquinones Chemical class 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 229960001701 chloroform Drugs 0.000 claims description 8
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical group [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000011968 lewis acid catalyst Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- NVJSPQCVDHGYRE-UHFFFAOYSA-N quinoline-5,8-dione Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=N1 NVJSPQCVDHGYRE-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- QQUYEYJPZLCULC-UHFFFAOYSA-N 2-bromo-8-hydroxynaphthalene-1,4-dione Chemical class O=C1C=C(Br)C(=O)C2=C1C=CC=C2O QQUYEYJPZLCULC-UHFFFAOYSA-N 0.000 claims description 3
- AEXYBXXYRZKXQL-UHFFFAOYSA-N 4-methyl-1h-quinoline-2,5,8-trione Chemical compound O=C1C=CC(=O)C2=C1NC(=O)C=C2C AEXYBXXYRZKXQL-UHFFFAOYSA-N 0.000 claims description 3
- POGRUZKQEAYHPM-UHFFFAOYSA-N 6,7-dimethoxynaphthalene-1,4-dione Chemical class O=C1C=CC(=O)C2=C1C=C(OC)C(OC)=C2 POGRUZKQEAYHPM-UHFFFAOYSA-N 0.000 claims description 3
- NTBVZFSCKSYPMP-UHFFFAOYSA-N 6-bromoquinoline-5,8-dione Chemical compound C1=CC=C2C(=O)C(Br)=CC(=O)C2=N1 NTBVZFSCKSYPMP-UHFFFAOYSA-N 0.000 claims description 3
- GOCLHSLGUKQMTC-UHFFFAOYSA-N 7-bromoquinoline-5,8-dione Chemical compound C1=CN=C2C(=O)C(Br)=CC(=O)C2=C1 GOCLHSLGUKQMTC-UHFFFAOYSA-N 0.000 claims description 3
- FNAYBDIYFZJMER-UHFFFAOYSA-N 7-chloro-4-methyl-1H-quinoline-2,5,8-trione Chemical compound ClC1=CC(C=2C(=CC(NC2C1=O)=O)C)=O FNAYBDIYFZJMER-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 150000004057 1,4-benzoquinones Chemical class 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- KQPYUDDGWXQXHS-UHFFFAOYSA-N juglone Chemical class O=C1C=CC(=O)C2=C1C=CC=C2O KQPYUDDGWXQXHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 abstract 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 abstract 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 abstract 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract 2
- 229960000948 quinine Drugs 0.000 abstract 2
- 240000006409 Acacia auriculiformis Species 0.000 abstract 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 abstract 1
- 229910052697 platinum Inorganic materials 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- XNMQEEKYCVKGBD-UHFFFAOYSA-N dimethylacetylene Natural products CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- -1 methoxyl group Chemical group 0.000 description 19
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical class C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 12
- YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- GVRYUHXXENMGEV-UHFFFAOYSA-N 4-methylbenzo[g]quinoline-5,10-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1N=CC=C2C GVRYUHXXENMGEV-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KMYXGXIBPDCBER-UHFFFAOYSA-N CC#CC(NC(C(C1=CC=CC=C11)=O)=CC1=O)=O Chemical class CC#CC(NC(C(C1=CC=CC=C11)=O)=CC1=O)=O KMYXGXIBPDCBER-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229930013930 alkaloid Natural products 0.000 description 4
- QVJDTKXZVZTKLX-UHFFFAOYSA-K trichlorogold;triphenylphosphane Chemical compound Cl[Au](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QVJDTKXZVZTKLX-UHFFFAOYSA-K 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- ZETGBHQWYABAJF-UHFFFAOYSA-N C(C#CC)(=O)NC=1C(C=2C=CC=NC2C(C1)=O)=O Chemical compound C(C#CC)(=O)NC=1C(C=2C=CC=NC2C(C1)=O)=O ZETGBHQWYABAJF-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229910003803 Gold(III) chloride Inorganic materials 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- RMLHVYNAGVXKKC-UHFFFAOYSA-N [SH2]=N.C(F)(F)F Chemical class [SH2]=N.C(F)(F)F RMLHVYNAGVXKKC-UHFFFAOYSA-N 0.000 description 2
- 150000001345 alkine derivatives Chemical group 0.000 description 2
- GPJKOFLDDKEODA-UHFFFAOYSA-N amphimedine Chemical compound C1=CC=CC2=NC(C=3C(=CN(C(C=3)=O)C)C3=O)=C4C3=NC=CC4=C21 GPJKOFLDDKEODA-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000005899 aromatization reaction Methods 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- RJHLTVSLYWWTEF-UHFFFAOYSA-K gold trichloride Chemical group Cl[Au](Cl)Cl RJHLTVSLYWWTEF-UHFFFAOYSA-K 0.000 description 2
- 229940076131 gold trichloride Drugs 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- QSJNAFJALFWFMT-UHFFFAOYSA-N meridine Chemical compound N1C=CC(=O)C2=C1C(=O)C1=NC=CC3=C(C=CC=C4)C4=NC2=C13 QSJNAFJALFWFMT-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- BWQKHOMAOVUASZ-UHFFFAOYSA-N sampangine Chemical compound C1=NC(C(=O)C=2C3=CC=CC=2)=C2C3=NC=CC2=C1 BWQKHOMAOVUASZ-UHFFFAOYSA-N 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- GVUUJWJLSSTXPE-UHFFFAOYSA-N C(C#CC)(=O)NC1=CC(C=2C=CC=NC2C1=O)=O Chemical compound C(C#CC)(=O)NC1=CC(C=2C=CC=NC2C1=O)=O GVUUJWJLSSTXPE-UHFFFAOYSA-N 0.000 description 1
- FLAWDLVEUSERAI-UHFFFAOYSA-N C(C#CC)(=O)NC=1C(C2=C(C=CC=C2C(C1)=O)O)=O Chemical class C(C#CC)(=O)NC=1C(C2=C(C=CC=C2C(C1)=O)O)=O FLAWDLVEUSERAI-UHFFFAOYSA-N 0.000 description 1
- OOXAGJRHVNUKAX-UHFFFAOYSA-N C(C#CC)(=O)NC=1C(C2=CC(=C(C=C2C(C1)=O)OC)OC)=O Chemical class C(C#CC)(=O)NC=1C(C2=CC(=C(C=C2C(C1)=O)OC)OC)=O OOXAGJRHVNUKAX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
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- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- VLCMRTMCMQJSKM-UHFFFAOYSA-N phenyl-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CN=C2C(C(F)(F)F)=CC=CC2=C1C1=CC=CC=C1 VLCMRTMCMQJSKM-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthesis method of azepine anthraquinone. The azepine anthraquinone is obtained by carrying out intramolecular 6-endo-dig cycloisomerisation reaction shown as in formula (1) on N-propargyl quinine with a 1,5-eneyne structure under the action of a metal catalyst, and purifying, wherein the intramolecular 6-endo-dig cycloisomerisation reaction is homogeneous phase metal catalytic reaction, the metal catalyst is gold salt, platinum salt or univalent gold complex; and the use level of the metal catalyst is 0.01-0.5 equivalent weight of the N--propargyl quinine. The gold slat is auri chloridum (AuCl3) or aurous chloride (AuCl); the platinum salt is platinum tetrachloride, platinum bichloride or potassium chloroplatinate; and the univalent gold complex is PPh3AuOTf, PPh3AuSbF6, PPh3AuNTf2 or LAuNTf2, wherein L is nitrogen heterocyclic ring carbene ligand. The invention realizes the synthesis of the azepine anthraquinone by utilizing metal catalytic intramolecular eneyne cyclization reaction, and has the advantages of simple and easy-accessible raw materials and moderate reaction conditions.
Description
Technical field
The present invention relates to a kind of synthetic method of azepine anthraquinone.
Background technology
Azepine anthraquinone is to have the mother nucleus structure that important biomolecule is learned active natural alkaloid, common structure comprises benzo [g] quinoline-5,10-diketone, pyrido [3,2-g] quinoline-5, or derivatives thereofs such as 10-diketone, wherein the simplest azepine anthraquinone Alkaloid is Cleistopholine.The Cleistopholine derivative that has hydroxyl and methoxyl group substituted radical on some phenyl ring (shown in the following A of concrete structure, is worked as R
1=R
2=R
3During=H, A is Cleistopholine; The Cleistopholine derivative comprises following situation: R
1=R
2=H, R
3=OMe; R
1=H, R
2=R
3=OMe; R
1=OH, R
2=OMe, R
3=H; R
1=OH, R
2=R
3=OMe) be found in succession, all have tangible anti-microbial activity and cytotoxicity (M.H.Chaves, L.de A.Santo, J.H.G.Lago, N.F.Roque, J.Nat.Prod.2001,64,240.) through the active testing said derivative.
Benzo [g] quinoline-5,10-diketone pyrido [3,2-g] quinoline-5,10-diketone A
Because this class rigid-skeleton alkaloid has effective biological activity, the research interest that directly causes pharmaceutical chemistry and synthetic chemistry worker, attempt to obtain azepine anthraquinone in a large number on the one hand, remedy the deficiency of natural resource by the rational chemical synthesis route of development; Offer help for solving relevant chemicobiology problem (such as structure and activity relationship, Biological mechanism of action) on the other hand.Moreover, in the complete synthesis strategy of many condensed ring marine alkaloids (as Sampangine, Meridine, Amphimedine), azepine anthraquinone is designed to effectively synthetic building block always.(T.F.Molinski，Chem.Rev.1993，93，1825.)
The route of chemosynthesis azepine anthraquinone is to adopt Hetero-Diels-Alder cycloaddition method at present.This 4+2 synthesis strategy is proposed by Ghosez at first, α wherein, and beta-unsaturated aldehyde and 1, the hydrazone of 1-dimethylhydrazine formation is as the diene body; Quinone is shown below as dienophile (B.Serckx-Poncin, A.-M.Hesbain-Frisque, L.Ghosez, Tetrahedron Lett.1982,23,3261.).The synthetic azepine anthraquinone of Hetero-Diels-Alder cycloaddition method exists limitation: after (1) diene body and the quinone cycloaddition, the aromatization that removes dimethylamine is influenced (when R is aryl by substrate structure obviously, need to use strong oxidizer Manganse Dioxide to carry out dehydroaromatizationof), severe reaction conditions, more bad is that aromatization can discharge the equimolar amount dimethylamine, and dimethylamine can carry out oxidation-amination side reaction with dienophile.(2) when the molecular structure of dienophile quinone is asymmetric, generate two kinds of isomer easily, directly cause the reduction of target product productive rate, separation difficulty (For a review:F.Pautet, P.Nebois, Z.Bouaziz, H.Fillion, Heterocycles, 2001,54,1095.).
Summary of the invention
The invention provides a kind of synthetic method of azepine anthraquinone, reaction conditions is gentle relatively.
The synthetic method of described azepine anthraquinone is: by having 1, the N-propargyl quinone (III) of 5-eneyne structure is under the effect of metal catalyst, and after intramolecularly 6-endo-dig cycloisomerisation reaction as the formula (1), purifying obtains azepine anthraquinone (IV),
Wherein, R is aryl or C
1-C
6Alkyl; ML is a metal catalyst,
The reaction of intramolecularly 6-endo-dig cycloisomerisation is the homogeneous phase metal catalysed reaction, and wherein metal catalyst is golden salt, platinum salt or monovalence gold complex, and amount of metal catalyst is 0.01 equivalent to 0.5 equivalent of N-propargyl quinone.Wherein golden salt is gold trichloride (AuCl
3) or gold monochloride (AuCl), platinum salt is Tetrachloroplatinum, platinum dichloride or potassium platinichloride, the monovalence gold complex is PPh
3AuOTf, PPh
3AuSbF
6, PPh
3AuNTf
2Or LAuNTf
2, wherein L is the nitrogen heterocyclic ring carbenes.Described monovalence gold complex Preparation of catalysts is a prior art, by gold trichloride (I) title complex (as triphenyl phosphorus gold trichloride (I)) and silver salt such as AgOTf, AgSbF
6, AgNTf
2The reaction in preparation.
Intramolecularly 6-endo-dig cycloisomerisation is reflected in the 3rd solvent carries out, temperature of reaction be 0 ℃ to the 3rd solvent refluxing temperature, purify and to obtain azepine anthraquinone in finishing back of reaction, described the 3rd solvent is toluene, ethylene dichloride, dioxane, tetrahydrofuran (THF) or C
1-C
5Monocarboxylic acid.
Purify after the reaction of intramolecularly 6-endo-dig cycloisomerisation finishes and be meant that the rapid column chromatography separation obtains azepine anthraquinone.Can carry out concentrating under reduced pressure as the case may be before chromatography, concentrated solution is removed steps such as catalyzer through organic solvent extraction, washing, drying.
Described have 1, the N-propargyl quinone (III) of 5-eneyne structure can be obtained by known response, as: being undertaken purifying behind as the formula (2) oxidation-amination reaction by quinone (I-1) and propargylamine (II) obtains, or undertaken purifying behind as the formula (3) the nucleophilic substitution reaction by halo quinone (I-2) and propargylamine (II) and obtain
Wherein X is the chlorine or bromine atom.
Described quinone is a p-benzoquinones, 1,4-naphthoquinones, 6,7-dimethoxy-1,4-naphthoquinones, 8-hydroxyl-1,4-naphthoquinones, 8-methoxyl group-1,4-naphthoquinones, 4-methyl-2-oxo-5,8-quinoline quinone or 5,8-quinoline quinone, described halo quinone are 2-bromo-8-hydroxyl-1,4-naphthoquinones, 2-bromo-8-methoxyl group-1,4-naphthoquinones, 6-bromo-5,8-quinoline quinone, 7-bromo-5,8-quinoline quinone or 7-chloro-4-methyl-2-oxo-5,8-quinoline quinone.
In oxidation-amination reaction or the nucleophilic substitution reaction, the propargylamine consumption is 1.0 equivalent to 3.0 equivalents of quinone, purify behind oxidation-amination reaction or the nucleophilic substitution reaction and be meant, with the mixture concentrating under reduced pressure behind oxidation-amination reaction or the nucleophilic substitution reaction, then use organic solvent extraction, extract the back and merge organic layer, organic layer is through drying, concentrated, column chromatography purification or the aftertreatment of process recrystallization obtain N-propargyl quinone then, and described organic solvent is ethyl acetate, ether, methylene dichloride or trichloromethane.
Add the Lewis acid catalyst in oxidation-amination reaction, in first solvent, carry out, catalyst consumption is 0.01 equivalent to 0.5 equivalent of quinone, described first solvent is that carbochain is monohydroxy-alcohol, benzene, toluene or the dimethyl sulfoxide (DMSO) of C1-C4, temperature of reaction is extremely-78 ℃ of solvent refluxing temperature, and the reaction times is 10 minutes to 24 hours.Described Lewis acid catalyst is a kind of or wherein a kind of hydrate in sodium chloraurate, Cerium II Chloride, cupric chloride, the iron(ic) chloride.
The product N-propargyl quinone (III) of oxidation-amination reaction can be: 2-[3-(4-aminomethyl phenyl)-2-propine amido]-1, (III a) for the 4-naphthoquinones, 2-[3-(4-p-methoxy-phenyl)-2-propine amido]-1,4-naphthoquinones (III b), 2-[3-(4-nitrophenyl)-2-propine amido]-1,4-naphthoquinones (III c), 2-[3-(2-nitrophenyl)-2-propine amido]-1,4-naphthoquinones (III d), 2-(3-phenyl-2-propine amido)-1,4-naphthoquinones (III e), 2-[3-(2-bromophenyl)-2-propine amido]-1,4-naphthoquinones (III f), 2-[3-(2-methoxycarbonyl phenyl)-2-propine amido]-1,4-naphthoquinones (III g), 2-(2-butyne amido)-1,4-naphthoquinones (III h), 2-(2-butyne amido)-6,7-dimethoxy-1,4-naphthoquinones (III i), 6-(2-butyne amido)-5,8-quinoline quinone (III l), 7-(2-butyne amido)-4-methyl-2,5,8-quinoline triketone (III n).
Need to add mineral alkali or organic bases in the nucleophilic substitution reaction of halo quinone and propargylamine and be alkaline condition to keep reaction system, organic bases or mineral alkali consumption are 1.0 equivalent to 2.0 equivalents of halo quinone.Mineral alkali can be metal carbonate, as yellow soda ash, salt of wormwood or cesium carbonate; Organic bases can be itrogenous organic substance such as triethylamine, diisopropylethylamine, 7-1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU), pyridine, 2,6-lutidine or 2.
The halo quinone is according to bibliographical information method synthetic (L.F.Tietze, K.M.Gericke, R.R.Singidi, I.Schuberth, Org.Biomol.Chem.2007,5,1191; L.F.Tietze, K.M.Gericke, I.Schuberth, Eur.J.Org.Chem.2007,4563; D.L.Boger, S.R.Duff, J.S.Panek, M.Yasuda, J.Org.Chem.1985,50,5782; C.Avendano, E.De la Cuesta, C.Gesto, Synthesis, 1991,727).
Described nucleophilic substitution reaction carries out in second solvent, the propargylamine consumption is 1.0 equivalent to 3.0 equivalents of quinone, described second solvent is that carbochain is monohydroxy-alcohol, methylene dichloride, the trichloromethane or 1 of C1-C4, the 2-ethylene dichloride, temperature of reaction be 0 ℃ to the second solvent refluxing temperature, the reaction times is 10 minutes to 24 hours.
The product of halo quinone and propargylamine nucleophilic substitution reaction (III) can be: 2-(2-butyne amido)-8-methoxyl group-1,4-naphthoquinones (IIIj), 2-(2-butyne amido)-8-hydroxyl-1,4-naphthoquinones (III k), 6-(2-butyne amido)-5,8-quinoline quinone (III l), 7-(2-butyne amido)-5,8-quinoline quinone (III m), 7-(2-butyne amido)-4-methyl-2,5,8-quinoline triketone (III n).
The gained azepine anthraquinone can be: 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa), 4-(4-p-methoxy-phenyl)-benzo [g] quinoline-5,10-diketone (IVb), 4-(4-nitrophenyl)-benzo [g] quinoline-5,10-diketone (IVc), 4-(2-nitrophenyl)-benzo [g] quinoline-5,10-diketone (IVd), 4-phenyl-benzo [g] quinoline-5,10-diketone (IVe), 4-(2-bromophenyl)-benzo [g] quinoline-5,1-diketone (IVf), 4-(2-methoxycarbonyl phenyl)-benzo [g] quinoline-5,10-diketone (IVg), 4-methyl-benzo [g] quinoline-5,10-diketone (IVh), 7,8-dimethoxy-4 '-methyl-benzo [g] quinoline-5,10-diketone (IVi), 4-methyl-9-methoxyl group-benzo [g] quinoline-5,10-diketone (IVj), 9-hydroxy-4-methyl-benzo [g] quinoline-5,10-diketone (IVk), 4-methyl-pyrido [2,3-g] quinoline-5,10-diketone (IVl), 4-methyl-pyrido [3,2-g] quinoline-5,10-diketone (IVm), 4,6-dimethyl-pyrido [3,2-g] quinoline-2,5,10-triketone (IVn).
The invention has the beneficial effects as follows: compared with the prior art, the present invention uses metal catalytic intramolecularly eneyne annulation structure pyridine ring, thereby realize the synthetic of azepine anthraquinone, required 1,5-eneyne structure N-propargyl quinone can be obtained by currently known methods, having raw material is simple and easy to, the advantage of reaction conditions gentleness, simultaneously, for the situation that the azepine anthraquinone isomer may occur, good known response obtains specified 1 can to select the chemical regions selectivity, 5-eneyne structure, closed loop obtains the azepine anthraquinone of single structure then, carries out nucleophilic substitution reaction as adopting halo quinone and propargylamine, the specific position that is implemented in quinone imports the alkynes side chain, for described azepine anthraquinone is 4-methyl-pyrido [2,3-g] quinoline-5,10-diketone (IVl) or 4,6-dimethyl-pyrido [3,2-g] quinoline-2,5, during 10-triketone (IVn), also can be respectively with 5,8-quinoline quinone and 4-methyl-2-oxo-5, the 8-quinoline quinone is a raw material, imports the alkynes side chain through oxidation-amination reaction at specific position.The inventive method has overcome aromizing dehydrogenation reaction and the limitation that the azepine anthraquinone isomer occurs in traditional Hetero-Diels-Alder synthetic route.The gained azepine anthraquinone has anti-microbial activity and cytotoxicity, has the purposes of excellent antibiotic medicine and antitumor drug aspect.
Embodiment
Embodiment 1:4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
1,2-[3-(4-aminomethyl phenyl)-2-propine amido]-1,4-naphthoquinones (a) synthetic of III
Fill 1 in single neck bottle, 4-naphthoquinones (5.0mmol), 3-(4-aminomethyl phenyl)-2-propargylamine (6.0mmol) and 10mL dehydrated alcohol stir adding NaAuCl down
42H
2O (0.05mmol).Room temperature reaction 4 hours.Reaction mixture filters and obtains the reddish-brown solid.Obtain 2-[3-(4-aminomethyl phenyl)-2-propine amido with ethyl alcohol recrystallization then]-1, the 4-naphthoquinones.188-190 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 8.08 (dd, J
1=16.5Hz, J
2=7.8Hz, 2H), 7.73 (t, J=7.5Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.32 (d, J=8.1Hz, 2H), 7.11 (d, J=7.5Hz, 2H), 6.12 (br, s, 1H), 5.90 (s, 1H), 4.20 (d, J=5.4Hz, 2H), 2.34 (s, 3H).
2,4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
(14.9mg 0.03mmol) adds and to fill silver trifluoromethanesulfonate (7.8mg 0.03mmol) and in the 6.0mL acetum, stirs and adds 2-[3-(4-aminomethyl phenyl)-2-propine amido-1,4-naphthoquinones (0.3mmol) after 5 minutes triphenyl phosphorus gold trichloride (I).Reaction is warming up to 80 ℃ of reactions 1 hour.Remove solvent under reduced pressure, raffinate is dissolved in methylene dichloride (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone yellow solid through the rapid column chromatography separation and purification.mp?243-245℃；
1HNMR(300MHz，CDCl
3)δ9.04(d，J＝5.1Hz，1H)，8.41-8.38(m，1H)，8.16-8.13(m，1H)，7.85-7.77(m，2H)，7.52(d，J＝4.8Hz，1H)，7.31(d，J＝8.1Hz，2H)，7.25-7.22(m，2H)，2.47(s，3H)。
Embodiment 2:4-(4-p-methoxy-phenyl)-benzo [g] quinoline-5,10-diketone (IVb) synthetic
1,2-[3-(4-p-methoxy-phenyl)-2-propine amido]-1,4-naphthoquinones (III b) synthetic
By 1,4-naphthoquinones (5.0mmol), 3-(4-p-methoxy-phenyl)-2-propargylamine (6.0mmol) obtain through oxidation-amination reaction, 2-[3-among reaction conditions and the purification step embodiment 1 (4-aminomethyl phenyl)-2-propine amido]-1, (III is a) for the 4-naphthoquinones.Product mp172-175 ℃;
1H NMR (300MHz, CDCl
3) δ 8.10 (d, J=7.5Hz, 1H), 8.05 (d, J=7.5Hz, 1H), 7.72 (t, J=7.5Hz, 1H), 7.61 (t, J=7.2Hz, 1H), 7.36 (d, J=8.7Hz, 2H), 6.82 (d, J=9.0Hz, 2H), 6.10 (br s, 1H), 5.89 (s, 1H), 4.18 (d, J=5.7Hz, 2H), 3.79 (s, 3H).
2,4-(4-p-methoxy-phenyl)-benzo [g] quinoline-5,10-diketone (IVb) synthetic
4-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa).175-177 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 9.00 (d, J=4.8Hz, 1H), 8.38-8.35 (m, 1H), 8.15-8.12 (m, 1H), 7.83-7.75 (m, 2H), 7.50 (d, J=4.8Hz, 1H), 7.30-7.25 (m, 2H), 7.03-6.98 (m, 2H), 3.88 (m, 1H).
Embodiment 3:4-(4-nitrophenyl)-benzo [g] quinoline-5,10-diketone (IVc) synthetic
1,2-[3-(4-nitrophenyl)-2-propine amido]-1,4-naphthoquinones (III c) synthetic
By 1,4-naphthoquinones (5.0mmol), 3-(4-nitrophenyl)-2-propargylamine (6.0mmol) obtain through oxidation-amination reaction, 2-[3-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-2-propine amido]-1, (III is a) for the 4-naphthoquinones.Product mp228-230 ℃;
1H NMR (300MHz, CDCl
3) δ 8.21-8.18 (m, 2H), 8.01-7.94 (m, 2H), 7.84 (td, J
1=7.5Hz, J
2=1.5Hz, 1H), 7.75 (td, J
1=7.5Hz, J
2=1.5Hz, 1H), 7.70-7.66 (m, 2H), 5.89 (s, 1H), 4.38 (d, J=5.7Hz, 2H).
2,4-(4-nitrophenyl)-benzo [g] quinoline-5,10-diketone (IVc) synthetic
4-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa).270-272 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 9.15 (d, J=4.8Hz, 1H), 8.42-8.35 (m, 3H), 8.11 (d, J=6.9Hz, 1H), 7.88-7.79 (m, 2H), 7.52-7.47 (m, 3H).
Embodiment 4:4-(2-nitrophenyl)-benzo [g] quinoline-5,10-diketone (IVd) synthetic
1,2-[3-(2-nitrophenyl)-2-propine amido]-1,4-naphthoquinones (IIId) synthetic
By 1,4-naphthoquinones (5.0mmol), 3-(2-nitrophenyl)-2-propargylamine (6.0mmol) obtain through oxidation-amination reaction, 2-[3-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-2-propine amido]-1, (III is a) for the 4-naphthoquinones.Product mp195-197 ℃;
1H NMR (300MHz, DMSO-d
6) δ 8.06 (d, J=7.8Hz, 1H), 7.99 (dd, J
1=7.5Hz, J
2=1.2Hz, 1H), 7.95 (dd, J
1=7.5Hz, J
2=1.2Hz, 1H), 7.90 (t, J=6.0Hz, 1H), 7.83 (td, J
1=7.5Hz, J
2=1.5Hz, 1H), 7.76-7.68 (m, 3H), 7.64-7.59 (m, 1H), 5.89 (s, 1H), 4.37 (d, J=6.3Hz, 2H).
2,4-(2-nitrophenyl)-benzo [g] quinoline-5,10-diketone (IVd) synthetic
4-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa).254-256 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 9.12 (d, J=5.1Hz, 1H), 8.38 (dd, J
1=7.5Hz, J
2=1.2Hz, 1H), 8.34 (dd, J
1=7.5Hz, J
2=1.2Hz, 1H), 8.05 (dd, J
1=7.2Hz, J
2=1.5Hz, 1H), 7.84-7.73 (m, 3H), 7.67 (td, J
1=8.1Hz, J
2=1.5Hz, 1H), 7.45 (d, J=4.5Hz, 1H), 7.27 (dd, J
1=7.2Hz, J
2=1.5Hz, 1H).
Embodiment 5:4-phenyl-benzo [g] quinoline-5,10-diketone (IVe) synthetic
1,2-(3-phenyl-2-propine amido)-1,4-naphthoquinones (IIIe) synthetic
By 1,4-naphthoquinones (5.0mmol), 3-phenyl-2-propargylamine (6.0mmol) obtain through oxidation-amination reaction, 2-[3-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-2-propine amido]-1, (III is a) for the 4-naphthoquinones.175-177 ℃ of product mp;
1HNMR (300MHz, CDCl
3) δ 8.10 (d, J=7.5Hz, 1H), 8.05 (d, J=7.5Hz, 1H), 7.72 (t, J=7.3Hz, 1H), 7.62 (t, J=7.5Hz, 1H), 7.43-7.41 (m, 2H), 7.31-7.29 (m, 3H), 6.12 (br s, 1H), 5.90 (s, 1H), 4.21 (d, J=5.4Hz, 2H).
2,4-phenyl-benzo [g] quinoline-5,10-diketone (IVe) synthetic
4-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa).199-201 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 9.05 (d, J=4.8Hz, 1H), 8.40-8.37 (m, 1H), 8.14-8.11 (m, 1H), 7.85-7.83 (m, 2H), 7.53-7.46 (m, 4H), 7.35-7.30 (m, 2H).
Embodiment 6:4-(2-bromophenyl)-benzo [g] quinoline-5,10-diketone (IVf) synthetic
1,2-[3-(2-bromophenyl)-2-propine amido]-1,4-naphthoquinones (III f) synthetic
By 1,4-naphthoquinones (5.0mmol), 3-(2-bromophenyl)-2-propargylamine (6.0mmol) obtain through oxidation-amination reaction, 2-[3-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-2-propine amido]-1, (III is a) for the 4-naphthoquinones.180-182 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 8.11 (dd, J
1=7.8Hz, J
2=1.2Hz, 1H), 8.06 (dd, J
1=7.8Hz, J
2=1.2Hz, 1H), 7.73 (td, J
1=7.5Hz, J
2=1.2Hz, 1H), 7.63 (td, J
1=7.8Hz, J
2=1.5Hz, 1H), 7.56 (dd, J
1=7.8Hz, J
2=1.2Hz, 1H), 7.45 (dd, J
1=7.5Hz, J
2=1.8Hz, 1H), 7.25 (td, J
1=7.5Hz, J
2=1.2Hz, 1H), 7.17 (td, J
1=7.8Hz, J
2=1.8Hz, 1H), 6.16 (br s, 1H), 5.97 (s, 1H), 4.28 (d, J=5.7Hz, 2H).
2,4-(2-bromophenyl)-benzo [g] quinoline-5,10-diketone (IVf) synthetic
4-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa).257-259 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 9.14 (d, J=4.8Hz, 1H), 8.42-8.39 (m, 1H), 8.16-8.13 (m, 1H), 7.86-7.76 (m, 2H), 7.71 (dd, J
1=7.8Hz, J
2=0.9Hz, 1H), 7.50-7.45 (m, 2H), 7.36 (td, J
1=7.5Hz, J
2=1.5Hz, 1H), 7.23 (dd, J
1=7.5Hz, J
2=1.5Hz, 1H).
Embodiment 7:4-(2-methoxycarbonyl phenyl)-benzo [g] quinoline-5,10-diketone (IVg) synthetic
1,2-[3-(2-methoxycarbonyl phenyl)-2-propine amido]-1,4-naphthoquinones (III g) synthetic
By 1,4-naphthoquinones (5.0mmol), 3-(2-methoxycarbonyl phenyl)-2-propargylamine (6.0mmol) obtain 2-[3-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-2-propine amido through oxidation-amination reaction]-1, (III is a) for the 4-naphthoquinones.Product mp188-189 ℃;
1H NMR (300MHz, DMSO-d
6) δ 8.00-7.80 (m, 5H), 7.73 (t, J=7.2Hz, 1H), 7.57-7.45 (m, 3H), 5.89 (s, 1H), 4.33 (d, J=5.7Hz, 2H), 3.78 (s, 3H).
2,4-(2-methoxycarbonyl phenyl)-benzo [g] quinoline-5,10-diketone (IVg) synthetic
4-among reaction conditions and purification step such as the embodiment 1 (4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa).207-210 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 9.08 (d, J=4.8Hz, 1H), 8.39 (dd, J
1=7.5Hz, J
2=1.2Hz, 1H), 8.20 (dd, J
1=8.1Hz, J
2=1.2Hz, 1H), 8.07 (dd, J
1=7.5Hz, J
2=1.5Hz, 1H), 7.83-7.72 (m, 2H), 7.66 (td, J
1=7.5Hz, J
2=1.5Hz, 1H), 7.57 (td, J
1=7.8Hz, J
2=0.9Hz, 1H), 7.42 (d, J=4.8Hz, 1H), 7.18 (d, J=7.5Hz, 1H), 3.63 (s, 3H).
Embodiment 8:4-methyl-benzo [g] quinoline-5,10-diketone (IVh) synthetic
1,2-(2-butyne amido)-1,4-naphthoquinones (III h) synthetic
Fill 1 in single neck bottle, 4-naphthoquinones (5.0mmol), 2-butyne amine (7.5mmol) and 10mL anhydrous methanol stir adding CeCl down
3.H
2O (0.5mmol).Room temperature reaction 12 hours.Directly separation obtains 2-(2-butyne amido)-1,4-naphthoquinones through rapid column chromatography for reaction mixture concentrating under reduced pressure, concentrated solution.190-192 ℃ of product mp;
1H NMR (300MHz, CDCl3) δ 8.10 (dd, J
1=7.5Hz, J
2=0.6Hz, 1H), 8.04 (dd, J
1=7.5Hz, J
2=0.6Hz, 1H), 7.73 (td, J
1=7.5Hz, J
2=1.2Hz, 1H), 7.62 (td, J
1=7.5Hz, J
2=1.2Hz, 1H), 6.02 (br s, 1H), 5.81 (s, 1H), 3.91 (q, J=2.4Hz, 2H), 1.83 (t, J=2.4Hz, 3H).
2,4-methyl-benzo [g] quinoline-5,10-diketone (IVh) synthetic
(8mg, 0.03mmol) with the 6.0mL toluene solution, whipped state adds 2-(2-butyne amido)-1,4-naphthoquinones (0.3mmol) down to fill platinum dichloride in single neck bottle.After the back flow reaction 10 hours, cooling.Mixing solutions directly by column chromatographic isolation and purification, obtains 4-methyl-benzo [g] quinoline-5,10-diketone (alkaloid Cleistopholine).200-203 ℃ of product mp.
1H?NMR(300MHz，CDCl
3)δ8.92(d，J＝4.8Hz，1H)，8.37-8.34(m，1H)，8.28-8.25(m，1H)，7.84-7.81(m，2H)，7.51(d，J＝4.8Hz，1H)，2.92(s，3H)。
Embodiment 9:7,8-dimethoxy-4 '-methyl-benzo [g] quinoline-5,10-diketone (IVi) synthetic
1,2-(2-butyne amido)-6,7-dimethoxy-1,4-naphthoquinones (III i) synthetic
By 6,7-dimethoxy-1,4-naphthoquinones (5.0mmol) and 2-butyne amine (7.5mmol) obtain through oxidation-amination reaction, 2-among reaction conditions and purification step such as the embodiment 8 (2-butyne amido)-1,4-naphthoquinones (IIIh).240-242 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 7.54 (s, 1H), 7.46 (s, 1H), 5.95 (br s, 1H), 5.68 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.83 (s, 3H).
2,7,8-dimethoxy-4 '-methyl-benzo [g] quinoline-5,10-diketone (IV i) synthetic
4-methyl-benzo [g] quinoline-5 among reaction conditions and purification step such as the embodiment 8,10-diketone (IVh).Product mp255-257 ℃;
1H NMR (300MHz, CDCl
3) δ 8.83 (d, J=4.8Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.43 (dd, J
1=4.8Hz, J
2=0.3Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 2.87 (s, 3H).
Embodiment 10:4-methyl-9-methoxyl group-benzo [g] quinoline-5,10-diketone (IVj) synthetic
1,2-(2-butyne amido)-8-methoxyl group-1,4-naphthoquinones (IIIj) synthetic
Fill 2-bromo-8-methoxyl group-1 in single neck bottle, 4-naphthoquinones (5.0mmol), triethylamine (10mmol) and 10mL dehydrated alcohol, system is cooled to 0 ℃; Stir and drip 2-butyne amine (7.5mmol) down.Dropwise, continued room temperature reaction 12 hours.Directly separation obtains 2-(2-butyne amido)-8-methoxyl group-1,4-naphthoquinones through rapid column chromatography for reaction mixture concentrating under reduced pressure, concentrated solution.mp?232℃；
1H?NMR(300MHz，CDCl
3)δ7.78(dd，J
1＝7.8Hz，J
2＝1.2Hz，1H)，7.66(t，J＝8.4Hz，1H)，7.18(dd，J
1＝7.8Hz，J
2＝0.9Hz，1H)，6.09(br?s，1H)，5.75(s，1H)，4.00(s，3H)，3.93-3.89(m，2H)，1.82(t，J＝2.4Hz，3H)。
2,4-methyl-9-methoxyl group-benzo [g] quinoline-5,10-diketone (IVj) synthetic
4-methyl-benzo [g] quinoline-5 among reaction conditions and purification step such as the embodiment 8,10-diketone (IVh).Product mp207-210 ℃;
1H NMR (300MHz, CDCl
3) δ 8.85 (d, J=4.8Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.71 (t, J=8.1Hz, 1H), 7.41 (d, J=5.1Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 4.03 (s, 3H), 2.84 (s, 3H).
Embodiment 11:9-hydroxy-4-methyl-benzo [g] quinoline-5,10-diketone (IVk) synthetic
1,2-(2-butyne amido)-8-hydroxyl-1,4-naphthoquinones (III k) synthetic
By 2-bromo-8-hydroxyl-1,4-naphthoquinones (5.0mmol) and 2-butyne amine (7.5mmol) nucleo philic substitution reaction obtain, reaction conditions and and purification step such as embodiment 10 in 2-(2-butyne amido)-8-methoxyl group-1,4-naphthoquinones (IIIj).180-182 ℃ of product mp;
1HNMR (300MHz, CDCl
3) δ 11.53 (s, 1H), 7.63 (s, 1H), 7.61 (d, J=3.0Hz, 1H), 7.14 (dd, J
1=6.3Hz, J
2=3.3Hz, 1H), 5.95 (br s, 1H), 5.78 (s, 1H), 3.95-3.91 (m, 2H), 1.83 (t, J=2.7Hz, 3H).
2,9-hydroxy-4-methyl-benzo [g] quinoline-5,10-diketone (IVk) synthetic
4-methyl-benzo [g] quinoline-5 among reaction conditions and purification step such as the embodiment 8,10-diketone (IVh).Product mp215-217 ℃;
1H NMR (300MHz, CDCl
3) δ 12.41 (s, 1H), 8.89 (d, J=4.8Hz, 1H), 7.78 (dd, J
1=7.5Hz, J
2=1.2Hz, 1H), 7.71 (t, J=7.8Hz, 1H), 7.50 (dd, J
1=4.8Hz, J
2=0.6Hz, 1H), 7.33 (dd, J
1=8.2Hz, J
2=1.4Hz, 1H), 2.89 (s, 3H).
Embodiment 12:4-methyl-pyrido [2,3-g] quinoline-5,10-diketone (IVl) synthetic
1,6-(2-butyne amido)-5,8-quinoline quinone (III l) synthetic
By 6-bromo-5,8-quinoline quinone (5.0mmol) and 2-butyne amine (7.5mmol) nucleo philic substitution reaction obtain, 2-among reactions steps such as the embodiment 10 (2-butyne amido)-8-methoxyl group-1,4-naphthoquinones (IIIj); Perhaps by 5,8-quinoline quinone (5.0mmol) and 2-butyne amine (7.5mmol) obtain through oxidation-amination reaction, 2-among reactions steps such as the embodiment 8 (2-butyne amido)-1, and 4-naphthoquinones (III h), productive rate is respectively 75%, 65%.
1H?NMR(300MHz，CDCl
3)δ8.96(dd，J
1＝4.8Hz，J
2＝1.6Hz，1H)，8.33(dd，J
1＝7.8Hz，J
2＝1.8Hz，1H)，7.84(t，J＝6.0Hz，1H)，7.73(dd，J
1＝7.8Hz，J
2＝4.5Hz，1H)，5.86(s，1H)，4.00(q，J＝2.70Hz，2H)，1.79(t，J＝2.2Hz，3H)。
2,4-methyl-pyrido [2,3-g] quinoline-5,10-diketone (IVl) synthetic
(14.9mg 0.03mmol) adds and to fill hexafluoro-antimonic acid silver (10.3mg 0.03mmol) and in the 6.0mL acetum, stirs and adds 6-(2-butyne amido)-5,8-quinoline quinone (0.3mmol) after 5 minutes triphenyl phosphorus gold trichloride (I).Reaction is warming up to 100 ℃ of reactions 1 hour.Remove solvent under reduced pressure, raffinate is dissolved in methylene dichloride (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-methyl-pyrido [2,3-g] quinoline-5, the 10-diketone through the rapid column chromatography separation and purification.mp?259℃；
1H?NMR(300MHz，CDCl
3)δ9.12(dd，J
1＝4.2Hz，J
2＝1.6Hz，1H)，8.93(d，J＝5.1Hz，1H)，8.60(dd，J
1＝7.8Hz，J
2＝1.5Hz，1H)，7.79(dd，J
1＝8.1Hz，J
2＝4.8Hz，1H)，7.53(dd，J
1＝5.1Hz，J
2＝0.6Hz，1H)，2.90(s，3H)。
Embodiment 13:4-methyl-pyrido [3,2-g] quinoline-5,10-diketone (IVm) synthetic
1,7-(2-butyne amido)-5,8-quinoline quinone (III m) synthetic
By 7-bromo-5,8-quinoline quinone (5.0mmol) and 2-butyne amine (7.5mmol) nucleo philic substitution reaction obtain, 2-among reaction conditions and purification step such as the embodiment 10 (2-butyne amido)-8-methoxyl group-1,4-naphthoquinones (IIIj).218 ℃ of product mp;
1H NMR (300MHz, CDCl
3) δ 8.91 (dd, J
1=4.5Hz, J
2=1.5Hz, 1H), 8.42 (dd, J
1=8.1Hz, J
2=1.5Hz, 1H), 7.64 (dd, J
1=7.8Hz, J
2=4.8Hz, 1H), 6.18 (br s, 1H), 5.87 (s, 1H), 3.95 (q, J=2.7Hz, 2H), 1.82 (t, J=2.4Hz, 3H).
2,4-methyl-pyrido [3,2-g] quinoline-5,10-diketone (IVm) synthetic
4-methyl-pyrido among reaction conditions and purification step such as the embodiment 12 [2,3-g] quinoline-5,10-diketone (IVl).Product mp273 ℃;
1H NMR (300MHz, CDCl
3) δ 9.13 (dd, J
1=4.8Hz, J
2=1.8Hz, 1H), 8.93 (d, J=4.8Hz, 1H), 8.68 (dd, J
1=7.8Hz, J
2=1.5Hz, 1H), 7.76 (dd, J
2=8.1Hz, J
2=4.6Hz, 1H), 7.55 (d, J=4.8Hz, 1H), 2.95 (s, 3H).
Embodiment 14:4,6-dimethyl-pyrido [3,2-g] quinoline-2,5,10-triketone (IVn) synthetic
1,7-(2-butyne amido)-4-methyl-2,5,8-quinoline triketone (III n) synthetic
7-chloro-4-methyl-2-oxo-5,8-quinoline quinone (5.0mmol) and 2-butyne amine (7.5mmol) nucleo philic substitution reaction obtain, 2-among reaction conditions and purification step such as the embodiment 10 (2-butyne amido)-8-methoxyl group-1,4-naphthoquinones (IIIj); Perhaps by 4-methyl-2-oxo-5,8-quinoline quinone (5.0mmol) and 2-butyne amine (7.5mmol) obtain through oxidation-amination reaction, 2-among reaction conditions and purification step such as the embodiment 8 (2-butyne amido)-1,4-naphthoquinones (III h), productive rate is respectively 80%, 75%.201-203 ℃ of product mp;
1H NMR (300MHz, DMSO-d
6) δ 11.30 (br s, 1H), 8.16 (br s, 1H), 6.36 (d, J=0.9Hz, 1H), 5.60 (s, 1H), 4.00 (q, J=2.7Hz, 2H), 2.45 (d, J=0.6Hz, 3H), 1.78 (t, J=2.4Hz, 3H).
2,4,6-dimethyl-pyrido [3,2-g] quinoline-2,5,10-triketone (IVn) synthetic
Triphenyl phosphorus gold trichloride (I) (14.9mg, 0.03mmol) add and to fill two (fluoroform sulfimides) silver (11.6mg 0.03mmol) and in the 6.0mL dichloroethane solution, stirs and adds 7-(2-butyne amido)-4-methyl-2 after 5 minutes, 5,8-quinoline triketone (0.3mmol).Reaction was warming up to back flow reaction 5 hours.Remove solvent under reduced pressure, raffinate is dissolved in chloroform (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4,6-dimethyl-pyrido [3,2-g] quinoline-2,5,10-triketone through the rapid column chromatography separation and purification.mp?247℃；
1HNMR(300MHz，DMSO-d
6)δ8.84(d，J＝4.8Hz，1H)，8.30(br?s，1H)，7.65(dd，J
1＝5.1Hz，J
2＝0.6Hz，1H)，6.58(d，J＝1.2Hz，1H)，2.74(s，3H)，2.56(d，J＝0.9Hz，3H)。
Embodiment 15:4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
1,2-[3-(4-aminomethyl phenyl)-2-propine amido]-1,4-naphthoquinones (a) synthetic of III
Reaction conditions and purification step are as embodiment 1.
2,4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
With 2-[3-(4-aminomethyl phenyl)-2-propine amido-1,4-naphthoquinones (0.3mmol) is dissolved in the 6.0mL tetrahydrofuran (THF), and adding AuCl under the stirring at room state (7.0mg, 0.03mmol).Be warming up to back flow reaction then 4 hours, and removed solvent under reduced pressure, raffinate is dissolved in methylene dichloride (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5, the 10-diketone through the rapid column chromatography separation and purification.Productive rate is 25%, hydrogen spectrum data such as embodiment 1.
Embodiment 16:4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
1,2-[3-(4-aminomethyl phenyl)-2-propine amido]-1,4-naphthoquinones (a) synthetic of III
Reaction conditions and purification step are as embodiment 1.
2,4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
With 2-[3-(4-aminomethyl phenyl)-2-propine amido-1,4-naphthoquinones (0.3mmol) is dissolved in the 6.0mL dioxane, and the stirring at room state adds AuCl down
3(9.1mg, 0.03mmol).Be warming up to back flow reaction then 2 hours, and removed solvent under reduced pressure, raffinate is dissolved in methylene dichloride (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5, the 10-diketone through the rapid column chromatography separation and purification.Productive rate is 55%, hydrogen spectrum data such as embodiment 1.
Embodiment 17:4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
1,2-[3-(4-aminomethyl phenyl)-2-propine amido]-1,4-naphthoquinones (a) synthetic of III
Reaction conditions and purification step are as embodiment 1.
2,4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
LAuCl (L=IPr) (18.6mg, 0.03mmol) add and to fill two (fluoroform sulfimides) silver (11.6mg, 0.03mmol) and the 6.0mL dichloroethane solution in, stir and add 2-[3-(4-aminomethyl phenyl)-2-propine amido-1,4-naphthoquinones (0.3mmol) after 5 minutes.Reaction was warming up to back flow reaction 6 hours.Remove solvent under reduced pressure, raffinate is dissolved in chloroform (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5, the 10-diketone through the rapid column chromatography separation and purification.Productive rate is 64%, hydrogen spectrum data such as embodiment 1.
Embodiment 18:4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
1,2-[3-(4-aminomethyl phenyl)-2-propine amido]-1,4-naphthoquinones (a) synthetic of III
Reaction conditions and purification step are as embodiment 1.
2,4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
(10mg, 0.03mmol) with the 6.0mL acetum, whipped state adds 2-[3-(4-aminomethyl phenyl)-2-propine amido-1,4-naphthoquinones (0.3mmol) down to fill Tetrachloroplatinum in single neck bottle.After the back flow reaction 1 hour, cooling.Remove solvent under reduced pressure, raffinate is dissolved in chloroform (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5, the 10-diketone through the rapid column chromatography separation and purification.Productive rate is 58%, hydrogen spectrum data such as embodiment 1.
Embodiment 19:4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
1,2-[3-(4-aminomethyl phenyl)-2-propine amido]-1,4-naphthoquinones (a) synthetic of III
Reaction conditions and purification step are as embodiment 1.
2,4-(4-aminomethyl phenyl)-benzo [g] quinoline-5,10-diketone (IVa) synthetic
(12.5mg, 0.03mmol) with the 6.0mL acetum, whipped state adds 2-[3-(4-aminomethyl phenyl)-2-propine amido-1,4-naphthoquinones (0.3mmol) down to fill Tetrachloroplatinum in single neck bottle.After the back flow reaction 2 hours, cooling.Remove solvent under reduced pressure, raffinate is dissolved in chloroform (20mL), and organic phase is through saturated sodium bicarbonate solution (10mL), water (10mL) washing then.Use the anhydrous magnesium sulfate drying after-filtration, the dense back concentrated solution that contracts of filtrate obtains 4-(4-aminomethyl phenyl)-benzo [g] quinoline-5, the 10-diketone through the rapid column chromatography separation and purification.Productive rate is 50%, hydrogen spectrum data such as embodiment 1.
Among the above embodiment, shown in the structural formula of N-propargyl quinone (III) and azepine anthraquinone (IV) and yield see the following form.
Claims (9)
1. the synthetic method of an azepine anthraquinone is characterized in that, by having 1, the N-propargyl quinone of 5-eneyne structure is under the effect of metal catalyst, and after intramolecularly 6-endo-dig cycloisomerisation reaction as the formula (1), purifying obtains azepine anthraquinone,
Wherein, R is aryl or C
1-C
6Alkyl; ML is a metal catalyst,
The reaction of intramolecularly 6-endo-dig cycloisomerisation is the homogeneous phase metal catalysed reaction, and wherein metal catalyst is golden salt, platinum salt or monovalence gold complex, and amount of metal catalyst is 0.01 equivalent to 0.5 equivalent of N-propargyl quinone.
2. the synthetic method of azepine anthraquinone as claimed in claim 1 is characterized in that, golden salt is AuCl
3Or AuCl, platinum salt is Tetrachloroplatinum, platinum dichloride or potassium platinichloride, the monovalence gold complex is PPh
3AuOTf, PPh
3AuSbF
6, PPh
3AuNTf
2Or LAuNTf
2, wherein L is the nitrogen heterocyclic ring carbenes.
3. the synthetic method of azepine anthraquinone as claimed in claim 1, it is characterized in that describedly having 1, the N-propargyl quinone of 5-eneyne structure is undertaken purifying behind as the formula (2) oxidation-amination reaction by quinone and propargylamine and obtains, or undertaken purifying behind as the formula (3) the nucleophilic substitution reaction by halo quinone and propargylamine and obtain
Wherein X is the chlorine or bromine atom.
4. the synthetic method of azepine anthraquinone as claimed in claim 3 is characterized in that, quinone is a p-benzoquinones, 1,4-naphthoquinones, 6,7-dimethoxy-1,4-naphthoquinones, 8-hydroxyl-1,4-naphthoquinones, 8-methoxyl group-1,4-naphthoquinones, 4-methyl-2-oxo-5,8-quinoline quinone or 5,8-quinoline quinone, described halo quinone are 2-bromo-8-hydroxyl-1,4-naphthoquinones, 2-bromo-8-methoxyl group-1,4-naphthoquinones, 6-bromo-5,8-quinoline quinone, 7-bromo-5,8-quinoline quinone or 7-chloro-4-methyl-2-oxo-5,8-quinoline quinone.
5. the synthetic method of azepine anthraquinone as claimed in claim 3, it is characterized in that, in oxidation-amination reaction or the nucleophilic substitution reaction, the propargylamine consumption is 1.0 equivalent to 3.0 equivalents of quinone, purify behind oxidation-amination reaction or the nucleophilic substitution reaction and be meant, with the mixture concentrating under reduced pressure behind oxidation-amination reaction or the nucleophilic substitution reaction, then use organic solvent extraction, extract the back and merge organic layer, organic layer is through drying, concentrate, column chromatography purification or the aftertreatment of process recrystallization obtain N-propargyl quinone then, and described organic solvent is an ethyl acetate, ether, methylene dichloride or trichloromethane.
6. as the synthetic method of each described azepine anthraquinone among the claim 3-5, it is characterized in that, add the Lewis acid catalyst in oxidation-amination reaction, in first solvent, carry out, the consumption of Lewis acid catalyst is 0.01 equivalent to 0.5 equivalent of quinone, described first solvent is that carbochain is monohydroxy-alcohol, benzene, toluene or the dimethyl sulfoxide (DMSO) of C1-C4, and temperature of reaction is extremely-78 ℃ of the first solvent refluxing temperature, and the reaction times is 10 minutes to 24 hours.
7. as the synthetic method of each described azepine anthraquinone among the claim 3-5, it is characterized in that, add mineral alkali or organic bases in the nucleophilic substitution reaction and be alkaline condition to keep reaction system, organic bases or mineral alkali consumption are 1.0 equivalent to 2.0 equivalents of halo quinone, nucleophilic substitution reaction carries out in second solvent, described second solvent is that carbochain is monohydroxy-alcohol, methylene dichloride, the trichloromethane or 1 of C1-C4, the 2-ethylene dichloride, temperature of reaction be 0 ℃ to the solvent refluxing temperature, the reaction times is 10 minutes to 24 hours.
8. as the synthetic method of each described azepine anthraquinone among the claim 1-5, it is characterized in that, intramolecularly 6-endo-dig cycloisomerisation is reflected in the 3rd solvent carries out, temperature of reaction be 0 ℃ to the 3rd solvent refluxing temperature, purify after reaction finishes and obtain azepine anthraquinone, described the 3rd solvent is toluene, ethylene dichloride, dioxane, tetrahydrofuran (THF) or C
1-C
5Monocarboxylic acid.
9. the synthetic method of azepine anthraquinone as claimed in claim 8 is characterized in that, purifying after the reaction of intramolecularly 6-endo-dig cycloisomerisation finishes is meant that separation obtains azepine anthraquinone through rapid column chromatography.
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| CN113372298A (en) * | 2021-05-21 | 2021-09-10 | 温州医科大学 | Preparation method of 2-iodine-3-amino naphthoquinone compound |
| CN114196973A (en) * | 2022-01-17 | 2022-03-18 | 南京工业大学 | Method for electrochemically synthesizing aza-anthraquinone derivative |
| US11771685B2 (en) | 2018-07-29 | 2023-10-03 | Musc Foundation For Research Development | Compounds for the treatment of neurological or mitochondrial diseases |
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| DD298427A5 (en) * | 1989-10-30 | 1992-02-20 | Zentralinstitut F. Mikrobiologie Und Experimentelle Therapie,De | PROCESS FOR PREPARING 3-METHYL-5,6 (7), 8-TRI-HYDROXY-2-AZA-ANTHRACETHONE (9,10) |
| DE4231632A1 (en) * | 1992-09-22 | 1994-03-24 | Knoell Hans Forschung Ev | Substd. 2-aza-anthraquinone derivs. - antivirals, antibacterials and antifungals for treating disease in humans and animals |
| ES2088822B1 (en) * | 1994-02-24 | 1997-08-01 | Univ Madrid Complutense | NEW ANTRAQUINONIC DERIVATIVES WITH ANTITUMORAL ACTIVITY AND ITS APPLICATIONS. |
-
2009
- 2009-11-23 CN CN2009102345212A patent/CN101712648B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11771685B2 (en) | 2018-07-29 | 2023-10-03 | Musc Foundation For Research Development | Compounds for the treatment of neurological or mitochondrial diseases |
| CN113372298A (en) * | 2021-05-21 | 2021-09-10 | 温州医科大学 | Preparation method of 2-iodine-3-amino naphthoquinone compound |
| CN113372298B (en) * | 2021-05-21 | 2022-04-19 | 温州医科大学 | Preparation method of 2-iodine-3-amino naphthoquinone compound |
| CN114196973A (en) * | 2022-01-17 | 2022-03-18 | 南京工业大学 | Method for electrochemically synthesizing aza-anthraquinone derivative |
| CN114196973B (en) * | 2022-01-17 | 2022-12-09 | 南京工业大学 | Method for electrochemically synthesizing aza-anthraquinone derivative |
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