CN100396682C - 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 - Google Patents
用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 Download PDFInfo
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- CN100396682C CN100396682C CNB031030971A CN03103097A CN100396682C CN 100396682 C CN100396682 C CN 100396682C CN B031030971 A CNB031030971 A CN B031030971A CN 03103097 A CN03103097 A CN 03103097A CN 100396682 C CN100396682 C CN 100396682C
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- Prior art keywords
- alkyl
- aryl
- substituted
- benzyl
- item
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 311
- 238000000034 method Methods 0.000 title claims abstract description 222
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000000543 intermediate Substances 0.000 title abstract description 22
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 421
- 125000003118 aryl group Chemical group 0.000 claims description 362
- 125000000217 alkyl group Chemical group 0.000 claims description 284
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 260
- -1 replacement Chemical group 0.000 claims description 141
- 238000006243 chemical reaction Methods 0.000 claims description 115
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 100
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 96
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 78
- 125000001072 heteroaryl group Chemical group 0.000 claims description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 30
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims 4
- 125000004429 atom Chemical group 0.000 claims 3
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 claims 2
- WSXJPXFVULHYMX-KRWDZBQOSA-N 7-[(1s)-1-hydroxypropyl]-8-methyl-11h-indolizino[1,2-b]quinolin-9-one Chemical compound C1=CC=C2C=C(CN3C4=CC(=C(C3=O)C)[C@@H](O)CC)C4=NC2=C1 WSXJPXFVULHYMX-KRWDZBQOSA-N 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- WSXJPXFVULHYMX-UHFFFAOYSA-N S-Mappicine Natural products C1=CC=C2C=C(CN3C4=CC(=C(C3=O)C)C(O)CC)C4=NC2=C1 WSXJPXFVULHYMX-UHFFFAOYSA-N 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 abstract description 3
- 229960004768 irinotecan Drugs 0.000 abstract description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 257
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 150
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 89
- 239000000203 mixture Substances 0.000 description 80
- 239000000047 product Substances 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 65
- 239000002904 solvent Substances 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- 230000037361 pathway Effects 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- 239000002253 acid Substances 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000003921 oil Substances 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 26
- 239000012071 phase Substances 0.000 description 26
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 24
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 23
- 238000010586 diagram Methods 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 22
- 239000008346 aqueous phase Substances 0.000 description 21
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 20
- 238000001819 mass spectrum Methods 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000002156 mixing Methods 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 125000003107 substituted aryl group Chemical group 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 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 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000000010 aprotic solvent Substances 0.000 description 12
- 229940127093 camptothecin Drugs 0.000 description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 12
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 12
- 230000035484 reaction time Effects 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 150000002009 diols Chemical class 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 150000002576 ketones Chemical class 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
- 150000001298 alcohols Chemical class 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 239000003880 polar aprotic solvent Substances 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 235000009518 sodium iodide Nutrition 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 7
- 239000004367 Lipase Substances 0.000 description 7
- 102000004882 Lipase Human genes 0.000 description 7
- 108090001060 Lipase Proteins 0.000 description 7
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000005708 Sodium hypochlorite Substances 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 235000019421 lipase Nutrition 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 7
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 7
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 7
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 150000004678 hydrides Chemical class 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 6
- 229910000105 potassium hydride Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000012039 electrophile Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 239000003456 ion exchange resin Substances 0.000 description 5
- 229920003303 ion-exchange polymer Polymers 0.000 description 5
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical class C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 5
- 229960002218 sodium chlorite Drugs 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- SQSYNRCXIZHKAI-UHFFFAOYSA-N 2,6-dichloroisonicotinic acid Chemical compound OC(=O)C1=CC(Cl)=NC(Cl)=C1 SQSYNRCXIZHKAI-UHFFFAOYSA-N 0.000 description 4
- CSGQJHQYWJLPKY-UHFFFAOYSA-N CITRAZINIC ACID Chemical compound OC(=O)C=1C=C(O)NC(=O)C=1 CSGQJHQYWJLPKY-UHFFFAOYSA-N 0.000 description 4
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- YGHUUVGIRWMJGE-UHFFFAOYSA-N chlorodimethylsilane Chemical compound C[SiH](C)Cl YGHUUVGIRWMJGE-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 229940102396 methyl bromide Drugs 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
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- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- PGFPZGKEDZGJQZ-UHFFFAOYSA-N n,n-dimethylmethanamine oxide;dihydrate Chemical compound O.O.C[N+](C)(C)[O-] PGFPZGKEDZGJQZ-UHFFFAOYSA-N 0.000 description 1
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- 125000006608 n-octyloxy group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
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- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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- 230000000171 quenching effect Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DHALMIBUKCNMLD-UHFFFAOYSA-N tert-butyl n-(2-formylphenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=C1C=O DHALMIBUKCNMLD-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004360 trifluorophenyl group Chemical group 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 150000004794 vinyl magnesium halides Chemical class 0.000 description 1
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
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- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41964395A | 1995-04-07 | 1995-04-07 | |
| US08/419,643 | 1995-04-07 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96193138A Division CN1100058C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体及方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1434044A CN1434044A (zh) | 2003-08-06 |
| CN100396682C true CN100396682C (zh) | 2008-06-25 |
Family
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Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031030971A Expired - Fee Related CN100396682C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 |
| CN96193138A Expired - Fee Related CN1100058C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体及方法 |
| CNB031031005A Expired - Fee Related CN100537538C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 |
| CNB031030998A Expired - Fee Related CN1241926C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的新的中间体和方法 |
| CN03103098XA Expired - Fee Related CN1434043B (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 |
Family Applications After (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96193138A Expired - Fee Related CN1100058C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体及方法 |
| CNB031031005A Expired - Fee Related CN100537538C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 |
| CNB031030998A Expired - Fee Related CN1241926C (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的新的中间体和方法 |
| CN03103098XA Expired - Fee Related CN1434043B (zh) | 1995-04-07 | 1996-04-01 | 用于制备喜树碱衍生物(cpt-11)以及相关化合物的中间体和方法 |
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|---|---|
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| EP (1) | EP0835257B1 (enExample) |
| JP (2) | JP4281075B2 (enExample) |
| KR (1) | KR100423627B1 (enExample) |
| CN (5) | CN100396682C (enExample) |
| AT (1) | ATE224899T1 (enExample) |
| AU (1) | AU717179B2 (enExample) |
| CA (1) | CA2214793C (enExample) |
| CZ (1) | CZ297862B6 (enExample) |
| DE (1) | DE69623960T2 (enExample) |
| DK (1) | DK0835257T3 (enExample) |
| ES (1) | ES2183943T3 (enExample) |
| HK (2) | HK1054234B (enExample) |
| HU (1) | HUP9801436A3 (enExample) |
| IL (1) | IL117684A (enExample) |
| MX (1) | MX9707706A (enExample) |
| NO (2) | NO320482B1 (enExample) |
| NZ (1) | NZ306664A (enExample) |
| PL (2) | PL186564B1 (enExample) |
| PT (1) | PT835257E (enExample) |
| RU (1) | RU2164917C2 (enExample) |
| SI (1) | SI0835257T1 (enExample) |
| TW (1) | TW438775B (enExample) |
| WO (1) | WO1996031513A1 (enExample) |
| ZA (1) | ZA962747B (enExample) |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG104284A1 (en) * | 1996-10-30 | 2004-06-21 | Tanabe Seiyaku Co | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof |
| WO2000020405A1 (en) * | 1998-10-07 | 2000-04-13 | Mitsubishi Chemical Corporation | Mixtures of optical isomers of 1,2-disubstituted-2,3-epoxypropanes, process for producing the same, pesticides containing the same as the active ingredient and intermediates thereof |
| FR2794123B1 (fr) | 1999-05-28 | 2001-07-27 | Aventis Pharma Sa | Preparation de derives de la camptothecine et de la nothapodytine |
| EP1229934B1 (en) | 1999-10-01 | 2014-03-05 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US6855294B2 (en) | 2000-11-22 | 2005-02-15 | Resonance, Inc. | Apparatus and methods for efficient generation of chlorine dioxide |
| TWI245768B (en) * | 2001-02-21 | 2005-12-21 | Yakult Honsha Kk | Process for synthesizing camptothecin related compound(s) |
| US6723853B2 (en) * | 2001-08-27 | 2004-04-20 | University Of Pittsburgh | Intermediates and methods of preparation of intermediates in the enantiomeric synthesis of (20R)homocamptothecins and the enantiomeric synthesis of (20R)homocamptothecins |
| JP3839813B2 (ja) * | 2002-04-17 | 2006-11-01 | ファルマシア コーポレイション | カンプトテシン誘導体の調製に有用な化合物 |
| US7151179B2 (en) | 2003-05-12 | 2006-12-19 | Scinopharm Taiwan, Ltd. | Process for the preparation of 7-alkyl-10-hydroxy-20(S)-camptothecin |
| CZ299329B6 (cs) * | 2003-08-26 | 2008-06-18 | Pliva-Lachema A.S. | Zpusob výroby 7-ethyl-10-[ 4-(1-piperidino)-1-piperidino]karbonyloxykamptothecinu |
| US8394365B2 (en) | 2003-09-17 | 2013-03-12 | Nektar Therapeutics | Multi-arm polymer prodrugs |
| CN1852740B (zh) * | 2003-09-17 | 2011-05-11 | 耐科塔医药公司 | 多支链聚合物的药物前体 |
| CZ299593B6 (cs) | 2003-12-16 | 2008-09-10 | Pliva-Lachema A. S. | Zpusob výroby 7-ethyl-10-hydroxykamptothecinu |
| US20050197355A1 (en) * | 2004-03-02 | 2005-09-08 | Henegar Kevin E. | Compounds useful in preparing camptothecin derivatives |
| US20050267141A1 (en) * | 2004-05-28 | 2005-12-01 | Phytogen Life Sciences Inc. | Process to prepare camptothecin derivatives |
| US20050272757A1 (en) * | 2004-06-04 | 2005-12-08 | Phytogen Life Sciences Inc. | Process to prepare camptothecin derivatives and novel intermediate and compounds thereof |
| US20080182990A1 (en) * | 2004-08-09 | 2008-07-31 | Shilpa Medicare Limited | Process for the Preparation of Irinotecan Hydrochloride Trihydrate |
| US20060046993A1 (en) * | 2004-09-01 | 2006-03-02 | Pharmacia Italia S.P.A. | Crystalline polymorphic form of irinotecan hydrochloride |
| ES2333462T3 (es) * | 2005-02-07 | 2010-02-22 | Fermion Oy | Procedimiento para la preparacion de 7-etil-10-hidroxi camptotecina. |
| JP5133703B2 (ja) * | 2005-02-08 | 2013-01-30 | フェルミオン オサケ ユキチュア | [1,4’]ビピペリジニル−1’−カルボニルクロリドまたはその塩酸塩の製造方法 |
| US7767813B2 (en) * | 2005-02-08 | 2010-08-03 | Fermion Oy | Preparation method |
| TWI375678B (en) * | 2005-06-09 | 2012-11-01 | Yakult Honsha Kk | A method of preparation of a tricyclic ketone |
| EP1803725A1 (en) * | 2005-12-13 | 2007-07-04 | W.C. Heraeus GmbH | Methods for preparing irinotecan |
| US7462627B2 (en) * | 2006-02-09 | 2008-12-09 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
| US7671067B2 (en) * | 2006-02-09 | 2010-03-02 | Enzon Pharmaceuticals, Inc. | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
| KR101441709B1 (ko) | 2006-11-30 | 2014-09-18 | 넥타르 테라퓨틱스 | 중합체 컨쥬게이트의 제조 방법 |
| EP2109448B1 (en) * | 2007-02-09 | 2013-09-11 | Enzon Pharmaceuticals, Inc. | Treatment of resistant or refractory cancers with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin |
| CN104277144A (zh) * | 2008-07-31 | 2015-01-14 | 卢布里佐尔公司 | 共聚物及其润滑组合物 |
| EP2331140B1 (en) * | 2008-08-11 | 2018-07-04 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
| WO2010025337A1 (en) * | 2008-08-29 | 2010-03-04 | Enzon Pharmaceuticals, Inc. | Method of treating ras associated cancer |
| RS59607B1 (sr) | 2008-09-23 | 2020-01-31 | Nektar Therapeutics | Metod metronomskog doziranja kamptotecinskih prolekova (npr. peg-irinotekan) |
| JP2012506380A (ja) * | 2008-10-21 | 2012-03-15 | エンゾン ファーマシューティカルズ,インコーポレーテッド | 7−エチル−10−ヒドロキシカンプトテシンのマルチアーム型ポリマーコンジュゲートによる神経芽腫の治療 |
| WO2012032531A1 (en) * | 2010-09-06 | 2012-03-15 | Avra Laboratories Pvt. Ltd. | Process for the manufacture of irinotecan hydrochloride by total synthesis |
| US10894087B2 (en) | 2010-12-22 | 2021-01-19 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
| US20130331443A1 (en) | 2010-12-22 | 2013-12-12 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| JO3283B1 (ar) | 2011-04-26 | 2018-09-16 | Sanofi Sa | تركيب يتضمن أفليبيرسيبت, حمض فولينيك, 5- فلورويوراسيل (5- Fu) وإرينوسيتان (FOLFIRI) |
| SI3170005T1 (sl) | 2014-07-18 | 2019-08-30 | Sanofi | Postopek napovedovanja izida zdravljenja z afliberceptom, pacienta, pri katerem obstaja sum, da je zbolel za rakom |
| ES2806624T3 (es) | 2015-10-27 | 2021-02-18 | California Pacific Medical Center | Derivados de podofilotoxina y su uso |
| US10087194B2 (en) * | 2015-10-27 | 2018-10-02 | California Pacific Medical Center | Podophyllotoxin derivatives and their use |
| SG11201807965YA (en) | 2016-03-15 | 2018-10-30 | Oryzon Genomics Sa | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
| CN105965710B (zh) * | 2016-06-28 | 2019-03-22 | 常州大学 | 一种硅棒金钢线切割树脂板的制备方法及应用 |
| US11434196B2 (en) | 2019-01-15 | 2022-09-06 | Laurus Labs Limited | Process for preparation of 2-Amino-5-hydroxy propiophenone |
| CN112300184B (zh) * | 2019-08-02 | 2022-12-06 | 华东师范大学 | 一种三元环化合物的制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5053512A (en) * | 1987-04-14 | 1991-10-01 | Research Triangle Institute | Total synthesis of 20(S) and 20(R)-camptothecin and compthothecin derivatives |
| US5405963A (en) * | 1993-06-10 | 1995-04-11 | Smithkline Beecham Corporation | Process for asymmetric total synthesis of camptothecin analogues |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5217499A (en) * | 1975-07-31 | 1977-02-09 | Nippon Chemiphar Co Ltd | Preparation of mappicine |
| EP0220601B1 (en) * | 1985-10-21 | 1991-12-11 | Daiichi Seiyaku Co., Ltd. | Pyranoindolizine derivatives and preparation process thereof |
| US4981968A (en) * | 1987-03-31 | 1991-01-01 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
| US4894456A (en) * | 1987-03-31 | 1990-01-16 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
| US5883255A (en) * | 1990-10-31 | 1999-03-16 | Smithkline Beecham Corporation | Substituted indolizino 1,2-b!quinolinones |
| GB9316352D0 (en) * | 1993-08-06 | 1993-09-22 | Erba Carlo Spa | Process for the preparation of 9-amino camptothecin |
| GB9319944D0 (en) * | 1993-09-28 | 1993-11-17 | Erba Carlo Spa | Process for the preparation of 9-amino camptothecin |
-
1996
- 1996-03-27 IL IL11768496A patent/IL117684A/en not_active IP Right Cessation
- 1996-03-27 TW TW085103680A patent/TW438775B/zh not_active IP Right Cessation
- 1996-04-01 CN CNB031030971A patent/CN100396682C/zh not_active Expired - Fee Related
- 1996-04-01 AT AT96912468T patent/ATE224899T1/de active
- 1996-04-01 KR KR1019970707091A patent/KR100423627B1/ko not_active Expired - Fee Related
- 1996-04-01 ES ES96912468T patent/ES2183943T3/es not_active Expired - Lifetime
- 1996-04-01 WO PCT/US1996/004163 patent/WO1996031513A1/en not_active Ceased
- 1996-04-01 MX MX9707706A patent/MX9707706A/es not_active IP Right Cessation
- 1996-04-01 EP EP96912468A patent/EP0835257B1/en not_active Expired - Lifetime
- 1996-04-01 DE DE69623960T patent/DE69623960T2/de not_active Expired - Lifetime
- 1996-04-01 PL PL96355318A patent/PL186564B1/pl not_active IP Right Cessation
- 1996-04-01 CZ CZ0311097A patent/CZ297862B6/cs not_active IP Right Cessation
- 1996-04-01 SI SI9630551T patent/SI0835257T1/xx unknown
- 1996-04-01 CA CA002214793A patent/CA2214793C/en not_active Expired - Fee Related
- 1996-04-01 US US09/230,245 patent/US6121451A/en not_active Expired - Fee Related
- 1996-04-01 RU RU97118673/04A patent/RU2164917C2/ru not_active IP Right Cessation
- 1996-04-01 HU HU9801436A patent/HUP9801436A3/hu unknown
- 1996-04-01 PL PL96322651A patent/PL186446B1/pl not_active IP Right Cessation
- 1996-04-01 NZ NZ306664A patent/NZ306664A/xx not_active IP Right Cessation
- 1996-04-01 CN CN96193138A patent/CN1100058C/zh not_active Expired - Fee Related
- 1996-04-01 AU AU55278/96A patent/AU717179B2/en not_active Ceased
- 1996-04-01 PT PT96912468T patent/PT835257E/pt unknown
- 1996-04-01 CN CNB031031005A patent/CN100537538C/zh not_active Expired - Fee Related
- 1996-04-01 JP JP53035696A patent/JP4281075B2/ja not_active Expired - Fee Related
- 1996-04-01 CN CNB031030998A patent/CN1241926C/zh not_active Expired - Fee Related
- 1996-04-01 CN CN03103098XA patent/CN1434043B/zh not_active Expired - Fee Related
- 1996-04-01 DK DK96912468T patent/DK0835257T3/da active
- 1996-04-04 ZA ZA9602747A patent/ZA962747B/xx unknown
-
1997
- 1997-10-06 NO NO19974608A patent/NO320482B1/no not_active IP Right Cessation
-
2000
- 2000-02-22 US US09/511,006 patent/US6235907B1/en not_active Expired - Fee Related
- 2000-10-13 US US09/687,227 patent/US6444820B1/en not_active Expired - Fee Related
-
2003
- 2003-09-11 HK HK03106488.3A patent/HK1054234B/zh not_active IP Right Cessation
- 2003-09-11 HK HK03106509.8A patent/HK1054236B/zh not_active IP Right Cessation
-
2005
- 2005-01-25 NO NO20050408A patent/NO329776B1/no not_active IP Right Cessation
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2007
- 2007-10-25 JP JP2007277903A patent/JP2008069170A/ja active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5053512A (en) * | 1987-04-14 | 1991-10-01 | Research Triangle Institute | Total synthesis of 20(S) and 20(R)-camptothecin and compthothecin derivatives |
| US5405963A (en) * | 1993-06-10 | 1995-04-11 | Smithkline Beecham Corporation | Process for asymmetric total synthesis of camptothecin analogues |
| US5541329A (en) * | 1993-06-10 | 1996-07-30 | Smithkline Beecham Corporation | Intermediates prepared in an asymmetric total synthesis of camptothecin analogs |
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