CN1482908A - 吲哚并咔唑的相转移催化苷化方法 - Google Patents
吲哚并咔唑的相转移催化苷化方法 Download PDFInfo
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- CN1482908A CN1482908A CNA018214029A CN01821402A CN1482908A CN 1482908 A CN1482908 A CN 1482908A CN A018214029 A CNA018214029 A CN A018214029A CN 01821402 A CN01821402 A CN 01821402A CN 1482908 A CN1482908 A CN 1482908A
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- Prior art keywords
- alkyl
- formula
- aryl
- chemical compound
- alkylidene
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- 238000005858 glycosidation reaction Methods 0.000 title claims abstract description 14
- VVVPGLRKXQSQSZ-UHFFFAOYSA-N indolo[3,2-c]carbazole Chemical compound C1=CC=CC2=NC3=C4C5=CC=CC=C5N=C4C=CC3=C21 VVVPGLRKXQSQSZ-UHFFFAOYSA-N 0.000 title description 3
- 229960005544 indolocarbazole Drugs 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 48
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 230000008569 process Effects 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 54
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 16
- -1 9-fluorenyl methyl carbonyl Chemical group 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 230000004913 activation Effects 0.000 claims description 10
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical group [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 150000002243 furanoses Chemical class 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 230000003213 activating effect Effects 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 229910002056 binary alloy Inorganic materials 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical group [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 150000003215 pyranoses Chemical class 0.000 claims 3
- 229930182470 glycoside Natural products 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 7
- 241000124008 Mammalia Species 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 230000004614 tumor growth Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- 238000004364 calculation method Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 150000003214 pyranose derivatives Chemical class 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 101710183280 Topoisomerase Proteins 0.000 description 4
- 229940125532 enzyme inhibitor Drugs 0.000 description 4
- 239000002532 enzyme inhibitor Substances 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- QNMMYUBZGLXCCK-UHFFFAOYSA-N pyrrolo[3,2-a]carbazole Chemical class N1=C2C=CC=CC2=C2C1=C1C=CN=C1C=C2 QNMMYUBZGLXCCK-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 2
- FPMICYBCFBLGOZ-UHFFFAOYSA-N 6-phenylmethoxy-1h-indole Chemical compound C=1C=C2C=CNC2=CC=1OCC1=CC=CC=C1 FPMICYBCFBLGOZ-UHFFFAOYSA-N 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 150000004816 dichlorobenzenes Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000003408 phase transfer catalysis Methods 0.000 description 2
- 230000037452 priming Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 1
- BPMIHKHNNNNQIO-YFEREJOUSA-N (3r,4s,5r,6r)-3,4,5-tribenzyl-6-(1-hydroxy-2-phenylethyl)oxane-2,3,4,5-tetrol Chemical compound OC([C@@H]1[C@]([C@@](O)(CC=2C=CC=CC=2)[C@](O)(CC=2C=CC=CC=2)C(O)O1)(O)CC=1C=CC=CC=1)CC1=CC=CC=C1 BPMIHKHNNNNQIO-YFEREJOUSA-N 0.000 description 1
- QISMFQNPTWLXMQ-GASJEMHNSA-N (3r,4s,5s,6r)-2-fluoro-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1OC(O)(F)[C@H](O)[C@@H](O)[C@@H]1O QISMFQNPTWLXMQ-GASJEMHNSA-N 0.000 description 1
- NGMXFJBRMSEJIO-IGBKFWFVSA-N (3r,4s,5s,6s)-6-[amino(hydroxy)methyl]oxane-2,3,4,5-tetrol Chemical compound NC(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O NGMXFJBRMSEJIO-IGBKFWFVSA-N 0.000 description 1
- YEHSYXLCIYFVLZ-IGBKFWFVSA-N (3r,4s,5s,6s)-6-[azido(hydroxy)methyl]oxane-2,3,4,5-tetrol Chemical compound [N-]=[N+]=NC(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O YEHSYXLCIYFVLZ-IGBKFWFVSA-N 0.000 description 1
- PWKRGOPUVNGKKZ-RCSKTBSMSA-N (3s,4s,5s,6r)-3-fluoro-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1OC(O)[C@@](O)(F)[C@@H](O)[C@@H]1O PWKRGOPUVNGKKZ-RCSKTBSMSA-N 0.000 description 1
- PDWIQYODPROSQH-PYHARJCCSA-N 2-deoxy-D-ribofuranose Chemical compound OC[C@H]1OC(O)C[C@@H]1O PDWIQYODPROSQH-PYHARJCCSA-N 0.000 description 1
- UFUQBRMYERTCQH-UHFFFAOYSA-N 3-bromo-1-methylpyrrole-2,5-dione Chemical class CN1C(=O)C=C(Br)C1=O UFUQBRMYERTCQH-UHFFFAOYSA-N 0.000 description 1
- AQZMINLSVARCSL-UHFFFAOYSA-N 4-chloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile Chemical compound ClC1=CC(=O)C(C#N)=C(C#N)C1=O AQZMINLSVARCSL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical compound CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MPVYUOZJQRVUGW-UHFFFAOYSA-N N1C=CC2=CC=CC=C12.C1=CN=C2C=CC3=C4C=CC=CC4=NC3=C21 Chemical class N1C=CC2=CC=CC=C12.C1=CN=C2C=CC3=C4C=CC=CC4=NC3=C21 MPVYUOZJQRVUGW-UHFFFAOYSA-N 0.000 description 1
- SLSKZXFHTNGVJQ-UHFFFAOYSA-N OC.CC(C)=O.CCCCCC.CCOC(C)=O Chemical compound OC.CC(C)=O.CCCCCC.CCOC(C)=O SLSKZXFHTNGVJQ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N Xylose Natural products O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Abstract
本发明涉及新型的制备可用于制备吲哚并吡咯并咔唑衍生物的中间体的苷化方法,所述吲哚吡咯并咔唑衍生物可抑制肿瘤细胞的生长并因此可用于治疗哺乳动物等的癌症。
Description
发明背景
本发明涉及新型的制备可用于制备吲哚并吡咯并咔唑衍生物的中间体的苷化方法,所述吲哚吡咯并咔唑衍生物可抑制肿瘤细胞的生长并因此可用于治疗哺乳动物等的癌症。
在癌症化疗领域,已有大量化合物被作为抗肿瘤剂付诸使用。但是还是需要开发出更有效的对抗各种肿瘤的化合物(参见日本癌症学会47届例会论文集,12-15页(1988年))。这种需要导致了吲哚并咔唑衍生物的开发(参见美国专利4,487,925;4,552,842;4,785,085;5,591,842和5,922,860号;日本专利20277/91号;Journal ofAntibiotics(抗生素杂志),44卷723-728页(1991);WO 91/18003;WO98/07433;和EP 0545195 A1)。这些化合物均表现出了拓扑异构酶抑制剂的作用,因此可用于癌症的治疗(Cancer Chemother.Pharmacol.34(suppl):S41-S45(1994))。
由于这些化合物在治疗各种癌症上获得成功,因此需要开发其改良的合成方法。(参见Bioorg & Med.Chem.Letters 2000,10,419;Tetrahedron 1997,53,5937;Tetrahedron 1997,53,585;和Synthesis1976,414)。但是现有技术的方法仍存在着各种问题,包括使用不符合需要的溶剂、汞或银盐,低的收率和形成不想要的副产物而需要漫长繁琐的纯化步骤。
因此本发明的一个目标是提供一种制备可用于制备吲哚并吡咯并咔唑衍生的抗肿瘤物质的中间体,并同时克服现有合成技术中固有问题的新途径。
发明简述
本发明是一种新型的制备可用于制备吲哚并吡咯并咔唑衍生物的中间体的苷化方法,所述吲哚并吡咯并咔唑衍生物可抑制肿瘤细胞的生长,并因此可用于治疗哺乳动物等的癌症,如下式I所示的化合物:
本发明的详细说明
本发明的一个实施方案通过一种制备式I化合物的方法来举例说明:
1)H,
2)卤素,
3)OH,
4)CN,
5)NC,
6)CF3,
7)(C=O)NO2,
8)(C=O)C1-C6烷基,
9)(C=O)OC1-C6烷基,
10)OCH2OCH2CH2Si(CH3)3,
11)NO2,
12)9-芴基甲基羰基
13)NR5R6,
14)OC1-C6烷基,
15)C1-C6烷基,
16)C1-C6亚烷基芳基,和
17)OC1-C6亚烷基芳基;R和R1独立为:
1)H,
2)(C=O)C1-C6烷基,
3)(C=O)CF3,
4)(C=O)OC1-C6烷基,
5)9-芴基甲基羰基,
6)呋喃糖基,或
7)吡喃糖基,条件是R和R1之一为呋喃糖基或吡喃糖基;R2和R3独立为OH或H,或R2和R3一起形成一个桥氧基;R4为:
1)H,
2)C1-C10烷基,
3)CHO
4)(C=O)C1-C10烷基,
5)(C=O)OC1-C10烷基,
6)C0-C10亚烷基芳基,或
7)C0-C10亚烷基-NR5R6;R5和R6独立为:
1)H,
2)(C1-C8烷基)-(R7)2,
3)(C=O)O(C1-C8烷基),
4)9-芴基甲基羰基,
5)OCH2OCH2CH2Si(CH3)3,
6)(C=O)(C1-C8烷基),
7)(C=O)CF3,或
8)(C2-C8链烯基)-(R7)2,或R5和R6与其连接的氮一起形成N-苯二酰亚氨基;R7为:
1)H,
2)OH,
3)OC1-C6烷基,或
4)芳基,所述芳基任选最多被两个选自OH、O(C1-C6烷基)和(C1-C3亚烷基)-OH的基团取代;该方法包括下面步骤:
(a)使呋喃糖或吡喃糖与活化剂反应而产生活化糖;和
(b)在碱金属氢氧化物的水溶液和相转移催化剂的存在下,在两相体系中使所述活化糖与式IV的化合物偶联而形成式I的化合物,
式中如果Q为O、S、CH2或N-R并且R不是H,则R1a为H,否则R1a选自R1。
另一个实施方案是上述的方法,其中当R或R1分别定义为呋喃糖基或吡喃糖基时,R和R1独立选自式IIA的呋喃糖基或式IIB的吡喃糖基:
1)H
2)C1-C6烷基,
3)OH,
4)卤素,
5)O(C1-C6烷基),
6)O(C1-C6亚烷基)-芳基,
7)OSO2(C1-C6烷基),
8)OSO2芳基,
9)OCH2OCH2CH2Si(CH3)3,
10)O(C=O)(C1-C6烷基),
11)O(C=O)CF3,
12)叠氮基,或者
13)NR5R6,或者在相同碳上的两个R8一起成为氧桥基、=N-R5或=N-R7;和
在步骤(a)中的呋喃糖或吡喃糖分别是式IIIA的呋喃糖或式IIIB的吡喃糖:
在另一个实施方案中,步骤(a)中的活性剂选自酰卤、磺酸盐、磷酸盐、硼酸盐或乙酸盐,并且步骤(b)中的两相***包括选自烃、腈、醚、卤代烃、酮或非极性非质子溶剂的有机溶剂。
再一个实施方案是上述方法中所述活性剂选自SOCl2或草酰氯的方法。
另一个实施方案是上述方法中所述两相***包括甲基叔丁基醚、二氯甲烷或三氟甲苯的方法。
在还一个实施方案中,步骤(b)中的相转移催化剂是(Ra)4M+A-;
Ra独立为H或C1-C18脂族烃;
M为N或P;和
A为OH、F、Br、Cl、I、HSO4、CN、MeSO3或PhCH2CO2。
一个优选的实施方案是上述方法中所述相转移催化剂为三辛基甲基氯化铵的方法。
另一个优选实施方案是在上述方法中,所述步骤(b)的碱金属氢氧化物水溶液的浓度为约5-95%重量,并且所述碱金属氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾和氢氧化铯。
优选的还有其中碱金属氢氧化物水溶液的浓度为约45-50%重量/体积,并且所述碱金属氢氧化物为氢氧化钾或氢氧化钠的方法。
一种更优选的实施方案是式V化合物的制备方法,
1)H,
2)C1-C10烷基,
3)CHO
4)(C=O)C1-C10烷基,
5)(C=O)OC1-C10烷基,
6)C0-C10亚烷基芳基,或
7)C0-C10亚烷基-NR5R6;R5和R6独立为:
1)H,
2)(C1-C8烷基)-(R7)2,
3)(C=O)O(C1-C8烷基),
4)9-芴基甲基羰基,
5)OCH2OCH2CH2Si(CH3)3,
6)(C=O)(C1-C8烷基),
7)(C=O)CF3,或
8)(C2-C8链烯基)-(R7)2,或R5和R6与其连接的氮一起形成N-苯二酰亚氢基;R7为:
1)H,
2)OH,
3)OC1-C6烷基,或
4)芳基,所述芳基任选最多被两个选自OH、O(C1-C6烷基)和(C1-C3亚烷基)-OH的基团取代;R9为:
1)H
2)C1-C6烷基,
3)(C1-C6亚烷基)-芳基,
4)SO2(C1-C6烷基),
5)SO2芳基,
6)CH2OCH2CH2Si(CH3)3,
7)(C=O)(C1-C6烷基),或
8)(C=O)CF3;该方法包括下面步骤:
(a)使式VI的糖衍生物与酰氯反应产生活性糖;和
(b)在碱金属氢氧化物的水溶液和三辛基甲基氯化铵的存在下,在叔丁基甲基醚中使所述活化糖与式VII的化合物偶联产生式V的化合物:
再一个优选的实施方案是式VIII化合物的制备方法:
(a)使式IX的糖衍生物与亚硫酰氯反应产生活性糖;
(b)在氢氧化钾或氢氧化钠的水溶液和三辛基甲基氯化铵的存在下,在叔丁基甲基醚中使所述活化糖与式X的化合物偶联:
(c)通过在氢气的存在下使苷化产物XI与催化钯反应而脱保护形成脱保护的苷化产物XII;
(d)使所述脱保护的苷化产物XII与碱金属氢氧化物的水溶液反应而形成酸酐XIII;和
(e)使所述酸酐XIII与2-肼基-1,3-丙二醇反应产生式VIII的化合物。
同样优选的是制备式V化合物的上述方法,其中步骤(A)在约-10℃至约30℃的温度下,在叔丁基甲基醚或四氢呋喃中进行,步骤(B)在约0℃至约40℃的温度下进行。
最后的一个实施方案是上述方法中在步骤(b)中氢氧化钾或氢氧化钠在加入三辛基甲基氯化铵前加入的方法。
本发明的化合物可具有不对称中心、手性轴和手性面(如在E.L.Eliel和S.H.Wilen,Stereochemistry of Carban Compounds,John Wiley &Sons,New York,1994,1119-1190页中所述),并且作为外消旋物、外消旋混合物存在和作为单独的非对映体存在,包括光学异构体在内的所有可能的异构体和其混合物均包括在本发明中。此外,本发明公开的混合物可以互变异构体的形式存在,并且虽然只描述了一种互变异构体结构,但两者互变异构体形式均将包括在本发明的范围内。
当任何组分中的任何变量(如X1、X2、R8、R9等)出现一次以上时,其每次出现时的定义独立于其它次出现的情况。同样,只有取代基和变量的组合可产生稳定化合物时,这种组合才是可以的。从取代基引出到环体系的线表明所指示的键可连接到任何可取代环碳原子上。如果环体系为多环体系,那么认为所述键只连接到近位环上的任何适合碳原子上。
应理解在本发明化合物上的取代基和取代方式可通过本领域技术人员选择确定,从而提供化学稳定、并且易于通过本领域人们熟悉的技术以及下面所述方法由易获原料合成的化合物。
本文中所用的术语“烷基”将包括具有特定碳原子数的支链、直链和环状的饱和脂族烃基。例如在“C1-C6烷基”中的C1-C6定义为包括具有1、2、3、4、5或6个以线形、支化或环状排列的碳原子的基团。例如“C1-C6烷基”具体包括甲基、乙基、丙基、丁基、戊基、己基等,以及环烷基,如环丙基、甲基环丙基、二甲基环丁基、环丁基、环戊基和环己基等。烷基取代基可为未取代或被一个到三个选自以下基团的取代基取代:卤素、C1-C6烷基、OH、OC1-C6烷基、O(C=O)C1-C6烷基、O(C=O)OC1-C6烷基、氨基、酰胺基、CO2H、CN、NO2、N3、C1-C6全氟烷基和OC1-C6全氟烷基。“烷氧基”代表通过氧桥连接的具有所示碳原子数的烷基。
术语“链烯基”是指包含2到10个碳原子和至少一个碳碳双键的直链、支链或环状非芳香烃基。优选存在一个碳碳双键,并且最多可存在4个非芳香碳碳双键。因此“C2-C6链烯基”是指具有2到6个碳原子的链烯基。链烯基包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。链烯基的直链、支链或环部分可包含双键并且可被取代(如果所显示的为取代的链烯基)。
在某些情况下,取代基可被限定在包括0个碳的范围,如(C0-C6)亚烷基-NR5R6。如果R5和R6取H时,该定义将包括NH2,以及-CH2NH2、-CH2CH2NH2、CH(CH3)CH2CH(CH3)NH2、-CH2CH(NH2)CH3等。在这些情况下意味着在二价基团上的取代基可在任何位置连接并且并不限于末端位置。
本文中所用的术语“芳基”将用于取代和未取代的苯基或萘基。如果被取代,其可被一到三个选自以下基团的取代基取代:卤素、C1-C6烷基、OH、OC1-C6烷基、O(C=O)C1-C6烷基、O(C=O)OC1-C6烷基、氨基、酰胺基、CO2H、CN、NO2、N3、C1-C6全氟烷基和OC1-C6全氟烷基。
如本领域技术人员所知的,本文中所用的术语“卤代”或“卤素”将包括氯、氟、溴和碘。
当使用如“(C1-C8烷基)-R7)2”的定义时,意味着变量R7连接在沿烷基部分的任何位置上。因此,如果R7在此被定义为OH,该定义将包括CH2OH、CH2CH2OH、CH(CH3)CH(OH)CH3、CH(CH3)CH(OH)CH2-CH(OH)CH3等。
术语“亚烷基”和“亚链烯基”简单地指分别具有指定二价碳数目的如上定义的烷基或链烯基。例如“C1-C4亚烷基”包括-CH2-、-CH2CH2-、-CH(CH3)CH2-等。
R和R1的定义包括呋喃糖和吡喃糖衍生物。优选的糖衍生物为O-保护的吡喃糖,如D-吡喃葡萄糖、6-脱氧-6,6-二氟-D-吡喃葡萄糖;6-脱氧-6-叠氮基-D-吡喃葡萄糖;6-氨基-6-脱氧-D-吡喃葡萄糖;6-叠氮基-d-吡喃葡萄糖;6-氨基-D-吡喃葡萄糖;4-脱氧-4,4-二氟-6-脱氧-6-叠氮基-D-吡喃葡萄糖;2-氟-D-吡喃葡萄糖;D-吡喃半乳糖;4-脱氧-D-吡喃半乳糖;4-脱氧-D-吡喃葡萄糖;和4-甲氧基-D-吡喃葡萄糖。(参见例如通过引用并入本文的WO 98/07433)。优选的呋喃糖包括呋喃木糖、呋喃***糖、呋喃核糖、呋喃阿洛糖和2-脱氧呋喃核糖。
R9通常可以是任何已知的O-保护基团。这种保护基团的例子包括但不限于:苄基、对硝基苄基、甲苯基等。一种更优选的保护基团是苄基(Bn),即CH2Ph。其它适合的保护基团为本领域技术人员所熟悉,其例子可参见Peter G.M.Wuts和Theodora W.Greene的Protective Groups in Organic Synthesis;John Wiley & Sons,第三版(1999)。
本文中所用的术语“两相***”是指含水相和有机相的两相溶剂体系。
用于活化糖以偶联的活化剂可由本领域技术人员容易地选定。这种试剂的例子包括酰卤(如SOCl2、POCl3、SOBr2、POBr3、PBr3和草酰氯)、磺酰卤等。优选的试剂是亚硫酰氯和草酰氯。最优选的是亚硫酰氯。其它可用于活化中的试剂包括三苯基膦/I2和三苯基膦/叠氮基二羧酸酯。
适用于活化糖的反应的溶剂可由普通化学技术人员确定。优选的溶剂是烃(如甲苯、二甲苯、庚烷和己烷)、腈(如乙腈)、醚(如叔丁基甲基醚和四氢呋喃)、卤代烃(如二氯甲烷、四氯化碳、氯仿、三氟甲苯和二氯苯)、酮(如甲基异丁酮和丙酮)、和非极性非质子溶剂(如N,N-二甲基甲酰胺和1-甲基-2-吡咯烷酮)。更优选的溶剂为叔丁基甲基醚和四氢呋喃。最优选的溶剂是叔丁基甲基醚。
所述活化反应可在约-50℃到约200℃的温度下进行。优选的温度为约-10℃到约30℃。
同样,适用于两相偶联反应的溶剂可由本领域技术人员容易地确定。适合的溶剂包括烃(如甲苯、二甲苯、庚烷和己烷)、腈(如乙腈)、醚(如叔丁基甲基醚和四氢呋喃)、卤代烃(如二氯甲烷、四氯化碳、氯仿、三氟甲苯和二氯苯)、酮(如甲基异丁酮和丙酮)和非极性非质子溶剂(如N,N-二甲基甲酰胺和1-甲基-2-吡咯烷酮)。优选的溶剂为叔丁基甲基醚、二氯甲烷和三氟甲苯。
所述活化反应可在约-50℃到约200℃的温度下进行。优选的温度为约0到40℃。
优选用于偶联反应的碱有碱金属氢氧化物,如氢氧化锂、氢氧化钠、氢氧化钾和氢氧化铯。更优选氢氧化钾和氢氧化钠。水中的碱浓度可在约5-95%重量的范围内变化。更优选的浓度为约45-50%重量。
在偶联反应中优选的相转移试剂为通式(Ra)4M+A-的试剂,其中Ra独立为H或C1-C18脂族烃;M为N或P;和A为OH、F、Br、Cl、I、HSO4、CN、MeSO3或PhCH2CO2。一种优选的相转移催化剂为三辛基甲基氯化铵。其它适合的相转移催化剂包括但不限于三[2-(2-甲氧基乙氧基)乙基]胺(TDA-1);BnEt3N+Cl-;和(Bu)3NH+HSO4 -。
流程说明
流程A举例说明了一种制备苷化基料A-6的可用通用方法。其它方法为本领域人们所熟悉,其中一些描述于通过引用并入本文的Kojiri等人的美国专利5,922,860号(2000年7月13日授权)。流程B显示了A-6的相转移催化苷化反应以制备B-3类型的中间体。流程C和D显示了可能的进一步的修饰,以形成已知可用作拓扑异构酶抑制剂的化合物。
流程A
R1为H或Q为N-H
流程B
流程C
流程D
实施例
本文中提供的实施例用于帮助对本发明的进一步理解。所用的具体材料、种类和条件用于进一步说明本发明,而非构成对本发明合理范围的限定。
用于本发明苷化反应的中间体5可通过Kojiri等人的美国专利5,922,860号(2000年7月13日授权)的方法获得,该专利文献在此通过引用并入本文。在下面的实施例1到5中对该方法作简要说明。
实施例1
式1所示的化合物的制备:
将284g 6-苄氧吲哚溶解于3升THF中,加入2.7升六甲基二硅氨基锂(lithium hexmethyldisilazide)(1M的THF溶液)。在氮气气氛中、在-10℃下搅拌该混合物45分钟后,用1小时向其中添加3升含340g 2,3-二溴-N-甲基马来酰亚胺的THF溶液。添加完成后,将得到的混合物在0℃下搅拌15分钟。将反应混合物倾入到10升2N盐酸溶液中,并用30升乙酸乙酯萃取。有机层用碳酸氢钠饱和水溶液洗涤,然后用氯化钠饱和水溶液洗涤,干燥并浓缩。得到的残渣从甲醇中重结晶而410.0266[C20H15N2O3Br]IR(KBr,cm-1):3330,3318,1762,1701,1606,1511,1450,1165,1135,1041,794.1H-NMR(300 MHz,CDCl3,δppm):8.60(1H,brs),7.96(1H,d,J=8.1Hz),7.94(1H,d,J=2.5Hz),7.33-7.47(5H,m),7.00(1H,dd,J=2.5,8.8Hz),6.97(1H,d,J=2.5Hz),5.13(2H,s),3.16(3H,s).获得所需的化合物1。HRMS(m/z):测定值410.0292,计算值
实施例2
式2所示的化合物的制备:
将1.00g实施例1获得的化合物1、637mg二碳酸二叔丁酯和3mg 4-N,N-二甲氨基吡啶溶解于200mL THF中,将所得溶液在室温下搅拌1小时。将反应混合物浓缩后,得到的残渣在乙酸乙酯-己烷中重结晶而获得所需的化合物(2)。
IR (KBr,cm-1):1740,1714,1614,1527,1487,1443,1373,1227,1153.HRMS(m/z):测定值510.0771,计算值510.0791[C25H23N2O5Br]1H-NMR(300MHz,CDCl3,δ.ppm):8.10(1H,s),7.91(1H,d,J=2.3Hz),7.73(1H,d,J=8.9Hz),7.34-7.50(5H,m),7.03(1H,dd,J=2.3,8.5Hz),5.16(2H,s),3.18(3H,s),1.68(9H,s).
实施例3
式3所示化合物的制备:
将218.4mg 6-苄氧基吲哚溶解于20mL THF中,加入2.35mL六甲基二硅氨基锂(1M的THF溶液)。在氮气气氛中,在0℃下搅拌该混合物15分钟后,用10分钟时间向其中滴加10mL含500mg从实施例2获得的化合物(2)的THF溶液。添加完成后,将得到的混合物在室温下搅拌0.5小时。将反应混合物倾入到100mL 2N盐酸溶液中,用400mL乙酸乙酯提取。有机层用水、饱和碳酸氢钠水溶液洗涤并然后用饱和氯化钠水溶液洗涤,干燥并浓缩。得到的残渣在甲
苯-己烷中重结晶而获得所需的化合物(3)。
HRMS(m/z):测定值653.2556,计算值653.2526[C40H35N3O6]IR(KBr,cm-1):1740,1701,1646,1623,1543,1445,1155.1H-NMR(300MHz,CDCl3,δ ppm):8.41(1H,brs),7.97(1H,s),7.84(1H,brs),7.68(1H,brs),7.16-7.43(10H,m),6.98(1H,d,J=9.2Hz),6.85(1H,brs),6.74(1H,d,J=9.2Hz),6.58(1H,d,J=9.2Hz),6.52(1H,d,J=9.2Hz),5.05(2H,s),5.02(2H,s),3.19(3H,s),1.67(9H,s).
实施例4
式4所示化合物的制备
将100mg在实施例3获得的化合物(3)溶解于10mL甲胺(40%的甲醇溶液)中,将该溶液在室温下搅拌30分钟。将反应混合物浓缩后,得到的残渣在二氯甲烷-丙酮-己烷重结晶而获得68.6mg所需化合物(4)。
HRMS(m/z):测定值553.1982,计算值553.2002[C35H27N3O4]IR(KBr,cm-1):3419,3350,1759,1697,1620,1533,1454,1383,1292,1167.1H-NMR(300MHz,DMSO-d6,δppm):11.48(2H,s),7.62(2H,s),7.28-7.45(10H,m),6.95(2H,d,J=1.2Hz),6.70(2H,d,J=8.7Hz),6.39(2H,dd,J=1.2,8.7Hz),5.04(4H,s),3.03(3H,s).
实施例5
式5所示化合物的制备
将1.01g实施例4中获得的化合物(4)和456.1mg 2,3-二氯-5,6-二氰基-1,4-苯醌溶解于50mL甲苯中,将该溶液在110℃下搅拌40分钟。使反应混合物回到室温后,过滤除去不溶物并用30mL甲醇洗涤。残渣在二甲亚砜-二氯甲烷-甲醇中重结晶而获得所需化合物(5)。
HRMS(m/z):测定值551.1829,计算值551.1845[C35H25N3O4]IR(KBr,cm.-1):3257,1740,1675,1620,1571,1402,1246,1178.1H-NMR(300MHz,DMSO-d6,δppm):11.46(2H,s),8.79(2H,d,J=8.5Hz,7.53(4H,d,8.5Hz),7.35-7.44(8H,m),7.02(2H,dd,8.5,0.8Hz),5.25(4H,s),3.13(3H,s).
实施例6
步骤1:
将100g(185mmol)2,3,4,6-四苄基-D-吡喃葡萄糖(6-1)与360mLDFM在23℃下混合,然后冷却到9℃。用15分钟缓慢加入亚硫酰氯(16.2mL;222mol),其间温度升到20℃。将溶液温热到约30℃并持续1小时。然后将溶液冷却到-10℃,加入10%重量的KOH(约150mL),其间温度不超过0℃。将溶液温热到22℃。水层用叔丁基甲基醚(MTBE)萃取(1×300mL)。然后将合并的有机层用盐水(1×150mL)和水(1×200mL)洗涤。将溶液减压浓缩到350mL水平,不经纯化直接用于下一步骤。
步骤2:
将72g(131mmol)上面实施例5的化合物5溶解于600mL MTBE中,并在23℃下搅拌10分钟。然后加入上面步骤1制备的6-2溶液,10分钟后,加入45%重量KOH水溶液(300mL)。另过10分钟后,用22分钟缓慢加入40%重量的Aliquat336(72g溶解于110g MTBE中的溶液)。Aliquat336为Milwaukee,Wisconsin.的Aldrich ChemicalCo.,Inc出售的三辛基甲基氯化铵的商品名。将溶液保存在23℃下6小时,然后加入350mL水并让其混合5分钟。分离各层并用MTBE(1×300mL)洗涤水层。然后将合并的有机层用10%重量柠檬酸(1×300mL)和水(1×300mL)洗涤。将有机层在22℃下搅拌过夜,其间产物(6-3)开始结晶。接着在常压(沸点55℃)下将溶液浓缩到625mL水平。这时,将溶液冷却到23℃并用1小时缓慢加入甲醇(225mL)。然后将淤浆冷却到-5℃,并保持45分钟。分离固体物并用冷却的1∶1甲醇/MTBE(2×400mL)洗涤。在25-40℃下真空干燥,经液相色谱纯度得到超过99%纯度的产物6-3。
下面实施例(得自Kojiri等人的美国专利5,922,869号并已通过引用并入本文)举例说明所述苷化产物在已知拓扑异构酶抑制剂(9)合成中的用途。
实施例7
式7所示化合物的制备:
将100mg化合物6-3溶解于6mL氯仿-甲醇(2∶1)中,并往其中加入催化量的钯黑。将该混合物在氢气气氛下搅拌2小时。过滤除去催化剂后,将滤液浓缩。得到的残渣从甲醇-丙酮-乙酸乙酯-己烷中重结晶,用Sephadex LH-20展开,用氯仿-甲醇-乙醇-四氢呋喃(5∶2∶2∶1)洗脱,并从丙酮-甲醇-己烷中重结晶而得到所需的化合物(7)。测定值533.1429,计算值533.1434[C27H23N3O9]IR(KBr,cm-1):3328,1733,1683,1678,1540,1417,1126,1081,611.1H-NMR(300MHz,DMSO-d6,δppm):11.20(1H,s),9.76(1H,s),9.74(1H,s),8.88(1H,d,J=8.6Hz),8.80(1H,d,J=8.6Hz),7.18(1H,d,J=2.1Hz),6.99(1H,d,J=2.1Hz),6.82(1H,dd,J=2.1,8.6Hz),6.80(1H,dd,J=2.1,8.6Hz),5.97(1H,J=8.9Hz),5.86(1H,t,J=4.0Hz),5.33(1H,d,J=4.9Hz),5.12(1H,d,J=4.3Hz),4.94(1H,d,J=5.2Hz),4.02(1H,dd,J=3.0,10.7Hz),3.94(1H,m),3.78(1H,m),3.52(2H,m),3.16(3H,s).
实施例8
式8所示化合物的制备:
将1.2g化合物(7)溶解于40mL 10%氢氧化钾水溶液中,并将该溶液在室温下搅拌1小时。通过加入40mL 2N盐酸中和反应混合物,然后用1L甲乙酮萃取。有机层用饱和氯化钠水溶液洗涤、干燥并浓缩。得到的残渣在丙酮-庚烷中重结晶而获得所需的化合物(8)。
HRMS(m/z):测定值520.1147,计算值520.1118[C26H20N2O10]IR(KBr,cm-1):3311,1810,1739,1652,1626,1558,1405,1091,611.1H-NMR(300MHz,DMSO-d6,δppm):11.4(1H,s),9.95(1H,s),9.92(1H,s),8.69(1H,d,J=7.7Hz),8.63(1H,d,J=7.7Hz),7.25(1H,d,J=1.5Hz),7.03(1H,d,J=1.5Hz),6.90(1H,dd,J=1.5,7.7Hz),6.87(1H,d,J=1.5,7.7Hz),6.06(1H,d,J=8.0Hz),5.95(1H,t,J=4.6Hz),5.38(1H,d,J=5.1Hz),5.16(1H,d,J=5.2Hz),4.99(1H,d,J=5.2Hz),3.30-4.10(6H,m).
实施例9
式9所示拓扑异构酶抑制剂的制备:
将500g化合物8溶解于50mL DMF中,加入152mg 2-肼基-1,3-丙二醇。将该混合物在80℃搅拌1小时。将反应混合物浓缩后,将得到的残渣用Sephadex LH-20纯化(氯仿-甲醇-乙醇-水=5∶2∶2∶1)而获得化合物9。
HRMS(m/z):测定值609.1816,计算值609.1833[C29H28N4O11]IR(KBr,cm.sup.-1):3415,3353,1749,1652,1575,1540,1375,1197,609.1H-NMR(300MHz,DMSO-d6,δppm):11.20(1H,s),9.78(1H,s),9.75(1H,s),8.87(1H,d,J=8.6Hz),8.79(1H,d,J=8.6Hz),7.18(1H,d,J=2.0Hz),6.98(1H,d,J=2.0Hz),6.82(1H,dd,J=2.0,8.6Hz),6.80(1H,dd,J=2.0,8.6Hz),5.97(1H,J=8.3Hz),5.86(1H,d,J=3.8Hz),5.55(1H,d,J=2.6Hz),5.32(1H,d,J=4.6Hz),5.11(1H,d,J=5.3Hz),4.91(1H,d,J=5.1Hz),4.53(2H,t,J=5.4Hz),4.02(1H,m),3.85-3.95(2H,m),3.78(1H,m),3.40-3.60(6H,m),3.20-3.30(1H,m).
Claims (13)
1.一种制备式I化合物的方法:
式中:
Q为O、N-R、S或CH2;
X1和X2独立选自;
1)H,
2)卤素,
3)OH,
4)CN,
5)NC,
6)CF3,
7)(C=O)NO2,
8)(C=O)C1-C6烷基,
9)(C=O)OC1-C6烷基,
10)OCH2OCH2CH2Si(CH3)3,
11)NO2,
12)9-芴基甲基羰基
13)NR5R6,
14)OC1-C6烷基,
15)C1-C6烷基,
16)C1-C6亚烷基芳基,和
17)OC1-C6亚烷基芳基;R和R1独立为:
1)H,
2)(C=O)C1-C6烷基,
3)(C=O)CF3,
4)(C=O)OC1-C6烷基,
5)9-芴基甲基羰基,
6)呋喃糖基,或
7)吡喃糖基,条件是R和R1之一为呋喃糖基或吡喃糖基;R2和R3独立为OH或H,或R2和R3一起形成一个桥氧基;R4为:
1)H,
2)C1-C10烷基,
3)CHO
4)(C=O)C1-C10烷基,
5)(C=O)OC1-C10烷基,
6)C0-C10亚烷基芳基,或
7)C0-C10亚烷基-NR5R6;R5和R6独立为:
1)H,
2)(C1-C8烷基)-(R7)2,
3)(C=O)O(C1-C8烷基),
4)9-芴基甲基羰基,
5)OCH2OCH2CH2Si(CH3)3,
6)(C=O)(C1-C8烷基),
7)(C=O)CF3,或
8)(C2-C8链烯基)-(R7)2,或R5和R6与其连接的氮一起形成N-苯二酰亚氨基;R7为:
1)H,
2)OH,
3)OC1-C6烷基,或
4)芳基,所述芳基任选最多被两个选自OH、O(C1-C6烷基)和(C1-C3亚烷基)-OH的基团取代;该方法包括下面步骤:
(a)使呋喃糖或吡喃糖与活化剂反应而产生活化糖;和
(b)在碱金属氢氧化物的水溶液和相转移催化剂的存在下,在两相体系中使所述活化糖与式IV的化合物偶联而形成式I的化合物,
式中如果Q为O、S、CH2或N-R并且R不是H,则R1a为H,否则R1a选自R1。
2.权利要求1的方法,其中当R或R1分别定义为呋喃糖基或吡喃糖基时,R和R1独立选自式IIA的呋喃糖基或式IIB的吡喃糖基:
R8独立选自:
1)H
2)C1-C6烷基,
3)OH,
4)卤素,
5)O(C1-C6烷基),
6)O(C1-C6亚烷基)-芳基,
7)OSO2(C1-C6烷基),
8)OSO2芳基,
9)OCH2OCH2CH2Si(CH3)3,
10)O(C=O)(C1-C6烷基),
11)O(C=O)CF3,
12)叠氮基,或者
13)NR5R6,或者在相同碳上的两个R8一起成为氧桥基、=N-R5或=N-R7;和
在步骤(a)中的呋喃糖或吡喃糖分别是式IIIA的呋喃糖或式IIIB的吡喃糖:
3.权利要求2的方法,其中步骤(a)中的活性剂选自酰卤,并且步骤(b)中的两相***包括选自烃、腈、醚、卤代烃、酮或非极性非质子溶剂的有机溶剂。
4.权利要求3的方法,其中所述活性剂选自SOCl2或草酰氯。
5.权利要求3的方法,其中所述两相体系包括甲基叔丁基醚、二氯甲烷或三氟甲苯。
6.权利要求3的方法,其中所述步骤(b)中的相转移催化剂是(Ra)4M+A-;
Ra独立为H或C1-C18脂族烃;
M为N或P;和
A为OH、F、Br、Cl、I、HSO4、CN、MeSO3或PhCH2CO2。
7.权利要求6的方法,其中所述相转移催化剂是三辛基甲基氯化铵。
8.权利要求3的方法,其中所述步骤(b)的碱金属氢氧化物水溶液的浓度为约5-95%重量,并且所述碱金属氢氧化物选自氢氧化锂、氢氧化钠、氢氧化钾和氢氧化铯。
9.权利要求8的方法,其中所述碱金属氢氧化物水溶液的浓度为约45-50%重量/体积,并且所述碱金属氢氧化物为氢氧化钾或氢氧化钠。
10.一种式V化合物的制备方法,
式中:
R4为:
1)H,
2)C1-C10烷基,
3)CHO
4)(C=O)C1-C10烷基,
5)(C=O)OC1-C10烷基,
6)C0-C10亚烷基芳基,或
7)C0-C10亚烷基-NR5R6;R5和R6独立为:
1)H,
2)(C1-C8烷基)-(R7)2,
3)(C=O)O(C1-C8烷基),
4)9-芴基甲基羰基,
5)OCH2OCH2CH2Si(CH3)3,
6)(C=O)(C1-C8烷基),
7)(C=O)CF3,或
8)(C2-C8链烯基)-(R7)2,或R5和R6与其连接的氮一起形成N-苯二酰亚氨基;R7为:
1)H,
2)OH,
3)OC1-C6烷基,或
4)芳基,所述芳基任选最多被两个选自OH、O(C1-C6烷基)和(C1-C3亚烷基)-OH的基团取代;R9为:
1)H
2)C1-C6烷基,
3)(C1-C6亚烷基)-芳基,
4)SO2(C1-C6烷基),
5)SO2芳基,
6)CH2OCH2CH2Si(CH3)3,
7)(C=O)(C1-C6烷基),或
8)(C=O)CF3;该方法包括下面步骤:
(a)使式VI的糖衍生物与酰氯反应产生活性糖;和
(b)在碱金属氢氧化物的水溶液和三辛基甲基氯化铵的存在下,在叔丁基甲基醚中使所述活化糖与式VII的化合物偶联形成式V的化合物:
12.权利要求10的方法,其中所述步骤(A)在约-10℃至约30℃的温度下,在叔丁基甲基醚或四氢呋喃中进行,并且步骤(B)在约0℃至约40℃的温度下进行。
13.权利要求12的方法,其中步骤(b)中氢氧化钾或氢氧化钠在加入三辛基甲基氯化铵前加入。
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US6555677B2 (en) * | 2000-10-31 | 2003-04-29 | Merck & Co., Inc. | Phase transfer catalyzed glycosidation of an indolocarbazole |
US7429572B2 (en) * | 2003-05-30 | 2008-09-30 | Pharmasset, Inc. | Modified fluorinated nucleoside analogues |
JPWO2005026185A1 (ja) * | 2003-09-16 | 2006-11-16 | 萬有製薬株式会社 | 抗腫瘍性新規インドロピロロカルバゾール誘導体 |
WO2005116044A1 (ja) * | 2004-05-28 | 2005-12-08 | Banyu Pharmaceutical Co.,Ltd | インドロピロロカルバゾール誘導体の製造法 |
CN101023094B (zh) * | 2004-07-21 | 2011-05-18 | 法莫赛特股份有限公司 | 烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备 |
SI3109244T1 (sl) * | 2004-09-14 | 2019-06-28 | Gilead Pharmasset Llc | Priprava 2'fluoro-2'-alkil-substituiranih ali drugih neobvezno substituiranih ribofuranozil pirimidinov in purinov in njihovih derivatov |
US7537774B2 (en) * | 2005-12-23 | 2009-05-26 | Orion Therapeautics, Llc | Therapeutic formulation |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
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WO2010075554A1 (en) | 2008-12-23 | 2010-07-01 | Pharmasset, Inc. | Synthesis of purine nucleosides |
PA8855701A1 (es) | 2008-12-23 | 2010-07-27 | Análogos de nucleósidos | |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
TWI583692B (zh) | 2009-05-20 | 2017-05-21 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
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US5668271A (en) | 1991-11-29 | 1997-09-16 | Banyu Pharmaceutical Co., Ltd. | Indolopyrrolocarbazole derivatives |
US5591842A (en) | 1991-11-29 | 1997-01-07 | Banyu Pharmaceutical Co., Ltd. | Indolopyrrolocarbazole derivatives |
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US5437996A (en) | 1992-11-24 | 1995-08-01 | Banyu Pharmaceutical Co., Ltd. | Microtetraspora strain for preparation of indolopyrrolocarbazole derivatives |
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US5804564A (en) | 1994-05-09 | 1998-09-08 | Banyu Pharmaceutical Co., Ltd. | Antitumor indolopyrrolocarbazole derivatives |
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