TW202313600A - 一種b肝病毒核衣殼抑制劑的製備方法 - Google Patents
一種b肝病毒核衣殼抑制劑的製備方法 Download PDFInfo
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- TW202313600A TW202313600A TW111127582A TW111127582A TW202313600A TW 202313600 A TW202313600 A TW 202313600A TW 111127582 A TW111127582 A TW 111127582A TW 111127582 A TW111127582 A TW 111127582A TW 202313600 A TW202313600 A TW 202313600A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 241000700721 Hepatitis B virus Species 0.000 title abstract description 7
- 108090001074 Nucleocapsid Proteins Proteins 0.000 title abstract description 6
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- -1 amino, hydroxyl Chemical group 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 239000012948 isocyanate Substances 0.000 claims description 6
- 150000002513 isocyanates Chemical class 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 238000005576 amination reaction Methods 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- RDZHCKRAHUPIFK-UHFFFAOYSA-N 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(I)C(=O)N(I)C1=O RDZHCKRAHUPIFK-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical compound [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 claims description 2
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 claims description 2
- 239000005750 Copper hydroxide Substances 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- YXLXNENXOJSQEI-UHFFFAOYSA-L Oxine-copper Chemical compound [Cu+2].C1=CN=C2C([O-])=CC=CC2=C1.C1=CN=C2C([O-])=CC=CC2=C1 YXLXNENXOJSQEI-UHFFFAOYSA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- RAOSIAYCXKBGFE-UHFFFAOYSA-K [Cu+3].[O-]P([O-])([O-])=O Chemical compound [Cu+3].[O-]P([O-])([O-])=O RAOSIAYCXKBGFE-UHFFFAOYSA-K 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 2
- 229940116318 copper carbonate Drugs 0.000 claims description 2
- 229940108925 copper gluconate Drugs 0.000 claims description 2
- 229910001956 copper hydroxide Inorganic materials 0.000 claims description 2
- 229910000431 copper oxide Inorganic materials 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- HFYRAUCEONFIPJ-UHFFFAOYSA-N copper(1+);1,10-phenanthroline;trifluoromethane Chemical compound [Cu+].F[C-](F)F.C1=CN=C2C3=NC=CC=C3C=CC2=C1 HFYRAUCEONFIPJ-UHFFFAOYSA-N 0.000 claims description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- PHECBGBJCLDCMF-UHFFFAOYSA-L copper;1,10-phenanthroline;dichloride Chemical compound Cl[Cu]Cl.C1=CN=C2C3=NC=CC=C3C=CC2=C1 PHECBGBJCLDCMF-UHFFFAOYSA-L 0.000 claims description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 2
- HFDWIMBEIXDNQS-UHFFFAOYSA-L copper;diformate Chemical compound [Cu+2].[O-]C=O.[O-]C=O HFDWIMBEIXDNQS-UHFFFAOYSA-L 0.000 claims description 2
- BSXVKCJAIJZTAV-UHFFFAOYSA-L copper;methanesulfonate Chemical compound [Cu+2].CS([O-])(=O)=O.CS([O-])(=O)=O BSXVKCJAIJZTAV-UHFFFAOYSA-L 0.000 claims description 2
- QYCVHILLJSYYBD-UHFFFAOYSA-L copper;oxalate Chemical compound [Cu+2].[O-]C(=O)C([O-])=O QYCVHILLJSYYBD-UHFFFAOYSA-L 0.000 claims description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 2
- FWBOFUGDKHMVPI-UHFFFAOYSA-K dicopper;2-oxidopropane-1,2,3-tricarboxylate Chemical compound [Cu+2].[Cu+2].[O-]C(=O)CC([O-])(C([O-])=O)CC([O-])=O FWBOFUGDKHMVPI-UHFFFAOYSA-K 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 claims description 2
- IRPLSAGFWHCJIQ-UHFFFAOYSA-N selanylidenecopper Chemical compound [Se]=[Cu] IRPLSAGFWHCJIQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims 6
- 229910052802 copper Inorganic materials 0.000 claims 6
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims 1
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 229960001367 tartaric acid Drugs 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 27
- 230000001738 genotoxic effect Effects 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 231100000024 genotoxic Toxicity 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000000243 solution Substances 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 7
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 7
- 229940126657 Compound 17 Drugs 0.000 description 7
- 229940126639 Compound 33 Drugs 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
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- 239000002904 solvent Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 5
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- GDVQAJIJTGEYHX-UHFFFAOYSA-N copper(1+);ethane Chemical compound [Cu+].[CH2-]C GDVQAJIJTGEYHX-UHFFFAOYSA-N 0.000 description 1
- PDZKZMQQDCHTNF-UHFFFAOYSA-M copper(1+);thiocyanate Chemical compound [Cu+].[S-]C#N PDZKZMQQDCHTNF-UHFFFAOYSA-M 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- RSJOBNMOMQFPKQ-UHFFFAOYSA-L copper;2,3-dihydroxybutanedioate Chemical compound [Cu+2].[O-]C(=O)C(O)C(O)C([O-])=O RSJOBNMOMQFPKQ-UHFFFAOYSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- HMRCZKQIOFZACX-UHFFFAOYSA-N lithium;trimethylsilylazanide Chemical compound [Li+].C[Si](C)(C)[NH-] HMRCZKQIOFZACX-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- XRURWFXKCKASSN-UHFFFAOYSA-N n,n'-bis(furan-2-ylmethyl)oxamide Chemical compound C=1C=COC=1CNC(=O)C(=O)NCC1=CC=CO1 XRURWFXKCKASSN-UHFFFAOYSA-N 0.000 description 1
- NOSYGNWELJYIQH-UHFFFAOYSA-N n,n'-bis(thiophen-2-ylmethyl)oxamide Chemical compound C=1C=CSC=1CNC(=O)C(=O)NCC1=CC=CS1 NOSYGNWELJYIQH-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 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 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical class CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本發明涉及一種B肝病毒核衣殼抑制劑的製備方法。具體地,本發明所述方法通過優化工藝獲得了一種新的製備式I化合物(各基團如說明書所定義)的方法。該方法可以顯著提高收率、提高產品純度且可以在產物中顯著降低基因毒性雜質。本發明還公開了用於製備式I化合物的新中間體。
Description
本發明涉及醫藥和精細化工領域,具體地涉及一種B肝病毒核衣殼抑制劑的製備方法及用於該抑制劑製備的新中間體。
式I所代表的化合物系列為B肝病毒核衣殼抑制劑,由上海摯盟醫藥科技有限公司開發,是一類在臨床實驗階段的新型B型病毒性肝炎的藥物。目前上市的B肝藥物可以有限控制B肝病毒的複製,並延緩肝硬化的進展,但是很少可以達到治癒慢性B肝的目的。式I化合物通過抑制HBV病毒核衣殼形成來提高慢性B肝的功能性治癒率,臨床前研究結果顯示其具有很好的安全性和有效性。
因此,開發並優化上述化合物的製備工藝,對於降低其生產成本、推動其市場化、早日惠及更多患者具有重要意義。
本發明的目的在於提供一種高收率、條件溫和、產物純度高、低副反應、操作方便且可避免使用具有基因毒性的中間體的製備式I化合物的方法。
本發明的目的還在於提供一種用於製備式I化合物的新中間體,即式II化合物和式III化合物。
本發明的第一方面,提供了一種式I化合物、或其藥學上可接受的鹽、或其互變異構體、或其立體異構體、或其外消旋體的製備方法,包括如下步驟:
1)在催化劑存在下,將式II化合物進行成環得到式I化合物;
其中,R
1、R
2、R
3、R
4和R
5各自獨立地選自下組:氫、氘、鹵素、取代或未取代的C1-C6烷基、胺基、羥基、硝基,所述取代指被一個或多個(如2、3、4或5個)選自下組的取代基取代:鹵素、硝基、胺基、羥基;
R
6選自下組:氫、氘、鹵素、胺基、羥基;
n為0、1、2、3或4;
Q選自下組:被一個或多個鹵素取代的或未取代的C6-C10芳基、被一個或多個鹵素取代的或未取代的含1-3個選自N、O和S的雜原子的6-10元雜芳基;
X為鹵素。
在另一優選例中,式I所述立體異構體為R異構體。
在另一優選例中,式I所述立體異構體為S異構體。
在另一優選例中,R
1、R
2、R
3、R
4和R
5各自獨立地選自下組:氫、氘、鹵素。
在另一優選例中,n為0。
在另一優選例中,Q為鹵素取代的C6-C10芳基,優選為鹵素取代的苯基、氘與鹵素共同取代的苯基。
在另一優選例中,X為溴或碘。
在另一優選例中,步驟1)中,所述催化劑選自下組物質或其水合物:碘化(亞)銅、氯化(亞)銅、溴化(亞)銅、硫酸銅、銅粉、氧化(亞)銅、氫氧化(亞)銅、醋酸(亞)銅、檸檬酸銅、甲磺酸銅、氟硼酸銅、鹼式碳酸銅、葡萄糖酸銅、酒石酸(亞)銅、乙醯丙酮銅、8-羥基喹啉銅、硫氰酸(亞)銅、硝酸(亞)銅、氰化(亞)銅、草酸銅、磷酸銅、三氟甲磺酸(亞)銅、甲酸銅、硒化銅、二氯(1,10-菲咯啉)銅、(1,10-菲咯啉)(三氟甲基)銅、CuTC、或其組合。
在本發明中,CuTC是指噻吩-2-甲酸亞銅(I)。
在另一優選例中,步驟1)中,所述催化劑為銅粉。
在另一優選例中,步驟1)中,所述催化劑與式II化合物的莫耳比為0.2-3,較佳地0.4-2,更佳地0.6-1.5,最佳地0.8-1.2。
在另一優選例中,步驟1)在40-150℃下進行,較佳地50-130℃,更佳地60-110℃。
在另一優選例中,步驟1)的反應時間為0.1-36 h,較佳地0.3-10 h,更佳地0.4-5 h。
在另一優選例中,步驟1)中,所述催化劑選自下組:氧化亞銅、氯化亞銅、碘化亞銅、或其組合。
在另一優選例中,步驟1)在催化劑和配體的共同存在下進行,所述催化劑和式II化合物的莫耳比為0.0001-1(較佳地0.001-0.5,更佳地0.005-0.2,最佳地0.01-0.1);
所述催化劑和所述配體的莫耳比為0.2-5.0(較佳地0.5-2.0,更佳地0.8-1.2)。
在另一優選例中,步驟1)在鹼存在下進行。
在另一優選例中,步驟1)中,所述鹼選自下組:1,5-二氮雜二環[5.4.0]十一-5-烯、1,8-二氮雜二環十一碳-7-烯(DBU)、碳酸銫、碳酸鈉、碳酸鉀、第三丁醇鈉、第三丁醇鉀、磷酸鉀、氫氧化鉀、氫氧化鈉、氫氧化鋰、二(三甲基矽基)胺基鋰、二(三甲基矽基)胺基鉀、二(三甲基矽基)胺基鈉、或其組合。
在另一優選例中,步驟1)中,所述鹼與式II化合物的莫耳比為0.5-5.0,較佳地1.0-2.0。
在另一優選例中,在步驟1)之前,所述方法還包括如下步驟:
2)將式III化合物與鹵代試劑反應以得到式II化合物;
式III化合物中,R
1、R
2、R
3、R
4、R
5、R
6、n、X和Q如上文所定義。
在另一優選例中,步驟2)中,所述鹵代試劑選自下組:N-碘代丁二醯亞胺(NIS)、碘、1,3-二碘-5,5-二甲基海因、N-溴代丁二醯亞胺、溴素、1,3-二溴-5,5-二甲基海因、氯氣、N-氯代丁二醯亞胺、N-溴代琥珀醯亞胺(NBS)、或其組合。
在另一優選例中,步驟2)中,所述鹵代試劑與式III化合物的莫耳比為0.8-2,較佳地0.9-1.8,更佳地1.1-1.5。
在另一優選例中,步驟2)在40-100℃下進行,較佳地50-90℃,更佳地55-85℃。
在另一優選例中,在步驟2)之前,所述製備方法還包括如下步驟:
3)將式IV化合物與羰基化試劑反應得到式IV-1異氰酸酯中間體;
4)將步驟3)所得式IV-1異氰酸酯中間體不經分離,在體系中直接與胺基化試劑反應以得到式III化合物;
式IV化合物和式IV-1異氰酸酯中間體中,R
1、R
2、R
3、R
4、R
5、R
6、n和Q如上文所定義。
在另一優選例中,式IV化合物為R異構體。
在另一優選例中,步驟3)中,所述羰基化試劑選自下組:三光氣、CDI、異氰酸鉀、或其組合;和/或
步驟4)中,所述胺基化試劑選自下組:氨水、氨氣、胺的有機溶液、或其組合。
在另一優選例中,步驟3)中,所述羰基化試劑為三光氣。
在另一優選例中,步驟3)中,所述羰基化試劑與所述式IV化合物的莫耳比為0.2-2,較佳地0.25-1.5,更佳地0.3-1.2。
在另一優選例中,步驟3)和/或步驟4)在選自下組的鹼存在下進行:吡啶、三乙胺、咪唑、或其組合。
在另一優選例中,步驟3)和/或步驟4)中,所述鹼為吡啶。
在另一優選例中,步驟3)和/或步驟4)中,所述鹼與所述式IV化合物的莫耳比為0.5-5,較佳地為1.0-4.0,更佳地為2.0-3.5。
在另一優選例中,所述胺基化試劑與所述式IV化合物的莫耳比為1.0-30,較佳地3-20,更佳地為8.0-15。
在另一優選例中,步驟3)和/或步驟4)在選自下組的溶劑中進行:四氫呋喃、甲基四氫呋喃、二氯甲烷、二氧六環、甲苯、二甲苯、乙酸乙酯、乙腈、乙二醇二甲醚、或其組合。
在另一優選例中,步驟3)和/或步驟4)在二氯甲烷中進行。
在另一優選例中,步驟3)是在-40-40℃下進行的,較佳地-30-30℃,更佳地-20-20℃。
在另一優選例中,步驟4)是在-40-10℃下進行的,較佳地-30-5℃,更佳地-20-0℃。
在另一優選例中,步驟4)在10-40℃之間用水淬滅反應。
本發明的第四方面,提供了一種本發明第二方面所述的式II所示中間體或本發明第三方面所述式III所示中間體的用途,用於製備本發明第一方面所述的式I化合物、或其藥學上可接受的鹽、或其互變異構體、或其立體異構體、或其外消旋體。
應理解,在本發明範圍內中,本發明的上述各技術特徵和在下文(如實施例)中具體描述的各技術特徵之間都可以互相組合,從而構成新的或優選的技術方案。限於篇幅,在此不再一一累述。
本發明人經過長期而深入的研究,通過優化工藝獲得了一種製備式I化合物的新方法及用於製備式I化合物的新中間體。該方法收率高、產物純度高、條件溫和、操作安全方便且可在最後三步避免產生具有基因毒性的中間體。具體地,本發明所述方法從苯胺類關鍵中間體出發,成脲後利用Ullmann反應關環合成本發明的B肝病毒核衣殼抑制劑。在此基礎上,發明人完成了本發明。
術語
在本發明中,除非特別指出,所用術語具有本領域技術人員公知的一般含義。
在本發明中,術語“鹵素”指F、Cl、Br或I,優選為Cl、Br或I。
在本發明中,“C1-C6烷基”是指包括1-6個碳原子的直鏈或支鏈的烷基,例如甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、新戊基、特戊基、或類似基團。
在本發明中,術語“C6-C10芳基”是指在環上不含雜原子的具有6-10個碳原子的芳香族環基,如苯基、萘基等。
術語“多個”是指2、3或4個。
術語“6-10元雜芳基”是指含1-3個選自N、O和S的雜原子以及3-9個碳原子的芳香雜環。非限制性例子包括:呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述雜芳基環可以稠合於芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為雜芳基環。雜芳基可以是任選取代的或未取代的。
術語“室溫”是指10-40℃,較佳地15-30℃,更佳地20-30℃。
通過本發明所述合成方法製得的式I化合物具有顯著更高的收率和更高的純度,且合成過程中的操作簡單,不涉及硝化等危險係數較高的操作,同時避免了使用柱層析等不適合大生產的工藝操作。合成該化合物的最後三步中間體經AMES檢測均為陰性,均不含有基因毒性。降低了該化合物中基因毒性雜質超標的風險。
如本文所用,術語“藥學上可接受的鹽”指本發明化合物與酸或鹼所形成的適合用作藥物的鹽。藥學上可接受的鹽包括無機鹽和有機鹽。一類優選的鹽是本發明化合物與酸形成的鹽。適合形成鹽的酸包括但並不限於:鹽酸、氫溴酸、氫氟酸、硫酸、硝酸、磷酸等無機酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、酒石酸、檸檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、對甲苯磺酸、苯磺酸、萘磺酸等有機酸;以及脯胺酸、苯丙胺酸、天冬胺酸、麩胺酸等胺基酸。
另一類優選的鹽是本發明化合物與鹼形成的鹽,例如鹼金屬鹽(例如鈉鹽或鉀鹽)、鹼土金屬鹽(例如鎂鹽或鈣鹽)、銨鹽(如低級的烷醇銨鹽以及其它藥學上可接受的胺鹽),例如甲胺鹽、乙胺鹽、丙胺鹽、二甲基胺鹽、三甲基胺鹽、二乙基胺鹽、三乙基胺鹽、第三丁基胺鹽、乙二胺鹽、羥乙胺鹽、二羥乙胺鹽、三羥乙胺鹽,以及分別由嗎啉、哌嗪、離胺酸形成的胺鹽。
現有合成方法
以化合物
為例,參見WO2017173999 A1實施例6的公開,該化合物是如下製備的:
如WO2017173999 A1實施例6所示,步驟3需要以醋酸酐為溶劑,以濃硝酸進行硝化反應,反應條件比較劇烈。硝化反應會產生大量熱量和潛在的多次硝化的風險,不利於放大生產,後期生產上存在較高的安全隱患。
以WO2017173999 A1實施例6所示,由中間體26開始需經過4步生成最終的關環反應,4步反應的收率分別為65.3%、32.6%、69.3%、24.9%,收率較低。且最後一步反應需要經柱層析純化得到產品,不太適合大生產的需求。
以WO2017173999 A1實施例6所示,在上述製備路線中,步驟3-5生成的中間體27、28、29均含有硝基苯或鄰苯二胺結構,具有潛在風險。原料藥中任何一種中間體均需要開發ppm級別的分析方法並進行嚴格控制,以上中間體的殘留會影響原料藥的質量控制,如果清除不乾淨,無法滿足嚴格的臨床需求,不利於大規模製備安全合規的臨床樣品。
本發明合成方法
與上述現有合成方法不同的是,以化合物4
為例,本發明採用了如下所示的合成路線:
包括如下步驟:
1)
化合物 24與
化合物 31在對甲苯磺酸的催化下生成
化合物 32;
2)
化合物 32在雷尼鎳的催化下被氫氣還原為
化合物 33;
3)利用手性色譜或超臨界流體色譜(SFC)或者其他拆分手段將消旋的
化合物 33拆分,得到手性純的
化合物 34;
4)
化合物 34與三光氣和氨水在吡啶的作用下生成
化合物 17;
5)
化合物 17在吡啶對甲苯磺酸鹽的催化下生成
化合物 9;
6)
化合物 9在銅粉和DBU催化下反應生成
化合物 4。
步驟1)在單一溶劑或者組合溶劑中進行,包括但不限於甲苯、二甲苯、甲醇、乙醇、或其組合。優選甲苯。
步驟1)中的酸包括但不限於對甲苯磺酸、甲磺酸、三氟甲磺酸、樟腦磺酸,優選對甲苯磺酸。
步驟1)中酸的用量相對於化合物31的質量比為0.1-1,優選0.25。
步驟1)中化合物24的用量相對於化合物31的莫耳比為0.90 eq.-1.5 eq.,優選1.2 eq.。
步驟1)中的溫度為60-120℃,優選110-120℃。
步驟2)中硝基的還原可用鐵粉、鋅粉、保險粉、二氯化錫等還原劑,也可用催化氫化的方式還原。
步驟2)中的硝基的催化氫化反應使用的催化劑包括但不限於鈀碳、鉑碳、雷尼鎳,氫氧化鈀碳,優選雷尼鎳。
步驟2)中如使用雷尼鎳進行硝基的催化氫化反應,其相對於化合物32的質量比為0.1-0.5,優選0.3。
步驟2)在單一溶劑或者組合溶劑中進行,包括但不限於乙醇、甲醇、乙酸乙酯、甲苯、二甲苯、甲基四氫呋喃、四氫呋喃和水,優選乙酸乙酯。
應理解,本發明式IV化合物(如化合物33)可採用上述製備方法製得,也可採用現有技術已知的製法製得,或者也可為市售商品。
與上述現有合成方法相比,本發明所述合成方法通過優化原步驟3)及之後工藝製得了化合物4代表的式I化合物。三步反應的收率分別為90.86%、86.9%、83.5%,總收率65.9%。總收率較之前文獻中消旋體合成的四步反應(收率分別為70%、93.8%、90%、75.4%)總收率44.6%有顯著提升。在本發明所述合成方法中,中間體17、中間體9經檢測不含警示結構,有效避免了相關雜質殘留對化合物4代表的式I化合物的影響。本方法最後三步避免了使用柱層析純化,有效提高了純化效率。本方法同時避免了原合成工藝中硝化等安全風險較高的操作,更利於放大生產。該方法具備高收率、雜質可控、操作方便,適合公斤級製備等優點。
經鑒定,本發明式II化合物和式III化合物大多不含有一級苯胺或硝基苯等警示結構,非常利於目標產物式I化合物的質控。
與現有技術相比,本發明具有以下主要優點:
(1)所述製法具有收率高、工藝操作安全、易於放大、條件溫和、化學合成步驟不需柱層析分離等優點;所述製法還具有成本低的優點;
(2)所述製法可避免使用具有警示結構的中間體,有效減少了製備過程和終產品中雜質控制的難度。
下面結合具體實施例,進一步闡述本發明。應理解,這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未註明具體條件的實驗方法,通常按照常規條件或按照製造廠商所建議的條件。除非另外說明,否則百分比和份數按重量計算。
除非另行定義,文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外,任何與所記載內容相似或均等的方法及材料皆可應用於本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。
室溫下,反應釜中依次加入甲苯(303 kg)、化合物31(35 kg)和對甲苯磺酸(7 kg),升溫至105~115℃,攪拌分水1小時。降溫至60~80℃,將化合物24(28.33 kg)加入反應釜,升溫至110~120℃,回流分水反應12個小時。降溫至78~80℃,加入額外的對甲苯磺酸(180 g)和化合物24(505 g)繼續加熱回流分水7-8 h,HPLC中控顯示大部分化合物31轉化完全;反應體系降溫至50-55℃,加入甲醇(35.4 kg)並攪拌2小時,降溫後過濾,所得濾餅用少量甲苯/甲醇溶液淋洗。濾餅乾燥後得到40.5 kg化合物32,收率72.5%,HPLC純度98%。MS:[M+H]
+=551.4/553.4。
室溫下,在反應瓶中加入乙酸乙酯(8 L)、化合物32(178.3 g,1.0 eq.)、三乙胺(80 mL)和雷尼鎳(48 g,27%)。反應體系用氫氣置換三次,室溫反應8 h,HPLC中控顯示化合物32轉化完全。過濾,濾液濃縮得到160.4 g的化合物33,收率95.1%,HPLC純度98.2%。MS:[M+H]
+=521.5/523.5。
取5 g消旋的化合物33,使用手性色譜拆分,以甲醇為主要流動相。經過手性拆分得到1.3 g化合物34(
ee>99%)和1.78 g化合物34-S。
在-10℃下配置二氯甲烷(6 L)的三光氣(BTC)(170.75 g,0.58 mol)溶液。將化合物34(600 g,1.15 mol)的二氯甲烷(4.8 L)溶液,緩慢滴加到上述三光氣的二氯甲烷溶液中。攪拌30分鐘。在-5℃以下,滴加吡啶(273.07 g,3.45 mol)的二氯甲烷(1.2 L)溶液,加完後繼續攪拌20分鐘。在-5℃以下,滴加氨水(0.9 L),繼續保持攪拌至少30分鐘。
HPLC顯示反應完成,用水洗滌兩遍後濃縮。所得產物用乙酸乙酯溶解後加入正庚烷打漿。收集濾餅,烘乾得到590 g化合物17,收率90.86%,純度98.45%。MS:[M+H]
+= 563.01/565.02。
將化合物17(190 g,0.337 mol)溶解在乙腈(1.3 L)中,加入PPTS(即吡啶對甲苯磺酸鹽)(42.3 g,0.168 mol)及NIS(即N-碘代丁二醯亞胺)(90.88 g,0.4 mol)。56℃反應過夜後有大量固體析出。HPLC檢測合格後,降溫到20-30℃,向其中加5%的亞硫酸鈉溶液洗滌。抽濾收集固體,所得固體用MTBE(甲基第三丁醚)洗滌。烘乾得到202 g化合物9,收率86.9%,純度98.75%。MS:[M+H]
+=689.84/691.84。
將化合物9(200 g,0.29 mol)溶解在DMSO(1.6 L)中,向其中加入銅粉(18.5 g,0.29 mol)和1,5-二氮雜二環[5.4.0]十一-5-烯(48.5 g,0.319 mol),在106℃下反應2小時,HPLC監控合格後,加活性炭。過濾,收集濾液。將濾液加到7%的醋酸水溶液中,攪拌20分鐘。抽濾,收集濾餅。所得濾餅用乙酸乙酯和THF溶解。用7%稀醋酸和7%碳酸氫鈉(2.0 L)分別洗滌有機相。所得有機相用無水硫酸鈉乾燥。濃縮除去有機溶劑。在丙酮中打漿後過濾,收集濾餅,乾燥得到136 g化合物4,收率83.5%,純度99.33%。MS:[M+H]
+=562.5/563.4。
1H NMR (600 MHz, DMSO-
d 6) δ 10.48 – 10.43 (m, 2H), 8.73 (s, 1H), 7.93 – 7.87 (m, 2H), 7.75 – 7.69 (m, 2H), 7.67 – 7.60 (m, 2H), 7.33 – 7.26 (m, 2H), 6.73 (d,
J= 7.8 Hz, 1H), 6.64 (s, 1H), 6.61 (dd,
J= 8.0, 1.6 Hz, 1H), 6.03 (d,
J= 1.8 Hz, 1H), 4.30 – 4.21 (m, 2H), 3.70 (dt,
J= 14.3, 7.3 Hz, 1H), 2.92 (dt,
J= 14.3, 7.3 Hz, 1H), 2.69 (dt,
J= 14.5, 7.4 Hz, 1H), 2.62 (dt,
J= 14.1, 7.0 Hz, 1H).
將化合物9(1 g,1.45 mmol)、氧化亞銅(10 mg,0.07 mmol)、配體L19(20 mg,0.07 mmol)和碳酸銫(1.89 g,5.79 mmol)溶解在二甲亞碸中,在75℃下反應24小時。HPLC監控反應完成後,降溫至室溫,加入50 mL水和50 mL乙酸乙酯並分液。水相用乙酸乙酯萃取三次後,合併有機相乾燥並濃縮後得到粗品。粗品在乙酸乙酯和石油醚得混合溶液中打漿,得到化合物4的成品(520 mg,純度95.15%,收率65%)。MS:[M+H]
+=562.1/564.1。
在本發明中,配體L19為N
1,N
2-雙[(2-噻吩基)甲基]草酸醯胺(N
1,N
2-bis(thiophen-2-ylmethyl)oxalamide)。
與WO2017173999 A1實施例3相比,其經由共同中間體(本專利中化合物34)開始需經過硝化、水解、還原和CDI關環一共4步生成最終的關環反應,4步反應的收率分別為70%、94%、90%、75%,總收率44%,合成步驟較長且收率較低。另外,其最後一步反應還需要經柱層析純化得到產品,不太適合大生產的需求。本專利描述的合成路線僅需三步,合成總收率最高可以達到66%。生產效率和總收率均有顯著提升。
與WO2017173999 A1實施例3相比,其最後三步使用到的中間體與該專利中實施例6類似,均含有硝基苯或鄰苯二胺的警示結構,具有潛在風險。原料藥中相關中間體均需要開發ppm級別的分析方法並進行嚴格控制。這樣的路線不利於大規模製備安全合規的臨床樣品。本專利的合成路線避免了使用含有類似結構的化合物,化合物17和化合物9在Ames實驗中呈陰性,具有更好的安全性。相應生產中的控制也變得更為簡便。
將化合物9(1.0 g,1.45 mmol)、氯化亞銅(7.17 mg,0.072 mmol)、配體L21(18 mg,4.35 mmol)和碳酸銫(1.416 g,4.35 mmol)溶解在二甲亞碸(10 mL)中,在70℃下反應16小時。HPLC監控反應完成後,降溫至室溫,加入50 mL水和50 mL乙酸乙酯並分液。水相用乙酸乙酯萃取三次後,合併有機相乾燥並濃縮後得到粗品。粗品在乙酸乙酯和石油醚得混合溶液中打漿,得到化合物4得成品(650 mg,純度99.76%,收率80%)。MS:[M+H]+=562.0/564.1。
在本發明中,配體L21為N
1,N
2-雙[(2-呋喃基)甲基]草酸醯胺(N
1,N
2-bis(furan-2-ylmethyl)oxalamide)。
本發明實施例6-8與WO2017173999 A1實施例3(對比例1)和實施例6(對比例2)的對比小結如下表所示。
實施例6 | 實施例7 | 實施例8 | 對比例1 | 對比例2 | |
自化合物34至產物 的合成步驟 | 3 | 3 | 3 | 4 | 4 |
自化合物34至產物 的合成總收率 | 65.9% | 51.3% | 63.2% | 44.6% | 3.7% |
將化合物
17(1.5 g,2.66 mmol,1.0 eq)溶於乙腈( 20 mL)中,然後加入NBS(570 mg,3.19 mmol,1.2 eq),反應液在室溫下攪拌2小時。反應液用乙酸乙酯(40 mL)稀釋,然後分別用飽和亞硫酸鈉水溶液(20 mL x 2)洗滌和飽和碳酸氫鈉水溶液(20 mL x 2)洗滌。分出的有機相用飽和食鹽水洗滌,無水硫酸鈉乾燥後濃縮得到化合物
35(1.7 g,99%)為黃色固體。LCMS: [M+H]
+= 644.1。
將化合物
35(100 mg,0.155 mmol,1.0 eq)溶於DMSO( 2 mL)中,然後依次加入碘化亞銅(29.6 mg,0.155 mmol,1.0 eq)和DBU(47.6 mg,0.310 mmol,2.0 eq),氮氣置換三次後反應液在氮氣保護下120℃攪拌21小時。冷卻到室溫,反應液用乙酸乙酯(40 mL)稀釋,然後分別用檸檬酸水溶液(5%,10 mL x 2)和飽和食鹽水洗滌,無水硫酸鈉乾燥後濃縮,得到的殘留物用矽膠柱層析(石油醚/乙酸乙酯=1/20)純化後得到化合物
4(34 mg,純度99%)為白色固體。LCMS: [M+H]
+= 562.1。
1H NMR (400 MHz, CDCl
3)
δ9.88 - 9.48 (m, 2H), 7.85 (s, 1H), 7.62 - 7.52 (m, 6H), 7.14 - 7.10 (m, 2H), 6.79 - 6.63 (m, 3H), 5.90 (s, 1H), 4.43 - 4.26 (m, 2H), 3.96 - 3.80 (m, 1H), 3.08 - 2.96 (m, 1H), 2.78 - 2.68 (m, 2H).
將化合物
36(2.5 g,19.51 mmol,1.0 eq)溶於甲醇(30 mL)中。然後加入甲酸銨(6.2 g,97.55 mmol,5.0 eq),反應液在室溫下攪拌10分鐘。將鈀碳(10%,300 mg)加入反應液中,升溫至70℃並攪拌20分鐘。冷卻至室溫後過濾,將濾液濃縮,得到的殘留物用快速矽膠柱層析(石油醚/乙酸乙酯=5/1)純化後得到化合物
37(1.5 g,78%)為無色油狀物。LCMS: [M+H]
+=99.2。
將化合物
37(3.7 g,37.693 mmol,1.0 eq)溶於氯仿(75 mL)中,然後加入四丁基三溴化銨(19 g,39.578 mmol,1.05 eq)。反應液在室溫下攪拌1小時。將反應液倒入飽和碳酸氫鈉水溶液中至pH值為8。將分離出的有機相用飽和食鹽水洗,無水硫酸鈉乾燥後濃縮,得到的殘留物用矽膠柱層析(中性氧化鋁,石油醚/乙酸乙酯=20/1至12/1)純化後得到化合物
38(2.6 g,39%)為棕色固體。LCMS: [M+H]
+=176.0。
將化合物
38(1.5 g,8.523 mmol,1.0 eq)溶於醋酸(24 mL)中,然後加入濃鹽酸(48 mL)。冷卻至-5℃,然後滴加亞硝酸鈉(0.7 g,10.227 mol,1.2 eq)的水(9 mL)溶液。反應液在-5℃下攪拌0.5小時,然後滴加氯化亞錫(4.0 g,21.307 mmol,2.5 eq)的濃鹽酸(9 mL)溶液,滴加過程中反應液溫度維持在0℃至5℃之間。滴加完畢後反應液在0℃至5℃之間攪拌40分鐘。過濾,固體用冷卻的濃鹽酸水溶液洗滌。將固體收集後冷凍乾燥得到化合物
39(1.74 g,87%)為白色固體。LCMS: [M+H]
+=191.0。
將化合物
39(1.74 g,7.647 mmol,1.0 eq)溶於乙醇(8 mL)中,然後加入化合物
41(1.05 g,7.647 mmol,1.0 eq)和醋酸鉀(0.75 g,7.647 mmol,1.0 eq),反應液在88℃下攪拌2小時。冷卻至室溫後將反應液濃縮,殘留物用乙酸乙酯溶解,然後用水洗,飽和食鹽水洗,無水硫酸鈉乾燥後濃縮,將石油醚(30 mL)加入到殘留物中並攪拌半小時。過濾,得到的固體用石油醚洗滌,真空乾燥後得到化合物
40(1.34 g,56 %)為棕色固體。LCMS: [M+H]
+=311.1。
將DMF(692 mg,9.473 mmol,2.2 eq)冷卻至0℃,然後滴加三氯氧磷(1.45 g,9.473 mmol,2.2 eq)。滴加完畢後反應液在0℃攪拌半小時,然後將化合物
40(1.34 g,4.306 mmol,1.0 eq)的DMF(9 mL)溶液滴加到上述反應液中。滴加完畢後升至室溫並攪拌40分鐘,然後升至70℃並攪拌5小時。冷卻至室溫,然後將反應液倒入冰水中。過濾,將固體收集後用甲苯共沸除水,得到的殘留物用矽膠柱層析(石油醚/乙酸乙酯=5/1至2/1)純化得到化合物
42(1.0 g,66 %)為白色固體。LCMS: [M+H]
+=349.0。
將化合物
42(1.0 g,2.863 mmol,1.0 eq)溶於甲苯(100 mL)中,然後加入化合物
24(0.77 g,3.436 mmol,1.2 eq)和對甲苯磺酸一水合物(0.27 g,1.432 mmol,0.5 eq)。反應液在148℃下攪拌4小時,冷卻至室溫,將反應液用乙酸乙酯(50 mL)稀釋,然後用飽和食鹽水洗,無水硫酸鈉乾燥後濃縮,得到的殘留物用矽膠柱層析(石油醚/乙酸乙酯=1/1)純化得到化合物
43(1.27 g,80%)為白色固體。LCMS: [M+H]
+=555.0。
將化合物
43(1.27 g,2.286 mmol,1.0 eq)溶於乙醇(40 mL)中,然後加入氯化亞錫(10.84 g,57.166 mmol,25.0 eq),反應液在90℃下攪拌1.5小時,冷卻至室溫,將反應液用碳酸鈉水溶液(2 N)調節pH值為9,然後用乙酸乙酯(100 mL)稀釋。過濾,將濾液用水洗,飽和食鹽水洗,無水硫酸鈉乾燥後濃縮得到化合物
44(1.1 g,91%) 為白色固體。LCMS: [M+H]
+=525.1。
將化合物
44(0.9 g,1.717 mmol,1.0 eq)溶於四氫呋喃(35 mL)中,然後冷卻至0℃。加入三光氣(0.25 g,0.858 mmol,0.5 eq)後升至室溫並在室溫下攪拌2小時。冷卻至0℃,然後加入氨水(2.5 mL)。反應液升至室溫並攪拌半小時。將反應液用乙酸乙酯(50 mL)稀釋,然後依次用水洗,飽和食鹽水洗,無水硫酸鈉乾燥後濃縮得到化合物
21(0.95 g,97%)為白色固體。LCMS: [M+H]
+=568.1。
將化合物
21(950 mg,1.675 mmol,1.0 eq)溶於乙腈(35 mL)中,然後加入對甲苯磺酸一水合物(64 mg,0.335 mmol,0.2 eq)和NIS(565 mg,2.513 mmol,1.5 eq),反應液在80℃下攪拌16小時。冷卻至室溫,將反應液用亞硫酸鈉水溶液(0.2 N)調節pH值為8,然後濃縮除去乙腈。將殘留物用乙酸乙酯(50 mL)稀釋,然後用飽和食鹽水洗,無水硫酸鈉乾燥後濃縮,得到的殘留物用矽膠柱層析(石油醚/乙酸乙酯=1/1至1/5)純化得到化合物
13(605 mg,52%)為棕色固體。LCMS: [M+H]
+=693.9。
將化合物
13(400 mg,0.576 mmol,1.0 eq)溶於DMSO(30 mL)中,然後加入DBU(175 mg,1.152 mmol,2.0 eq)和碘化亞銅(109 mg,0.576 mmol,1.0 eq),反應液在120℃下攪拌0.5小時。冷卻至室溫,將反應液用乙酸乙酯(80 mL)稀釋,然後依次用水洗,飽和食鹽水洗,無水硫酸鈉乾燥後濃縮,得到的殘留物用矽膠柱層析(二氯甲烷/甲醇=40/1至30/1)純化得到化合物
5(244 mg,純度99.34%,收率75%)為黃色固體。LCMS: [M+H]
+=566.1。
在本發明提及的所有文獻都在本申請中引用作為參考,就如同每一篇文獻被單獨引用作為參考那樣。此外應理解,在閱讀了本發明的上述講授內容之後,本領域技術人員可以對本發明作各種改動或修改,這些等價形式同樣落於本申請所附申請專利範圍所限定的範圍。
無。
Claims (10)
- 一種式I化合物、或其藥學上可接受的鹽、或其互變異構體、或其立體異構體、或其外消旋體的製備方法,其中,包括如下步驟: 1)在催化劑存在下,將式II化合物進行成環得到式I化合物; 其中,R 1、R 2、R 3、R 4和R 5各自獨立地選自下組:氫、氘、鹵素、取代或未取代的C1-C6烷基、胺基、羥基、硝基,所述取代指被一個或多個(如2、3、4或5個)選自下組的取代基取代:鹵素、硝基、胺基、羥基; R 6選自下組:氫、氘、鹵素、胺基、羥基; n為0、1、2、3或4; Q選自下組:被一個或多個鹵素取代的或未取代的C6-C10芳基、被一個或多個鹵素取代的或未取代的含1-3個選自N、O和S的雜原子的6-10元雜芳基; X為鹵素。
- 如請求項1所述的製備方法,其中,步驟1)中,所述催化劑選自下組物質或其水合物:碘化(亞)銅、氯化(亞)銅、溴化(亞)銅、硫酸銅、銅粉、氧化(亞)銅、氫氧化(亞)銅、醋酸(亞)銅、檸檬酸銅、甲磺酸銅、氟硼酸銅、鹼式碳酸銅、葡萄糖酸銅、酒石酸(亞)銅、乙醯丙酮銅、8-羥基喹啉銅、硫氰酸(亞)銅、硝酸(亞)銅、氰化(亞)銅、草酸銅、磷酸銅、三氟甲磺酸(亞)銅、甲酸銅、硒化銅、二氯(1,10-菲咯啉)銅、(1,10-菲咯啉)(三氟甲基)銅、CuTC、或其組合。
- 如請求項4所述的製備方法,其中,步驟2)中,所述鹵代試劑選自下組:N-碘代丁二醯亞胺(NIS)、碘、1,3-二碘-5,5-二甲基海因、N-溴代丁二醯亞胺、溴素、1,3-二溴-5,5-二甲基海因、氯氣、N-氯代丁二醯亞胺、N-溴代琥珀醯亞胺(NBS)、或其組合。
- 如請求項6所述的製備方法,其中,步驟3)中,所述羰基化試劑選自下組:三光氣、CDI、異氰酸鉀、或其組合;和/或 步驟4)中,所述胺基化試劑選自下組:氨水、氨氣、胺的有機溶液、或其組合。
- 一種請求項8所述的式II所示中間體或請求項9所述式III所示中間體的用途,其中,用於製備請求項1所述的式I化合物、或其藥學上可接受的鹽、或其互變異構體、或其立體異構體、或其外消旋體。
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