CN111138455A - 一种手性四氢呋喃并恶嗪稠合苯并咪唑衍生物及其制备方法和用途 - Google Patents
一种手性四氢呋喃并恶嗪稠合苯并咪唑衍生物及其制备方法和用途 Download PDFInfo
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- CN111138455A CN111138455A CN202010045033.3A CN202010045033A CN111138455A CN 111138455 A CN111138455 A CN 111138455A CN 202010045033 A CN202010045033 A CN 202010045033A CN 111138455 A CN111138455 A CN 111138455A
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- China
- Prior art keywords
- chiral
- oxazine
- compound
- benzimidazole derivative
- tetrahydrofurane
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract 11
- TYUWJVSASWTIFV-UHFFFAOYSA-N 3,4,4a,6-tetrahydro-2H-furo[2,3-e]oxazine Chemical compound O1NCCC2C1=CCO2 TYUWJVSASWTIFV-UHFFFAOYSA-N 0.000 title claims description 3
- BDKIFFMJZJUCTB-UHFFFAOYSA-N 2H-oxazine oxolane Chemical compound O1CCCC1.O1NC=CC=C1 BDKIFFMJZJUCTB-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000003443 antiviral agent Substances 0.000 claims abstract description 5
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims abstract description 4
- 229930091371 Fructose Natural products 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 241000700605 Viruses Species 0.000 claims description 6
- -1 chloro, bromo, iodo Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 3
- 230000003097 anti-respiratory effect Effects 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- UICXTANXZJJIBC-UHFFFAOYSA-N 1-(1-hydroperoxycyclohexyl)peroxycyclohexan-1-ol Chemical compound C1CCCCC1(O)OOC1(OO)CCCCC1 UICXTANXZJJIBC-UHFFFAOYSA-N 0.000 claims description 2
- RFSCGDQQLKVJEJ-UHFFFAOYSA-N 2-methylbutan-2-yl benzenecarboperoxoate Chemical compound CCC(C)(C)OOC(=O)C1=CC=CC=C1 RFSCGDQQLKVJEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 2
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 206010051511 Viral diarrhoea Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 235000000346 sugar Nutrition 0.000 abstract description 7
- 230000004071 biological effect Effects 0.000 abstract description 5
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- 229960002737 fructose Drugs 0.000 abstract description 3
- 150000004987 o-phenylenediamines Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000006049 ring expansion reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000003541 multi-stage reaction Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 238000012827 research and development Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 28
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 150000001556 benzimidazoles Chemical class 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 4
- 241000725643 Respiratory syncytial virus Species 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 4
- 230000000975 bioactive effect Effects 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- TTXGKCVKGXHPRI-UHFFFAOYSA-N 4,5-dibromobenzene-1,2-diamine Chemical compound NC1=CC(Br)=C(Br)C=C1N TTXGKCVKGXHPRI-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
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- 229940125782 compound 2 Drugs 0.000 description 2
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- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- RSFQXXPRDCNQRF-UHFFFAOYSA-N 3,5-dibromo-4-methylbenzene-1,2-diamine Chemical compound BrC=1C(=C(C=C(C=1C)Br)N)N RSFQXXPRDCNQRF-UHFFFAOYSA-N 0.000 description 1
- PWJODKIVFMVMBJ-UHFFFAOYSA-N 3,5-dichloro-4-methoxybenzene-1,2-diamine Chemical compound COC1=C(C=C(C(=C1Cl)N)N)Cl PWJODKIVFMVMBJ-UHFFFAOYSA-N 0.000 description 1
- YEMVEDUUCIAMFN-UHFFFAOYSA-N 3,5-diiodo-4-methylbenzene-1,2-diamine Chemical compound IC=1C(=C(C=C(C=1C)I)N)N YEMVEDUUCIAMFN-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- IWFHBRFJOHTIPU-UHFFFAOYSA-N 4,5-dichlorobenzene-1,2-diamine Chemical compound NC1=CC(Cl)=C(Cl)C=C1N IWFHBRFJOHTIPU-UHFFFAOYSA-N 0.000 description 1
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 description 1
- BSMPRJISGCTCDC-UHFFFAOYSA-N 4-chloro-5-fluorobenzene-1,2-diamine Chemical compound NC1=CC(F)=C(Cl)C=C1N BSMPRJISGCTCDC-UHFFFAOYSA-N 0.000 description 1
- KWEWNOOZQVJONF-UHFFFAOYSA-N 4-fluorobenzene-1,2-diamine Chemical compound NC1=CC=C(F)C=C1N KWEWNOOZQVJONF-UHFFFAOYSA-N 0.000 description 1
- AGAHETWGCFCMDK-UHFFFAOYSA-N 4-methoxybenzene-1,2-diamine Chemical compound COC1=CC=C(N)C(N)=C1 AGAHETWGCFCMDK-UHFFFAOYSA-N 0.000 description 1
- DGRGLKZMKWPMOH-UHFFFAOYSA-N 4-methylbenzene-1,2-diamine Chemical compound CC1=CC=C(N)C(N)=C1 DGRGLKZMKWPMOH-UHFFFAOYSA-N 0.000 description 1
- BGJNRQSGJHVURK-UHFFFAOYSA-N 5-chloroisoindole-1,3-dione Chemical compound ClC1=CC=C2C(=O)NC(=O)C2=C1 BGJNRQSGJHVURK-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010023856 Laryngeal squamous cell carcinoma Diseases 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
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- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- GBKAVPJYGIOOHR-UHFFFAOYSA-N spiro[benzimidazole-2,2'-oxolane] Chemical class C1CC2(N=C3C=CC=CC3=N2)OC1 GBKAVPJYGIOOHR-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
本发明公开了一种手性四氢呋喃并恶嗪稠合苯并咪唑衍生物及其制备方法和应用,属于糖化学及药物化学领域。其具有如下通式所示结构:
Description
技术领域
本发明属于糖化学及药物化学领域,具体涉及新型苯并咪唑类衍生物及其制备方法和其生物活性。
背景技术
杂环是药物化学研究中最为活跃的领域之一。苯并咪唑是一个双环芳氮杂环系统,拥有广泛的生物学活性,被称为“万能钥匙”,是许多天然或合成生物活性化合物的重要母核。大多数的具有生物活性的苯并咪唑化合物的取代位置在1、2、5(6)位,可以是单、二或三取代的苯并咪唑衍生物。苯并咪唑类化合物的生物活性主要有抗高血压、抗炎、抗肿瘤及抗病毒等。因此合成新型苯并咪唑是发现新型药物的有效途径。
苯并咪唑经典的制备方法是在酸催化下羧酸与邻苯二胺缩合而得,也可以通过在氧化剂的存在下醛或酮与邻苯二胺缩合反应制备。
另外,糖做为重要的天然手性化合物,一直在生物体中扮演着重要角色。同时将糖的手性中心部分或全部引入目标化合物中得到具有手性中心的生物活性化合物将赋予化合物特殊的生物活性。目前未见由糖合成苯并咪唑类似物的相关文献报道。
发明内容
本发明目的在于提供一系列手性四氢呋喃并恶嗪稠合苯并咪唑衍生物;另一目的在于提供其制备方法及应用。
为实现本发明目的,本发明通过手性原料1,4:3,6-二缩水-D-果糖与邻苯二胺类化合物缩合、氧化和重排以及其它进一步的结构修饰,得到一系列四氢呋喃并恶嗪稠合苯并咪唑衍生物。
所述的四氢呋喃并恶嗪稠合苯并咪唑衍生物以通式1表示。
其中,R代表氢、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4烷硫基、三氟甲基、三氟甲氧基或卤素。R在苯环上单取代、二取代或三取代。
所述R基团,其中C1-4烷基、C 1-4烷氧基、C 1-4烷氨基和C1-4烷硫基中的烷基为直链或支链的烷基。
所述R基团,其中的卤素是指氟、氯、溴和碘原子的一种或两种取代。
优选:R代表氢,C 1-2烷基,C 1-2烷氧基,氟、氯、溴原子;R在苯环上单取代、二取代或三取代。
所述通式1所示化合物为单一化合物,或为两种取代位置异构体的混合物。
所述通式1所示化合物含有三个手性碳原子,构型分别为:3R,3aR,11aS。
制备上述通式1所示化合物的方法如下:
将1,4:3,6-二缩水果糖(化合物A)和邻苯二胺(化合物B)溶于有机溶剂1中,搅拌反应,反应结束减压浓缩。将所得浓缩物,溶于有机溶剂2中,加入氧化剂搅拌反应,反应结束后过滤,减压浓缩,柱层析分离得到通式1所示产物。
化合物B所示邻苯二胺分别为一取代、二取代或三取代邻苯二胺,其中R分别为氢、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4烷硫基、三氟甲基、三氟甲氧基和卤素等基团的一种、两种或三种,例如:4-甲氧基、4,5-二甲基、4-甲氨基、4-丙硫基、4-丁基、3-氟、4-氯、4-溴、4,5-二氯、4-氯-5-氟、6-溴-4-三氟甲氧基、4-氯-6-溴、3,5-二氯-4-甲基、3,5-二溴-4-甲基、3,5-二碘-4-甲基或3,5-二氯-4-甲氧基等。
上述反应中所使用的有机溶剂1和2分别为水、二氯甲烷、氯仿、四氢呋喃、二氧六环、乙腈、乙醇、甲醇、异丙醇、N,N-二甲基甲酰胺中的一种,有机溶剂1和2可以是相同或不同的溶剂。
上述反应中所用氧化剂为有机氧化剂、无机氧化剂、氧气或空气。其中,有机氧化剂为过氧化苯甲酰、过氧乙酸溶液、2,3-二氯-5,6-二氰基对苯醌、过氧苯甲酸叔戊酯和过氧化环己酮的一种,无机氧化剂为三氯化铁、高锰酸钾、碘、二氧化锰、双氧水或次氯酸钠中的一种。
上述反应中采用的反应温度为10-70℃。
上述反应中每步反应时间为0.5-6小时。
根据取代邻苯二胺取代基的不同,得到产物可能为苯环两种取代位置异构体的混合物,通过重结晶可得到一种或两种纯的异构体。
如上所示四氢呋喃并恶嗪稠合苯并咪唑衍生物具有体外抗病毒活性,如:其中部分化合物表现出较好的抗牛病毒性腹泻病毒(BVDV)活性;其中部分化合物表现出较好的抗呼吸道合包病毒(RSV)活性。可将其作为活性成分应用于抗病毒药物。
本发明的优点在于:
1、本发明将糖的手性与生物活性分子苯并咪唑融合,得到新型的具有较好生物活性的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物。为糖的手性利用提供了一个新的途径。
2、本发明首次采用分子中具有三个手性碳和一个酮羰基的1,4:3,6-二缩水水果糖和邻苯二胺为原料,通过一锅多步反应立体选择性得到手性四氢呋喃并恶嗪稠合苯并咪唑衍生物。
3、本发明通过σ键迁移扩环反应,从四氢呋喃螺苯并咪唑衍生物扩环得到恶嗪稠苯并咪唑衍生物。
4、初步体外活性评价发现,某些化合物有抗病毒活性,为发现新型抗病毒药物开辟了新的途径。作为药物的手性合成中间体,具有进一步研究开发的价值,为丰富苯并咪唑的合成方法和发现新的生物活性物质开辟了一条新的途径。
具体实施方式
为对本发明进行更好地说明,举实施例如下:
实施例1:化合物1(通式1,R=H)的合成
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL乙腈中,加入等摩尔量的邻苯二胺(216mg,2mmol),室温反应5小时。反应结束后,在体系中加2mL双氧水,于50℃反应5小时。减压浓缩反应液,硅胶柱层析分离(EA:MeOH=20:1),得到白色固体产物(化合物1)。1HNMR(400MHz,DMSO-d6)δ7.63(d,J=5.1Hz,1H),7.50(d,J=4.6Hz,1H),7.26(m,2H),6.02(s,1H),5.46(d,J=6.5Hz,1H),5.13(d,J=15.6Hz,1H),4.86(d,J=15.6Hz,1H),4.55(m,1H),4.37(s,1H),4.03(t,J=7.1Hz,1H),3.73(t,J=8.3Hz,1H).
实施例2:化合物2(通式1,R=8,9-diBr)的合成
4,5-二溴邻苯二胺(532mg,2mmol),操作同化合物1的制备,得淡黄色固体(化合物2)。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.93(s,1H),6.04(d,J=2.8Hz,1H),5.49(d,J=6.8Hz,1H),5.14(d,J=15.9Hz,1H),4.86(d,J=15.9Hz,1H),4.51(m,1H),4.40(m,1H),4.02(t,J=7.3Hz,1H),3.71(dd,J=7.9,9.1Hz,1H).
实施例3:化合物3(通式1,R=8-F/9-F)的合成
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL无水乙醇中,加入等摩尔量4-氟邻苯二胺(252mg,2mmol),50℃反应3小时。反应结束后减压浓缩,加入10mL二氯甲烷溶解,在体系中加800mg二氧化锰,于室温下反应3小时。过滤,减压浓缩,硅胶柱层析分离得浅黄色固体(化合物3,8-氟和9-氟产物混合物,比例1:0.42)。8-氟产物:1H NMR(400MHz,DMSO)δ7.50(dd,J=8.7,4.8Hz,1H),7.45(dd,J=9.7,2.3Hz,1H),7.13(dt,J=9.9,2.4Hz,1H),6.01(d,J=3.0Hz,1H),5.48(d,J=6.8Hz,1H),5.12(d,J=15.7Hz,1H),4.85(d,J=15.7Hz,1H),4.52(m,1H),4.37(dd,J=7.4,3.8Hz,1H),4.02(t,J=7.3Hz,1H),3.72(dd,J=9.3,7.7Hz,1H).(9-氟取代产物数据略)
实施例4:化合物4(通式1,R=8-OMe)的合成
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL乙腈中,加入等摩尔量4-甲氧基邻苯二胺(276mg,2mmol),室温反应5小时。反应结束后,在体系中加800mg二氧化锰,于室温下反应3小时。过滤,减压浓缩,柱层析分离(DCM:MeOH=10:1),得白色固体(8-甲氧基和少许9-甲氧基异构体混合物),重结晶得8-甲氧基产物。1H NMR(400MHz,DMSO-d6):δ7.37(d,J=8.7Hz,1H),7.15(d,J=2.3Hz,1H),6.88(dd,J=8.7,2.4Hz,1H),5.96(d,J=2.9Hz,1H),5.44(d,J=6.9Hz,1H),5.08(d,J=15.6Hz,1H),4.82(d,J=15.6Hz,1H),4.52(m,1H),4.34(dd,J=4.2,3.2Hz,1H),4.01(t,J=7.3Hz,1H),3.79(s,3H),3.71(dd,J=9.6,7.4Hz,1H).
实施例5:化合物5(通式1,R=8,9-diCl)的合成
以4,5-二氯邻苯二胺代替4,5-二溴邻苯二胺,采用与化合物2制备相同的方法,得到化合物5。1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.80(s,1H),6.04(d,J=3.0Hz,1H),5.47(d,J=6.8Hz,1H),5.13(d,J=15.9Hz,1H),4.87(d,J=15.9Hz,1H),4.52(m,1H),4.40(dd,J=3.2,4.4Hz,1H),4.03(t,J=7.3Hz,1H),3.71(dd,J=7.6,9.4Hz,1H).
实施例6:化合物6(通式1,R=8-Me/9-Me)的合成
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL甲醇中,加入等摩尔量4-甲基邻苯二胺(244mg,2mmol),于40℃反应4小时。反应结束后,浓缩,加入5mL二氯甲烷溶解,加入800mg二氧化锰,于室温下反应3小时。过滤,减压浓缩,柱层析分离(DCM:MeOH=10:1),得白色固体(化合物6,8-甲基产物:9-甲基产物约为1:0.55)。8-甲基产物:1H NMR(400MHz,DMSO-d6)δ7.42(s,1H),7.36(d,J=8.1Hz,1H),7.07(dd,J=8.1,0.8Hz,1H),5.96(d,J=2.9Hz,1H),5.44(d,J=6.9Hz,1H),5.09(d,J=15.6Hz,1H),4.82(d,J=15.6Hz,1H),4.52(m,1H),4.35(m,1H),4.01(t,J=7.3Hz,1H),3.72(dd,J=9.6,7.4Hz,1H),2.41(s,3H).(9-甲基产物数据略)
实施例7:化合物7(通式1,R=8-Cl/9-Cl)的合成
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL乙醇中,加入等摩尔量4-氯邻苯二胺(285mg,2mmol)和催化量的碘,室温反应5小时。反应结束后,浓缩,柱层析分离(DCM:MeOH=10:1),得白色固体(化合物7,8-氯产物:9-氯产物约为1:0.4)。8-氯产物:1H NMR(400MHz,DMSO-d6)δ7.68(d,J=1.9Hz,1H),7.50(d,J=8.7Hz,1H),7.28(dd,J=8.7,1.9Hz,1H),6.00(d,J=3.0Hz,1H),5.45(d,J=5.4Hz,1H),5.11(d,J=15.7Hz,1H),4.84(d,J=15.7Hz,1H),4.51(m,1H),4.37(m,1H),4.01(t,J=7.3Hz,1H),3.72(d,J=9.8,7.6Hz,1H).(9-氯产物数据略)
实施例8:化合物8(通式1,R=8-Cl-9-F/8-F-9-Cl)的合成
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL乙醇中,加入4-氯-5-氟邻苯二胺(322mg,2mmol),于50℃反应3小时。浓缩反应液,加入5mL二氧六环溶解,加入800mg二氧化锰,于室温下反应3小时。过滤,减压浓缩,柱层析分离(DCM:MeOH=10:1),得白色固体(化合物8,8-氯-9-氟产物和8-氟-9-氯产物两种位置异构体的混合物,摩尔比约4:1)。8-氯-9-氟产物:1H NMR(400MHz,DMSO-d6)δ7.97–7.48(m,2H),6.02(d,J=2.9Hz,1H),5.49(d,J=6.0Hz,1H),5.14(d,J=15.8Hz,1H),4.86(d,J=15.8Hz,1H),4.53(s,1H),4.45–4.32(m,1H),4.03(t,J=7.3Hz,1H),3.72(t,J=8.5Hz,1H).(8-氟-9-氯产物数据略)
实施例9:化合物9(通式1,R=8-Br/9-Br)的合成
4-溴邻苯二胺(372mg,2mmol),操作同化合物1,柱层析分离(EA:MeOH=20:1),得类白色固体(8-溴和9-溴两种位置异构体的混合物,摩尔比约为1:0.55)。8-溴产物:1H NMR(400MHz,DMSO-d6):δ7.70(d,J=1.8Hz,1H),7.59(d,J=8.6Hz,1H),7.39(dd,J=1.8,8.6Hz,1H),6.04(d,J=3.0Hz,1H),5.13(dd,J=15.7,4.3Hz,1H),4.83(d,J=15.7Hz,1H),4.50–4.56(m,1H),4.39(dd,J=7.4,3.2Hz,1H),4.03(t,J=7.3Hz,1H),3.72(dd,J=7.3,9.5Hz,1H).(9-溴产物数据略)
实施例10:化合物10(通式1,R=7,9-diCl-8-OMe)的合成
4-甲氧基-3,5-二氯邻苯二胺代替4-甲基邻苯二胺,采用与化合物6制备操作类似的方法得到化合物10。1H NMR(400MHz,DMSO-d6):δ8.19(s,1H),6.12(d,J=1.8Hz,1H),5.53(d,J=6.4Hz,1H),5.26(d,J=16.2Hz,1H),4.93(d,J=16.2Hz,1H),4.54(m,1H),4.45(m,1H),4.06(t,J=7.2Hz,1H),3.97(s,3H),3.73(t,J=8.6Hz,1H).
实施例11:化合物11(通式1,R=7,9-diBr-8-Me/8,10-diBr-9-Me)
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL乙醇中,加入等摩尔的4-甲基-3,5-二溴邻苯二胺,于50℃反应3小时。浓缩反应液,加入5mL二氧六环溶解,加入过量的双氧水,于室温下反应5小时。减压浓缩,柱层析分离(DCM:MeOH=10:1),得白色固体产物11(8-甲基取代/9-甲基取代产物约为1:0.15)。7,9-二溴-8-甲基取代产物:1H NMR(400MHz,DMSO-d6):δ7.92(s,1H),6.44(s,1H),5.45(d,J=7.0Hz,1H),5.14(d,J=15.8Hz,1H),4.89(d,J=15.8Hz,1H),4.59(m,1H),4.35(s,1H),4.01(t,J=7.2Hz,1H),3.75(dd,J=8.0,8.9Hz,1H),2.61(s,3H).(8,10-二溴-9-甲基异构体数据略)
实施例12:化合物12(通式1,R=7,9-diI-8-Me/8,10-diI-9-Me)
将1,4:3,6-二缩水-D-果糖(288mg,2mmol)溶于5mL乙醇中,加入等摩尔的4-甲基-3,5-二碘邻苯二胺,于50℃反应3小时。浓缩反应液,加入5mL二氯甲烷溶解,加入过量的二氧化锰,于室温下反应5小时。过滤,滤液减压浓缩,柱层析分离(DCM:MeOH=10:1),得白色固体产物12(8-甲基取代/9-甲基取代产物约为1:0.85)。7,9-二碘-8-甲基取代产物:1HNMR(400MHz,DMSO-d6):δ8.13(s,1H),6.63(s,1H),5.47(d,J=6.1Hz,1H),5.13(d,J=15.6Hz,1H),4.88(d,J=15.6Hz,1H),4.60(m,1H),4.37(s,1H),4.01(t,J=7.2Hz,1H),3.75(t,J=8.5Hz,1H),2.84(s,3H).(8,10-二碘-9-甲基异构体数据略)
实施例13:体外抗BVDV活性
将实施例所得的化合物采用MTT法测定对马-达氏牛肾细胞(MDBK)的细胞毒性,用感染牛病毒性腹泻病毒(BVDV)的MDBK细胞进行抗病毒活性评价,其中三个化合物的结果如下:
EC<sub>50</sub>(μM) | CC<sub>50</sub>(μM) | SI(CC<sub>50</sub>/EC<sub>50</sub>) | |
化合物1 | 2.50 | >50 | >20 |
化合物4 | 1.25 | >50 | >40 |
化合物5 | 1.25 | >50 | >40 |
利巴韦林 | 2.50 | - | - |
实施例14:体外抗呼吸道合包病毒(RSV)活性
将实施例所得的化合物,采用MTT法测定对人喉表皮样癌细胞的细胞毒性(Hep-2),用感染呼吸道合包病毒(RSV)的Hep-1细胞进行抗病毒活性评价,其中三个化合物的结果如下:
EC<sub>50</sub>(μM) | CC<sub>50</sub>(μM) | SI(CC<sub>50</sub>/EC<sub>50</sub>) | |
化合物2 | 31.94±7.27 | 181.22±5.09 | 5.67 |
化合物11 | 9.53±1.98 | 148.79±38.89 | 15.61 |
化合物12 | 24.43±9.53 | 177.42±38.43 | 7.26 |
利巴韦林 | 18.53±29.53 | 440.67±35.48 | 13.78 |
。
Claims (8)
2.如权利要求1所述的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物,其特征在于,R代表氢,C1-2烷基,C1-2烷氧基,氟、氯、溴、碘;R在苯环上单取代、二取代或三取代。
3.如权利要求1或2所述的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物,其特征在于,通式化合物含有三个手性碳,构型分别为:3R,3aR,11aS。
5.制备权利要求1所述的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物的方法,其特征在于,通式1所示化合物通过如下方法实现:
将1,4:3,6-二缩水果糖(化合物A)和邻苯二胺类化合物(化合物B)溶于有机溶剂1中,搅拌反应,反应结束减压浓缩;将所得浓缩物溶于有机溶剂2中,加入氧化剂搅拌反应,反应结束后过滤,减压浓缩,柱层析分离得到通式1所示产物;
所使用的有机溶剂1和有机溶剂2分别为水、二氯甲烷、氯仿、四氢呋喃、二氧六环、乙腈、乙醇、甲醇、异丙醇、N,N-二甲基甲酰胺中的一种,有机溶剂1和2相同或不同;
所用氧化剂为氧气或空气;过氧化苯甲酰、过氧乙酸溶液、2,3-二氯-5,6-二氰基对苯醌、过氧苯甲酸叔戊酯或过氧化环己酮;三氯化铁、高锰酸钾、碘、二氧化锰、双氧水或次氯酸钠。
6.如权利要求1-4其中所述的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物的用途,其特征在于,将其作为活性成份,用于制备抗病毒药物或作为制备抗病毒药物的先导物使用。
7.如权利要求6所述的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物的用途,其特征在于,作为制备抗牛病毒性腹泻病毒(BVDV)药物或作为制备抗BVDV药物的先导物。
8.如权利要求6所述的手性四氢呋喃并恶嗪稠合苯并咪唑衍生物的用途,其特征在于,作为制备抗呼吸道合胞病毒(RSV)药物或作为制备抗RSV药物的先导物。
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