CN117447462A - 一种手性三氮唑-噁唑啉化合物及其制备方法与应用 - Google Patents
一种手性三氮唑-噁唑啉化合物及其制备方法与应用 Download PDFInfo
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- CN117447462A CN117447462A CN202311413313.5A CN202311413313A CN117447462A CN 117447462 A CN117447462 A CN 117447462A CN 202311413313 A CN202311413313 A CN 202311413313A CN 117447462 A CN117447462 A CN 117447462A
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- compound
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- organic solvent
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- triazole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- -1 triazole-oxazoline compound Chemical class 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 150000001543 aryl boronic acids Chemical class 0.000 claims abstract description 10
- 238000011065 in-situ storage Methods 0.000 claims abstract description 6
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 6
- 238000007112 amidation reaction Methods 0.000 claims abstract description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 3
- 230000018044 dehydration Effects 0.000 claims abstract description 3
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 3
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 65
- 239000003960 organic solvent Substances 0.000 claims description 40
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000011261 inert gas Substances 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 claims description 13
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 11
- 150000003997 cyclic ketones Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 10
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 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 claims description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 8
- 229940125773 compound 10 Drugs 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 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 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 8
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 claims description 7
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 claims description 7
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical group CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- GEJJWYZZKKKSEV-KBPBESRZSA-N (1s,2s)-2-amino-1,2-diphenylethanol Chemical group C1([C@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KBPBESRZSA-N 0.000 claims description 2
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical group OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 claims description 2
- VPSSPAXIFBTOHY-LURJTMIESA-N (2s)-2-amino-4-methylpentan-1-ol Chemical group CC(C)C[C@H](N)CO VPSSPAXIFBTOHY-LURJTMIESA-N 0.000 claims description 2
- GUQUYKTWVBJKFL-UHFFFAOYSA-N 4,5-dibromo-2h-triazole Chemical compound BrC1=NNN=C1Br GUQUYKTWVBJKFL-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- GHUURDQYRGVEHX-UHFFFAOYSA-N prop-1-ynylbenzene Chemical compound CC#CC1=CC=CC=C1 GHUURDQYRGVEHX-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- UZIXCCMXZQWTPB-UHFFFAOYSA-N trimethyl(2-phenylethynyl)silane Chemical compound C[Si](C)(C)C#CC1=CC=CC=C1 UZIXCCMXZQWTPB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010668 complexation reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000000536 complexating effect Effects 0.000 abstract description 2
- 150000003852 triazoles Chemical class 0.000 abstract 2
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract 1
- 230000009435 amidation Effects 0.000 abstract 1
- 150000001414 amino alcohols Chemical class 0.000 abstract 1
- 238000012650 click reaction Methods 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 150000002940 palladium Chemical class 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 20
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- 238000004440 column chromatography Methods 0.000 description 18
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- 239000012074 organic phase Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- 239000003446 ligand Substances 0.000 description 11
- 238000010586 diagram Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- HOIXVJDJSJNGFM-CYBMUJFWSA-N (3r)-3-methyl-3-phenylcyclohexan-1-one Chemical compound C=1C=CC=CC=1[C@]1(C)CCCC(=O)C1 HOIXVJDJSJNGFM-CYBMUJFWSA-N 0.000 description 4
- JSBDDSODFASDNZ-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole 2H-triazole Chemical compound N1N=NC=C1.O1C=NCC1 JSBDDSODFASDNZ-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 2
- NZSQBRZWARZNQH-ZWOACCQCSA-N C1(CC1)NC(=O)O[C@H]1C(C2CC[C@]3([C@@]4(CC[C@@]5(C(C4CCC3[C@]2(CC1)C)[C@@H](CC5)[C@H](C)O)C(=O)O)C)C)(C)C Chemical compound C1(CC1)NC(=O)O[C@H]1C(C2CC[C@]3([C@@]4(CC[C@@]5(C(C4CCC3[C@]2(CC1)C)[C@@H](CC5)[C@H](C)O)C(=O)O)C)C)(C)C NZSQBRZWARZNQH-ZWOACCQCSA-N 0.000 description 2
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 2
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 125000000623 heterocyclic group Chemical group 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- FARHYDJOXLCMRP-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]pyrazol-3-yl]oxyacetic acid Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(N1CC2=C(CC1)NN=N2)=O)OCC(=O)O FARHYDJOXLCMRP-UHFFFAOYSA-N 0.000 description 1
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 1
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- 238000007259 addition reaction Methods 0.000 description 1
- 238000007294 asymmetric addition reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
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- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
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- C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明的一种手性三氮唑‑噁唑啉化合物及其制备方法与应用属于有机合成技术领域。所述手性三氮唑‑噁唑啉化合物,结构式为:制备方法包括点击反应、三氮唑N2取代反应、Suzuki偶联、三氮唑酯水解、与手性胺基醇酰胺化后脱水缩合等步骤。通过加入所述手性三氮唑‑噁唑啉化合物和钯盐化合物原位络合生成催化剂后在前手性有机化合物的碳碳双键上进行芳基硼酸的不对称加成制备手性有机化合物。本发明制备新型三氮唑‑噁唑啉化合物具有原料成本低、合成步骤少、实验场地要求低、反应条件相对温和、操作简单等优点。
Description
技术领域:
本发明属于有机合成技术领域,具体涉及一种新型手性三氮唑-噁唑啉化合物的合成方法及其作为配体在钯催化苯硼酸对β-取代不饱和环酮的不对称1,4加成反应的催化性质探究。
背景技术:
手性噁唑啉配体在不对称合成的领域中具有及其优异的性质,尤其与铜、钯、钌等过渡金属结合后的催化反应在近三十年来一直作为有机合成化学的热点研究问题而存在,其高效的催化活性和手性选择性和低成本的制备方法使其获得了广泛的应用。1,2,3-三氮唑是一种拥有多个配位位点与多种配位方式的杂环结构,兼有易于制备与修饰的优点,作为配体也有一系列催化实例被报道。
目前存在的问题是:1,2,3-三氮唑结构较少被应用于不对称催化领域,相关报道和应用也不多见。虽然有部分手性配体具有1,2,3-三氮唑结构,但是1,2,3-三氮唑更多的是作为一种连接结构存在,而非参与配位。手性噁唑啉骨架与1,2,3-三氮唑结构尚未有结合成为手性配体并进行催化应用的例子,而两种杂环的连接在技术上具备可行性,相关合成工作对于配体库的扩充具备一定意义。
发明内容:
本发明的目的在于,克服背景技术存在的问题,提供一种手性三氮唑-噁唑啉配体及其制备方法,并将其应用于芳基硼酸对β-取代环烯酮的不对称加成反应中。本发明的方法以简单易得、价格低廉的非手性试剂和手性纯原料出发,通过一系列简单易操作的反应途径,高效合成系列三氮唑-噁唑啉手性配体。
本发明的技术方案如下:
一种手性三氮唑-噁唑啉化合物,其特征在于,所述化合物是高光学纯的,记为化合物1,结构式如下所示:
其中R1是氢、甲基或苯基;R2是特丁基、苯基;R3是氢或苯基。
如上述所示,
当R1为氢,R2为特丁基,R3为氢时,记为化合物1a;
当R1为甲基,R2为苯基,R3为氢时,记为化合物1b;
当R1为苯基,R2为特丁基,R3为氢时,记为化合物1c;
当R1为苯基,R2为苯基,R3为氢时,记为化合物1d;
当R1为苯基,R2为苯基,R3为苯基时,记为化合物1e;
所述化合物1a~1e的结构式分别如下:
一种手性三氮唑-噁唑啉化合物的制备方法,其特征在于,步骤包括S1、S2、S5、S6、S7或S3、S4、S5、S6、S7;
S1:在惰性气体保护下,在有机溶剂中,在氧化剂作用下,叠氮化钠与化合物2在15~30℃条件下反应12~36小时,得到化合物3;所述化合物2、叠氮化钠、氧化剂的摩尔比为1:1.5:2;所述化合物2与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述化合物2为苯基乙炔基三甲基硅烷或1-苯基-1-丙炔,所述氧化剂为碘苯二乙酸;
作为优选,所述惰性气体为氮气和/或氩气;所述溶剂为无水乙腈;反应温度优选为25℃。
S2:在惰性气体保护下,于有机溶剂中,在碱和催化剂作用下,化合物3与化合物4结合,在50~70℃条件下反应24~36小时,得到化合物5;所述化合物3、化合物4、碱、催化剂的摩尔比是1:1.05:3:0.05,化合物3与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述碱为碳酸钾,催化剂为碘化钾,化合物4为2-溴-2-甲基丙酸乙酯;
作为优选,所述有机溶剂为丙酮。
S3:在惰性气体保护下,于有机溶剂中,在碱和催化剂作用下,化合物6与化合物4结合,在50~70℃条件下反应24~36小时,得到化合物7;所述化合物3、化合物4、碱、催化剂的摩尔比是1:1.05:3:0.05,化合物6与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述碱为碳酸钾,催化剂为碘化钾,化合物6为4,5-二溴三氮唑;
作为优选,所述有机溶剂为丙酮。
S4:在惰性气体保护下,于有机溶剂与水的混合溶剂中,加入化合物7、碱、苯硼酸,在钯催化剂作用下,在80~100℃条件下反应24~36小时得到化合物8;所述化合物7、苯硼酸、碱、钯催化剂的摩尔比是1:3:4:0.1,化合物7与所述混合溶剂的摩尔体积比为0.2mmol:1mL;其中,所述碱为碳酸钾,钯催化剂为四(三苯基膦)钯;
作为优选,所述混合溶剂为体积比3:1的1,4-二氧六环与水的混合溶剂。
S5:在有机溶剂与水的混合溶剂中,在强碱作用下,化合物5或化合物8在20~50℃条件下发生酯水解反应,反应时长为2-12小时,随后通过盐酸中和后得到化合物9;所述化合物5或化合物8与强碱的摩尔比是1:8,化合物5或8与有机溶剂的摩尔体积比为1mmol:1mL;
作为优选,所述强碱为氢氧化钠,所述混合溶剂为体积比2:1的乙醇与水的混合溶剂,所述盐酸为2mol/L的浓盐酸。
S6:在惰性气体保护下,于有机溶剂中,依次加入化合物9、N-甲基吗啉、氯甲酸异丁酯和化合物10,化合物9与化合物10在0~20℃条件下发生酰胺化反应,反应时间为12~18小时,得到化合物11;所述化合物9、N-甲基吗啉、氯甲酸异丁酯、化合物10的摩尔比是1:1.05:2.5:1.2;所述化合物9与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述化合物10为S-叔亮氨醇、L-苯甘氨醇或(S,S)-(-)-2-氨基-1,2-二苯基乙醇;
作为优选,所需的惰性气体为氮气和/或氩气;所述有机溶剂为无水四氢呋喃。
S7:在惰性气体保护下,于有机溶剂中,在对二甲氨基吡啶、对甲苯磺酰氯与有机胺作用下,化合物11在20~80℃条件下进行脱水缩合反应,反应时间为15~30小时,得到化合物1,即手性三氮唑-噁唑啉化合物;所述化合物11、对二甲氨基吡啶、对甲苯磺酰氯、有机胺的摩尔比是1:0.2:3:8;所述化合物11与有机溶剂的摩尔体积比为0.1mmol:1mL。
作为优选,所述惰性气体为氮气和/或氩气;所述有机溶剂为1,2-二氯乙烷;所述有机胺为三乙胺;反应温度为80℃。
本发明上述方法可以制备一系列新型手性三氮唑-噁唑啉配体。
一种手性三氮唑-噁唑啉化合物的应用,通过加入所述手性三氮唑-噁唑啉化合物和钯盐化合物原位络合生成催化剂后在前手性有机化合物的碳碳双键上进行芳基硼酸的不对称加成制备手性有机化合物,ee值可以达到90%。具体步骤为:在氧气气氛下,依次加入芳基硼酸,化合物1,三氟乙酸钯,路易斯酸,加入有机溶剂,室温搅拌5分钟后加入β取代不饱和环酮,随后20~80℃加热封管反应12~60小时,得到手性产物。
作为优选,所述化合物1是化合物1a或1d,所述β-不饱和环酮、芳基硼酸、化合物1a或1d、三氟乙酸钯、路易斯酸摩尔比为1:2:0.1:0.075:0.15或1:2:0.17:0.15:0.15;所述β-不饱和环酮与有机溶剂的摩尔体积比为0.25mmol:1mL。
作为优选,所述有机溶剂为1,2-二氯乙烷;所述路易斯酸为三氟甲磺酸镱。
作为优选,封管反应的反应温度为60或40℃,反应时间为60小时。
本发明的有益效果是:
1、本发明制备的新型三氮唑-噁唑啉化合物具有原料成本低,合成步骤少,实验场地要求低,反应条件相对温和,操作简单的特点。
2、本发明所述的新型三氮唑-噁唑啉化合物具有和过渡金属原位结合生成催化剂后进行不对称催化的能力,所得的手性产物可以具备较高的对映体过量值,具有实际应用价值。
附图说明:
图1为实施例9制备的产物化合物1a的1H NMR谱图(溶剂为氘代氯仿)。
图2为实施例9制备的产物化合物1a的13C NMR谱图(溶剂为氘代氯仿)。
图3为实施例10制备的产物化合物1b的1H NMR谱图(溶剂为氘代氯仿)。
图4为实施例10制备的产物化合物1b的13C NMR谱图(溶剂为氘代氯仿)。
图5为实施例17制备的产物化合物1c的1H NMR谱图(溶剂为氘代氯仿)。
图6为实施例17制备的产物化合物1c的13C NMR谱图(溶剂为氘代氯仿)。
图7为实施例18制备的产物化合物1d的1H NMR谱图(溶剂为氘代氯仿)。
图8为实施例18制备的产物化合物1d的13C NMR谱图(溶剂为氘代氯仿)。
图9为实施例19制备的产物化合物1e的1H NMR谱图(溶剂为氘代氯仿)。
图10为实施例19制备的产物化合物1e的13C NMR谱图(溶剂为氘代氯仿)。
图11为实施例20制备的产物化合物(R)-3-methyl-3-phenylcyclohexan-1-one的1H NMR谱图(溶剂为氘代氯仿)。
图12为实施例20制备的产物化合物(R)-3-methyl-3-phenylcyclohexan-1-one的13C NMR谱图(溶剂为氘代氯仿)。
图13为实施例21制备的产物化合物(R)-3-(4-fluorobenzyl)-3-phenylcyclo-hexan-1-one的1H NMR谱图(溶剂为氘代氯仿)。
图14为实施例21制备的产物化合物(R)-3-(4-fluorobenzyl)-3-phenylcyclo-hexan-1-one的13C NMR谱图(溶剂为氘代氯仿)。
图15为实施例21制备的产物化合物(R)-3-(4-fluorobenzyl)-3-phenylcyclo-hexan-1-one的19F NMR谱图(溶剂为氘代氯仿)。
具体实施方式:
下面结合具体实例,进一步阐明本发明。应该理解,这些实施例仅用于说明本发明,而不用于限定本发明的保护范围。在实际应用中技术人员根据本发明做出的改进和调整,仍属于本发明的保护范围。
除特别说明,本发明使用的设备和试剂为本技术领域常规市购产品。
本发明合成化合物1a与化合物1b的路线如下:
实施例1:化合物3a的制备
在烘箱干燥后冷却的100mL圆底烧瓶中,在惰性气体保护下,向2a(2.5mmol)的无水乙腈溶液中依次加入叠氮化钠(3.75mmol)与碘苯二乙酸(5.0mmol),室温搅拌12小时,反应完成后,加入硅胶混匀,减压条件下除去溶剂后,将残渣进行柱层析操作,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物3a,为黄色晶体。
1H NMR(400MHz,Chloroform-d)δ7.68–7.62(m,2H),7.48–7.38(m,3H),0.32(s,9H).13C NMR(101MHz,CDCl3)δ153.03,132.20,128.80,128.41,128.30,126.15,77.45,77.13,76.81,-0.79.HRMS(EI+)m/z calc’d for C11H16N3Si[M+H]+:218.1108,found218.1124.
实施例2:化合物3b的制备
在烘箱干燥后冷却的100mL圆底烧瓶中,在惰性气体保护下,向2b(2.5mmol)的无水乙腈溶液中依次加入叠氮化钠(3.75mmol)与碘苯二乙酸(5.0mmol),室温搅拌16小时,反应完成后,加入硅胶混匀,减压条件下除去溶剂后,将残渣进行柱层析操作,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物3b,为白色晶体。
1H NMR(400MHz,Chloroform-d)δ7.77–7.68(m,2H),7.50–7.44(m,2H),7.42–7.36(m,1H),2.55(s,3H).13C NMR(101MHz,CDCl3)δ130.75,128.84,128.25,127.29,77.39,77.08,76.76,11.36.HRMS(EI+)m/z calc’d for C9H10N3[M+H]+:160.0870,found160.0880.
实施例3:化合物5a的制备
在100mL圆底烧瓶中,向3a(2.0mmol)的丙酮溶液中加入碳酸钾(6.0mmol),将反应体系加热至60℃,再依次加入化合物7(2.10mmol)与碘化钾(0.10mmol)。反应36小时后,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=5:1,得到化合物5a,为无色液体。
1H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.81(dt,J=6.6,1.3Hz,2H),7.46–7.38(m,2H),7.37–7.30(m,1H),4.17(t,J=7.1Hz,2H),2.00(s,6H),1.19(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.03,147.55,131.01,130.56,128.93,128.86,128.44,126.07,77.46,77.15,76.83,68.00,61.98,30.82,25.36,14.04.HRMS(EI+)m/z calc’dfor C14H18N3O2[M+H]+:260.1394,found 260.1397.
实施例4:化合物5b的制备
在100mL圆底烧瓶中,向3b(2.0mmol)的丙酮溶液中加入碳酸钾(6.0mmol),将反应体系加热至60℃,再依次加入化合物7(2.10mmol)与碘化钾(0.10mmol)。反应36小时后,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=5:1,得到化合物5b,为无色液体。
1H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.81(dt,J=6.6,1.3Hz,2H),7.46–7.38(m,2H),7.37–7.30(m,1H),4.17(t,J=7.1Hz,2H),1.93(s,1H),1.19(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.03,147.55,131.01,130.56,128.93,128.86,128.44,126.07,77.46,77.15,76.83,68.00,61.98,30.82,25.36,14.04.HRMS(EI+)m/z calc’dfor C14H18N3O2[M+H]+:260.1394,found 260.1397.
实施例5,化合物9a的制备
向50mL的烧瓶中,向乙醇:水为2:1的混合溶剂中依次加入5a(1.0mmol)与氢氧化钠(8.0mmol),加热到50℃,反应两小时后,逐滴加入2mol/L浓盐酸,加入量需依据所测pH判定,当pH小于1后,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,得到黄色固体产物9a。
1H NMR(400MHz,DMSO-d6)δ13.33(s,1H),8.32(d,J=2.1Hz,1H),7.88(d,J=7.5Hz,2H),7.48(t,J=7.6Hz,2H),7.43–7.35(m,1H),1.91(s,6H).13C NMR(101MHz,DMSO)δ173.56,147.09,131.81,130.57,129.48,128.95,126.11,67.90,40.57,40.37,40.16,39.95,39.74,39.53,39.32,25.43.HRMS(EI+)m/z calc’d for C12H12N3O2[M-H]-:230.0935,found 230.0944.
实施例6,化合物9b的制备
向50mL的烧瓶中,向乙醇:水为2:1的混合溶剂中依次加入5b(1.0mmol)与氢氧化钠(8.0mmol),加热到50℃,反应两小时后,逐滴加入2mol/L浓盐酸,加入量需依据所测pH判定,当pH小于1后,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,得到淡黄色固体产物9b。
1H NMR(400MHz,DMSO-d6)δ13,51–13.01(s,1H),7.77–7.63(m,2H),7.50(t,J=7.6Hz,2H),7.41(t,J=7.4Hz,1H),2.46(s,3H),1.86(s,6H).13C NMR(101MHz,DMSO)δ173.62,144.36,140.65,131.39,129.32,128.45,127.30,67.45,40.59,40.38,40.17,39.96,39.76,39.55,39.34,25.41,12.11.HRMS(EI+)m/z calc’dfor C13H14N3O2[M-H]-:244.1091,found 244.1118.
实施例7,化合物11a的制备
向烘箱高温除水的25mLShelenk瓶中,加入3a(1.0mmol)的无水四氢呋喃溶液,在0℃下,依次逐滴加入N-甲基吗啉(2.5mmol)和氯甲酸异丁酯(1.05mmol),反应30分钟后,再逐滴加入10a(1.2mmol)的四氢呋喃溶液,之后升至室温反应,12小时后,将反应体系加水稀释后,使用二氯甲烷萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物11a,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.86–7.77(m,2H),7.49–7.42(m,2H),7.42–7.35(m,1H),5.96(d,J=8.7Hz,1H),3.83–3.68(m,2H),3.42(dd,J=10.4,7.1Hz,1H),2.50(s,1H),2.02(d,J=2.3Hz,7H),0.80(s,9H).13C NMR(101MHz,CDCl3)δ173.15,148.55,131.63,129.80,129.05,128.94,126.05,77.43,77.32,77.12,76.80,69.68,63.13,60.16,33.41,26.71,26.01,25.78.HRMS(EI+)m/z calc’d for C18H27N4O2[M+H]+:330.2129,found 330.2126.
实施例8,化合物11b的制备
向烘箱高温干燥的25mL Schlenk瓶中,加入3b(1.0mmol)的无水四氢呋喃溶液,在0℃下,依次逐滴加入N-甲基吗啉(2.5mmol)和氯甲酸异丁酯(1.05mmol),反应30分钟后,再逐滴加入10b(1.2mmol)的四氢呋喃溶液,之后升至室温反应,12小时后,将反应体系加水稀释后,使用二氯甲烷萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物11b,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.71–7.66(m,2H),7.49–7.43(m,2H),7.42–7.34(m,2H),7.32–7.29(m,2H),7.17(dd,J=7.9,1.7Hz,2H),6.77(d,J=7.3Hz,1H),5.00(dt,J=7.3,4.7Hz,1H),3.85(d,J=7.2Hz,1H),3.80(t,J=4.8Hz,2H),2.52(s,3H),2.00(s,3H),1.96(s,3H).13C NMR(101MHz,CDCl3)δ172.47,141.81,138.70,130.84,128.89,128.82,128.32,127.86,127.31,126.44,77.41,77.29,77.09,76.77,68.94,66.46,58.52,55.87,25.86,25.79,18.48,11.87.HRMS(EI+)m/z calc’d for C21H25N4O2[M+H]+:365.1973,found 365.1975.
实施例9,化合物1a的制备
向烘箱高温干燥的25mL Shelenk瓶中,在惰性气体保护下,加入11a(0.5mmol)的无水1,2-二氯乙烷(5mL)溶液,再依次加入对二甲氨基吡啶(0.1mmol),对甲苯磺酰氯(1.5mmol)和三乙胺(4.0mmol),随后加热到80℃,反应15小时后,将反应降至室温,减压条件下除去溶剂,加入二氯甲烷稀释,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=4:1,得到化合物1a,为淡黄色固体。
1H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.83–7.77(m,2H),7.45–7.38(m,2H),7.36–7.30(m,1H),4.22–4.06(m,2H),3.92(dd,J=10.1,7.0Hz,1H),2.04–2.01(m,6H),0.90(s,9H).13C NMR(101MHz,CDCl3)δ167.27,147.47,130.88,130.65,128.82,128.34,126.03,77.41,77.09,76.77,75.56,69.61,63.92,34.06,26.38,26.15,25.73.HRMS(EI+)m/z calc’d for C18H25N4O[M+H]+:313.2023,found 313.2034.[α]20 D-47.88(c 1.00,CHCl3).
实施例10,化合物1b的制备
向烘箱高温干燥的25mL Shelenk瓶中,在惰性气体保护下,加入11b(0.5mmol)的无水1,2-二氯乙烷(5mL)溶液,再依次加入对二甲氨基吡啶(0.1mmol),对甲苯磺酰氯(1.5mmol)和三乙胺(4.0mmol),随后加热到80℃,反应15小时后,将反应降至室温,减压条件下除去溶剂,加入二氯甲烷稀释,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=4:1,得到化合物1b,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.78–7.71(m,2H),7.48–7.41(m,2H),7.38–7.26(m,6H),5.26(dd,J=10.1,7.5Hz,1H),4.64(dd,J=10.2,8.4Hz,1H),4.15(dd,J=8.5,7.5Hz,1H),2.52(s,3H),2.06(d,J=2.0Hz,6H).13C NMR(101MHz,CDCl3)δ169.20,144.91,142.22,140.96,131.56,128.79,128.65,127.88,127.75,127.31,126.86,77.42,77.10,76.79,75.96,69.72,63.51,26.60,26.03,12.07.HRMS(EI+)m/z calc’d for C21H23N4O[M+H]+:347.1867,found 347.1875.[α]20 D-90.92(c 1.22,CHCl3).
本发明合成化合物1c,化合物1d与化合物1e的路线如下:
实施例11,化合物7的制备
在100mL圆底烧瓶中,向6(2.0mmol)的丙酮溶液中加入碳酸钾(6.0mmol),将反应体系加热至60℃,再依次加入化合物4(2.10mmol)与碘化钾(0.10mmol)。反应36小时后,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=5:1,得到化合物7,为浅黄色液体。
1H NMR(400MHz,Chloroform-d)δ4.11(q,J=7.7,7.2Hz,2H),1.85(s,6H),1.14(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ171.01,124.68,77.44,77.12,76.80,69.61,62.33,24.81,13.95.HRMS(EI+)m/z calc’d for C8H12Br2N3O2[M+H]+:341.9271,found341.9271.
实施例12,化合物8的制备
向烘箱高温干燥后的100mL Schlenk瓶中,在惰性气体保护下,依次加入化合物7(1.5mmol),苯硼酸(4.5mmol),碳酸钾(6.0mmol),四三苯基膦钯(0.15mmol),加入1,4-二氧六环与水的混合溶剂(v:v=3:1,7.5mL),封管100℃反应36小时后,将体系降至室温,加水稀释,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=5:1,得到化合物8,为无色液体。
1H NMR(400MHz,Chloroform-d)δ7.61–7.51(m,4H),7.38–7.30(m,6H),4.20(q,J=7.1Hz,2H),2.02(s,6H),1.22(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.02,144.36,131.26,128.49,128.41,128.25,68.01,61.91,25.37,14.05.HRMS(EI+)m/z calc’d for C20H22N3O2[M+H]+:336.1707,found 336.1714.
实施例13,化合物9c的制备
向50mL的烧瓶中,向乙醇:水为2:1的混合溶剂中依次加入5b(1.0mmol)与氢氧化钠(8.0mmol),加热到50℃,反应两小时后,逐滴加入2mol/L浓盐酸,加入量需依据所测pH判定,当pH小于1后,使用乙酸乙酯萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,得到淡黄色固体产物9c。
1H NMR(400MHz,DMSO-d6)δ13.35(s,1H),7.66–7.10(m,10H),1.92(s,6H).13C NMR(101MHz,DMSO)δ173.44,143.87,131.18,129.23,129.01,128.44,68.18,40.63,40.42,40.21,40.00,39.79,39.58,39.37,25.45.HRMS(EI+)m/z calc’dfor C18H16N3O2[M-H]-:306.1248,found 306.1256.
实施例14,化合物11c的制备
向烘箱高温除水的25mLShelenk瓶中,加入9c(1.0mmol)的无水四氢呋喃溶液,在0℃下,依次逐滴加入N-甲基吗啉(2.5mmol)和氯甲酸异丁酯(1.05mmol),反应30分钟后,再逐滴加入10a(1.2mmol)的四氢呋喃溶液,之后升至室温反应,12小时后,将反应体系加水稀释后,使用二氯甲烷萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物11c,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.61–7.48(m,4H),7.42–7.33(m,6H),6.11(d,J=8.6Hz,1H),3.82–3.70(m,2H),3.46(dd,J=10.8,7.3Hz,1H),2.06(s,6H),0.81(s,9H).13C NMR(101MHz,CDCl3)δ173.24,145.37,130.55,128.73,128.33,77.42,77.10,76.78,69.65,63.17,60.19,33.44,26.71,25.98,25.63.HRMS(EI+)m/z calc’d for C24H31N4O2[M+H]+:407.2442,found 407.2431.
实施例15,化合物11d的制备
向烘箱高温除水的25mLShelenk瓶中,加入9c(1.0mmol)的无水四氢呋喃溶液,在0℃下,依次逐滴加入N-甲基吗啉(2.5mmol)和氯甲酸异丁酯(1.05mmol),反应30分钟后,再逐滴加入10b(1.2mmol)的四氢呋喃溶液,之后升至室温反应,12小时后,将反应体系加水稀释后,使用二氯甲烷萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物11d,为白色晶体。
1H NMR(400MHz,Chloroform-d)δ7.58–7.51(m,4H),7.37(p,J=3.5Hz,6H),7.25(dq,J=4.8,2.7,1.8Hz,3H),7.17(dd,J=7.3,2.3Hz,2H),6.92(d,J=7.2Hz,1H),5.01(dt,J=7.2,4.6Hz,1H),3.85–3.73(m,2H),2.07(s,3H),2.02(s,3H).13C NMR(101MHz,CDCl3)δ172.18,145.30,138.71,130.65,128.91,128.69,128.39,127.87,126.45,77.41,77.10,76.78,69.48,66.48,55.90,25.94,25.78.HRMS(EI+)m/z calc’d for C26H27N4O2[M+H]+:427.2129,found 427.2124.
实施例16,化合物11e的制备
向烘箱高温除水的25mLShelenk瓶中,加入9c(1.0mmol)的无水四氢呋喃溶液,在0℃下,依次逐滴加入N-甲基吗啉(2.5mmol)和氯甲酸异丁酯(1.05mmol),反应30分钟后,再逐滴加入10c(1.2mmol)的四氢呋喃溶液,之后升至室温反应,12小时后,将反应体系加水稀释后,使用二氯甲烷萃取,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=1:1,得到化合物11e,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.60–7.50(m,4H),7.44–7.34(m,6H),7.23–7.01(m,7H),6.90(d,J=8.1Hz,1H),6.88–6.81(m,4H),5.26(dd,J=8.3,4.2Hz,1H),4.93(d,J=4.2Hz,1H),2.86(s,1H),2.03(d,J=2.4Hz,3H),1.96(s,3H).13C NMR(101MHz,CDCl3)δ171.92,145.21,139.06,137.17,130.70,128.71,128.41,128.23,127.96,127.89,127.70,127.43,126.54,77.43,77.12,77.04,76.80,69.46,59.34,25.79,25.69.HRMS(EI+)m/zcalc’d for C32H31N4O2[M+H]+:503.2442,found 503.2440.
实施例17,化合物1c的制备
向烘箱高温干燥的25mL Shelenk瓶中,在惰性气体保护下,加入11c(0.5mmol)的无水1,2-二氯乙烷(5mL)溶液,再依次加入对二甲氨基吡啶(0.1mmol),对甲苯磺酰氯(1.5mmol)和三乙胺(4.0mmol),随后加热到80℃,反应15小时后,将反应降至室温,减压条件下除去溶剂,加入二氯甲烷稀释,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=4:1,得到化合物1c,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.60–7.49(m,4H),7.34(dd,J=5.1,2.0Hz,6H),4.24–4.08(m,2H),3.93(dd,J=10.1,7.0Hz,1H),2.04(d,J=2.5Hz,6H),0.93(s,9H).13CNMR(101MHz,CDCl3)δ167.30,144.22,131.41,128.46,128.44,128.18,77.39,77.07,76.76,75.57,69.61,63.97,34.10,26.50,26.12,25.78.HRMS(EI+)m/z calc’d forC24H29N4O[M+H]+:389.2336,found 389.2331.[α]20 D-47.96(c1.00,CHCl3).
实施例18,化合物1d的制备
向烘箱高温干燥的25mL Shelenk瓶中,在惰性气体保护下,加入11d(0.5mmol)的无水1,2-二氯乙烷(5mL)溶液,再依次加入对二甲氨基吡啶(0.1mmol),对甲苯磺酰氯(1.5mmol)和三乙胺(4.0mmol),随后加热到80℃,反应15小时后,将反应降至室温,减压条件下除去溶剂,加入二氯甲烷稀释,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=4:1,得到化合物1d,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.68–7.55(m,4H),7.42–7.27(m,11H),5.28(dd,J=10.1,7.4Hz,1H),4.67(dd,J=10.1,8.5Hz,1H),4.19(dd,J=8.5,7.4Hz,1H),2.12(d,J=6.8Hz,6H).13C NMR(101MHz,CDCl3)δ168.97,144.39,142.25,131.30,128.81,128.70,128.54,128.46,128.31,127.79,126.94,77.41,77.09,76.77,76.05,69.79,64.09,26.81,25.91.HRMS(EI+)m/z calc’d for C26H25N4O[M+H]+:409.2021,found 409.2023.[α]20 D-153.16(c 1.00,CHCl3).
实施例19,化合物1e的制备
向烘箱高温干燥的25mL Shelenk瓶中,在惰性气体保护下,加入11e(0.5mmol)的无水1,2-二氯乙烷(5mL)溶液,再依次加入对二甲氨基吡啶(0.1mmol),对甲苯磺酰氯(1.5mmol)和三乙胺(4.0mmol),随后加热到80℃,反应15小时后,将反应降至室温,减压条件下除去溶剂,加入二氯甲烷稀释,有机相合并后使用饱和食盐水洗涤三次,Na2SO4干燥后,减压条件下除去溶剂,将残余物进行柱层析,洗脱剂为石油醚:乙酸乙酯=4:1,得到化合物1e,为白色固体。
1H NMR(400MHz,Chloroform-d)δ7.69–7.62(m,4H),7.45–7.36(m,11H),7.32(s,5H),5.35(d,J=6.8Hz,1H),5.16(d,J=6.8Hz,1H),2.24(d,J=1.4Hz,6H).13C NMR(101MHz,CDCl3)δ168.29,144.50,142.03,140.64,131.34,128.99,128.89,128.56,128.49,128.43,128.35,127.97,126.83,125.59,89.86,78.88,77.44,77.12,76.80,64.32,26.51,26.32.HRMS(EI+)m/z calc’d for C32H29N4O[M+H]+:485.2336,found485.2340.[α]20 D-117.80(c 1.00,CHCl3).
实施例20化合物1a与三氟乙酸钯原位络合催化芳基硼酸对β取代不饱和环酮的反应制备化合物(R)-3-methyl-3-phenylcyclohexan-1-one
向烘箱高温干燥的10mL Schlenk瓶中,在氧气气氛下,依次加入芳基硼酸(0.50mmol),化合物1a(0.025mmol),三氟乙酸钯(0.0188mmol),三氟甲磺酸镱(0.0375mmol),加入1,2-二氯乙烷(1mL),室温搅拌5分钟后加入β取代不饱和环酮(0.25mmol),随后升温至60℃,封管反应60小时后,降至室温,真空条件下除去溶剂后,将残余物进行柱层析操作,洗脱剂为石油醚:乙酸乙酯=5:1,得到产物(R)-3-methyl-3-phenylcyclohexan-1-one。淡黄色液体,产率95%,[α]20 D-31.84(c0.750,CHCl3,-46%ee).HPLC(Daicel Chiralpak OJ-H,n-hexane/2-propanol=99:1,flow rate=1mL/min,λ=214nm,tmajor=12.032,tminor=14.137).1H NMR(400MHz,Chloroform-d)δ7.36(d,J=4.3Hz,4H),7.27–7.18(m,1H),2.92(d,J=14.2Hz,1H),2.47(d,J=14.2Hz,1H),2.35(t,J=6.8Hz,2H),2.22(dddd,J=13.5,8.0,3.6,1.5Hz,1H),1.93(dddd,J=17.7,10.9,7.8,3.3Hz,2H),1.76–1.60(m,1H),1.36(s,3H).13C NMR(101MHz,CDCl3)δ211.70,147.47,128.59,126.26,125.65,77.41,77.30,77.09,76.77,53.14,42.90,40.88,37.99,29.88,22.08.HRMS(EI+)m/z calc’d for C13H17O[M+H]+:189.1274,found 189.1293.
实施例21化合物1d与三氟乙酸钯原位络合催化芳基硼酸对β取代不饱和环酮的反应制备化合物(R)-3-(4-fluorobenzyl)-3-phenylcyclohexan-1-one
向烘箱高温干燥的10mL Schlenk瓶中,在氧气气氛下,依次加入芳基硼酸(0.50mmol),化合物1d(0.0425mmol),三氟乙酸钯(0.0375mmol),三氟甲磺酸镱(0.0375mmol),加入1,2-二氯乙烷(1mL),室温搅拌5分钟后加入β取代不饱和环酮(0.25mmol),随后升温至60℃,封管反应60小时后,降至室温,真空条件下除去溶剂后,将残余物进行柱层析操作,洗脱剂为石油醚:乙酸乙酯=5:1,得到产物(R)-3-(4-fluorobenzyl)-3-phenylcyclohexan-1-one。淡黄色液体,产率60%,[α]20 D-18.86(c0.79,CHCl3,90%ee).HPLC(Daicel Chiralpak AD-H,n-hexane/2-propanol=95:5,flowrate=1.00mL/min,λ=214nm,tmajor=6.533,tminor=7.810).1H NMR(400MHz,Chloroform-d)δ7.29(dd,J=8.2,6.7Hz,2H),7.23–7.19(m,1H),7.18–7.12(m,2H),6.83–6.76(m,2H),6.65–6.57(m,2H),2.95–2.82(m,2H),2.82–2.75(m,1H),2.46(d,J=14.3Hz,1H),2.35(ddd,J=13.8,5.3,2.7Hz,1H),2.26(dd,J=8.3,5.5Hz,2H),1.99(ddd,J=13.9,11.1,3.5Hz,1H),1.90(ddd,J=13.9,5.5,3.6Hz,1H),1.56(t,J=4.3Hz,1H).13C NMR(101MHz,CDCl3)δ211.20,161.68(d,J=244.6Hz),143.80,132.36(d,J=3.03Hz),131.77(d,J=7.7Hz),126.53,114.52(d,J=21.0Hz),77.40,77.08,76.76,50.18,49.57,47.36,40.88,35.91,21.50.19F NMR(376MHz,CDCl3)δ-116.73.HRMS(EI+)m/z calc’dfor C19H20FO[M+H]+:283.1493,found 203.1506.
以上列举详细说明是针对本发明之一可行实施例的具体说明,该实施例并非用以限制。本发明的专利范围,凡未脱离本发明所为的等效实施或变更,均应包含于本案的专利范围中。
Claims (10)
1.一种手性三氮唑-噁唑啉化合物,其特征在于,所述化合物是高光学纯的,记为化合物1,结构式如下所示:
其中R1是氢、甲基或苯基;R2是特丁基、苯基;R3是氢或苯基。
2.根据权利要求1所述的一种手性三氮唑-噁唑啉化合物,其特征在于,
当R1为氢,R2为特丁基,R3为氢时,记为化合物1a;
当R1为甲基,R2为苯基,R3为氢时,记为化合物1b;
当R1为苯基,R2为特丁基,R3为氢时,记为化合物1c;
当R1为苯基,R2为苯基,R3为氢时,记为化合物1d;
当R1为苯基,R2为苯基,R3为苯基时,记为化合物1e;
所述化合物1a~1e的结构式分别如下:
3.一种权利要求1所述的手性三氮唑-噁唑啉化合物的制备方法,其特征在于,步骤包括以下S1、S2、S5、S6、S7或S3、S4、S5、S6、S7;
S1:在惰性气体保护下,在有机溶剂中,在氧化剂作用下,叠氮化钠与化合物2在15~30℃条件下反应12~36小时,得到化合物3;所述化合物2、叠氮化钠、氧化剂的摩尔比为1:1.5:2;所述化合物2与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述化合物2为苯基乙炔基三甲基硅烷或1-苯基-1-丙炔,所述氧化剂为碘苯二乙酸;
S2:在惰性气体保护下,于有机溶剂中,在碱和催化剂作用下,化合物3与化合物4结合,在50~70℃条件下反应24~36小时,得到化合物5;所述化合物3、化合物4、碱、催化剂的摩尔比是1:1.05:3:0.05,化合物3与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述碱为碳酸钾,催化剂为碘化钾,化合物4为2-溴-2-甲基丙酸乙酯;
S3:在惰性气体保护下,于有机溶剂中,在碱和催化剂作用下,化合物6与化合物4结合,在50~70℃条件下反应24~36小时,得到化合物7;所述化合物3、化合物4、碱、催化剂的摩尔比是1:1.05:3:0.05,化合物6与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述碱为碳酸钾,催化剂为碘化钾,化合物6为4,5-二溴三氮唑;
S4:在惰性气体保护下,于有机溶剂与水的混合溶剂中,加入化合物7、碱、苯硼酸,在钯催化剂作用下,在80~100℃条件下反应24~36小时得到化合物8;所述化合物7、苯硼酸、碱、钯催化剂的摩尔比是1:3:4:0.1,化合物7与所述混合溶剂的摩尔体积比为0.2mmol:1mL;其中,所述碱为碳酸钾,钯催化剂为四(三苯基膦)钯;
S5:在有机溶剂与水的混合溶剂中,在强碱作用下,化合物5或化合物8在20~50℃条件下发生酯水解反应,反应时长为2-12小时,随后通过盐酸中和后得到化合物9;所述化合物5或化合物8与强碱的摩尔比是1:8,化合物5或8与有机溶剂的摩尔体积比为1mmol:1mL;
S6:在惰性气体保护下,于有机溶剂中,依次加入化合物9、N-甲基吗啉、氯甲酸异丁酯和化合物10,化合物9与化合物10在0~20℃条件下发生酰胺化反应,反应时间为12~18小时,得到化合物11;所述化合物9、N-甲基吗啉、氯甲酸异丁酯、化合物10的摩尔比是1:1.05:2.5:1.2;所述化合物9与有机溶剂的摩尔体积比为0.2mmol:1mL;其中,所述化合物10为S-叔亮氨醇、L-苯甘氨醇或(S,S)-(-)-2-氨基-1,2-二苯基乙醇;
S7:在惰性气体保护下,于有机溶剂中,在对二甲氨基吡啶、对甲苯磺酰氯与有机胺作用下,化合物11在20~80℃条件下进行脱水缩合反应,反应时间为15~30小时,得到化合物1,即手性三氮唑-噁唑啉化合物;所述化合物11、对二甲氨基吡啶、对甲苯磺酰氯、有机胺的摩尔比是1:0.2:3:8;所述化合物11与有机溶剂的摩尔体积比为0.1mmol:1mL。
4.根据权利要求3所述的一种手性三氮唑-噁唑啉化合物的制备方法,其特征在于,步骤S1、S6、S7中所述惰性气体为氮气和/或氩气,步骤S1所述的有机溶剂为无水乙腈,步骤S2、S3所述的有机溶剂为丙酮,步骤S4所述混合溶剂为体积比3:1的1,4-二氧六环与水的混合溶剂,步骤S6所述有机溶剂为无水四氢呋喃,步骤S7所述有机溶剂为1,2-二氯乙烷,所述有机胺为三乙胺。
5.根据权利要求3所述的一种手性三氮唑-噁唑啉化合物的制备方法,其特征在于,步骤S1的反应温度为25℃,步骤S7的反应温度为80℃。
6.根据权利要求3所述的一种手性三氮唑-噁唑啉化合物的制备方法,其特征在于,步骤S5所述强碱为氢氧化钠,所述混合溶剂为体积比2:1的乙醇与水的混合溶剂,所述盐酸为2mol/L的浓盐酸。
7.一种权利要求1所述的手性三氮唑-噁唑啉化合物的应用,通过加入所述手性三氮唑-噁唑啉化合物和钯盐化合物原位络合生成催化剂后在前手性有机化合物的碳碳双键上进行芳基硼酸的不对称加成制备手性有机化合物,具体步骤为:在氧气气氛下,依次加入芳基硼酸,化合物1,三氟乙酸钯,路易斯酸,加入有机溶剂,室温搅拌5分钟后加入β取代不饱和环酮,随后20~80℃加热封管反应12~60小时,得到手性产物。
8.根据权利要求7所述的一种手性三氮唑-噁唑啉化合物的应用,其特征在于,所述化合物1是化合物1a或1d,所述β-不饱和环酮、芳基硼酸、化合物1a或1d、三氟乙酸钯、路易斯酸摩尔比为1:2:0.1:0.075:0.15或1:2:0.17:0.15:0.15;所述β-不饱和环酮与有机溶剂的摩尔体积比为0.25mmol:1mL。
9.根据权利要求7所述的一种手性三氮唑-噁唑啉化合物的应用,其特征在于,所述有机溶剂为1,2-二氯乙烷;所述路易斯酸为三氟甲磺酸镱。
10.根据权利要求7所述的一种手性三氮唑-噁唑啉化合物的应用,其特征在于,封管反应的反应温度为60或40℃,反应时间为60小时。
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