CN109678810A - A kind of 1,2- oxaza butane compounds and the preparation method and application thereof - Google Patents
A kind of 1,2- oxaza butane compounds and the preparation method and application thereof Download PDFInfo
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- CN109678810A CN109678810A CN201910061361.XA CN201910061361A CN109678810A CN 109678810 A CN109678810 A CN 109678810A CN 201910061361 A CN201910061361 A CN 201910061361A CN 109678810 A CN109678810 A CN 109678810A
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- Prior art keywords
- pyrimidine radicals
- compound
- compounds
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- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005902 aminomethylation reaction Methods 0.000 claims abstract description 11
- 239000012312 sodium hydride Substances 0.000 claims abstract description 11
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 8
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims abstract description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000004820 halides Chemical class 0.000 claims abstract description 7
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- 239000000654 additive Substances 0.000 claims description 10
- 230000000996 additive effect Effects 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 10
- 239000012141 concentrate Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 150000004700 cobalt complex Chemical group 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000002480 mineral oil Substances 0.000 claims description 4
- 235000010446 mineral oil Nutrition 0.000 claims description 4
- 239000005416 organic matter Substances 0.000 claims description 4
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003865 brosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)S(*)(=O)=O 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- QSNFOTSEFALLLC-UHFFFAOYSA-L C(=O)=[Co](I)I Chemical compound C(=O)=[Co](I)I QSNFOTSEFALLLC-UHFFFAOYSA-L 0.000 claims description 2
- 229910021580 Cobalt(II) chloride Inorganic materials 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 claims description 2
- UMYVESYOFCWRIW-UHFFFAOYSA-N cobalt;methanone Chemical compound O=C=[Co] UMYVESYOFCWRIW-UHFFFAOYSA-N 0.000 claims description 2
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 claims description 2
- 229910001386 lithium phosphate Inorganic materials 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- NQPIEWBAWBFGOB-UHFFFAOYSA-N methyl 1h-indole-2-carboxylate Chemical class C1=CC=C2NC(C(=O)OC)=CC2=C1 NQPIEWBAWBFGOB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 claims description 2
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 125000000950 dibromo group Chemical group Br* 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 abstract 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000010941 cobalt Substances 0.000 description 4
- 229910017052 cobalt Inorganic materials 0.000 description 4
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 4
- 150000002475 indoles Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 150000001491 aromatic compounds Chemical class 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- SZKXDURZBIICCF-UHFFFAOYSA-N cobalt;pentane-2,4-dione Chemical compound [Co].CC(=O)CC(C)=O SZKXDURZBIICCF-UHFFFAOYSA-N 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- MXRPXKYWAYTGJY-UHFFFAOYSA-N 4-bromo-2-methyl-1h-indole Chemical compound C1=CC=C2NC(C)=CC2=C1Br MXRPXKYWAYTGJY-UHFFFAOYSA-N 0.000 description 1
- XXYNZSATHOXXBJ-UHFFFAOYSA-N 4-hydroxyisoindole-1,3-dione Chemical compound OC1=CC=CC2=C1C(=O)NC2=O XXYNZSATHOXXBJ-UHFFFAOYSA-N 0.000 description 1
- 229910021584 Cobalt(II) iodide Inorganic materials 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940011182 cobalt acetate Drugs 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- AVWLPUQJODERGA-UHFFFAOYSA-L cobalt(2+);diiodide Chemical compound [Co+2].[I-].[I-] AVWLPUQJODERGA-UHFFFAOYSA-L 0.000 description 1
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- KNFXXAGQEUUZAZ-UHFFFAOYSA-N ethyl ethaneperoxoate Chemical compound CCOOC(C)=O KNFXXAGQEUUZAZ-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000002921 oxetanes Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of 1,2- oxaza butane compounds and the preparation method and application thereof.The present invention with glycol dibromide, triethylamine by reacting to obtain compound III n-Hydroxyphthalimide；Compound III is reacted to obtain yellow compound IV with hydrobromic acid；By compounds Ⅳ, pyridine, halides R1X reacts to obtain compound V；Compound V is reacted to obtain 1,2- oxaza butane compounds with sodium hydride.This 1,2- oxaza butane compounds can be used for the aminomethylation or methylolation of 1- pyrimidine radicals benzazolyl compounds, and the reaction process has many advantages, such as that regioselectivity is good, yield is high, process conditions are simple, reaction condition is mild, green, Atom economy is high, wide application range of substrates.
Description
Technical field
The invention belongs to methodology of organic synthesis technical fields, more particularly to one kind 1,2- oxaza butane compounds
And the preparation method and application thereof.
Background technique
Aminomethyl and methylol segment aromatic compound are widely present in biologically active natural products, drug molecule
In functional material, organic synthesis field needs to find the side that aminomethyl and methylol are efficiently precisely introduced in aroma system
Method.
The method for introducing aminomethyl and methylol in aromatic compound at present includes: (1) Mannich reaction；(2) high living
Property aryl organometallics reagent nucleophilic addition is occurred to imines or aldehyde；(3) transition metal-catalyzed aryl halides and work
Cross-coupling reaction occurs for the amine or aldehyde of change.However, these three types of reactions all have certain limitation.For example, Mannich reacts
Substrate spectrum be only limitted to the aromatic compound containing donor residues, and chemo-selective is poor；Prepare aryl organometallics reagent
Stringent anhydrous and oxygen-free is needed to operate, and functional group's tolerance of substrate is poor；Transition metal-catalyzed cross-coupling reaction needs
Aryl halides are prepared, and end of reaction can generate the waste of halides, Atom economy is poor.
Therefore, this field still lacks a kind of efficient, Atom economy, mild condition, wide application range of substrates to fragrance
Compound selectively aminomethylation and methylolation reagent.
Summary of the invention
The purpose of the present invention is to provide a kind of 1,2- oxaza butane compounds.
A further object of the present invention is to provide the preparation methods of above-mentioned 1,2- oxaza butane compounds.
A further object of the present invention is to provide above-mentioned 1,2- oxaza butane compounds in 1- pyrimidine radicals indoles
Close the application in terms of the aminomethylation of object.
A further object of the present invention is to provide above-mentioned 1,2- oxaza butane compounds in 1- pyrimidine radicals indoles
Close the application in terms of the methylolation of object.
The invention is realized in this way one kind 1,2- oxaza butane compounds, the chemical structural formula of the compound
As shown in following formula (I):
In formula (I), R1For p-toluenesulfonyl, benzenesulfonyl, to fluorophenylsulphonyl, to chlorobenzenesulfonyl, to bromobenzene sulphur
Acyl group, to tnBuoromethyl-benzenesulfonyl, to MethOxybenzenesulfonyl, to tert-butyl benzene sulfonyl, bromobenzenesulfonyl, 2,4,6-
Trimethylphenysulfonyl, 2- naphthalene sulfonyl base, tertbutyloxycarbonyl or benzyloxycarbonyl group.
Preferably, method includes the following steps:
(1) 1,2- Bromofume, triethylamine is added into the n,N-Dimethylformamide solution containing compound ii, at room temperature
Stirring becomes colourless to reaction solution, and the solid being precipitated in reaction solution is collected, is recrystallized to give compound III；Wherein, describedization
Conjunction object II is n-Hydroxyphthalimide, the n-Hydroxyphthalimide, n,N-Dimethylformamide solution, two
Bromoethane, triethylamine molal volume ratio be 60mmol:80mL:120mmol:120mmol；
(2) hydrobromic acid that mass concentration is 48% is added into the glacial acetic acid solution of compound III, is stirred at 130 DEG C anti-
It answers 5 minutes, filtrate is concentrated to get yellow compound IV by cooling, filtering；Wherein, the compound III, glacial acetic acid solution, hydrogen
The molal volume ratio of bromic acid is 120mmol:10mL:15mL；
(3) pyridine is added into compounds Ⅳ, reaction is stirred at room temperature after five minutes, halides are added into reaction solution
R1X after being stirred at room temperature 5 hours, 1.0M hydrochloric acid solution is added dropwise into reaction solution to neutrality, extraction, column chromatographic purifying obtain
Compound V；Wherein, the compounds Ⅳ, pyridine, halides molal volume ratio be 8.7mmol:15mL:20.9mmol；Institute
State halides R1In X, R1For p-toluenesulfonyl, benzenesulfonyl, to fluorophenylsulphonyl, to chlorobenzenesulfonyl, brosyl
Base, to tnBuoromethyl-benzenesulfonyl, to MethOxybenzenesulfonyl, to tert-butyl benzene sulfonyl, bromobenzenesulfonyl, 2,4,6- tri-
Methyl benzenesulfonyl base, 2- naphthalene sulfonyl base, tertbutyloxycarbonyl or benzyloxycarbonyl group, X are halogen element；
(4) mine that point 2~3 batches of addition sodium hydride mass concentrations are 60% into the anhydrous tetrahydrofuran solution of compound V
After being stirred at room temperature 1.5 hours, 1.0M hydrochloric acid solution is added dropwise to neutrality, extraction, column chromatographic purifying toward reaction mixture in object oil
Obtain compound I；Wherein, the compound V, anhydrous tetrahydrofuran solution, sodium hydride molal volume ratio be 0.83mmol:
20mL:1.87mmol.
Preferably, described that the solid being precipitated in reaction solution is collected, is recrystallized specifically: by reaction solution in step (1)
The solid of precipitation is filtered out, and filters out the solid of precipitation after filtrate is diluted with ice water, is merged after solid is precipitated with ethyl alcohol weight
Crystalline deposit object；
In step (3), the extraction is that organic matter is extracted by ethyl acetate, ethyl acetate/stone in the column chromatography
The mass ratio of oily ether is 1:3；
In step (4), the extraction is that organic matter is extracted by ethyl acetate, ethyl acetate/stone in the column chromatography
The mass ratio of oily ether is 1:2.
The present invention further discloses above-mentioned 1,2- oxaza butane compounds in 1- pyrimidine radicals benzazolyl compounds
Application in terms of aminomethylation or methylolation.
Preferably, the chemical structural formula of the 1- pyrimidine radicals benzazolyl compounds is shown below:
In above formula, R2For methyl, methoxyl group, ester group, halogen, nitro or amino.
Preferably, the aminomethylation process is the following steps are included: by 1- pyrimidine radicals benzazolyl compounds and 1,2- oxygen azepine
Cyclobutane compound is added in organic solvent, adds catalyst and additive, it is stirred to react 0.5 at 40~80 DEG C~
3 hours, reaction solution is concentrated, concentrate is chromatographed to obtain 1- pyrimidine radicals -2- aminomethyl chemical combination through column after removing organic solvent
Object；Wherein, the catalyst is cobalt complex；The additive is alkali；
The 1- pyrimidine radicals benzazolyl compounds and 1,2- oxaza butane compounds, organic solvent, catalyst, addition
The molal volume ratio of agent is 1.0mmol:2.0mmol:10mL:0.05mmol:0.1mmol.
Preferably, the 1- pyrimidine radicals benzazolyl compounds are 1- (2- pyrimidine radicals) indoles, 1- (2- pyrimidine radicals) 2- methyl Yin
Diindyl, 1- (2- pyrimidine radicals) -4- methyl indol, 1- (2- pyrimidine radicals) -4- bromo indole, 1- (2- pyrimidine radicals) -4- methoxy-Indole, 1-
(2- pyrimidine radicals) -4- benzyloxy indole, 1- (2- pyrimidine radicals) -4- amino indole, 1- (2- pyrimidine radicals) -4- nitroindoline, 4- (1-
(2- pyrimidine radicals)) indolecarboxylic acid methyl esters, 1- (2- pyrimidine radicals) -5- fluoro indole, 1- (2- pyrimidine radicals) -5- chloro-indole, 1- (2- pyrimidine
Base) -5- iodine indoles, 1- (2- pyrimidine radicals) -6- fluoro indole, at least one of 1- (2- pyrimidine radicals) -6- methoxy-Indole.
Preferably, the methylolation process specifically: by 1- pyrimidine radicals benzazolyl compounds and 1,2- oxaza butane
Class compound is added in organic solvent, adds catalyst and additive, is stirred to react at 40~80 DEG C 0.5~3 hour,
Reaction solution is concentrated, concentrate is chromatographed to obtain 1- pyrimidine radicals -2- aminomethyl compound through column after removing organic solvent；Its
In, the catalyst is cobalt complex；The additive is alkali；
The 1- pyrimidine radicals benzazolyl compounds and 1,2- oxaza butane compounds, organic solvent, catalyst, addition
The molal volume ratio of agent is 1.0mmol:1.1mmol:10mL:0.05mmol:0.1mmol.
Preferably, the organic solvent be acetonitrile, 1,2- dichloroethanes, methylene chloride, chloroform, chlorobenzene, dimethyl sulfoxide,
At least one of toluene, benzotrifluoride, mesitylene, ethyl alcohol, acetic acid, 1,4- dioxane, tetrahydrofuran；
The cobalt complex is Co (OAc)2、Co(acac)3、CoCl2、[Cp*Co(CO)I2]、[Cp*Co(C6H6)](PF6)2
At least one of；
The alkali is potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, lithium phosphate, phosphorus
At least one of sour hydrogen dipotassium, potassium dihydrogen phosphate, sodium benzoate, sodium hydroxide, lithium hydroxide.
Preferably, the organic solvent is toluene or ethyl alcohol；The cobalt complex is pentamethylcyclopentadiene base carbonyl two
Cobaltous iodide；The alkali is potassium acetate.
The present invention overcomes the deficiencies of the prior art and provide one kind 1,2- oxaza butane compounds and preparation method thereof
With application.Shown in the structural formula such as following formula (I) of 1,2- oxaza butane compounds of the present invention:
In formula (I), R1For p-toluenesulfonyl, benzenesulfonyl, to fluorophenylsulphonyl, to chlorobenzenesulfonyl, to bromobenzene sulphur
Acyl group, to tnBuoromethyl-benzenesulfonyl, to MethOxybenzenesulfonyl, to tert-butyl benzene sulfonyl, bromobenzenesulfonyl, 2,4,6-
Trimethylphenysulfonyl, 2- naphthalene sulfonyl base, tertbutyloxycarbonyl or benzyloxycarbonyl group.
Shown in the following reaction equation of preparation process of the 1,2- oxaza butane compounds:
The present invention further discloses above-mentioned 1,2- oxaza butane compounds in 1- pyrimidine radicals benzazolyl compounds
Application in terms of aminomethylation or methylolation, wherein the structural formula of 1- pyrimidine radicals benzazolyl compounds is shown below:
In above formula, R2For methyl, methoxyl group, ester group, halogen, nitro or amino.
Shown in the following reaction equation of aminomethylation process of the 1- pyrimidine radicals benzazolyl compounds:
Shown in the following reaction equation of methylolation process of the 1- pyrimidine radicals benzazolyl compounds:
Compared with the prior art the shortcomings that and deficiency, the invention has the following advantages: the present invention provides one kind efficiently
Ground is to aromatic selectivity aminomethylation and methylolation reagent, for the bioactivity containing aminomethylation and methylol point
The synthesis of son provides potential value, which has regioselectivity good, and yield is high, and process conditions are simple, reaction condition
Mildly, the advantages that green, Atom economy is high, wide application range of substrates.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of N- p-toluenesulfonyl -1,2- oxetanes in the embodiment of the present invention 1；
Fig. 2 is the carbon-13 nmr spectra figure of N- p-toluenesulfonyl -1,2- oxetanes in the embodiment of the present invention 1；
Fig. 3 is the hydrogen nuclear magnetic resonance of 1- in the embodiment of the present invention 4 (- 2- pyrimidine radicals) -2- para toluene sulfonamide methyl indol
Spectrogram；
Fig. 4 is the nuclear magnetic resonance carbon of 1- in the embodiment of the present invention 4 (- 2- pyrimidine radicals) -2- para toluene sulfonamide methyl indol
Spectrogram；
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of 1- in the embodiment of the present invention 7 (2- pyrimidine radicals) -2- skatoxyl；
Fig. 6 is the carbon-13 nmr spectra figure of 1- in the embodiment of the present invention 7 (2- pyrimidine radicals) -2- skatoxyl.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.
The dosage relation of each substance involved in each step converts to obtain in following embodiment with reaction equation, real
There can be variation slightly in the operating process of border, should not be only used for limiting unique dosage of each substance.
The preparation of 1 1,2- oxaza butane compounds of embodiment
(1) it is added into the N,N-dimethylformamide solution of 80mL hydroxyphthalimide containing 60mmolN-
120mmol 1,2- Bromofume, 120mmol triethylamine, stir at room temperature to reaction solution and become colourless, will be precipitated in reaction solution
Solid collect, and the solid of precipitation is filtered out after filtrate is diluted with ice water, it is heavy with ethyl alcohol recrystallization after solid is precipitated to merge
Starch, as compound III；
(2) hydrobromic acid that 15mL mass concentration is 48% is added into the 10mL glacial acetic acid solution of 120mmol compound III,
It is stirred to react at 130 DEG C 5 minutes, filtrate is concentrated to get yellow compound IV by cooling, filtering；
(3) 5mL pyridine is added into 8.7mmol compounds Ⅳ, reaction is stirred at room temperature after five minutes, into reaction solution
20.9mmol 4- toluene sulfonyl chloride is added, after being stirred at room temperature 5 hours, 1.0M hydrochloric acid solution is added dropwise extremely into reaction solution
Neutrality is extracted by ethyl acetate, obtains compound by column chromatography (mass ratio of ethyl acetate/petroleum ether is 1:3) purifying
Ⅴ；
(4) into the 20mL anhydrous tetrahydrofuran solution of 0.83mmol compound V, point 2~3 batches of addition sodium hydride quality are dense
The dosage of the mineral oil that degree is 60%, sodium hydride is 1.87mmol, after being stirred at room temperature 1.5 hours, is dripped toward reaction mixture
Add 1.0M hydrochloric acid solution to be extracted by ethyl acetate to neutrality, by column chromatography (mass ratio of ethyl acetate/petroleum ether is 1:
2) purifying obtains compound N-p-toluenesulfonyl -1,2- oxetanes I.
Compound I is analyzed, as shown in Fig. 1~2, compound I is N- to first it can be seen from Fig. 1, Fig. 2
Benzenesulfonyl -1,2- oxetanes.
Embodiment 2
(1) it is added into the N,N-dimethylformamide solution of 80mL n-Hydroxyphthalimide containing 60mmol
120mmol 1,2- Bromofume, 120mmol triethylamine, stir at room temperature to reaction solution and become colourless, will be precipitated in reaction solution
Solid collect, and the solid of precipitation is filtered out after filtrate is diluted with ice water, it is heavy with ethyl alcohol recrystallization after solid is precipitated to merge
Starch, as compound III；
(2) hydrobromic acid that 15mL mass concentration is 48% is added into the 10mL glacial acetic acid solution of 120mmol compound III,
It is stirred to react at 130 DEG C 5 minutes, filtrate is concentrated to get yellow compound IV by cooling, filtering；
(3) 5mL pyridine is added into 8.7mmol compounds Ⅳ, reaction is stirred at room temperature after five minutes, into reaction solution
20.9mmol benzene sulfonyl chloride is added, after being stirred at room temperature 5 hours, 1.0M hydrochloric acid solution is added dropwise into reaction solution to neutrality, leads to
The extraction of peracetic acid ethyl ester obtains compound V by column chromatography (mass ratio of ethyl acetate/petroleum ether is 1:3) purifying；
(4) into the 20mL anhydrous tetrahydrofuran solution of 0.83mmol compound V, point 2~3 batches of addition sodium hydride quality are dense
The dosage of the mineral oil that degree is 60%, sodium hydride is 1.87mmol, after being stirred at room temperature 1.5 hours, is dripped toward reaction mixture
Add 1.0M hydrochloric acid solution to be extracted by ethyl acetate to neutrality, by column chromatography (mass ratio of ethyl acetate/petroleum ether is 1:
2) purifying obtains benzenesulfonyl -1,2- oxetanes I.
Embodiment 3
(1) it is added into the N,N-dimethylformamide solution of 80mL n-Hydroxyphthalimide containing 60mmol
120mmol 1,2- Bromofume, 120mmol triethylamine, stir at room temperature to reaction solution and become colourless, will be precipitated in reaction solution
Solid collect, and the solid of precipitation is filtered out after filtrate is diluted with ice water, it is heavy with ethyl alcohol recrystallization after solid is precipitated to merge
Starch, as compound III；
(2) hydrobromic acid that 15mL mass concentration is 48% is added into the 10mL glacial acetic acid solution of 120mmol compound III,
It is stirred to react at 130 DEG C 5 minutes, filtrate is concentrated to get yellow compound IV by cooling, filtering；
(3) 5mL pyridine is added into 8.7mmol compounds Ⅳ, reaction is stirred at room temperature after five minutes, into reaction solution
20.9mmol is added to fluorophenylsulphonyl, after being stirred at room temperature 5 hours, 1.0M hydrochloric acid solution is added dropwise into reaction solution into
Property, it is extracted by ethyl acetate, compound V is obtained by column chromatography (mass ratio of ethyl acetate/petroleum ether is 1:3) purifying；
(4) into the 20mL anhydrous tetrahydrofuran solution of 0.83mmol compound V, point 2~3 batches of addition sodium hydride quality are dense
The dosage of the mineral oil that degree is 60%, sodium hydride is 1.87mmol, after being stirred at room temperature 1.5 hours, is dripped toward reaction mixture
Add 1.0M hydrochloric acid solution to be extracted by ethyl acetate to neutrality, by column chromatography (mass ratio of ethyl acetate/petroleum ether is 1:
2) purifying is obtained to fluorophenylsulphonyl -1,2- oxetanes I.
Embodiment 4
N- p-toluenesulfonyl-the 1,2- that will be prepared in 1.0mmol 1- (2- pyrimidine radicals) indoles and 2.0mmol embodiment 1
Oxetanes I is added in 10mL acetonitrile, add two hexafluorophosphoric acid cobalt of 0.05mmol pentamethylcyclopentadiene base and
0.1mmol potassium acetate is stirred to react 0.5~3 hour at 40~80 DEG C, reaction solution is concentrated, and concentrate is organic in removal
It chromatographs to obtain 1- (- 2- pyrimidine radicals) -2- para toluene sulfonamide methyl indol through column after solvent.
The compound is analyzed, as shown in figs. 34, compound I is that (- 2- is phonetic by 1- it can be seen from Fig. 3, Fig. 4
Piperidinyl) -2- para toluene sulfonamide methyl indol.
Embodiment 5
The N- tolysulfonyl that will be prepared in 1.0mmol 1- (2- pyrimidine radicals) -4- bromo indole and 2.0mmol embodiment 2
Base -1,2- oxetanes I is added in 10mL dimethyl sulfoxide, add 0.05mmol cobalt acetate (divalent cobalt) and
0.1mmol cesium carbonate is stirred to react 0.5~3 hour at 40~80 DEG C, reaction solution is concentrated, and concentrate is organic in removal
It chromatographs to obtain 1- pyrimidine radicals -2- para toluene sulfonamide methyl -4- bromo indole through column after solvent.
Embodiment 6
It will be prepared in 1.0mmol 1- (2- pyrimidine radicals) indoles and 2.0mmol embodiment 3 to fluorophenylsulphonyl -1,2- oxygen
Azetidine I is added to 10mL1, in 4- dioxane, adds 0.05mmol acetylacetone cobalt (trivalent cobalt) and 0.1mmol carbon
Sour caesium is stirred to react 0.5~3 hour at 40~80 DEG C, reaction solution is concentrated, by concentrate through column after removing organic solvent
Chromatography obtains 1- pyrimidine radicals -2- to fluorobenzenesulfonamide methyl indol.
Embodiment 7
Compound I prepared by 1.0mmol 1- (2- pyrimidine radicals) indoles and 1.1mmol embodiment 1 is added to 10mL acetonitrile
In, 0.05mmol pentamethylcyclopentadiene base carbonyl cobalt diiodide and 0.1mmol potassium acetate are added, is stirred at 40~80 DEG C
Reaction 0.5~3 hour, reaction solution is concentrated, concentrate is chromatographed to obtain 1- (2- pyrimidine radicals -) through column after removing organic solvent
2- skatoxyl.
The compound is analyzed, as shown in Fig. 5~6, compound I is that (2- is phonetic by 1- it can be seen from Fig. 5, Fig. 6
Piperidinyl) -2- skatoxyl.
Embodiment 8
Compound I prepared by 1.0mmol 1- (2- pyrimidine radicals) -4- bromo indole and 1.1mmol embodiment 2 is added to
In 10mL chlorobenzene, 0.05mmol cobalt chloride (divalent cobalt) and 0.1mmol sodium bicarbonate are added, is stirred to react at 40~80 DEG C
0.5~3 hour, reaction solution is concentrated, concentrate is chromatographed to obtain 1- (2- pyrimidine radicals) -2- hydroxyl through column after removing organic solvent
Methyl 4- bromo indole.
Embodiment 9
Compound I prepared by 1.0mmol 1- (2- pyrimidine radicals) -4- methyl indol and 1.1mmol embodiment 2 is added to
In 10mL1,4- dioxane, 0.05mmol acetylacetone cobalt (trivalent cobalt) and 0.1mmol sodium benzoate are added, 40~80
It is stirred to react at DEG C 0.5~3 hour, reaction solution is concentrated, concentrate is chromatographed to obtain 1- (2- through column after removing organic solvent
Pyrimidine radicals) -2- methylol -4- methyl indol.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. one kind 1,2- oxaza butane compounds, which is characterized in that the chemical structural formula of the compound such as following formula (I) institute
Show:
In formula (I), R1For p-toluenesulfonyl, benzenesulfonyl, to fluorophenylsulphonyl, to chlorobenzenesulfonyl, brosyl,
To tnBuoromethyl-benzenesulfonyl, to MethOxybenzenesulfonyl, to tert-butyl benzene sulfonyl, bromobenzenesulfonyl, 2,4,6- front three
Base benzenesulfonyl, 2- naphthalene sulfonyl base, tertbutyloxycarbonyl or benzyloxycarbonyl group.
2. the preparation method of 1,2- oxaza butane compounds described in claim 1, which is characterized in that this method includes
Following steps:
(1) 1,2- Bromofume, triethylamine is added into the n,N-Dimethylformamide solution containing compound ii, stirs at room temperature
Become colourless to reaction solution, the solid being precipitated in reaction solution is collected, is recrystallized to give compound III；Wherein, the compound
II is n-Hydroxyphthalimide, the n-Hydroxyphthalimide, n,N-Dimethylformamide solution, dibromo second
Alkane, triethylamine molal volume ratio be 60mmol:80mL:120mmol:120mmol；
(2) hydrobromic acid that mass concentration is 48% is added into the glacial acetic acid solution of compound III, is stirred to react 5 at 130 DEG C
Minute, filtrate is concentrated to get yellow compound IV by cooling, filtering；Wherein, the compound III, glacial acetic acid solution, hydrobromic acid
Molal volume ratio be 120mmol:10mL:15mL；
(3) pyridine is added into compounds Ⅳ, reaction is stirred at room temperature after five minutes, halides R is added into reaction solution1X,
After stirring 5 hours at room temperature, 1.0M hydrochloric acid solution is added dropwise into reaction solution to neutrality, extraction, column chromatographic purifying obtain compound
Ⅴ；Wherein, the compounds Ⅳ, pyridine, halides molal volume ratio be 8.7mmol:15mL:20.9mmol；It is described halogenated
Object R1In X, R1For p-toluenesulfonyl, benzenesulfonyl, to fluorophenylsulphonyl, to chlorobenzenesulfonyl, brosyl, to three
Methyl fluoride benzenesulfonyl, to MethOxybenzenesulfonyl, to tert-butyl benzene sulfonyl, bromobenzenesulfonyl, 2,4,6- trimethylbenzene
Sulfonyl, 2- naphthalene sulfonyl base, tertbutyloxycarbonyl or benzyloxycarbonyl group, X are halogen element；
(4) mineral oil that point 2~3 batches of addition sodium hydride mass concentrations are 60% into the anhydrous tetrahydrofuran solution of compound V,
After being stirred at room temperature 1.5 hours, 1.0M hydrochloric acid solution is added dropwise to neutrality toward reaction mixture, extraction, column chromatographic purifying obtain
Compound I；Wherein, the compound V, anhydrous tetrahydrofuran solution, sodium hydride molal volume ratio be 0.83mmol:20mL:
1.87mmol。
3. the preparation method of 1,2- oxaza butane compounds as claimed in claim 2, which is characterized in that in step
(1) described that the solid being precipitated in reaction solution is collected, is recrystallized in specifically: reaction solution to be filtered out to the solid of precipitation, and will
Filtrate filters out the solid of precipitation after being diluted with ice water, merge and use ethyl alcohol recrystallization sediment after solid is precipitated；
In step (3), the extraction is that organic matter is extracted by ethyl acetate, ethyl acetate/petroleum ether in the column chromatography
Mass ratio be 1:3；
In step (4), the extraction is that organic matter is extracted by ethyl acetate, ethyl acetate/petroleum ether in the column chromatography
Mass ratio be 1:2.
4. 1,2- oxaza butane compounds described in claim 1 1- pyrimidine radicals benzazolyl compounds aminomethylation or
Application in terms of methylolation.
5. application as claimed in claim 4, which is characterized in that the chemical structural formula of the 1- pyrimidine radicals benzazolyl compounds is as follows
Shown in formula:
In above formula, R2For methyl, methoxyl group, ester group, halogen, nitro or amino.
6. application as claimed in claim 5, which is characterized in that the aminomethylation process is the following steps are included: by 1- pyrimidine
Base benzazolyl compounds and 1,2- oxaza butane compounds are added in organic solvent, add catalyst and additive,
It is stirred to react at 40~80 DEG C 0.5~3 hour, reaction solution is concentrated, concentrate is chromatographed after removing organic solvent through column
Obtain 1- pyrimidine radicals -2- aminomethyl compound；Wherein, the catalyst is cobalt complex；The additive is alkali；
The 1- pyrimidine radicals benzazolyl compounds and 1,2- oxaza butane compounds, organic solvent, catalyst, additive
Molal volume ratio is 1.0mmol:2.0mmol:10mL:0.05mmol:0.1mmol.
7. application as claimed in claim 6, which is characterized in that the 1- pyrimidine radicals benzazolyl compounds are 1- (2- pyrimidine radicals) Yin
Diindyl, 1- (2- pyrimidine radicals) 2 methyl indole, 1- (2- pyrimidine radicals) -4- methyl indol, 1- (2- pyrimidine radicals) -4- bromo indole, 1- (2-
Pyrimidine radicals) -4- methoxy-Indole, 1- (2- pyrimidine radicals) -4- benzyloxy indole, 1- (2- pyrimidine radicals) -4- amino indole, 1- (2-
Pyrimidine radicals) -4- nitroindoline, 4- (1- (2- pyrimidine radicals)) indolecarboxylic acid methyl esters, 1- (2- pyrimidine radicals) -5- fluoro indole, (2- is phonetic by 1-
Piperidinyl) -5- chloro-indole, 1- (2- pyrimidine radicals) -5- iodine indoles, 1- (2- pyrimidine radicals) -6- fluoro indole, 1- (2- pyrimidine radicals) -6- first
At least one of oxygroup indoles.
8. application as claimed in claim 5, which is characterized in that the methylolation process specifically: by 1- pyrimidine radicals indoles
Compound and 1,2- oxaza butane compounds are added in organic solvent, add catalyst and additive, 40~
It is stirred to react at 80 DEG C 0.5~3 hour, reaction solution is concentrated, concentrate is chromatographed to obtain 1- through column after removing organic solvent
Pyrimidine radicals -2- aminomethyl compound；Wherein, the catalyst is cobalt complex；The additive is alkali；
The 1- pyrimidine radicals benzazolyl compounds and 1,2- oxaza butane compounds, organic solvent, catalyst, additive
Molal volume ratio is 1.0mmol:1.1mmol:10mL:0.05mmol:0.1mmol.
9. the application as described in claim 6 or 8, which is characterized in that the organic solvent is acetonitrile, 1,2- dichloroethanes, two
Chloromethanes, chloroform, chlorobenzene, dimethyl sulfoxide, toluene, benzotrifluoride, mesitylene, ethyl alcohol, acetic acid, 1,4- dioxane, four
At least one of hydrogen furans；
The cobalt complex is Co (OAc)2、Co(acac)3、CoCl2、[Cp*Co(CO)I2]、[Cp*Co(C6H6)](PF6)2In
It is at least one；
The alkali is potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, lithium phosphate, phosphoric acid hydrogen
At least one of dipotassium, potassium dihydrogen phosphate, sodium benzoate, sodium hydroxide, lithium hydroxide.
10. application as claimed in claim 9, which is characterized in that the organic solvent is toluene or ethyl alcohol；The cobalt complex
For pentamethylcyclopentadiene base carbonyl cobalt diiodide；The alkali is potassium acetate.
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| WO2017109513A1 (en) * | 2015-12-24 | 2017-06-29 | Respivert Limited | Indolinones compounds and their use in the treatment of fibrotic diseases |
| CN108727360A (en) * | 2018-07-10 | 2018-11-02 | 河南科技大学 | A kind of preparation method of 2- pyrrole radicals -1,3- morpholine class compounds |
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| WO2017109513A1 (en) * | 2015-12-24 | 2017-06-29 | Respivert Limited | Indolinones compounds and their use in the treatment of fibrotic diseases |
| CN108727360A (en) * | 2018-07-10 | 2018-11-02 | 河南科技大学 | A kind of preparation method of 2- pyrrole radicals -1,3- morpholine class compounds |
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| TOMAS JAVORSKIS ET AL.，: "N-Protected 1,2-Oxazetidines as a Source of Electrophilic Oxygen: Straightforward Access to Benzomorpholines and Related Heterocycles by Using a Reactive Tether", 《CHEMISTRY - A EUROPEAN JOURNAL》, vol. 21, no. 25, 8 May 2015 (2015-05-08), pages 9157 - 9164 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233782A (en) * | 2019-11-27 | 2020-06-05 | 重庆大学 | Asymmetric synthesis method for preparing 1, 2-azaoxetane compound |
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