CN106243126B - 取代的呋喃异喹啉酮类衍生物及其制备方法 - Google Patents
取代的呋喃异喹啉酮类衍生物及其制备方法 Download PDFInfo
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- CN106243126B CN106243126B CN201610634416.8A CN201610634416A CN106243126B CN 106243126 B CN106243126 B CN 106243126B CN 201610634416 A CN201610634416 A CN 201610634416A CN 106243126 B CN106243126 B CN 106243126B
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- -1 furans isoquinolines analog Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000002240 furans Chemical class 0.000 claims abstract description 9
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 93
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000001301 oxygen Substances 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- PEUAZQMQTCPVPZ-UHFFFAOYSA-N 3-methyl-1-benzofuran-4-ol Chemical compound C1=CC(O)=C2C(C)=COC2=C1 PEUAZQMQTCPVPZ-UHFFFAOYSA-N 0.000 claims description 35
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 27
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 22
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- 150000003053 piperidines Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 claims description 11
- MJSICWJVLIZECN-UHFFFAOYSA-N C(=O)OCC.O1C=CC2=C1C=CC=C2 Chemical class C(=O)OCC.O1C=CC2=C1C=CC=C2 MJSICWJVLIZECN-UHFFFAOYSA-N 0.000 claims description 10
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims description 9
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims description 8
- WZPPIJUBFVPIBN-UHFFFAOYSA-N 3-methyl-6,7-dihydro-1-benzofuran Chemical class C1CC=CC2=C1OC=C2C WZPPIJUBFVPIBN-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 229950002366 nafoxidine Drugs 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical class OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 6
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000012265 solid product Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 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
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical class O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 claims description 4
- WBIZZNFQJPOKDK-UHFFFAOYSA-N 4-hydroxy-2-methoxybenzaldehyde Chemical class COC1=CC(O)=CC=C1C=O WBIZZNFQJPOKDK-UHFFFAOYSA-N 0.000 claims description 4
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical class [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N Anisaldehyde Natural products COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- ZRSNZINYAWTAHE-PTQBSOBMSA-N 4-methoxybenzaldehyde Chemical group COC1=CC=C([13CH]=O)C=C1 ZRSNZINYAWTAHE-PTQBSOBMSA-N 0.000 claims description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical class COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 2
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical group [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 claims description 2
- NFVQZARWEPRICB-UHFFFAOYSA-N 3-methyl-1-benzofuran-2-ol Chemical compound CC1=C(OC2=C1C=CC=C2)O NFVQZARWEPRICB-UHFFFAOYSA-N 0.000 claims 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims 1
- WSASYMPVLSOFOW-UHFFFAOYSA-N C(C)CC(CC(=O)O)=O.ClC=C Chemical compound C(C)CC(CC(=O)O)=O.ClC=C WSASYMPVLSOFOW-UHFFFAOYSA-N 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 abstract description 2
- 125000002541 furyl group Chemical group 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- KGWNRZLPXLBMPS-UHFFFAOYSA-N 2h-1,3-oxazine Chemical class C1OC=CC=N1 KGWNRZLPXLBMPS-UHFFFAOYSA-N 0.000 description 14
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- TZBHPYXJOJGKDT-UHFFFAOYSA-N 1,3-oxazin-4-one Chemical compound O=C1C=COC=N1 TZBHPYXJOJGKDT-UHFFFAOYSA-N 0.000 description 4
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- GTWXSZIQNTUNKR-UHFFFAOYSA-N 1-benzofuran-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2OC=CC2=C1 GTWXSZIQNTUNKR-UHFFFAOYSA-N 0.000 description 2
- DGPBVJWCIDNDPN-UHFFFAOYSA-N 2-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=CC=C1C=O DGPBVJWCIDNDPN-UHFFFAOYSA-N 0.000 description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- OUFUBABGIIEJNV-QMMMGPOBSA-N (5s)-3,4,5-trimethyl-5,6,7,8-tetrahydrobenzo[f][1]benzofuran-9-ol Chemical compound CC1=C2[C@@H](C)CCCC2=C(O)C2=C1C(C)=CO2 OUFUBABGIIEJNV-QMMMGPOBSA-N 0.000 description 1
- TTZDOBVWBQXGDC-KPKJPENVSA-N (e)-2-(3,4-dihydroxybenzoyl)-3-(1h-indol-3-yl)prop-2-enenitrile Chemical compound C1=C(O)C(O)=CC=C1C(=O)C(\C#N)=C\C1=CNC2=CC=CC=C12 TTZDOBVWBQXGDC-KPKJPENVSA-N 0.000 description 1
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- GSWYUZQBLVUEPH-UHFFFAOYSA-N 3-(azaniumylmethyl)benzoate Chemical compound NCC1=CC=CC(C(O)=O)=C1 GSWYUZQBLVUEPH-UHFFFAOYSA-N 0.000 description 1
- ZPTMWVDSVJOEEB-UHFFFAOYSA-N 3-methyl-4-oxo-6,7-dihydro-5h-1-benzofuran-2-carboxylic acid Chemical compound C1CCC(=O)C2=C1OC(C(O)=O)=C2C ZPTMWVDSVJOEEB-UHFFFAOYSA-N 0.000 description 1
- HVXIXLZOMVQEPY-UHFFFAOYSA-N 3-methyl-6,7-dihydro-5h-1-benzofuran-4-one Chemical compound C1CCC(=O)C2=C1OC=C2C HVXIXLZOMVQEPY-UHFFFAOYSA-N 0.000 description 1
- 125000001750 3-nitrocinnamoyl group Chemical group 0.000 description 1
- CEYBVHFSZZQISA-UHFFFAOYSA-N 7-hydroxy-5-methoxy-2-methylchromen-4-one Chemical compound O1C(C)=CC(=O)C2=C1C=C(O)C=C2OC CEYBVHFSZZQISA-UHFFFAOYSA-N 0.000 description 1
- GVNXBKLYRMAHMR-UHFFFAOYSA-N Cc(c1c2OC(c(cc3)ccc3C#N)N3)c[nH]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3)ccc3C#N)N3)c[nH]c1ccc2C3=O GVNXBKLYRMAHMR-UHFFFAOYSA-N 0.000 description 1
- BCLVPDYDULTKNM-UHFFFAOYSA-N Cc(c1c2OC(c(cc3)ccc3N(C)C)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3)ccc3N(C)C)N3)c[o]c1ccc2C3=O BCLVPDYDULTKNM-UHFFFAOYSA-N 0.000 description 1
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- BYOFFXLMXZLQMZ-UHFFFAOYSA-N Cc1c[o]c(cc2)c1c(OC(c(cc1)ccc1O)N1)c2C1=O Chemical compound Cc1c[o]c(cc2)c1c(OC(c(cc1)ccc1O)N1)c2C1=O BYOFFXLMXZLQMZ-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 235000002789 Panax ginseng Nutrition 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- QICQRRAHXUYAHB-UHFFFAOYSA-N benzene;formonitrile Chemical compound N#C.C1=CC=CC=C1 QICQRRAHXUYAHB-UHFFFAOYSA-N 0.000 description 1
- 150000004054 benzoquinones Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- UDXHBCLNVLIJCT-UHFFFAOYSA-N cacalol Natural products CC1CCc2c(C)c3c(C)coc3c(O)c2C1 UDXHBCLNVLIJCT-UHFFFAOYSA-N 0.000 description 1
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- FUFIYZTYLVNRFU-UHFFFAOYSA-N ethyl 3-methyl-4-oxo-6,7-dihydro-5h-1-benzofuran-2-carboxylate Chemical compound C1CCC(=O)C2=C1OC(C(=O)OCC)=C2C FUFIYZTYLVNRFU-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- MQSHRYLNHIARIE-UHFFFAOYSA-N furan;isoquinoline Chemical class C=1C=COC=1.C1=NC=CC2=CC=CC=C21 MQSHRYLNHIARIE-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- FUWVSQIZKKGXNV-UHFFFAOYSA-N protopine n-oxide Chemical compound C1=C2C(=O)CC3=CC=C4OCOC4=C3C[N+](C)([O-])CCC2=CC2=C1OCO2 FUWVSQIZKKGXNV-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及医药化学领域,旨在提供一种取代的呋喃异喹啉酮类衍生物及其制备方法。该取代的呋喃异喹啉酮类衍生物具有如式(Ⅰ)所示的结构,其中,B环选自苯基或呋喃基;R1、R2、R3各自独立地选自氢原子、羟基、甲氧基、二甲胺基、硝基或氰基。该产品是一类具有新骨架的天然呋喃异喹啉酮类似物,具有潜在的药物活性,该类化合物的制备可以为呋喃异喹啉酮类的药物活性研究提供支撑。其制备方法步骤简单、易得,对于工业化生产有重要意义。
Description
技术领域
本发明涉及医药化学领域,更具体地,涉及一种取代的呋喃异喹啉酮类衍生物及其制备方法。
背景技术
异喹啉酮类化合物广泛存在于自然界,其衍生物具有舒张血管、抗肿瘤等多种生物活性.异喹啉酮类化合物的分子多样性、合成方法及生物活性研究近年来受到重视。
异喹啉环的合成一直受到有机合成化学家和药物合成化学家的特别重视.虽然近年来已有很多合成异喹啉衍生物方法的报道,但并不能令人满意,因为它们的反应条件往往比较苛刻,而产率并不高,且副产物多,提纯困难,有些方法还必须使用昂贵的催化剂,所以亟待开发简单有效的合成异喹啉及其衍生物的新方法。
甲基取代的呋喃环结构在天然产物中广泛存在,并具有多样的生物活性,例如丹参酮可以治疗心血管疾病,呋喃佛术烷具有植物化感作用,倍半萜类化合物cacalol具有抗高血糖和抗菌的作用。
因此呋喃环被甲基取代的呋喃异喹啉酮类化合物及其衍生物具有潜在的药物活性,并且该类化合物是一种具有全新骨架的异喹啉酮类化合物,迄今未被报道过,本专利发明了一种简单,快速的由4-羟基-3-甲基苯并呋喃-5-甲酰胺制备该类衍生物的方法。
发明内容
本发明要解决的技术问题是,克服现有技术中的不足,提供一种取代的呋喃异喹啉酮类衍生物及其制备方法。
为解决技术问题,本发明的解决方案是:
提供一种取代的呋喃异喹啉酮类衍生物,具有如式(Ⅰ)所示的结构:
其中,
B环选自苯基或呋喃基;
R1、R2、R3各自独立地选自氢原子、羟基、甲氧基、二甲胺基、硝基或氰基。
本发明中,该取代的呋喃异喹啉酮类衍生物具有下述任意一种结构:
本发明进一步提供了所述取代的呋喃异喹啉酮类衍生物的制备方法,包括以下步骤:
(1)将1,3-环己二酮和氢氧化钾均匀的分散于水中,常温搅拌5min后,加入氯乙酰乙酸乙酯的甲醇溶液;然后将体系在室温下搅拌5天,用4N的盐酸酸化;过滤酸化后的反应液,得到的固体产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯;
所述1,3-环己二酮与氢氧化钾、氯乙酰乙酸乙酯的摩尔比为1:1:1,每毫升水对应的1,3-环己二酮的投料量为0.1g,每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g;
(2)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇和水的混合溶剂溶解,溶解后将体系在室温下搅拌反应5h;将反应液用6N的盐酸调pH至1,过滤反应液,过滤得固体产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸;
所述混合溶剂是甲醇与水以2.5:1配制而成,每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g;所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6;
(3)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀分散于二甘醇中,加入铜粉和吡啶,然后将体系加热至175℃,保持搅拌10h;将体系冷却到室温,加入冰水,并用4N的盐酸酸化;用石油醚萃取酸化后的反应液三次,将合并的萃取液用水洗涤一次, 然后将萃取液用无水硫酸钠干燥、旋干,得固体产物:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮;
所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉、吡啶的摩尔比为1:1:2,每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g;
(4)在氮气保护下,将氢化钠均匀分散于乙二醇二甲醚溶液中,将体系冷却到0℃;然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液,保持体系在0℃搅拌30min;向体系中加入碳酸二甲酯的乙二醇二甲醚溶液,将体系加热到90℃;保持3h后,将体系冷却到室温,加入饱和的氯化铵溶液淬灭反应;用乙酸乙酯萃取3次,有机相用无水硫酸钠干燥、浓缩,得到产品:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯;
所述3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠、碳酸二甲酯的摩尔比为1:5:3,每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g;
(5)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中,向体系中加入2,3-二氯-5,6-二氰对苯醌,加热至130℃保持6h;将体系冷却到室温,过滤,浓缩滤液,将粗产品用硅胶色谱柱分离,得到纯净产物:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯;
所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2,每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g;
(6)将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液,每毫升饱和的氨的甲醇溶液对应4-羟基-3-甲基苯并呋喃-5-甲酸甲酯的投料量为0.06g;封口后加热到65℃,保持24h;蒸除反应液,得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺;
(7)将4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱均匀分散于反应溶剂a中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱的摩尔比在1:1~3:0.1~1之间,每毫升溶剂a对应的4-羟基-3-甲基苯并呋喃-5-甲酰胺的投料量为0.02至0.06g,获得原料混合物;
其中,醛选自4-甲氧基苯甲醛、2-甲氧基苯甲醛、3,4,5-三甲氧基苯甲醛、4-二甲胺基苯甲醛、4-羟基苯甲醛、4-羟基-2-甲氧基苯甲醛、4-硝基苯甲醛、4-氰基苯甲醛或2-呋喃甲醛中的任意一种;所述反应溶剂a为甲苯或苯;
(8)将原料混合物在110℃~130℃下反应1小时~24小时,蒸除反应溶剂,得粗产品,将粗产品用硅胶色谱柱分离,得到取代的呋喃异喹啉酮类衍生物的纯净产物。
本发明中,步骤(7)中所述的弱碱为哌啶或四氢吡咯(弱碱优选为哌啶,反应溶剂a优选为甲苯)。
与现有技术相比,本发明能够取得的有益效果:
(1)本发明提供的呋喃异喹啉酮类衍生物是一类具有新骨架的天然呋喃异喹啉酮类似物,具有潜在的药物活性,该类化合物的制备可以为呋喃异喹啉酮类的药物活性研究提供支撑。
(2)本发明提供的呋喃异喹啉酮类衍生物的制备方法,步骤简单,易得。对于工业化生产有重要意义。
附图说明
图1是本发明提供的取代的呋喃异喹啉酮类衍生物的合成示意图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
将1,3-环己二酮和氢氧化钾均匀的分散于水中,常温搅拌5min后,加入氯乙酰乙酸乙酯的甲醇溶液,然后将体系在室温下搅拌5天,然后将体系用4N的盐酸酸化,过滤酸化后的反应液,得到的固体即为产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯。该步骤中1,3-环己二酮与氢氧化钾及氯乙酰乙酸乙酯的摩尔比为1:1:1,每毫升水对应的1,3-环己二酮的投料量为0.1g,每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g。该步的产率为65%。所得产物的结构为:
分子式:C12H14O4
中文命名:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯
英文命名:ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate
分子量:222.09
外观:白色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ4.38(q,J=7.1Hz,2H),2.94(t,J=6.3Hz,2H),2.60–2.46(m,5H),2.20(p,J=6.4Hz,2H),1.40(t,J=7.1Hz,3H)ppm。
实施例2
将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇与水的混合溶剂溶解,溶解后将体系在室温下搅拌反应5h。然后将反应液用6N的盐酸调pH至1,过滤反应液,过滤所得的固体即为产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸。该步骤中所用的混合溶剂是甲醇与水以2.5:1配制而成。每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6。该步的产率为90%。所得产物的结构为:
分子式:C10H10O4
中文命名:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸
英文命名:3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylicacid
分子量:194.06
外观:白色固体
核磁共振氢谱:(400MHz,DMSO-d6)δ2.91(t,J=6.2Hz,2H),2.44(m,5H),2.08
(p,J=6.4Hz,2H)ppm。
实施例3
将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀的分散于二甘醇中,加入铜粉和吡啶,然后将体系加热至175℃,保持搅拌10h。将体系冷却到室温,加入冰水,并用4N的盐酸酸化,用石油醚萃取酸化后的反应液三次,将合并的萃取液用水洗涤一次,然后将萃取液用无水硫酸钠干燥,旋干。所得的固体即为产物:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮。该步骤中每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉及吡啶的摩尔比为1:1:2。该步的产率为85%。所得产物的结构为:
分子式:C9H10O2
中文命名:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮
英文命名:3-methyl-6,7-dihydrobenzofuran-4(5H)-one
分子量:150.07
外观:黄色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ7.11–6.98(m,1H),2.83(t,J=6.3Hz,2H),2.47(dd,J=7.2,5.8Hz,2H),2.26–2.06(m,5H)ppm。
核磁共振碳谱(101MHz,Chloroform-d)δ195.70,167.40,138.90,120.41,119.07,38.29,23.63,22.75,9.07ppm。
实施例4
在氮气保护下,将氢化钠均匀的分散于乙二醇二甲醚溶液中,将体系冷却到0℃,然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液,保持体系在0℃搅拌30min。然后向体系中加入碳酸二甲酯的乙二醇二甲醚溶液,然后将体系加热到90℃。保持3h后,将体系冷却到室温,加入饱和的氯化铵溶液淬灭反应,用乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,浓缩,即可得到该步的产品:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯。该步骤中3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠及碳酸二甲酯的摩尔比为1:5:3,每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g。该步的产率为87%。所得产物的结构为:
分子式:C11H12O4
中文命名:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯
英文命名:methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate
分子量:208.07
外观:白色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ7.09(d,J=1.6Hz,1H),3.77(s,3H),3.50(dd,J=9.1,4.7Hz,1H),3.02(dt,J=17.6,5.8Hz,1H),2.85(ddd,J=17.6,8.2,5.5Hz,1H), 2.54(dddd,J=13.6,9.2,8.2,5.4Hz,1H),2.34(dtd,J=13.6,5.8,4.7Hz,1H),2.19(d,J=1.4Hz,3H).
核磁共振碳谱(101MHz,Chloroform-d)δ189.80,170.49,166.90,139.42,119.74,119.33,53.68,52.36,25.83,22.10,8.90.
实施例5
将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中,向体系中加入2,3-二氯-5,6-二氰对苯醌,加热至130℃保持6h。将体系冷却到室温,过滤,浓缩滤液,将粗产品用硅胶色谱柱分离即可得到纯净的产物:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2,每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g。该步的产率为87%。所得产物的结构为:
分子式:C11H10O4
中文命名:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯
英文命名:methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate
分子量:206.06
外观:淡黄色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ11.43(s,1H),7.71(d,J=8.8Hz,1H),7.28(q,J=1.4Hz,1H),6.93(d,J=8.8Hz,1H),3.95(s,3H),2.41(d,J=1.4Hz,3H).
核磁共振碳谱(101MHz,Chloroform-d)δ171.28,160.21,159.02,140.65,125.86,117.59,116.87,105.68,103.85,52.10,9.59.
实施例6
将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液,封口,加热到65℃,保持24h,蒸除反应液,得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺。该步骤中每毫升饱和的氨的甲醇溶液对应的投料量为0.06g。该步的产率为100%。所得产物的结构为:
分子式:C10H9NO3
中文命名:4-羟基-3-甲基苯并呋喃-5-甲酰胺
英文命名:4-hydroxy-3-methylbenzofuran-5-carboxamide
分子量:191.06
外观:白色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ14.32(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J=8.8Hz,1H),7.65(q,J=1.3Hz,1H),7.02(d,J=8.8Hz,1H),2.33(d,J=1.4Hz,3H).
核磁共振碳谱(101MHz,DMSO-d6)δ173.38,158.90,158.44,141.19,124.09,117.13,115.87,106.98,102.54,9.35.
实施例7-1:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对甲氧基苯甲醛和哌啶的摩尔比为1:1:0.5之间,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率78%,该衍生物的结构为:
分子式:C18H15NO4
中文命名:2-(4-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:309.1
外观:浅黄色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ7.88(d,J=8.7Hz,1H),7.62–7.52(m,2H),7.33(q,J=1.3Hz,1H),7.19(d,J=8.6Hz,1H),7.05–6.95(m,2H),6.31(s,1H),6.22(s,1H),3.86(s,3H),2.27(d,J=1.4Hz,3H).
核磁共振碳谱:(101MHz,Chloroform-d)δ164.39,161.02,159.96,153.55,141.65,128.31,128.14,124.28,117.51,115.98,114.35,111.65,106.78,85.66,55.42,9.48.
实施例7-2:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、邻甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、邻甲氧基苯甲醛和哌啶的摩尔比为1:3:0.5,每毫升反应溶剂对应的投料量为0.02g,获得原料混合物。将原料混合物,在130℃下,反应1小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率78%,该衍生物的结构为:
分子式:C18H15NO4
中文命名:2-(2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:309.1
外观:白色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ7.89(d,J=8.6Hz,1H),7.74(dd,J=7.6,1.7Hz,1H),7.43(ddd,J=8.3,7.5,1.7Hz,1H),7.35(q,J=1.3Hz,1H),7.18(d,J=8.7Hz,1H),7.09(td,J=7.6,1.0Hz,1H),6.98(dd,J=8.3,1.0Hz,1H),6.69(s,1H),6.33(s,1H),3.88(s,3H),2.35(d,J=1.4Hz,3H).
核磁共振碳谱:(101MHz,Chloroform-d)δ164.53,159.86,156.34,153.59,141.63,130.88,126.85,124.28,124.22,121.01,117.56,115.94,111.71,110.71,106.68,81.11,55.51,9.54.
实施例7-3:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、3,4,5-三甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、3,4,5-三甲氧基苯甲醛和哌啶的摩 尔比为1:2:0.1,每毫升反应溶剂对应的投料量为0.06g,获得原料混合物。将原料混合物,在110℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:9-甲基-2-(3,4,5-三甲氧基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率75%,该衍生物的结构为:
分子式:C20H19NO6
中文命名:9-甲基-2-(3,4,5-三甲氧基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:369.1
外观:白色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ7.89(d,J=8.7Hz,1H),7.36(q,J=1.3Hz,1H),7.21(d,J=8.7Hz,1H),6.86(s,2H),6.30(s,2H),3.91(d,J=3.4Hz,9H),2.32(d,J=1.4Hz,3H).
核磁共振碳谱:(101MHz,Chloroform-d)δ164.37,159.97,153.62,153.31,141.80,139.13,131.43,124.22,117.52,115.83,111.69,106.92,103.70,85.71,60.90,56.22,9.54.
实施例7-4:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对二甲胺基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对二甲胺基苯甲醛和哌啶的摩尔比为1:2:1,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应24小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-(二甲胺基)苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:
分子式:C19H18N2O3
中文命名:2-(4-(二甲胺基)苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:322.1
外观:白色固体
核磁共振氢谱:(400MHz,Chloroform-d)δ7.89(d,J=8.6Hz,1H),7.53–7.44(m,2H),7.32(d,J=1.5Hz,1H),7.18(d,J=8.7Hz,1H),6.80(d,J=8.2Hz,2H),6.26(d,J=1.1Hz,1H),5.97(s,1H),3.03(s,6H),2.27(d,J=1.4Hz,3H).
核磁共振碳谱:(101MHz,DMSO-d6)δ164.05,159.43,153.35,147.88,141.04,127.54,123.80,117.76,117.01,115.59,111.65,111.17,106.12,85.68,39.98,9.00.
实施例7-5:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对羟基苯甲醛和哌啶均匀分散于反应溶剂苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对羟基苯甲醛和哌啶的摩尔比为1:2:0.5,每毫升反应溶剂对应的投料量为0.06g,获得原料混合物。将原料混合物,在120℃下,反应10小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-羟基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:
分子式:C17H13NO4
中文命名:2-(4-羟基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:295.1
外观:白色固体
核磁共振氢谱:(400MHz,DMSO-d6)δ9.72(s,1H),8.80(d,J=2.1Hz,1H),7.75(d,J=1.7Hz,1H),7.70(d,J=8.6Hz,1H),7.47–7.37(m,2H),7.26(d,J=8.6Hz,1H),6.86–6.78(m,2H),6.39(d,J=1.8Hz,1H),2.23(d,J=1.4Hz,3H).
核磁共振碳谱:(101MHz,DMSO-d6)δ163.13,158.71,158.41,152.57,142.49,128.57,127.22,123.64,116.92,115.12,115.07,112.31,105.99,85.13,9.11.
实施例7-6:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-羟基-2-甲氧基苯甲醛和哌啶均匀分散于反应溶剂苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-羟基-2-甲氧基苯甲醛和哌啶的摩尔比为1:2:0.5,每毫升反应溶剂对应的投料量为0.02g,获得原料混合物。将原料混合物,在120℃下,反应18小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-羟基-2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:
分子式:C18H15NO5
中文命名:2-(4-羟基-2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:325.1
外观:白色固体
核磁共振氢谱:(400MHz,DMSO-d6)δ9.30(s,1H),8.82(d,J=2.0Hz,1H),7.77(d,J=1.6Hz,1H),7.70(d,J=8.6Hz,1H),7.27(d,J=8.6Hz,1H),7.17(d,J=2.0Hz,1H),7.01(dd,J=8.2,2.0Hz,1H),6.82(d,J=8.1Hz,1H),6.39(d,J=1.8Hz,1H),3.79(s,3H),2.26(d,J=1.5Hz,3H).
核磁共振碳谱:(101MHz,DMSO-d6)δ163.11,158.71,152.55,147.62,147.41,142.55,127.56,123.65,119.97,116.93,115.05,112.35,110.89,106.04,99.49,85.18,55.52,9.14.
实施例7-7:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-硝基苯甲醛和四氢吡咯均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-硝基苯甲醛和四氢吡咯的摩尔比为1:3:1,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:9-甲基-2-(4-硝基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:
分子式:C17H12N2O5
中文命名:9-甲基-2-(4-硝基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:324.1
外观:浅黄色固体
核磁共振氢谱:(400MHz,DMSO-d6)δ9.14(d,J=2.6Hz,1H),8.40–8.24(m,2H),7.95–7.83(m,2H),7.79(q,J=1.2Hz,1H),7.70(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.74(d,J=2.4Hz,1H),2.30(d,J=1.4Hz,3H).
核磁共振碳谱:(101MHz,DMSO-d6)δ162.39,158.81,151.82,148.04,144.11,142.80,128.36,123.75,123.63,117.04,115.02,112.29,106.52,83.53,9.15.
实施例7-8:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-氰基苯甲醛和四氢吡咯均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-氰基苯甲醛和四氢吡咯的摩尔比为1:1:0.1,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈,得率62%,该衍生物的结构为:
分子式:C18H12N2O3
中文命名:4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈
英文命名:4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrile
分子量:304.1
外观:白色固体
核磁共振氢谱:(400MHz,DMSO-d6)δ9.13–9.05(m,1H),7.96(d,J=8.0Hz,2H),7.79(d,J=7.0Hz,3H),7.69(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.68(d,J=2.3Hz,1H),2.29(s,3H).
核磁共振碳谱:(101MHz,DMSO-d6)δ162.48,158.79,151.90,142.79,142.23,132.62,127.88,123.63,118.36,117.01,115.01,112.27,112.15,106.49,83.77,9.15.
实施例7-9:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、2-呋喃甲醛和四氢吡咯均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、2-呋喃甲醛和四氢吡咯的摩尔比为1:2:0.5,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在130℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈,得率60%,该衍生物的结构为:
分子式:C15H11NO4
中文命名:2-(呋喃-2-基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮
英文命名:2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量:269.1
外观:黄色固体
核磁共振氢谱:(500MHz,Chloroform-d)δ7.87(d,J=8.6Hz,1H),7.50(d,J=1.7Hz,1H),7.33(d,J=1.6Hz,1H),7.18(d,J=8.7Hz,1H),6.64(d,J=3.4Hz,1H),6.54(s,1H),6.48–6.41(m,2H),2.33(d,J=1.3Hz,3H).
核磁共振碳谱:(101MHz,Chloroform-d)δ163.76,159.98,152.58,148.87,143.93,141.75,140.75,124.14,115.98,111.63,110.76,110.40,106.99,79.17,9.42。
Claims (2)
1.一种取代的呋喃异喹啉酮类衍生物的制备方法,其特征在于,包括以下步骤:
(1)将1,3-环己二酮和氢氧化钾均匀的分散于水中,常温搅拌5min后,加入氯乙酰乙酸乙酯的甲醇溶液;然后将体系在室温下搅拌5天,用4N的盐酸酸化;过滤酸化后的反应液,得到的固体产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯;
所述1,3-环己二酮与氢氧化钾、氯乙酰乙酸乙酯的摩尔比为1:1:1,每毫升水对应的1,3-环己二酮的投料量为0.1g,每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g;
(2)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇与水的混合溶剂溶解,溶解后将体系在室温下搅拌反应5h;将反应液用6N的盐酸调pH至1,过滤反应液,过滤得固体产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸;
所述混合溶剂是甲醇与水以2.5:1配制而成,每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g;所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6;
(3)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀分散于二甘醇中,加入铜粉和吡啶,然后将体系加热至175℃,保持搅拌10h;将体系冷却到室温,加入冰水,并用4N的盐酸酸化;用石油醚萃取酸化后的反应液三次,将合并的萃取液用水洗涤一次,然后将萃取液用无水硫酸钠干燥、旋干,得固体产物:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮;
所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉、吡啶的摩尔比为1:1:2,每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g;
(4)在氮气保护下,将氢化钠均匀分散于乙二醇二甲醚溶液中,将体系冷却到0℃;然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液,保持体系在0℃搅拌30min;向体系中加入碳酸二甲酯的乙二醇二甲醚溶液,将体系加热到90℃;保持3h后,将体系冷却到室温,加入饱和的氯化铵溶液淬灭反应;用乙酸乙酯萃取3次,有机相用无水硫酸钠干燥、浓缩,得到产品:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯;
所述3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠、碳酸二甲酯的摩尔比为1:5:3,每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g;
(5)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中,向体系中加入2,3-二氯-5,6-二氰对苯醌,加热至130℃保持6h;将体系冷却到室温,过滤,浓缩滤液,将粗产品用硅胶色谱柱分离,得到纯净产物:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯;
所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2,每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g;
(6)将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液,每毫升饱和的氨的甲醇溶液对应4-羟基-3-甲基苯并呋喃-5-甲酸甲酯的投料量为0.06g;封口后加热到65℃,保持24h;蒸除反应液,得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺;
(7)将4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱均匀分散于反应溶剂a中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱的摩尔比在1:1~3:0.1~1之间,每毫升溶剂a对应的4-羟基-3-甲基苯并呋喃-5-甲酰胺的投料量为0.02至0.06g,获得原料混合物;
其中,醛选自4-甲氧基苯甲醛、2-甲氧基苯甲醛、3,4,5-三甲氧基苯甲醛、4-二甲胺基苯甲醛、4-羟基苯甲醛、4-羟基-2-甲氧基苯甲醛、4-硝基苯甲醛、4-氰基苯甲醛或2-呋喃甲醛中的任意一种;所述反应溶剂a为甲苯或苯;
(8)将原料混合物在110℃~130℃下反应1小时~24小时,蒸除反应溶剂,得粗产品,将粗产品用硅胶色谱柱分离,得到取代的呋喃异喹啉酮类衍生物的纯净产物;
步骤(8)中所述的取代的呋喃异喹啉酮类衍生物具有下述任意一种结构:
2.根据权利要求1的方法,其特征在于,步骤(7)中所述的弱碱为哌啶或四氢吡咯。
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