CN107778256B - 一种从邻氨基苯甲酰胺和不饱和醛合成喹唑啉酮的方法 - Google Patents
一种从邻氨基苯甲酰胺和不饱和醛合成喹唑啉酮的方法 Download PDFInfo
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- CN107778256B CN107778256B CN201610754880.0A CN201610754880A CN107778256B CN 107778256 B CN107778256 B CN 107778256B CN 201610754880 A CN201610754880 A CN 201610754880A CN 107778256 B CN107778256 B CN 107778256B
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- anthranilamide
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- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 238000000034 method Methods 0.000 title claims abstract description 14
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 title abstract 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 87
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 9
- 150000003624 transition metals Chemical class 0.000 claims abstract description 9
- 239000011541 reaction mixture Substances 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 239000002904 solvent Substances 0.000 claims description 53
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 150000001299 aldehydes Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- -1 methoxyphenyl Chemical group 0.000 claims description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 229910021640 Iridium dichloride Inorganic materials 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- 239000003208 petroleum Substances 0.000 description 26
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 26
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 9
- 229940117916 cinnamic aldehyde Drugs 0.000 description 9
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 2
- XXFMSJLOXUXPKJ-UHFFFAOYSA-N 2-(1-phenylbutyl)-3H-quinazolin-4-one Chemical compound C1(=CC=CC=C1)C(CCC)C1=NC2=CC=CC=C2C(N1)=O XXFMSJLOXUXPKJ-UHFFFAOYSA-N 0.000 description 2
- NSECWZAHDJRFQN-UHFFFAOYSA-N 2-(1-phenylheptan-2-yl)-3H-quinazolin-4-one Chemical compound C1(=CC=CC=C1)CC(CCCCC)C1=NC2=CC=CC=C2C(N1)=O NSECWZAHDJRFQN-UHFFFAOYSA-N 0.000 description 2
- DNHVWCLELDTBQK-UHFFFAOYSA-N 2-(1-phenyloctan-2-yl)-3H-quinazolin-4-one Chemical compound C1(=CC=CC=C1)CC(CCCCCC)C1=NC2=CC=CC=C2C(N1)=O DNHVWCLELDTBQK-UHFFFAOYSA-N 0.000 description 2
- VGQCGGFHDKPIHD-UHFFFAOYSA-N 2-(1-phenylpropan-2-yl)-3H-quinazolin-4-one Chemical compound C1(=CC=CC=C1)CC(C)C1=NC2=CC=CC=C2C(N1)=O VGQCGGFHDKPIHD-UHFFFAOYSA-N 0.000 description 2
- ZYVUPXXXDSXTKF-UHFFFAOYSA-N 2-(2-anthracen-9-ylethyl)-3H-quinazolin-4-one Chemical compound C1=CC=C2C(=C1)C=C3C=CC=CC3=C2CCC4=NC5=CC=CC=C5C(=O)N4 ZYVUPXXXDSXTKF-UHFFFAOYSA-N 0.000 description 2
- CWCHSIGPRZOUBM-UHFFFAOYSA-N 2-(2-bicyclo[2.2.1]heptanyl)-3H-quinazolin-4-one Chemical compound C12C(CC(CC1)C2)C1=NC2=CC=CC=C2C(N1)=O CWCHSIGPRZOUBM-UHFFFAOYSA-N 0.000 description 2
- AUEZMLBIHNUTTI-UHFFFAOYSA-N 2-(2-phenylethyl)-1h-quinazolin-4-one Chemical compound N1C2=CC=CC=C2C(=O)N=C1CCC1=CC=CC=C1 AUEZMLBIHNUTTI-UHFFFAOYSA-N 0.000 description 2
- LQDCVZFFWWGBKI-UHFFFAOYSA-N 2-(2-phenylethyl)-7-(trifluoromethyl)-3H-quinazolin-4-one Chemical compound FC(C1=CC=C2C(NC(=NC2=C1)CCC1=CC=CC=C1)=O)(F)F LQDCVZFFWWGBKI-UHFFFAOYSA-N 0.000 description 2
- VUDOFYCNPZJINY-UHFFFAOYSA-N 2-(4-methyl-1-phenylpentyl)-3H-quinazolin-4-one Chemical compound CC(C)CCC(C1=CC=CC=C1)C2=NC3=CC=CC=C3C(=O)N2 VUDOFYCNPZJINY-UHFFFAOYSA-N 0.000 description 2
- PYWDHNOWLJJAMW-UHFFFAOYSA-N 2-[2-(2-methoxyphenyl)ethyl]-3H-quinazolin-4-one Chemical compound COC1=C(C=CC=C1)CCC1=NC2=CC=CC=C2C(N1)=O PYWDHNOWLJJAMW-UHFFFAOYSA-N 0.000 description 2
- HTWVBFDYOFHGPO-UHFFFAOYSA-N 2-[2-(3-methoxyphenyl)ethyl]-3H-quinazolin-4-one Chemical compound COC=1C=C(C=CC=1)CCC1=NC2=CC=CC=C2C(N1)=O HTWVBFDYOFHGPO-UHFFFAOYSA-N 0.000 description 2
- SWKWNPFRCGYSDT-UHFFFAOYSA-N 2-[2-(4-bromophenyl)ethyl]-3H-quinazolin-4-one Chemical compound BrC1=CC=C(C=C1)CCC1=NC2=CC=CC=C2C(N1)=O SWKWNPFRCGYSDT-UHFFFAOYSA-N 0.000 description 2
- QQYNJWWPAYTRCJ-UHFFFAOYSA-N 2-[2-(4-fluorophenyl)ethyl]-3H-quinazolin-4-one Chemical compound FC1=CC=C(CCC2=NC3=CC=CC=C3C(N2)=O)C=C1 QQYNJWWPAYTRCJ-UHFFFAOYSA-N 0.000 description 2
- CHUOAFJOWNDACB-UHFFFAOYSA-N 2-[2-(furan-2-yl)ethyl]-3H-quinazolin-4-one Chemical compound O1C(=CC=C1)CCC1=NC2=CC=CC=C2C(N1)=O CHUOAFJOWNDACB-UHFFFAOYSA-N 0.000 description 2
- QNEJYHVIYJFNHC-UHFFFAOYSA-N 2-amino-4-chlorobenzamide Chemical compound NC(=O)C1=CC=C(Cl)C=C1N QNEJYHVIYJFNHC-UHFFFAOYSA-N 0.000 description 2
- MEWDLKFIQDINLZ-UHFFFAOYSA-N 2-cyclohexyl-1h-quinazolin-4-one Chemical compound N1C2=CC=CC=C2C(=O)N=C1C1CCCCC1 MEWDLKFIQDINLZ-UHFFFAOYSA-N 0.000 description 2
- DAQXBHJQHGIETF-UHFFFAOYSA-N 2-heptan-3-yl-1h-quinazolin-4-one Chemical compound C1=CC=C2C(=O)NC(C(CC)CCCC)=NC2=C1 DAQXBHJQHGIETF-UHFFFAOYSA-N 0.000 description 2
- FSGUDKUBZTYVKN-UHFFFAOYSA-N 2-pentan-2-yl-3H-quinazolin-4-one Chemical compound CC(CCC)C1=NC2=CC=CC=C2C(N1)=O FSGUDKUBZTYVKN-UHFFFAOYSA-N 0.000 description 2
- MFAZKHYKVSPPIB-UHFFFAOYSA-N 2-propyl-1h-quinazolin-4-one Chemical compound C1=CC=C2NC(CCC)=NC(=O)C2=C1 MFAZKHYKVSPPIB-UHFFFAOYSA-N 0.000 description 2
- AIRRZESINMKGEE-UHFFFAOYSA-N 3-benzyl-2-(2-phenylethyl)quinazolin-4-one Chemical compound C(C1=CC=CC=C1)N1C(=NC2=CC=CC=C2C1=O)CCC1=CC=CC=C1 AIRRZESINMKGEE-UHFFFAOYSA-N 0.000 description 2
- RWAXQNMFYWRTGR-UHFFFAOYSA-N 3-butyl-2-(2-phenylethyl)quinazolin-4-one Chemical compound C(CCC)N1C(=NC2=CC=CC=C2C1=O)CCC1=CC=CC=C1 RWAXQNMFYWRTGR-UHFFFAOYSA-N 0.000 description 2
- NNHALEQEFOCJQT-UHFFFAOYSA-N 6-bromo-2-(2-phenylethyl)-1h-quinazolin-4-one Chemical compound N=1C(=O)C2=CC(Br)=CC=C2NC=1CCC1=CC=CC=C1 NNHALEQEFOCJQT-UHFFFAOYSA-N 0.000 description 2
- ZDCKKYOGPSXJGX-UHFFFAOYSA-N 6-chloro-2-(2-phenylethyl)-1h-quinazolin-4-one Chemical compound N=1C2=CC=C(Cl)C=C2C(O)=NC=1CCC1=CC=CC=C1 ZDCKKYOGPSXJGX-UHFFFAOYSA-N 0.000 description 2
- RTBYWKZKROKRBY-UHFFFAOYSA-N 6-methoxy-2-(2-phenylethyl)-3H-quinazolin-4-one Chemical compound COC=1C=C2C(NC(=NC2=CC=1)CCC1=CC=CC=C1)=O RTBYWKZKROKRBY-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 239000001414 (2E)-2-(phenylmethylidene)octanal Substances 0.000 description 1
- YURDCJXYOLERLO-LCYFTJDESA-N (2E)-5-methyl-2-phenylhex-2-enal Chemical compound CC(C)C\C=C(\C=O)C1=CC=CC=C1 YURDCJXYOLERLO-LCYFTJDESA-N 0.000 description 1
- 239000001496 (E)-2-methyl-3-phenylprop-2-enal Substances 0.000 description 1
- PYLMCYQHBRSDND-VURMDHGXSA-N (Z)-2-ethyl-2-hexenal Chemical compound CCC\C=C(\CC)C=O PYLMCYQHBRSDND-VURMDHGXSA-N 0.000 description 1
- VLUMOWNVWOXZAU-VQHVLOKHSA-N (e)-2-methyl-3-phenylprop-2-enal Chemical compound O=CC(/C)=C/C1=CC=CC=C1 VLUMOWNVWOXZAU-VQHVLOKHSA-N 0.000 description 1
- IDEYZABHVQLHAF-GQCTYLIASA-N (e)-2-methylpent-2-enal Chemical compound CC\C=C(/C)C=O IDEYZABHVQLHAF-GQCTYLIASA-N 0.000 description 1
- YPAJRUMMODCONM-WDZFZDKYSA-N (e)-2-phenylpent-2-enal Chemical compound CC\C=C(\C=O)C1=CC=CC=C1 YPAJRUMMODCONM-WDZFZDKYSA-N 0.000 description 1
- XHYAQFCRAQUBTD-HWKANZROSA-N (e)-3-(3-methoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(\C=C\C=O)=C1 XHYAQFCRAQUBTD-HWKANZROSA-N 0.000 description 1
- YSIYEWBILJZDQH-OWOJBTEDSA-N (e)-3-(4-fluorophenyl)prop-2-enal Chemical compound FC1=CC=C(\C=C\C=O)C=C1 YSIYEWBILJZDQH-OWOJBTEDSA-N 0.000 description 1
- 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 description 1
- IDEYZABHVQLHAF-UHFFFAOYSA-N 2-Methyl-2-pentenal Natural products CCC=C(C)C=O IDEYZABHVQLHAF-UHFFFAOYSA-N 0.000 description 1
- WNUDRXQXKYNEAT-UHFFFAOYSA-N 2-[2-(3-methylphenyl)ethyl]-1h-quinazolin-4-one Chemical compound CC1=CC=CC(CCC=2NC3=CC=CC=C3C(=O)N=2)=C1 WNUDRXQXKYNEAT-UHFFFAOYSA-N 0.000 description 1
- OUHZMLIWMQFCIR-UHFFFAOYSA-N 2-amino-4-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=C(C(F)(F)F)C=C1N OUHZMLIWMQFCIR-UHFFFAOYSA-N 0.000 description 1
- RUHKZVAPXHIWJH-UHFFFAOYSA-N 2-amino-4-methylbenzamide Chemical compound CC1=CC=C(C(N)=O)C(N)=C1 RUHKZVAPXHIWJH-UHFFFAOYSA-N 0.000 description 1
- LHAJKJQNMKXZSZ-UHFFFAOYSA-N 2-amino-5-bromobenzamide Chemical compound NC(=O)C1=CC(Br)=CC=C1N LHAJKJQNMKXZSZ-UHFFFAOYSA-N 0.000 description 1
- DNRVZOZGQHHDAT-UHFFFAOYSA-N 2-amino-5-chlorobenzamide Chemical compound NC(=O)C1=CC(Cl)=CC=C1N DNRVZOZGQHHDAT-UHFFFAOYSA-N 0.000 description 1
- NWZIAOBMRQYTTD-UHFFFAOYSA-N 2-amino-5-methoxybenzamide Chemical compound COC1=CC=C(N)C(C(N)=O)=C1 NWZIAOBMRQYTTD-UHFFFAOYSA-N 0.000 description 1
- ANVAEYULLAJMQX-UHFFFAOYSA-N 2-amino-n-benzylbenzamide Chemical compound NC1=CC=CC=C1C(=O)NCC1=CC=CC=C1 ANVAEYULLAJMQX-UHFFFAOYSA-N 0.000 description 1
- MXZDMUOYQBHOCH-UHFFFAOYSA-N 2-amino-n-butylbenzamide Chemical compound CCCCNC(=O)C1=CC=CC=C1N MXZDMUOYQBHOCH-UHFFFAOYSA-N 0.000 description 1
- SJLLZWMNPJCLBC-UHFFFAOYSA-N 3-(3-methylphenyl)prop-2-enal Chemical compound CC1=CC=CC(C=CC=O)=C1 SJLLZWMNPJCLBC-UHFFFAOYSA-N 0.000 description 1
- XYRAWLRFGKLUMW-UHFFFAOYSA-N 3-(4-bromophenyl)prop-2-enal Chemical compound BrC1=CC=C(C=CC=O)C=C1 XYRAWLRFGKLUMW-UHFFFAOYSA-N 0.000 description 1
- YURDCJXYOLERLO-UHFFFAOYSA-N 5-Methyl-2-phenyl-2-hexenal Natural products CC(C)CC=C(C=O)C1=CC=CC=C1 YURDCJXYOLERLO-UHFFFAOYSA-N 0.000 description 1
- QSCTYRUNBGLXCC-UHFFFAOYSA-N 7-chloro-2-(2-phenylethyl)-3H-quinazolin-4-one Chemical compound ClC1=CC=C2C(NC(=NC2=C1)CCC1=CC=CC=C1)=O QSCTYRUNBGLXCC-UHFFFAOYSA-N 0.000 description 1
- NLNHLMFYYNUQGO-UHFFFAOYSA-N 7-methyl-2-(2-phenylethyl)-3H-quinazolin-4-one Chemical compound CC1=CC=C2C(NC(=NC2=C1)CCC1=CC=CC=C1)=O NLNHLMFYYNUQGO-UHFFFAOYSA-N 0.000 description 1
- KKVZAVRSVHUSPL-GQCTYLIASA-N Cassiastearoptene Chemical compound COC1=CC=CC=C1\C=C\C=O KKVZAVRSVHUSPL-GQCTYLIASA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- ACWQBUSCFPJUPN-UHFFFAOYSA-N Tiglaldehyde Natural products CC=C(C)C=O ACWQBUSCFPJUPN-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- HMKKIXGYKWDQSV-KAMYIIQDSA-N alpha-Amylcinnamaldehyde Chemical compound CCCCC\C(C=O)=C\C1=CC=CC=C1 HMKKIXGYKWDQSV-KAMYIIQDSA-N 0.000 description 1
- GUUHFMWKWLOQMM-NTCAYCPXSA-N alpha-hexylcinnamaldehyde Chemical compound CCCCCC\C(C=O)=C/C1=CC=CC=C1 GUUHFMWKWLOQMM-NTCAYCPXSA-N 0.000 description 1
- 229940072717 alpha-hexylcinnamaldehyde Drugs 0.000 description 1
- GUUHFMWKWLOQMM-UHFFFAOYSA-N alpha-n-hexylcinnamic aldehyde Natural products CCCCCCC(C=O)=CC1=CC=CC=C1 GUUHFMWKWLOQMM-UHFFFAOYSA-N 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- AJIBZRIAUXVGQJ-UHFFFAOYSA-N bicyclo[2.2.1]hept-2-ene-5-carbaldehyde Chemical compound C1C2C(C=O)CC1C=C2 AJIBZRIAUXVGQJ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 1
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 1
- DCFDVJPDXYGCOK-UHFFFAOYSA-N cyclohex-3-ene-1-carbaldehyde Chemical compound O=CC1CCC=CC1 DCFDVJPDXYGCOK-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- KKVZAVRSVHUSPL-UHFFFAOYSA-N o-methoxycinnamic aldehyde Natural products COC1=CC=CC=C1C=CC=O KKVZAVRSVHUSPL-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了一种从邻氨基苯甲酰胺和不饱和醛合成喹唑啉酮的方法。在反应容器中,加入邻氨基苯甲酰胺、过渡金属催化剂,甲苯和不饱和醛,反应混合物在110‑120℃下反应10‑12小时后,冷却到室温;然后通过分离,得到目标化合物。本发明使用容易获得的邻氨基苯甲酰胺和不饱和醛为起始原料,反应只生成水作为副产物,反应原子经济性高,因此,该反应符合绿色化学的要求,具有广阔的发展前景。
Description
技术领域
本发明属有机合成化学技术领域,具体涉及一种喹唑啉酮的方法。
背景技术
喹唑啉酮代表一类重要的含氮杂环骨架,它们存在于150多种天然存在的生物碱中,例如Rutaecarppine,Bouchardatine,Luotonin F,Sildenafil and Raltirexed((a)S.B.Mhaske,N.P.Argade,Tetrahedron,2006,62,9787–9826.(b)I.Khan,A.Ibrar,N.Abbas,A.Saeed,Eur.J.Med.Chem.2014,76,193-194 4)。
这类化合物也展现出广泛的生物活性,例如抗菌,抗病毒,抗过敏,抗肿瘤等等。(a)Kung,P.P.;Casper,M.D.;Cook,K.L.;Wilson-Lingard,L.;Risen,L.M.;Vickers,T.A.;Ranken,R.;Blyn,L.B.;Wyatt,R.;Cook,P.D.;Ecker,D.J.J.Med.Chem.1999,42,4705-4713.Liverton,N.J.;Armstrong,D.J.;Claremon,D.A.;Remy,D.C.;Baldwin,J.J.;Lynch,R.J.;Zhang,G.;Gould,R.J.Bioorg.Med.Chem.Lett.1998,8,483-487.b)Z.W.Wang,M.X.Wang,X.Yao,Y.Li,J.Tan,L.Z.Wang,W.T.Qiao,Y.Q.Geng,Y.X.Liu and Q.M.Wang,Eur.J.Med.Chem.,2012,53,275-282.c)Laszlo,S.E.;Quagliato,C.S.;Greenlee,W.J.;Patchett,A.A.;Chang,R.S.L.;Lotti,V.J.;Chen,T.B.;Scheck,S.A.;Faust,K.A.;Kivlighn,S.S.;Schorn,T.S.;Zingaro,G.J.;Siegl,P.K.S.J.Med.Chem.1993,36,3207-3210.d)M.M.Aly,Y.A.Mohamed,K.A.El-Bayouki,W.M.Basyouni,S.Y.Abbas,Eur.J.Med.Chem.,2010,45,3365-3373.e)Kobayashi,S.;Ueno,M.;Suzuki,R.;Ishitani,H.Tetrahedron Lett.1999,40,2175-2178.f)Cao,S.L.;Feng,Y.P.;Jiang,Y.Y.;Liu,S.Y.;Ding,G.Y.;Li,R.T.Bioorg.Med.Chem.Lett.2005,15,1915-1917)
传统上,这类化合物是通过邻氨基苯甲酰胺和醛发生缩合反应生成中间体,然后再发生 氧化反应来合成。尽管目前还广泛使用,这种方法要求当量或过量的有毒或者有害氧化剂,如KMnO4,MnO2,CuCl,DDQ,I2,t-BuOOH and PhI(OAc)2。反应也不可避免的生成大量副产物。
从可持续化学的角度,发展一个新的方法从更容易获得的原料在更环境友好的条件来合成喹唑啉酮显然是紧迫和很有意义的工作。
发明内容
本发明的目的在于提供一种合成喹唑啉酮的方法。
本发明通过下述技术方案实现:合成喹唑啉酮(式Ⅰ)的方法,
其包含邻氨基苯甲酰胺(式Ⅱ)
与不饱和醛(式III)
发生缩合反应生成含双键的2,3-二氢喹唑啉-4(3H)-酮(式IV)后
反应发生脱氢转移加氢反应
反应是在过渡金属催化剂存在下发生,其反应通式为
其中,R1选自甲基、甲氧基、卤素、三氟甲基;
R2代表烷基、苯基、甲基苯基、甲氧基苯基、卤代苯基、呋喃基、蒽基;
R3选自氢、烷基;
本发明合成喹唑酮的方法通过下述具体步骤实现:
氮气保护下,在反应容器中,加入邻氨基苯甲酰胺,过渡金属催化剂,溶剂甲苯,不饱和醛;反应混合物在110-120℃下反应10-12小时后,冷却到室温;然后通过分离,得到目标化合物。
其中所述的过渡金属催化剂为金属铱络合物[Cp*IrCl2]2(Cp*=pentamethylcyclopentadienyl),过渡金属催化剂的用量为邻氨基苯甲酰胺的1mol%,不饱和醛的摩尔量为邻氨基苯腈摩尔量的1.0-1.5equiv.。
同现有技术相比,本发明从邻氨基苯甲酰胺和不饱和醛作为起始原料,在过渡金属催化剂的参与下发生氢自动转移,得到喹唑啉酮,反应展现出三个显著的优点:1)使用商品化、容易获得的邻氨基苯甲酰胺和不饱和醛为起始原料;2)反应只生成水作为副产物;3)反应原子经济性高;因此,该反应符合绿色化学的要求,具有广阔的发展前景。
具体实施方式
展示一下实例来说明本发明的某些实施例,且不应解释为限制本发明的范围。对本发明 公开的内容可以同时从材料,方法和反应条件上进行许多改进,变化和改变。所有这些改进,变化和改变均确定地落入本发明的精神和范围之内。
实施例1:2-苯乙基喹唑啉-4(3H)-酮
2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:90%。
1H NMR(500MHz,DMSO-d6)δ12.26(br s,1H),8.08(d,J=7.2Hz,1H),7.78(t,J=6.7Hz,1H),7.62(d,J=7.6Hz,1H),7.46(t,J=6.6Hz,1H),7.30-7.26(m,4H),7.21-7.17(m,1H),3.05(t,J=7.3Hz,2H),2.89(t,J=7.3Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.7,156.5,148.8,140.7,134.3,128.3,126.8,126.0,126.0,125.7,120.8,36.3,32.4.
实施例2:2-(3-甲苯苯乙基)喹唑啉-4(3H)-酮
2-(3-methylphenethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),间甲基肉桂醛(146mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:88%。
1H NMR(500MHz,DMSO-d6)δ12.24(br s,1H),8.08(d,J=7.4Hz,1H),7.78(t,J=7.6Hz,1H),7.62(d,J=8.1Hz,1H),7.46(t,J=7.3Hz,1H),7.16(t,J=7.6Hz,1H),7.10(s,1H),7.05(d,J=7.5Hz,1H),7.00(d,J=7.2Hz,1H),3.01(t,J=8.0Hz,2H),2.87(t,J=8.0Hz,2H),2.26(s,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,156.6,148.9,140.6,137.3,134.3,129.0,128.2, 126.8,126.7,126.0,125.7,125.3,120.8,36.3,32.4,21.0.HRMS-EI(70eV)m/z cacld for C17H16N2ONa[M+Na]+287.1160,found 287.1166.
实施例3:2-(2-甲氧基苯乙基)喹唑啉-4(3H)-酮
2-(2-methoxyphenethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),邻甲氧基肉桂醛(162mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:91%。
1H NMR(500MHz,DMSO-d6)δ12.20(br s,1H),8.09(d,J=7.7Hz,1H),7.78(t,J=7.6Hz,1H),7.62(d,J=8.1Hz,1H),7.46(t,J=7.4Hz,1H),7.20-7.18(m,2H),6.95(d,J=8.5Hz,1H),6.86(t,J=7.3Hz,1H),3.76(s,3H),3.03(t,J=7.8Hz,2H),2.85(t,J=7.8Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.7,157.1,156.8,148.8,134.2,129.5,128.4,127.5,126.8,125.9,125.6,120.8,120.2,110.6,55.2,34.5,27.0.HRMS-EI(70eV)m/zcacld for C17H15N2O2[M-H]-279.1134,found 279.1140.
实施例4:2-(3-甲氧基苯乙基)喹唑啉-4(3H)-酮
2-(3-methoxyphenethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),间甲氧基肉桂醛(162mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:86%。
1H NMR(500MHz,DMSO-d6)δ12.24(br s,1H),8.08(d,J=7.7Hz,1H),7.78(t,J=7.4Hz, 1H),7.62(d,J=8.1Hz,1H),7.47(t,J=7.4Hz,1H),7.19(t,J=7.8Hz,1H),6.83-6.86(m,2H),6.75(d,J=7.8Hz,1H),3.71(s,3H),3.02(t,J=7.8Hz,2H),2.89(t,J=7.8Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,159.3,156.6,148.8,142.3,134.3,129.3,126.8,126.0,125.7,120.8,120.5,114.0,111.6,54.8,36.2,32.5.
实施例5:2-(4-氟苯乙基)喹唑啉-4(3H)-酮
2-(4-fluorophenethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),对氟肉桂醛(150mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:82%。
1H NMR(500MHz,DMSO-d6)δ12.25(br s,1H),8.08(d,J=7.9Hz,1H),7.78(t,J=7.6Hz,1H),7.61(d,J=8.1Hz,1H),7.46(t,J=7.5Hz,1H),7.32-7.30(m,2H),7.10(t,J=8.8Hz,2H),3.04(t,J=8.0Hz,2H),2.88(t,J=8.0Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.7,159.8,156.4,148.8,136.8,134.3,130.1(d,JC-F=7.7Hz),126.8,126.0,125.7,120.8,115.0(d,JC-F=21.0Hz),36.4,31.6.HRMS-EI(70eV)m/z cacld for C16H13N2OFNa[M+Na]+291.0910,found291.0917.
实施例6:2-(4-溴苯乙基)喹唑啉-4(3H)-酮
2-(4-bromophenethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(2.0mL),对溴肉桂醛(211mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:77%。
1H NMR(500MHz,DMSO-d6)δ12.23(br s,1H),8.08(d,J=7.8Hz,1H),7.78(t,J=7.8Hz,1H),7.61(d,J=8.1Hz,1H),7.48-7.45(m,3H),7.24(d,J=8.3Hz,2H),3.03(t,J=7.9Hz,2H),2.88(t,J=7.9Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.7,156.3,148.8,140.2,134.3,131.2,130.6,126.8,126.0,125.7,120.8,119.1,35.9,31.7.HRMS-EI(70eV)m/z cacld for C16H14BrN2O[M+H]-329.0290,found 329.0284.
实施例7:2-(1-苯基-2-丙基)喹唑啉-4(3H)-酮
2-(1-phenylpropan-2-yl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),α-甲基肉桂醛(146mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:80%。
1H NMR(500MHz,DMSO-d6)δ12.21(br s,1H),8.07(d,J=7.6Hz,1H),7.77(t,J=7.2Hz,1H),7.63(d,J=8.1Hz,1H),7.46(t,J=7.4Hz,1H),7.26-7.20(m,4H),7.15(t,J=7.0Hz,1H),3.15(dd,J=13.2Hz,J=7.2Hz,1H),3.05(sext,J=7.0Hz,1H),2.77(dd,J=13.2Hz,J=7.8Hz,1H),1.21(d,J=6.8Hz,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,160.4,148.8,139.7,134.3,128.9,128.2,126.9,126.1,126.0,125.6,120.9,40.6,40.2,18.2.HRMS-EI(70eV)m/z cacld for C17H16N2ONa[M+Na]+287.1160,found 287.1165.
实施例8:2-(1-苯基-2-庚基)喹唑啉-4(3H)-酮
2-(1-phenylheptan-2-yl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),α-戊基肉桂醛(202mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:84%。
1H NMR(500MHz,DMSO-d6)δ12.12(br s,1H),8.05(d,J=7.8Hz,1H),7.76(t,J=7.5Hz,1H),7.62(d,J=7.9Hz,1H),7.44(t,J=7.4Hz,1H),7.20(t,J=7.2Hz,2H),7.15-7.10(m,3H),3.09(dd,J=12.7Hz,J=8.7Hz,1H),2.99-2.94(m,1H),2.87(dd,J=13.0Hz,J=6.2Hz,1H),1.84-1.78(m,1H),1.59-1.54(m,1H),1.24-1.12(m,6H),0.80-0.73(m,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,159.8,148.9,139.6,134.6,128.8,128.2,126.9,126.0,125.9,125.7,120.7,46.5,39.3,32.8,31.1,26.3,21.8,13.8.HRMS-EI(70eV)m/zcacld for C21H23N2O[M-H]-319.1810,found 319.1816.
实施例9:2-(1-苯基-2-辛基)喹唑啉-4(3H)-酮
2-(1-phenyloctan-2-yl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),α-己基肉桂醛(216mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:88%。
1H NMR(500MHz,DMSO-d6)δ12.13(br s,1H),8.05(d,J=8.1Hz,1H),7.77(t,J=7.6Hz,1H),7.62(d,J=8.1Hz,1H),7.45(t,J=7.3Hz,1H),7.21(t,J=7.5Hz,2H),7.16-7.11(m,3H),3.10(dd,J=13.6Hz,J=8.5Hz,1H),3.00-2.94(m,1H),2.87(dd,J=13.4Hz,J=6.5Hz,1H),1.84-1.78(m,1H),1.60-1.54(m,1H),1.24-1.12(m,8H),0.79(t,J=6.9Hz,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.7,159.7,148.9,139.6,134.2,128.7,128.1,126.9,125.9,125.8,125.6,120.7,46.4,39.2,32.8,30.9,28.4,26.6,21.9,13.7.HRMS-EI(70eV)m/z cacld for C22H25N2O[M-H]-333.1967,found 333.1975.
实施例10:2-(2-(10-蒽基)乙基)喹唑啉-4(3H)-酮
2-(2-(anthracen-10-yl)ethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(5.0mL),9-蒽丙烯醛(232mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:81%。
1H NMR(500MHz,DMSO-d6)δ12.46(br s,1H),8.54(s,1H),8.47(d,J=8.7Hz,2H),8.12(t,J=8.2Hz,3H),7.82(t,J=7.4Hz,1H),7.72(d,J=8.1Hz,1H),7.58(t,J=7.4Hz,2H),7.55-7.48(m,3H),4.08(t,J=8.1Hz,2H),3.04(t,J=8.1Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.9,156.6,149.0,134.3,132.8,131.1,129.2,129.0,126.9,126.1,126.0,126.0,125.7,125.1,124.2,120.9,35.9,25.0.HRMS-EI(70eV)m/z cacld for C24H17N2O[M-H]-349.1341,found349.1348.
实施例11:2-(2-(2-呋喃基)乙基)喹唑啉-4(3H)-酮
2-(2-(furan-2-yl)ethyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),2-呋喃丙烯醛(122mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:87%。
1H NMR(500MHz,DMSO-d6)δ12.26(br s,1H),8.08(d,J=7.6Hz,1H),7.78(t,J=7.2Hz,1H),7.61(d,J=8.1Hz,1H),7.52(s,1H),7.46(t,J=7.5Hz,1H),6.34(s,1H),6.13(d,J=2.6Hz,1H),3.11(t,J=7.7Hz,2H),2.93(t,J=7.7Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.7,156.1,154.1,148.8,141.5,134.3,126.8,126.0,125.7,120.9,110.4,105.5,32.8,24.6.
实施例12:2-(1-苯丁基)喹唑啉-4(3H)-酮
2-(1-phenylbutyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),2-苯基-2-戊烯醛(160mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:83%。
1H NMR(500MHz,DMSO-d6)δ12.27(br s,1H),8.06(d,J=6.1Hz,1H),7.78(t,J=6.4Hz,1H),7.68(d,J=5.8Hz,1H),7.47-7.41(m,3H),7.31(t,J=5.7Hz,2H),7.24-7.19(m,1H),3.96-3.92(m,1H),2.30-7.20(m,1H),1.98-1.84(m,1H),1.31-1.15(m,2H),0.94-0.81(m,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,158.5,148.8,141.0,134.3,128.4,127.8,127.1,126.9,126.2,125.7,120.8,49.3,35.4,20.2,13.7.HRMS-EI(70eV)m/zcacld for C18H17N2O[M-H]-277.1341,found 277.1347.
实施例13:2-(4-甲基-1-苯戊基)喹唑啉-4(3H)-酮
2-(4-methyl-1-phenylpentyl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),5-甲基-2-苯基-2-己烯醛(188mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:89%。
1H NMR(500MHz,DMSO-d6)1H NMR(500MHz,DMSO-d6)δ12.25(br s,1H),8.06(d,J=7.6Hz,1H),7.78(t,J=7.2Hz,1H),7.67(d,J=7.5Hz,1H),7.47-7.43(m,3H),7.31(t,J=7.2Hz,2H),7.22(t,J=6.8Hz,1H),3.87(t,J=7.4Hz,1H),2.30-7.23(m,1H),1.98-1.89(m,1H),1.57-1.50(m,1H),1.17-1.04(m,2H),0.86(t,J=5.9Hz,6H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,158.5,148.8,141.1,134.4,128.4,127.8,127.2,126.9,126.2,125.7,120.8,49.9,36.3,31.1,27.3,22.4.HRMS-EI(70eV)m/z cacld for C20H21N2O[M-H]-305.1654,found 305.1660.
实施例14:2-丙基喹唑啉-4(3H)-酮
2-propylquinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),巴豆醛(105mg,1.5mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:84%。
1H NMR(500MHz,DMSO-d6)δ12.15(br s,1H),8.07(d,J=8.0Hz,1H),7.76(t,J=7.5Hz,1H),7.59(d,J=8.2Hz,1H),7.45(t,J=7.6Hz,1H),2.57(t,J=7.6Hz,2H),1.74(sext,J=7.4Hz,2H),0.93(t,J=7.4Hz,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.8,157.3,148.9,134.2,126.8,125.9,125.6,120.8,36.3,20.2,13.4.
实施例15:2-(2-戊基)喹唑啉-4(3H)-酮
2-(pentan-2-yl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),2-甲基-2-戊烯醛(98mg,1.0mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:80%。
1H NMR(500MHz,DMSO-d6)δ12.11(br s,1H),8.08(d,J=7.7Hz,1H),7.77(t,J=7.5Hz,1H),7.60(d,J=8.1Hz,1H),7.45(t,J=7.4Hz,1H),2.76(sext,J=6.9Hz,1H),1.82-1.74(m,1H),1.54-1.47(m,1H),1.35-1.14(m,5H),0.86(t,J=7.3Hz,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.9,161.1,148.9,134.1,126.9,125.8,125.6,120.8,38.5,36.6,19.9,18.5,13.8.
实施例16:2-(3-庚基)喹唑啉-4(3H)-酮
2-(heptan-3-yl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),2-乙基-2-己烯醛(126mg,1.0mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:86%。
1H NMR(500MHz,DMSO-d6)δ12.12(br s,1H),8.08(d,J=7.7Hz,1H),7.76(t,J=7.4Hz,1H),7.61(d,J=8.0Hz,1H),7.45(t,J=7.4Hz,1H),2.58-2.52(m,1H),1.80-1.71(m,2H),1.64-1.54(m,2H),1.28-1.18(m,3H),1.13-1.07(m,1H),0.82-0.78(m,6H);13C{1H}NMR(125MHz,DMSO-d6)δ161.9,160.3,149.0,134.2,126.9,125.8,125.6,120.8,46.4,32.6,29.1,26.3,22.1,13.7,11.7.
实施例17:2-环己基喹唑啉-4(3H)-酮
2-cyclohexylquinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),3-环己烯甲醛(110mg,1.0mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:89%。
1H NMR(500MHz,DMSO-d6)δ12.06(br s,1H),8.07(d,J=7.5Hz,1H),7.76(t,J=6.9Hz,1H),7.59(d,J=7.9Hz,1H),7.45(t,J=7.2Hz,1H),2.57(t,J=11.4Hz,1H),1.90(d,J=11.4Hz,2H),1.79(d,J=12.1Hz,2H),1.68(d,J=10.8Hz,1H),1.62-1.54(m,2H),1.34-1.21(m,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.9,160.7,148.9,134.2,126.9,125.9,125.6,120.9,42.8,30.2,25.5,25.3.
实施例18:2-(二环[2.2.1]-2-庚基)喹唑啉-4(3H)-酮
2-(bicyclo[2.2.1]heptan-2-yl)quinazolin-4(3H)-one
氮气保护下,将2-氨基苯甲酰胺(136mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),5-降冰片烯-2-甲醛(122mg,1.0mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:87%。
1H NMR(500MHz,DMSO-d6):δ12.13(br s,1H),8.06(d,J=8.0Hz,1H),7.75(t,J=7.7Hz,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=7.5Hz,1H),2.68(quart,J=3.5Hz,1H),2.45(d,J=3.0Hz,1H),2.32-2.29(m,1H),2.25-2.20(m,1H),1.58-1.45(m,4H),1.34(t,J=10.5Hz,1H),1.25-1.20(m,1H),1.08(d,J=9.2Hz,1H);13C{1H}NMR(125MHz,DMSO-d6)δ161.9,169.7,148.6,134.1,127.1,125.9,125.6,120.8,45.5,42.3,35.7,35.3,33.3,29.3,28.4.HRMS-EI(70eV)m/z cacld for C15H15N2O[M-H]-239.1184,found 239.1190.
实施例19:7-甲基-2-苯乙基喹唑啉-4(3H)-酮
7-methyl-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-4-甲基苯甲酰胺(150mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:80%。
1H NMR(500MHz,DMSO-d6)δ12.16(br s,1H),7.96(d,J=8.0Hz,1H),7.43(s,1H),7.30-7.26(m,5H),7.21-7.17(m,1H),3.04(t,J=7.8Hz,2H),2.88(t,J=7.8Hz,2H),2.44(s,3H);13C{1H}NMR(125MHz,DMSO-d6)δ161.6,156.5,149.0,144.7,140.7,128.3(2C),127.4,126.5,126.0,125.5,118.4,36.2,32.4,21.3.HRMS-EI(70eV)m/z cacld forC17H16N2ONa[M+Na]+287.1160,found 287.1168.
实施例20:6-甲氧基-2-苯乙基喹唑啉-4(3H)-酮
6-methoxy-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-5-甲氧基苯甲酰胺(166mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(5.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:77%。
1H NMR(500MHz,DMSO-d6):δ12.22(br s,1H),7.57(d,J=8.8Hz,1H),7.47(s,1H),7.38(d,J=8.7Hz,1H),7.31-7.24(m,4H),7.21-7.17(m,1H),3.85(s,3H),3.03(t,J=7.8Hz,2H),2.87(t,J=7.8Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.6,157.2,154.1,143.3,140.8,128.5,128.3(2C),126.0,123.7,121.5,105.7,55.5,36.1,32.5.HRMS-EI(70eV)m/z cacld for C17H17N2O2[M+H]+281.1290,found 281.1298.
实施例21:6-氯-2-苯乙基喹唑啉-4(3H)-酮
6-chloro-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-5-氯苯甲酰胺(171mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:84%。
1H NMR(500MHz,DMSO-d6):δ12.44(br s,1H),8.01(d,J=2.2Hz,1H),7.80(dd,J=8.7Hz,J=2.4Hz,1H),7.64(d,J=8.7Hz,1H),7.30-7.25(m,4H),7.21-7.17(m,1H),3.04(t,J=8.0Hz,2H),2.89(t,J=8.0Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ160.7,157.2,147.5,140.6,134.3,130.2,129.0,128.3,128.3,126.1,124.7,122.1,36.3,32.3.
实施例22:7-氯-2-苯乙基喹唑啉-4(3H)-酮
7-chloro-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-4-氯苯甲酰胺(171mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:86%。
1H NMR(500MHz,DMSO-d6)δ12.39(br s,1H),8.07(d,J=6.9Hz,1H),7.67(s,1H),7.50(d,J=6.1Hz,1H),7.33-7.23(m,4H),7.22-7.15(m,1H),3.04(s,2H),2.90(s,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.1,158.3,149.9,140.6,138.9,128.3,128.3,127.8,126.3,126.1,125.9,119.6,36.3,32.3.
实施例23:6-溴-2-苯乙基喹唑啉-4(3H)-酮
6-bromo-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-5-溴苯甲酰胺(215mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:83%。
1H NMR(500MHz,DMSO-d6)δ12.45(br s,1H),8.16(d,J=2.1Hz,1H),7.92(dd,J=8.6Hz,J=2.1Hz,1H),7.58(d,J=8.6Hz,1H),7.31-7.26(m,4H),7.19(t,J=6.5Hz,1H),3.05(t,J=8.0Hz,2H),2.89(t,J=8.0Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ160.6,157.4,147.7,140.6,137.1,129.2,128.3,128.3,127.8,126.1,122.4,118.3,36.3,32.3.
实施例24:7-三氟甲基-2-苯乙基喹唑啉-4(3H)-酮
7-trifluoromethyl-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-4-三氟甲基苯甲酰胺(204mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:86%。
1H NMR(500MHz,DMSO-d6)δ12.58(br s,1H),8.28(d,J=8.2Hz,1H),7.94(s,1H),7.77(d,J=8.2Hz,1H),7.31-7.27(m,4H),7.22-7.18(m,1H),3.07(t,J=8.0Hz,2H),2.93(t,J=8.0Hz,2H);13C{1H}NMR(125MHz,DMSO-d6)δ161.0,158.5,148.8,140.5,134.0(q,JC-F=32.1Hz),128.3,128.3,127.5,126.1,123.8,123.6,123.5(q,JC-F=272.0Hz),121.7,36.3,32.3.HRMS-EI(70eV)m/z cacld for C17H14N2OF3[M+H]+319.1058,found 319.1067.
实施例25:3-苄基-2-苯乙基喹唑啉-4(3H)-酮
3-benzyl-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-N-苄基苯甲酰胺(226mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:84%。
1H NMR(500MHz,DMSO-d6)δ8.32(d,J=8.0Hz,1H),7.76(t,J=7.6Hz,1H),7.71(d,J=8.0Hz,1H),7.48(t,J=7.6Hz,1H),7.32-7.24(m,5H),7.20(t,J=7.3Hz,1H),7.14(d,J=7.4Hz,4H),5.35(s,2H),3.11(t,J=8.0Hz,2H),3.04(t,J=8.0Hz,2H);13C{1H}NMR(125MHz,CDCl3)δ162.5,156.3,147.3,140.5,136.1,134.3,128.9,128.5,128.4,127.6,127.1,127.0,126.6,126.4,126.3,120.4,46.2,36.6,33.1.HRMS-EI(70eV)m/z cacld forC23H21N2O[M+H]+341.1654,found 341.1649.
实施例26:3-丁基-2-苯乙基喹唑啉-4(3H)-酮
3-butyl-2-phenethylquinazolin-4(3H)-one
氮气保护下,将2-氨基-N-丁基苯甲酰胺(192mg,1mmol),[Cp*IrCl2]2(8mg,0.01mmol,1mol%),甲苯(1.0mL),肉桂醛(132mg,1mmol)依次加到25mL Schlenk反应瓶中。混合物在120℃下反应12小时后,冷却到室温。真空减压除去溶剂,然后通过柱层析(展开剂:乙酸乙酯/石油醚)得到纯净的目标化合物,产率:82%。
1H NMR(500MHz,DMSO-d6)δ8.26(d,J=7.9Hz,1H),7.73(t,J=7.4Hz,1H),7.67(d,J=8.1Hz,1H),7.44(t,J=7.4Hz,1H),7.35-7.23(m,5H),4.04(t,J=7.8Hz,2H),3.22(t,J=7.9Hz,2H),3.12(t,J=7.9Hz,2H),1.68-1.63(m,2H),1.42(sext,J=7.5Hz,2H),0.96(t,J=7.4Hz,3H);13C{1H}NMR(125MHz,CDCl3)δ162.2,155.8,147.2,140.7,134.0,128.7,128.4,126.8,126.7,126.4,126.4,120.5,43.5,36.7,33.4,31.0,20.3,13.7.HRMS-EI(70eV)m/z cacld for C20H23N2O[M+H]+307.1810,found 307.1805. 。
Claims (3)
1.一种合成如式I所示的喹唑啉酮衍生物的方法,其特征在于,
是通过邻氨基苯甲酰胺Ⅱ
与不饱和醛III
发生缩合反应,生成含双键的2,3-二氢喹唑啉-4(3H)-酮IV后
再发生脱氢转移加氢反应,
其中,R1选自甲基、甲氧基、卤素、三氟甲基;
R2代表烷基、苯基、甲基苯基、甲氧基苯基、卤代苯基、呋喃基、蒽基;
R3选自氢、烷基;
包括如下步骤:氮气保护下,在反应容器中,加入邻氨基苯甲酰胺,过渡金属催化剂,溶剂甲苯,不饱和醛;反应混合物在110-120℃下反应,反应结束后冷却到室温;然后通过分离,得到目标化合物;
其中,过渡金属催化剂为金属铱络合物[Cp*IrCl2]2,Cp*=pentamethylcyclopentadienyl。
2.根据权利要求1所述的方法,其特征是,过渡金属催化剂用量相对于邻氨基苯酰胺为1mol%,不饱和醛摩尔量相对于邻氨基苯酰胺摩尔量为1.0-1.5equiv.。
3.根据权利要求1所述的方法,其特征是,反应时间为10-12小时。
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Benign and Efficient Synthesis of 2-Substituted 4(3H)-Quinazolinones Mediated by Iron(III) Chloride Hexahydrate in Refluxing Water;Guan-Wu Wang et al.;《Bull.Chem.Soc.Jpn.》;20060905;第79卷(第9期);1426-1430 * |
Efficient syntheses of 2,3-disubstituted natural quinazolinones via iridium catalysis;Jie Fang et al.;《Org.Biomol.Chem.》;20120125;第10卷;2389-2391 * |
One-Pot Synthesis of Quinazolinones via Iridium-Catalyzed Hydrogen Transfers;Jianguang Zhou et al.;《J.Org.Chem.》;20110818;第76卷;7730-7736 * |
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