1-甲基-5,6,7,8-四氢异喹啉酮-4-甲胺的合成研究
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摘要
以环己酮为起始原料,经缩合、酰化及酸性水解反应制得2-乙酰基环己酮(1);在三乙烯二胺催化下,1与氰基乙酰胺环化得四氢异喹啉酮(2)和四氢喹啉酮(3)混合物,在乙醇中回流并趁热过滤进行分离纯化得2和3; 2经催化加氢反应合成1-甲基-5,6,7,8-四氢异喹啉酮-4-甲胺,3步总收率39.8%,其结构经1H NMR、13C NMR、1H-15N HMBC和MS确证。
2-Acetyl-cyclohexanone(1) was prepared by condensation,acylation and acidic hydrolysis reaction using cyclohexanone as the starting material.The mixture of 1-methyl-3-oxo-2,3,5,6,7,8-hexahydro-isoquinoline-4-carbonitrile(2) and 4-methyl-2-oxo-1,2,5,6,7,8-hexahydro-quinoline-3-carbonitrile(3) were obtained by reaction of 2-cyano-acetamide with 1 in ethanol,using 1,4-diaza-bicyclo[2.2.2]octane as base.2 was separated from 3 by reflux in ethanol and filtration,and then hydrogenated in methanol catalyzed by Raney nickel to afford 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile with total yield of 39.4%.The structure was confirmed by ~1H NMR,~(13)C NMR,~1H-~(15)N HMBC and MS.
2-Acetyl-cyclohexanone(1) was prepared by condensation,acylation and acidic hydrolysis reaction using cyclohexanone as the starting material.The mixture of 1-methyl-3-oxo-2,3,5,6,7,8-hexahydro-isoquinoline-4-carbonitrile(2) and 4-methyl-2-oxo-1,2,5,6,7,8-hexahydro-quinoline-3-carbonitrile(3) were obtained by reaction of 2-cyano-acetamide with 1 in ethanol,using 1,4-diaza-bicyclo[2.2.2]octane as base.2 was separated from 3 by reflux in ethanol and filtration,and then hydrogenated in methanol catalyzed by Raney nickel to afford 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile with total yield of 39.4%.The structure was confirmed by ~1H NMR,~(13)C NMR,~1H-~(15)N HMBC and MS.
引文
[1]ABDELRAZEK F M,ELSAYED A N.About the reaction ofβ-dimethylamino-α,β-enones with active methylene nitriles[J].Journal of Heterocyclic Chemistry,2009,46(5):949-953.
[2]YERMOLAYEV S A,GOROBETS N Y,LUKINOVAE V,et al.An efficient synthesis of N1-substituted 2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide via enolate salts[J].Tetrahedron,2008,64(20):4649-4655.
[3]GIBSON K R,HITZEL L,MORTISHIRE-SMITH RJ,et al.Synthesis and conformational dynamics of tricyclic pyridones containing a fused seven-membered ring[J].The Journal of organic chemistry,2002,67(26):9354-9360.
[4]PASTELIN G,MENDEZ R,KABELA E,et al.The search for a digitalis substitute II milrinone(Win47203)its action on the heart-lung preparation of the dog[J].Life sciences,1983,33(18):1787-1796.
[5]ANGIBAUD P R,VENET M G,FILLIERS W,et al.Synthesis routes towards the farnesyl protein transferase inhibitor ZARNESTRATM[J].European Journal of Organic Chemistry,2004,2004(3):479-486.
[6]CARLES L,NARKUNAN K,PENLOU S,et al.2-Pyridones from cyanoacetamides and enecarbonyl compounds:Application to the synthesis of nothapodytine B[J].The Journal of organic chemistry,2002,67(12):4304-4308.
[7]ALOUIA A,CANTER J M,MONTENARO M J,et al.Cardiotonic activity of milrinone,a new and potent cardiac bipyridine,on the normal and failing heart of experimental animals[J].Journal of cardiovascular pharmacology,1983,5(5):792-803.
[8]DOBBIN P S,HIDER R C,HALL A D,et al.Synthesis,physicochemical properties,and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones:Orally active iron chelators with clinical potential[J].Journal of medicinal chemistry,1993,36(17):2448-2458.
[9]FARAH A E,ALOUSI A A.New cardiotonic agents:A search for digitalis substitute[J].Life sciences,1978,223-1(15):1139-1147.
[10]SUAREZ M,OCHOA E,VERDECIA Y,et al.Ajoint experimental and theoretical structural study of novel substituted 2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinolines[J].Tetrahedron,1999,55(3):875-884.
[11]COLLINS I,MOYES C,DAVEY W B,et al.3-Heteroaryl-2-pyridones:Benzodiazepine site ligands with functional selectivity forα2/α3-subtypes of human GABAA receptor-ion channels[J].Journal of medicinal chemistry,2002,45(9):1887-1900.
[12]奉强,何华龙,余洛汀,等.1/2,5-二取代吲唑-3-甲酰胺衍生物的合成及其抗肿瘤活性[J].合成化学,2017,25(9):721-729.
[13]SONG X J,GAO T T,YU L T,et al.Selective inhibition of EZH2 by ZLD1039 blocks H3K27 methylation and leads to potent anti-tumor activity in breast cancer[J].Sci Rep,2016,6:20864.
[14]GAO T T,ZHANG L D,YU L T,et al.A novel EZH2 and EZH1 small molecular inhibitor,blocks H3K27 methylation and diffuse large B cell lymphoma cell growth[J].RSC Adv,2016,6(34):28512-28521.
[15]ZHANG L D,SONG X J,YU L T,et al.Design,synthesis and biological evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors[J].RSC Adv,2015,5:25967-25977.
[16]MOHAMED H,DIDIER V.Clay catalysis:Stork’s alkylation and acylation of cyclohexanone without isolation of enamine[J].Synthetic Communications,1996,26:2901-2904.
[17]YANG X B,LI F L,KONZE K D,et al.Structureactivity relationship studies for enhancer of zeste homologue 2(EZH2)and enhancer of zeste homologue 1(EZH1)inhibitors[J].J Med Chem,2016,59:7617-7633.
[2]YERMOLAYEV S A,GOROBETS N Y,LUKINOVAE V,et al.An efficient synthesis of N1-substituted 2,5-dioxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide via enolate salts[J].Tetrahedron,2008,64(20):4649-4655.
[3]GIBSON K R,HITZEL L,MORTISHIRE-SMITH RJ,et al.Synthesis and conformational dynamics of tricyclic pyridones containing a fused seven-membered ring[J].The Journal of organic chemistry,2002,67(26):9354-9360.
[4]PASTELIN G,MENDEZ R,KABELA E,et al.The search for a digitalis substitute II milrinone(Win47203)its action on the heart-lung preparation of the dog[J].Life sciences,1983,33(18):1787-1796.
[5]ANGIBAUD P R,VENET M G,FILLIERS W,et al.Synthesis routes towards the farnesyl protein transferase inhibitor ZARNESTRATM[J].European Journal of Organic Chemistry,2004,2004(3):479-486.
[6]CARLES L,NARKUNAN K,PENLOU S,et al.2-Pyridones from cyanoacetamides and enecarbonyl compounds:Application to the synthesis of nothapodytine B[J].The Journal of organic chemistry,2002,67(12):4304-4308.
[7]ALOUIA A,CANTER J M,MONTENARO M J,et al.Cardiotonic activity of milrinone,a new and potent cardiac bipyridine,on the normal and failing heart of experimental animals[J].Journal of cardiovascular pharmacology,1983,5(5):792-803.
[8]DOBBIN P S,HIDER R C,HALL A D,et al.Synthesis,physicochemical properties,and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones:Orally active iron chelators with clinical potential[J].Journal of medicinal chemistry,1993,36(17):2448-2458.
[9]FARAH A E,ALOUSI A A.New cardiotonic agents:A search for digitalis substitute[J].Life sciences,1978,223-1(15):1139-1147.
[10]SUAREZ M,OCHOA E,VERDECIA Y,et al.Ajoint experimental and theoretical structural study of novel substituted 2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinolines[J].Tetrahedron,1999,55(3):875-884.
[11]COLLINS I,MOYES C,DAVEY W B,et al.3-Heteroaryl-2-pyridones:Benzodiazepine site ligands with functional selectivity forα2/α3-subtypes of human GABAA receptor-ion channels[J].Journal of medicinal chemistry,2002,45(9):1887-1900.
[12]奉强,何华龙,余洛汀,等.1/2,5-二取代吲唑-3-甲酰胺衍生物的合成及其抗肿瘤活性[J].合成化学,2017,25(9):721-729.
[13]SONG X J,GAO T T,YU L T,et al.Selective inhibition of EZH2 by ZLD1039 blocks H3K27 methylation and leads to potent anti-tumor activity in breast cancer[J].Sci Rep,2016,6:20864.
[14]GAO T T,ZHANG L D,YU L T,et al.A novel EZH2 and EZH1 small molecular inhibitor,blocks H3K27 methylation and diffuse large B cell lymphoma cell growth[J].RSC Adv,2016,6(34):28512-28521.
[15]ZHANG L D,SONG X J,YU L T,et al.Design,synthesis and biological evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors[J].RSC Adv,2015,5:25967-25977.
[16]MOHAMED H,DIDIER V.Clay catalysis:Stork’s alkylation and acylation of cyclohexanone without isolation of enamine[J].Synthetic Communications,1996,26:2901-2904.
[17]YANG X B,LI F L,KONZE K D,et al.Structureactivity relationship studies for enhancer of zeste homologue 2(EZH2)and enhancer of zeste homologue 1(EZH1)inhibitors[J].J Med Chem,2016,59:7617-7633.