R-278995, CRA-0450
Chemical Name: 1-[8-(2,4-Dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate
CAS No. 388122-48-3 (free base)
项目整合开发状态: Preclinical
项目研究机构: Johnson & Johnson (Originator), Taisho (Originator)
合成路线:Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III).This is condensed with ethyl acetoacetate (IV) to produce enamine (V),which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI).Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII).Finally,displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound
合成路线:Alternatively,hydroxyquinoline (I) is chlorinated in refluxing POCl3 to provide chloroquinoline (II).Substitution of (II) with 4-piperidone ethylene ketal (III) in boiling DMF furnishes the piperidinyl quinoline derivative (IV),which is further hydrolyzed to piperidone (V) under acidic conditions.Addition of cyanide to piperidone (V) gives rise to cyanohydrin (VI),and subsequent dehydration by means of POCl3/pyridine affords the unsaturated nitrile (VII).Finally,partial hydrolysis of nitrile (VII) with HCl in formic acid leads to the target amide compound
合成路线:In a related synthetic strategy,8-bromo-4-hydroxy-2-methylquinoline (I) is converted to aryl triflate (II) by using N-phenyl trifluoromethanesulfonimide and NaH.Displacement of the triflate group of (II) with 1,2,3,6-tetrahydropyridine-4-carboxamide (III) gives the tetrahydropyridyl quinoline (IV).The bromoquinoline (IV) is finally subjected to Suzuki coupling with 2,4-dichlorophenylboronic acid (V) to produce the title compound
📌 参考资料/链接：
参考文献标题:Tetrahydropyridino or piperidino heterocyclic derivs.
文献作者:Kameo,K.; Kumagai,T.; Nakazato,A.; Okubo,T.(Taisho Pharmaceutical Co.,Ltd.)
参考来源:EP 1299378; WO 0202549
📄 详细内容
合成路线:Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III).This is condensed with ethyl acetoacetate (IV) to produce enamine (V),which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI).Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII).Finally,displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound
参考文献标题:Synthesis,SAR and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinoquinoline derivative
文献作者:Kennis,L.; Kumagai,T.; Nakazato,A.; et al.
参考来源:224th ACS Natl Meet (Aug 18 2002,Boston) 2002,Abst MEDI 258
合成路线:Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III).This is condensed with ethyl acetoacetate (IV) to produce enamine (V),which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI).Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII).Finally,displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound
参考文献标题:Chemical modification of 4-carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine,CRA0316,for discovery CRH1 receptor antagonists
文献作者:Nakazato,A.; et al.
参考来源:Drugs Fut 2002,27(Suppl.A),