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
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
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