Reaction Steps
tert-Butyl 4-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenoxy}piperidine-1-carboxylate (4.03 g) and 10% Palladium on carbon (0.4 g) were stirred in ethanol (90 ml) under an atmosphere of hydrogen gas. After cessation of hydrogen uptake, the catalyst was removed by filtration through diatomaceous earth (Celite®). The filtrate was concentrated under reduced pressure to provide the crude tert-butyl 4-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}piperidine-1-carboxylate (3.50 g) which was used without further purification; NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.70 (m, 2H), 1.40 (s, 9H), 1.52 (m, 2H), 1.38 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 3.18 (m, 2H), 3.64 (m, 2H), 4.36 (m, 1H), 6.03 (s, 21, 6.71 (d, 1H), 6.96 (d, 1H), 7.31 (d, 1H), 7.34 (s, 1H), 7.62 (d, 1H), 7.79 (s, 1H), 8.37 (d, 1H), 9.72 (s, 1H); Mass Spectrum: M+Na+ 531. C) Triethyl orthoformate (1.0 ml) was added to a stirred mixture of tert-butyl 4-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}piperidine-1-carboxylate (1.02 g) and glacial acetic acid (0.057 ml) in ethanol (15 ml). The mixture was heated to 80° C. and stirred for 2 hours and then concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, brine, dried (magnesium sulfate) and concentrated to provide tert-butyl 4-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]piperidine-1-carboxylate (0.994 g) as a light brown solid; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 1.42 (s, 9H), 1.58 (m, 2H), 1.94 (m, 2H), 2.13 (s, 3H), 2.85 (m, 1H), 3.23 (m, 2H), 3.65 (m, 2H), 4.77 (m, 1H), 7.52 (d, 1H), 7.55 (d, 1H), 7.63 (s, 1H), 7.72 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.18 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 519.
