Lithium Hydroxide → 1-Amino-4-bromo-2-naphthoic acid

Participants

Reaction Conditions

Reaction Steps

Methyl 1-amino-4-bromo-2-naphthoate hydrobromide was prepared as described in Example 1. To a solution of methyl 1-amino-4-bromo-2-naphthoate hydrobromide (2.00 g, 5.54 mmol) in 20 mL of THF was added sodium hydroxide (11.1 mL, 20% aqueous, 55.4 mmol). Alternatively, lithium hydroxide could be used. The mixture was stirred at 50° C. for 20 h, then heated at 90° C. for 2 h. The solvent was removed in vacuo and hydrochloric acid (1N aqueous) was added until pH ˜2. The beige solid was collected via filtration, washed twice with water, and dried to provide 1-amino-4-bromo-2-naphthoic acid that gave a mass ion (ES+) of 266.0 (79Br) for [M+H]+. To a solution of the above compound (0.950 g, 3.57 mmol) in 5 mL of dichloromethane was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.82 g, 4.12 mmol), (1S,2S)-2-aminocyclohexanol (0.493 g, 4.28 mmol), and triethylamine (0.99 mL, 7.1 mmol). The mixture was stirred at rt for 15 h and then diluted with dichloromethane and water. The resultant beige solid was collected via filtration, washed with dichloromethane and water, and dried to provide 1-amino-4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-2-naphthamide that gave a mass ion (ES+) of 364.9 (81Br) for [M+H]+. A solution of the above compound in N,N-dimethylformamide dimethylacetal (3.06 mL, 22.8 mmol) was heated at 80° C. for 15 h. The reaction was cooled to rt, concentrated in vacuo, and dried to provide 6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one that gave a mass ion (ES+) of 374.8 (81Br) for [M+H]+. The titled compound was prepared by employing the procedures described in Example 1 that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 400.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.00-8.99 (m, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.95-7.76 (m, 1H), 7.68-7.63 (m, 2H), 7.27-7.17 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.62 (br s, 1H), 4.35 (s, 2H), 4.11 (br s, 1H), 2.48 (s, 3H), 2.29-2.20 (m, 1H), 1.95-1.90 (m, 3H), 1.65-1.39 (m, 5H).

Provenance & Evidence