Acetic Acid → 6-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)pyridin-2(1H)-one
Reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[N:20]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(O)(=O)C.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[NH:20][C:21](=[O:25])[CH:22]=[CH:23][CH:24]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1Participants
4
Conditions
- Temperature
- 100 °C
Procedure
To a solution of 7-(5-fluoro-2-methylphenyl)-N-(6-methoxypyridin-2-yl)isoquinolin-3-amine (80% pure, 175 mg, 0.390 mmol) in acetic acid (3 mL, 50 mmol) was added hydrogen bromide (2 mL, 20 mmol) (48% in acetic acid). The reaction mixture was stirred at 100° C. under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and then evaporated in vacuo. The resulting residue was dissolved in dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane) followed by reverse phase HPLC purification and lyophilization to yield 4.3 mg (3.2%) of 6-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)pyridin-2(1H)-one. LCMS (ESI): RT (min)=5.219, M+H=346.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.85 (broad s, 1H), 9.15 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.54-7.29 (m, 2H), 7.16 (t, J=9.6 Hz, 2H), 5.93 (m, 2H), 2.27 (s, 3H).