反应详情

温度

75 °C

(S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperidin-3-yl(ethyl)carbamate (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (30 mg, 40% over two steps). 1H NMR (500 MHz, d6-DMSO) δ 8.94 (s, 1H), 8.45-8.39 (m, 2H), 6.87 (d, J=5.6, 1H), 3.71 (d, J=11.1, 1H), 3.51 (d, J=12.0, 1H), 3.08-2.99 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.72-2.66 (m, 1H), 2.62 (m, 1H), 2.01 (m, 1H), 1.93 (m, 1H), 1.78 (m, 1H), 1.37 (m, 1H), 1.05 (t, J=7.1, 3H), NH signal not observed. LCMS (Method E): RT=2.576 min, M+H+=321.1.

1. customThe cooled reaction mixture
2. customproducing a cloudy precipitate
3. customThe solid was collected by centrifugation
4. dissolutiondissolved in dimethylsulfoxide (2 mL)
5. custompurified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min]