Hydrogen Bromide → (R)-4-(Piperidin-3-yloxy)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4',3'-d]pyrrole

Participants

Reaction Conditions

Reaction Steps

(R)-tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yloxy)piperidine-1-carboxylate (50 mg, 0.09 mmol) was dissolved in 1,4-dioxane (0.2 mL) and then treated with 48% HBr(aq) (0.2 mL) and heated at 75° C. for 5 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 pale yellow solid (10 mg, 30% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H), 8.77 (s, 1H), 8.39 (d, J=5.7, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 6.95 (d, J=5.9, 1H), 4.77-4.67 (m, 1H), 3.91 (s, 3H), 3.10-3.25 (m, 1H), 2.90-2.83 (m, 2H), 2.67 (m, 1H), 2.19 (m, 1H), 1.91-1.78 (m, 2H), 1.67-1.53 (m, 1H), piperidine NH not observed. LCMS (Method D): RT=5.567 min, M+H+=349.1.

Provenance & Evidence