Cesium carbonate → N-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine

Participants

Reaction Conditions

Reaction Steps

A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (125 mg, 0.46 mmol), 6-(2-methylpiperidin-1-yl)pyridin-2-amine (144 mg, 0.75 mmol), Pd2(dba)3 (29 mg, 0.05 mmol), BINAP (125 mg, 0.2 mmol), Cs2CO3 (489 mg, 1.5 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solution was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product which was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol, three drops of concentrated HCl was added, and the mixture was stirred for 5 minutes, then concentrated in vacuo to give N-(6-(2-methylpiperidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (18 mg, 10%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.99 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.05-7.98 (m, 3H), 7.60 (brs, 3H), 7.46-7.28 (m, 2H), 4.12 (brs, 1H), 3.92-3.81 (m, 1H), 3.65-3.56 (m, 1H), 2.07-1.66 (m, 6H), 1.17 (d, 3H, J=5.7 Hz). LC-MS: [M+H]+, 385, tR=2.081 min, HPLC: 99.49% at 214 nm, 99.48% at 254 nm, tR=3.588 min.

Provenance & Evidence