Potassium Carbonate → N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine

Participants

Reaction Conditions

Reaction Steps

A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, 0.55 mmol), phenylboronic acid (102 mg, 0.83 mmol), Pd2(dba)3 (33 mg, 0.056 mmol), X-phos (105 mg, 0.22 mmol) and K2CO3 (226 mg, 1.63 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product. This 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 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol and three drops of concentrated HCl added. The mixture was stirred for 5 minutes, then concentrated in vacuo to give a light yellow solid (80 mg, 40%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.87 (s, 1H), 8.37 (d, 1H, J=2.4 Hz), 8.10 (d, 1H, J=1.8 Hz), 8.01-7.98 (m, 2H), 7.60-7.53 (m, 4 h), 6.45 (d, 1H, J=7.8 Hz), 6.30 (d, 1H, J=8.4 Hz), 4.28-4.24 (m, 1H), 3.67-3.47 (m, 2H), 2.20-1.80 (m, 4 h), 1.20 (d, 1H, J=6.3 Hz). LC-MS: [M+H]+, 371, tR=1.97 min, HPLC: 97.57% at 214 nm, 99.43% at 254 nm, tR=7.473 min.

Provenance & Evidence