反应详情

温度

100 °C

A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.10 g, 0.30 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.096 g, 0.36 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.057 g, 0.122 mmol) and Na2CO3 (0.095 g, 0.912 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10) and 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: 30% acetonitrile/70% water (0.1% TFA V/V) initially, proceeding to 60% acetonitrile/40% water (0.1% TFA V/V) in a linear fashion over 9 min) to afford (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (32 mg, 25%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.97 (s, 1H), 9.26 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 8.13-8.11 (m, 1H), 7.71 (t, 1H, J=7.8 Hz), 7.51 (t, 1H, J=7.8 Hz), 6.69 (d, 1H, J=7.5 Hz), 6.16 (d, 1H, J=8.1 Hz), 4.22-4.17 (m, 1H), 3.63-3.54 (m, 1H), 3.44-3.39 (m, 1H), 2.06-1.95 (m, 3H), 1.67-1.61 (m, 1H), 1.07 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 415, tR=1.669 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.01 min.

1. concentrationthen concentrated in vacuo
2. customThe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10)
3. customfurther purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm