反应详情

A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminopropan-1-ol (10 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 20 h then extracted with ethyl acetate (50 mL) and washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) 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: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(1-hydroxypropan-2-yl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (8.7 mg, 14%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.91 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.17-8.00 (m, 4 h), 7.65 (t, 1H, J=7.8 Hz), 7.58-7.55 (m, 1H), 6.40 (d, 1H, J=7.5 Hz), 6.28 (d, 1H, J=8.4 Hz), 4.25-4.21 (m, 2H), 3.71-3.58 (m, 3H), 3.54-3.48 (m, 1H), 2.19-2.07 (m, 3H), 1.81 (brs, 1H), 1.29 (d, 3H, J=6.3 Hz), 1.19 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 472, tR=1.654 min, HPLC: 99.36% at 214 nm, 98.85% at 254 nm, tR=5.697 min.

1. extractionthen extracted with ethyl acetate (50 mL)
2. washwashed with water (2×2 mL)
3. customAfter drying
4. concentrationconcentration
5. customthe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50)
6. customfurther purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm
7. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min