反应详情

To a solution containing 1-(pyrimidin-2-yl)cyclopropanamine hydrochloride (0.0058 g, 0.034 mmol), diisopropylethylamine (0.36 mL, 0.21 mmol), 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-6-methyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)nicotinic acid (0.014 g, 0.026 mmol) and DMF (0.17 mL) was added HATU (0.020 g, 0.052 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. Purification of the resultant residue using preparative HPLC (Waters-Xbridge, 50×100 mm, 5 micron, C18 column; 0.1M ammonium acetate, 0-100% B (B=5% H2O/CH3CN)/A (A=95% H2O/CH3CN), 15 min. gradient) afforded 4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropyl carbamoyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 10.6 min. 1H NMR (400 MHz, MeOD) δ ppm 8.65 (2H, d, J=5.02 Hz), 8.55 (1H, d, J=7.03 Hz), 8.25 (1H, s), 7.83-7.93 (2H, m), 7.18-7.28 (3H, m), 6.95 (1H, t, J=6.90 Hz), 4.52 (2H, d, J=6.27 Hz), 3.99 (2H, dd, J=11.29, 3.01 Hz), 3.48 (2H, td, J=11.80, 2.01 Hz), 2.88-2.94 (3H, m), 2.48 (3H, d, J=1.00 Hz), 2.17-2.29 (1H, m), 1.83 (1H, d, J=1.76 Hz), 1.75-1.82 (3H, m), 1.48-1.60 (4H, m). LCMS: retention time: 2.333 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% CH3OH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3OH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 654 (MH+).

1. concentrationconcentrated
2. customPurification of the resultant residue