Ammonia → (S)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

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Reaktionsschritte

A mixture of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 10.1, 119 mg, 0.25 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (139 mg, 0.5 mmol), Pd(PPh3)2Cl2 (0.018 g, 0.025 mmol), Na2CO3 (0.106 g, 1.000 mmol), DME (1.061 mL), water (0.303 mL) and EtOH (0.152 mL) were added to a MW vial which was sealed, evacuated/purged 3 times with argon then subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL) and stirred overnight with Si-Thiol (Silicycle 1.43 mmol/g, 0.105 g, 0.150 mmol). The mixture was centrifuged and the supernatant was filtered through a 0.45 μm PTFE filter and the solvent was evaporated off under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc) to afford the protected intermediate which was treated with a mixture of DCM (2.5 mL) and TFA (0.963 mL, 12.50 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure and the residue treated with a solution of 7 N NH3 in MeOH (2 mL, 14 mmol). The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column DEAP, isocratic 28% in 9 min) to afford the title compound as a yellow oil. UPLC-MS (Condition 1) tR=1.87 min, m/z=464.1 [M+H]+, m/z=462.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.65 (m, 1H) 1.75-1.97 (m, 1H) 2.14-2.30 (m, 1H) 3.04 (dd, J=11.37, 6.97 Hz, 1H) 3.14-3.26 (m, 2H) 3.26-3.29 (m, 1H) 3.35-3.46 (m, 2H) 4.60 (t, J=5.14 Hz, 1H) 6.39 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.76 (br. s, 1H) 7.84-7.94 (m, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.74 (s, 1H) 10.18 (s, 1H) 12.87 (br. s, 1H).

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