Tetrahydrofuran → N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3,4-dihydroxybutyl)amino)-5-(1H-pyrazol-5-yl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 200 mg, 0.414 mmol), 3-buten-1-amine (50.5 μl, 0.497 mmol), DIPEA (145 μL, 0.828 mmol) and iPrOH (414 μL) were added to MW vial, which was sealed, purged with argon, and the RM was stirred at 130° C. for 5 h. iPrOH (1.5 μL) was added and the RM was stirred at 130° C. for 30 min. DIPEA (36.1 μL, 0.207 mmol), 3-buten-1-amine (16.83 μL, 0.166 mmol), and iPrOH (0.1 mL) were added and the RM was stirred at 130° C. for 2 h. The cooled RM was treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 40 g, n-heptane/EtOAc from 20% to 50% EtOAc). N-Methylmorpholin-N-oxide (9.50 mg, 0.081 mmol) and then osmium tetroxide EnCat™ (5.17 mg, 1.545 mmol) were then added to a stirred solution of the aforementioned intermediate (40 mg, 0.077 mmol) in THF (1 mL)/water (0.1 mL) and the RM was stirred at 50° C. for 26 h under an argon atmosphere A 10% aq. solution of KHSO4 was then added and the mixture was extracted with EtOAc. The combined extracts were washed with water, sat. aq. NH4Cl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was suspended in DCM, sonicated, filtered and dried to afford the title product as a white solid. UPLC-MS (Condition 8) tR=0.92 min, m/z=468.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.65 (m, 1H) 1.78-1.94 (m, 1H) 3.22-3.47 (m, 2H) 3.50-3.67 (m, 2H) 3.67-3.79 (m, 1H) 4.49-4.58 (m, 1H) 4.60-4.68 (m, 1H) 6.91-7.04 (m, 1H) 7.28-7.43 (m, 2H) 7.84-7.99 (m, 3H) 8.37-8.46 (m, 1H) 8.62-8.73 (m, 1H) 8.80-8.96 (m, 1H) 10.16-10.27 (m, 1H) 13.11-13.29 (m, 1H).

Provenance & Evidence