Ethylenediamine → 6-((2-Hydroxyethyl)(methyl)amino)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

5-Bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 19.1, 87 mg, 0.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (130 mg, 0.401 mmol), Pd(PPh3)2Cl2 (14.06 mg, 0.020 mmol), Na2CO3 (85 mg, 0.801 mmol), DME (850 μL), water (243 μL) and EtOH (121 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 h. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 83 mg, 0.120 mmol, centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column NH2, from 8% to 13% in 10 min). The resulting intermediate was treated with ethylene diamine (33.7 μL, 0.499 mmol) and 1 M TBAF in THF (1.496 mL, 1.496 mmol) and stirred at 75° C. for 24 h. The solvent was evaporated off under reduced pressure to give a, diluted with EtOAc (30 mL), washed 3 times with sat. aq. NaHCO3, brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a. The crude product was purified by preparative SFC (Column DEAP, isocratic 23% in 9 min) to yield the title product as yellow wax. UPLC-MS (Condition 3) tR=0.92 min, m/z=422.2 [M+H]+, m/z=420.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.77 (s, 3H) 3.44 (t, J=5.87 Hz, 2H) 3.55 (q, J=5.46 Hz, 2H) 4.63 (br. s, 1H) 6.48 (d, J=2.20 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.70-7.84 (m, 1H) 7.84-7.91 (m, 2H) 8.15 (d, J=1.96 Hz, 1H) 8.71 (d, J=2.20 Hz, 1H) 10.26 (s, 1H).

Provenance & Evidence