Trifluoroacetic acid → 4-(2-Hydroxyethoxy)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Participants

Reaction Conditions

Reaction Steps

A suspension of 3-bromo-4-hydroxy-N-(4-(trifluoromethoxy)phenyl)benzamide (50 mg, 0.133 mmol), 2-bromoethyl acetate (21.94 μL, 0.199 mmol) and powdered K2CO3 (92 mg, 0.665 mmol) in acetone (500 μL) was stirred at 75° C. for 16 h and the solvent was evaporated off under reduced pressure. The residue, together with pyrimidin-5-ylboronic acid (57.61 mg, 0.465 mmol), Pd(PPh3)2Cl2 (18.66 mg, 0.026 mmol) water (125 μL), EtOH (62 μL) and DME (550 μL) were added to a vial, which was sealed, evacuated/purged with argon and the RM stirred at 80° C. for 20 h. The RM was diluted with THF (3 mL) then stirred with Si-Thiol (Silicycle, 105 mg, 0.133 mmol) for 2 h, filtered and the filtrate was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, cyclohexane/EtOAc from 30% to 95% EtOAc) to afford the acylated product, which was treated with aq. 4 M NaOH (138 μL, 0.552 mmol) and MeOH (250 μL) at and stirred at RT for 4 h. The RM was acidified with TFA and purified by preparative HPLC (Condition 8, 50% for 0.2 min then 50% to 80% in 14 min) to afford the title compound as a beige solid. UPLC-MS (Condition 1) tR=2.24 min, m/z=420.0 [M+H]+, m/z=418 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.64-3.82 (m, 2H) 4.21 (t, J=4.6 Hz, 2H) 4.91 (t, J=5.4 Hz, 1H) 7.32-7.41 (m, 3H) 7.88 (d, J=9.0 Hz, 2H) 8.07 (dd, J=8.8, 2.2 Hz, 1H) 8.12 (d, J=2.2 Hz, 1H) 9.13 (s, 2H) 9.18 (s, 1H) 10.32 (s, 1H).

Provenance & Evidence