Trifluoroacetic acid → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-5-yl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

K3PO4 (135 mg, 0.635 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid (112 mg, 0.424 mmol) and Pd(PPh3)4 (12.24 mg, 10.59 mmol) were added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 100 mg, 0.212 mmol) in toluene (2 mL) and the RM was stirred at 110° C. for 2 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with water and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 99:1 to 94:6). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.462 mL, 5.99 mmol) and stirred for 1 h at RT. The RM was diluted with EtOAc (20 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 9:1). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated in DCM/n-hexane, filtered and dried to give the title product as a white solid. HPLC (Condition 5) tR=6.545 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=518.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.95 (m, 2H) 2.94 (d, J=11.34 Hz, 1H) 3.24 (m, 2H) 3.44 (m, 1H) 4.17-4.32 (m, 1H) 4.91 (br. s, 1H) 6.88 (s, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.86 (d, J=9.38 Hz, 2H) 8.12 (s, 1H) 8.81 (s, 1H) 10.17 (s, 1H) 13.94 (s, 1H).

Provenance & Evidence