Methyl vinyl ketone → (R,E)-6-(3-Hydroxypyrrolidin-1-yl)-5-(3-oxobut-1-en-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 250 mg, 0.560 mmol), Pd(OAc)2 (3.77 mg, 0.017 mmol), tri-o-tolylphosphine (20.46 mg, 0.067 mmol), but-3-en-2-one (55.1 μL, 0.672 mmol) and TEA (102 μL, 0.728 mmol) were added to a MW vial, which was sealed and purged with argon. DMF (1.87 mL) was added and the RM was stirred at 130° C. for 6 h. Additional but-3-en-2-one (22.96 μL, 0.280 mmol) was then added and mixture was stirred at 130° C. for 16 h. The RM was poured into water (25 mL) and extracted with DCM (3×20 mL). The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1) from 40% to 75% EtOAc-EtOH+0.1% NH4OH (9:1)). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was azeotroped with xylene and triturated in cyclohexane to yield the title compound as a yellow solid. UPLC-MS (Condition 1) tR=2.39 min, m/z=436.0 [M+H]+, m/z=434.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.91 (m, 1H) 1.91-2.00 (m, 1H) 2.35 (s, 3H) 3.43 (d, J=11.25 Hz, 1H) 3.59-3.67 (m, 1H) 3.78-3.88 (m, 2H) 4.34 (br. s, 1H) 4.99 (d, J=3.18 Hz, 1H) 6.61 (d, J=15.89 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.81-7.93 (m, J=16.14, 9.29 Hz, 3H) 8.29 (d, J=2.20 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.21 (s, 1H).

Provenance & Evidence