Potassium Carbonate → (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2-(3-fluoroazetidin-1-yl)-5-(5-isopropyl-2-methoxypyridin-3-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Participants

Reaction Conditions

Reaction Steps

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 14, 1.2 g, 2.153 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (0.716 g, 2.58 mmol), 1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (211 mg, 0.323 mmol) and K2CO3 (893 mg, 6.46 mmol) were added to a reaction vial that was evacuated and charged with nitrogen three times. The solid reactants were then mixed with THF (15 mL) and water (3 mL), degassed and refilled with nitrogen, capped and heated for 1 hour at 50° C. in a BIOTAGE microwave reactor, after which LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL sat′d NH4Cl soln. The ethyl acetate layer was washed with brine (100 mL) filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 30×300 mm RP column. After loading the column was eluted with a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions were concentrated and lyophilized to give a white solid. LCMS (M+H)+: 628.5 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.76 (s, 2H), 7.36 (d, J=2.2 Hz, 1H), 5.68 (d, J=8.6 Hz, 1H), 5.54 (m, 0.5H) 5.43 (m, 0.5H), 4.70 (d, J=17.2 Hz, 1H), 4.51 (m, 2H), 4.33 (m, 2H), 4.02 (d, J=17.4 Hz, 1H), 3.94 (s, 3H), 2.96 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.74 (d, J=6.7 Hz, 3H). SPA IC50: 11 nM.

Provenance & Evidence