反应详情

温度

60 °C

A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 17, 80 mg, 0.126 mmol) in 1 mL THF was added to 1 dram vial that contained 3,3-difluoroazetidine hydrochloride (11.8 mg, 0.126 mmol). Triethylamine (0.071 mL, 0.506 mmol) was added, the vial was capped and the reaction mixture heated to 60° C. for 3 hours. The mixture was cooled to ambient temperature and stirred overnight. Diluted the mixture with ethyl acetate (2 mL) and washed with H2O (3×1 mL), brine (1×1 mL), dried over MgSO4, filtered and concentrated in vacuo. Purified the residue by RP HPLC (Waters Sunfire C18 column; 19×100 mm; 5 μM; CH3CN/H2O (0.1% TFA); 20-90% gradient; 20 mL/minutes; 12 minutes run) and the corresponding fractions that contained product were lyophilized to afford 45 mg of a white powder as the titled compound. LCMS (M+H)+: 646.3. 1H NMR (500 MHz, CDCl3): δ: 0.73 (d, 3H, J=7.5 Hz), 1.28 (d, 6H, J=6.9 Hz), 2.95 (septet, 1H, J=7.5 Hz), 3.95 (s, 3H), 4.04 (d, 1H, J=7.5 Hz), 4.54-4.59 (m, 4H), 4.64 (d, 1H, J=7.5 Hz), 5.65 (d, 1H, J=8.5 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.73 (s, 2H), 7.90 (s, 1H), 8.13 (d, 1H, J=2.4 Hz), 8.23 (s, 1H). RTA IC50: 5 nM

1. customthe vial was capped
2. temperatureThe mixture was cooled to ambient temperature
3. washwashed with H2O (3×1 mL), brine (1×1 mL)
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customPurified the residue by RP HPLC (Waters Sunfire C18 column; 19×100 mm; 5 μM; CH3CN/H2O (0.1% TFA); 20-90% gradient; 20 mL/minutes; 12 minutes run)