2-Acetylpyridine → N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-[5-hydroxy-5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]-5-(5-methyl-2-pyridinyl)benzamide

Participants

Reaction Conditions

Reaction Steps

To a solution of 1-(2-pyridinyl)ethanone (1.04 mL, 9.26 mmol) in tetrahydrofuran (15 mL) at −20° C. was added dropwise lithium bis(trimethylsilyl)amide (1M in hexanes, 9.26 mL, 9.26 mmol). The reaction mixture was stirred at −20° C. for 30 min. The reaction mixture was cooled to −78° C. The reaction mixture was sequentially added (1 equivalent, ˜5 mL, per portion) to a solution of 3-({[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]amino}carbonyl)-N-hydroxy-5-(5-methyl-2-pyridinyl)benzenecarboximidoyl chloride (0.765 g, 1.85 mmol) in tetrahydrofuran (4 mL) at −78° C. After addition of 5 equivalents (˜25 mL), the reaction mixture was warmed to 0° C. Saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Two purifications by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol, then 50% hexane/ethyl acetate→95% ethyl acetate/methanol) gave the title compound (0.221 g) HRMS 498.1956 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.59 (d, J=4.9 Hz, 1H); 8.52 (s, 1H); 8.49 (t, J=1.6 Hz, 1H); 8.46-8.42 (m, 2H); 8.18 (s, 1H); 7.83 (tdd, J=7.7, 3.6, 1.6 Hz, 1H); 7.73 (dd, J=8.2, 2.3 Hz, 1H); 7.71-7.67 (m, 1H); 7.63 (dd, J=7.9, 4.9 Hz, 1H); 7.60 (d, J=8.2 Hz, 1H); 7.43-7.33 (m, 3H); 5.44-5.36 (m, 1H); 3.92 (dd, J=17.7, 4.8 Hz, 1H); 3.77 (dd, J=17.7, 2.7 Hz, 1H); 2.39 (s, 3H); 1.72 (s, 1H); 1.60 (d, J=6.8 Hz, 3H).

Provenance & Evidence