Potassium Carbonate → 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide

Participants

Reaction Steps

3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (442 mg, 1.1 mmol) (Intermediate 1) and 3-bromo-1-methyl-pyrrolidin-2-one (385 mg, 2.2 mmol) (Intermediate 4) were dissolved in DMF and treated with potassium carbonate (377 mg, 2.7 mmol) and stirred at room temperature for 21 hours. The DMF was evaporated, the residue was partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica eluting with 0-6% methanol in DCM to give the racemic product (420 mg). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ No. CE001 column eluting with methanol at a flow rate of 50 mL/min; 420 mg of racemic material was separated in 3 injections of 15 mL at 11 mg/ml in 1:1:1 acetonitrile/ethanol/methanol to afford the product (187 mg, 33%) which eluted before its enantiomer. 1H NMR δ (400 MHz, CDCl3): 2.08-2.18 (m, 1H), 2.28 (quintet, 2H), 2.47-2.57 (m, 1H), 2.48 (s, 3H), 2.86 (s, 3H), 3.29-3.37 (m, 1H), 3.42-3.48 (m, 1H), 4.18 (t, 2H), 4.64 (t, 2H), 4.86 (t, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 8.37 (s, 1H), 9.45 (s, 1H); m/z 503 (M+H)+

Provenance & Evidence