Sodium Iodide → 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-cyclopropyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide

Participants

Reaction Conditions

Reaction Steps

To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added NaI (62 mg, 0.41 mmol) and cyclopropylamine (56 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the racemic product (91 mg, 42%). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-cyclopropyl-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 column eluting with methanol at a flow rate of 60 mL/min. 91 mg of racemic material was separated in 1 injection of 5 mL at 18 mg/ml in methanol to afford the product which eluted before its enantiomer (27 mg, 12%). 1H NMR δ (300 MHz, CDCl3) 0.66-0.91 (m, 4H), 2.14 (sextet, 1H), 2.35 (quintet, 2H), 2.48-2.62 (m, 4H), 2.66-2.78 (m, 1H), 3.27-3.49 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.92 (t, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.57 (s, 1H), 9.51 (s, 1H); m/z 529 (M+H)+.

Provenance & Evidence