4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile → 3-(methoxymethyl)-5-(4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidin-1-yl)-1,2,4-oxadiazole

Participants

Reaction Steps

To a solution of 4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 98; 80 mg, 0.23 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.6 mL, 0.5 M in tetrahydrofuran, 0.3 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound as an off-white solid, 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=2.4 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.2 Hz, 2H), 4.38 (s, 2H), 4.25-4.10 (m, 2H), 3.46 (s, 3H), 3.15-2.95 (m, 2H), 3.08 (s, 3H), 2.20-2.05 (m, 1H), 1.95-1.80 (m, 2H), 1.60-1.40 (m, 3H), 1.20-0.85 (m, 2H), 0.80-0.55 (m, 2H), −0.08 (q, J=4.6 Hz, 1H). MS (ESI) m/z 437 [M+H]+. MP: 68-70° C. GPR119 Human EC50: 7 nM

Provenance & Evidence