反应详情

To a solution of 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 83; 150 mg, 0.444 mmol) and N-hydroxyisobutyrimidamide (54 mg, 0.53 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (1.1 mL, 0.5 M in tetrahydrofuran, 0.53 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 1 hour, 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 with silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (199:1, 1 L) to provide impure product (72 mg).

1. temperatureThe mixture was refluxed for 2 h
2. concentrationconcentrated to dryness under reduced pressure
3. dissolutionThe residue was dissolved in 2 mL of 4N HCl ethanol
4. temperatureThe solution was refluxed for 1 hour
5. temperaturecooled to RT
6. concentrationconcentrated to dryness under reduced pressure
7. dissolutionThe residue was dissolved in methanol (5 mL)
8. additionneutralized by the addition of excess potassium carbonate
9. additionmixed with silica gel (2 g)
10. concentrationconcentrated to dryness under reduced pressure
11. washeluted with dichloromethane/methanol (199:1, 1 L)