反应详情

To an ice-cooled solution of tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylate (0.220 g, 0.547 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). After 2 h, the reaction mixture was concentrated in vacuo (25 mm Hg). The resulting residue was dissolved in dichloromethane (10 mL), and the solution was washed with saturated aqueous sodium bicarbonate solution (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in tetrahydrofuran (2 mL). Oxetan-3-one (0.112 mL, 1.10 mmol, 2.00 equiv) and sodium triaetoxyborohydride (366 mg, 1.64 mmol, 3.00 equiv) were sequentially added to the solution at 24° C. After 35 min, the reaction mixture was partitioned between ethyl acetate (10 mL) and saturated aqueous ammonium chloride solution (10 mL). The organic was separated and the aqueous layer was further extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (98:2 dichloromethane/methanol+0.1% ammonium hydroxide) furnished product as a clear oil (166 mg, 85% yield). 1H NMR (CDCl3, 400 MHz), δ: 6.54 (s, 1H), 6.07 (s, 1H), 4.67 (t, J=6.3 Hz, 2H), 4.63 (t, J=6.3 Hz, 2H), 3.82 (t, J=13.2 Hz, 2H), 3.66 (t, J=7.2 Hz, 2H), 3.50 (m, 1H), 2.86 (m, 2H), 2.38-2.52 (m, 3H), 1.72-1.94 (m, 6H).

1. concentrationthe reaction mixture was concentrated in vacuo (25 mm Hg)
2. dissolutionThe resulting residue was dissolved in dichloromethane (10 mL)
3. washthe solution was washed with saturated aqueous sodium bicarbonate solution (5 mL)
4. dry with materialThe organic layer was dried over anhydrous sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated
7. dissolutionThe resulting residue was dissolved in tetrahydrofuran (2 mL)
8. waitAfter 35 min
9. customthe reaction mixture was partitioned between ethyl acetate (10 mL) and saturated aqueous ammonium chloride solution (10 mL)
10. customThe organic was separated
11. extractionthe aqueous layer was further extracted with ethyl acetate (2×5 mL)
12. dry with materialThe combined organic was dried over anhydrous sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customPurification by flash column chromatography (98:2 dichloromethane/methanol+0.1% ammonium hydroxide)