反应详情

温度

130 °C

A mixture of tert-butyl (R)-3-vinylpyrrolidine-1-carboxylate 9 (7.00 g, 35.5 mmol), 3-bromo-5-(tetrahydro-2H-pyran-4-yloxy)pyridine 12 (10.0 g, 38.8 mmol), palladium acetate (0.40 g, 1.8 mmol), tricyclohexylphosphine (1.0 g, 3.57 mmol) and diisopropylethylamine (15 mL) in 1-methyl-2-pyrrolidinone (130 mL) was stirred at 130° C. for 17 h. The reaction was cooled to ambient temperature, diluted with water (800 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography using 60-100% ethyl acetate in hexanes. This product was further purified on reverse phase HPLC using 0.05% trifluoroacetic acid in acetonitrile and 0.05% trifluoroacetic acid in water to obtain tert-butyl (R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (11.0 g) as a gum. 1H-NMR (CDCl3, 400 MHz): δ 8.41 (s, 1 H), 8.37 (d, J=2.3 Hz, 1 H), 7.68 (s, 1 H), 6.48 d, J=16.1 Hz, 1 H), 6.43 (dd, J=16.0, 6.4 Hz, 1 H), 4.71-4.66 (m, 1 H), 4.02-3.96 (m, 2 H), 3.68-3.52 (m, 4 H), 3.44-3.34 (m, 1 H), 3.28-3.15 (m, 1 H), 3.09-2.98 (m, 1 H), 2.18-2.04 (m, 3 H), 1.90-1.78 (m, 3 H), 1.48 (s, 9 H)

1. temperatureThe reaction was cooled to ambient temperature
2. extractionextracted with ethyl acetate (2×200 mL)
3. dry with materialThe combined organic extracts were dried over sodium sulfate
4. concentrationconcentrated
5. custompurified by silica gel column chromatography
6. customThis product was further purified on reverse phase