反应详情

Add 2M iso-propylmagnesium chloride (717 mL, 1.4 mol) to a −10° C. solution of 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl ester (175 g, 478 mmol) and N,O-dimethylhydroxylamine hydrochloride (56 g, 574 mmol) in THF (2 L). Stir the reaction for 45 min. and then slowly quench with a 1:1 mixture of sat. NH4Cl and water (750 mL). Extract the mixture with EtOAc (3×500 mL). Wash the organic phase with brine (1000 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 7:3 hexanes/EtOAc) gives the title compound (27 g, 52%). MS (m/e): 381 (M+H)+; m.p.=51–56° C.; 1H NMR (300 MHz, CDCl3) δ7.32–7.60 (m, 4H), 5.00 (d, J=14 Hz, 1H), 4.78–4.81 (m, 1H), 4.73 (d, J=14 Hz, 1H), 3.85–3.98 (m, 1H), 3.52–3.61 (m, 1H), 3.40 (s, 3H), 3.10–3.29 (m, 3H), 1.50–1.82 (m, 6H); HPLC >99%; TLC Rf=0.41 (1:1 Hexanes/EtOAc).

1. customthe reaction for 45 min.
2. customslowly quench with a 1:1 mixture of sat. NH4Cl and water (750 mL)
3. extractionExtract the mixture with EtOAc (3×500 mL)
4. washWash the organic phase with brine (1000 mL)
5. dry with materialdry over Na2SO4
6. filtrationfilter
7. concentrationconcentrate under reduced pressure
8. customPurification by flash chromatography (silica gel, 7:3 hexanes/EtOAc)