反应详情

Add sodium triacetoxyborohydride (20 g, 94.4 mmol) to a slurry of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-piperazin-1-yl-chroman-4-yl]benzamide hydrochloride (32.0 g, 78.5 mmol) and 3-oxetanone (6.87 g, 98.1 mmol) in acetonitrile (300 mL). Stir the slurry for 20 min. and add more sodium triacetoxyborohydride (20 g, 94.4 mmol) in one portion. Stir the brown mixture at 28° C. for approximately 2 hr. Add additional sodium triacetoxyborohydride (10 g, 47.2 mmol) and stir the mixture for 30 min. Add 3-oxetanone (2 g, 28.6 mmol) and after 20 min add additional 3-oxetanone (1 g, 14.3 mmol). Stir for 30 min., pour the mixture into a saturated aqueous sodium bicarbonate solution (1 L) and add dichloromethane (1 L). Separate the organic layer and concentrate in vacuo to obtain a pale grey solid. Purify the solid by silica gel column chromatography eluting with 3 to 6% isopropanol/dichloromethane to obtain the title compound as a white solid (19.2 g, 73%). LC-ES/MS m/z 428 [M+H]+.

1. stirringStir the brown mixture at 28° C. for approximately 2 hr
2. stirringstir the mixture for 30 min
3. stirringStir for 30 min.
4. customSeparate the organic layer
5. concentrationconcentrate in vacuo
6. customto obtain a pale grey solid
7. customPurify the solid by silica gel column chromatography
8. washeluting with 3 to 6% isopropanol/dichloromethane