反应详情

温度

65 °C

To Intermediate 10, 1-(4-bromo-2-chloro-5-fluorobenzoyl)pyrrolidine (48.0 g, 156.5 mmol) in THF (200 mL) at rt was slowly added a solution of BH3·THF complex (400 mL, 400 mmol, 1M THF). The resulting reaction was heated to 65° C. (oil bath) for 16 hr, and then the reaction was cooled to rt and slowly quenched with MeOH (dropwise addition). The reaction mixture was heated to reflux for 2 hr, cooled to rt, and concentrated under reduced pressure. This material was taken up in EtOAc and further quenched slowly with 6N HCl, then neutralized with aqueous NaOH (15%). The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75 L column, eluting with a gradient of 5%, 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to give the title compound (43 g, 94% yield) as a light yellow oil: Rf=0.6 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C11H12BrClFN, 292.6, found, 292 294, 296 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.51 (d, J=6.6 Hz, 1H), 7.33 (d, J=9.5 Hz, 1H), 3.66 (s, 2H), 2.59-2.55 (m, 4H), 1.82-1.79 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 158.3 (d, JC-F=247.2 Hz), 139.3, 133.3, 128.9, 117.8 (d, JC-F=24.9 Hz), 107.3 (d, JC-F=22.6 Hz), 56.7, 54.4, 23.9.

1. customThe resulting reaction
2. temperaturethe reaction was cooled to rt
3. customslowly quenched with MeOH (
4. additiondropwise addition)
5. temperatureThe reaction mixture was heated
6. temperatureto reflux for 2 hr
7. temperaturecooled to rt
8. concentrationconcentrated under reduced pressure
9. customfurther quenched slowly with 6N HCl
10. customThe layers were separated
11. extractionthe aqueous layer was back extracted with EtOAc
12. dry with materialThe combined organic layers were dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customPurification of this material
16. washeluting with a gradient of 5%, 10% MeOH/CH2Cl2
17. additionThe product containing fractions
18. customwere collected
19. concentrationconcentrated