反应详情

温度

-30 °C

To a solution of 3-bromo-5-fluorobenzonitrile (5.2 g, 0.26 mmol) in THF (26 mL) at −78° C. was slowly added isopropylmagnesium chloride (13.6 mL of a 2.0 M solution in diethyl ether, 0.27 mmol). The mixture was warmed and stirred at −30° C. for 1 hour then cooled to −78° C. The resulting aryl Grignard was added to a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (I-1) (7.8 g, 25 mmol) in THF (25 mL) at −78° C. The reaction mixture was stirred at 0° C. for 30 minutes. Methanol (20 mL) was added to the reaction mixture followed by NaBH4 (1.4 g, 37 mmol). The mixture was stirred to room temperature for 12 hours then poured into 10% aqueous NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate (I-10). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1 H), 7.38-7.33 (m, 1 H), 7.25-7.20 (m, 1 H), 4.95 (d, J=9.2 Hz, 1 H), 4.81 (bs, 1 H), 4.12-4.05 (m, 1 H), 3.76 (bs, 1 H), 3.45-3.35 (m, 1 H), 3.23-3.12 (m, 1 H), 1.87-1.71 (m, 2 H), 1.45 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H). MS m/z 461.2 (M+23)+.

1. customat −78° C.
2. temperatureThe mixture was warmed
3. temperaturethen cooled to −78° C
4. stirringThe reaction mixture was stirred at 0° C. for 30 minutes
5. stirringThe mixture was stirred to room temperature for 12 hours
6. extractionThe mixture was extracted with EtOAc
7. washwashed with brine
8. dry with materialdried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. customThe crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant