反应详情

温度

-45 °C

To a 100 L reactor charged with NaBH4 (1.16 kg, 30.5 mol, 2.0 equiv) and anhydrous THF (60 L) under nitrogen was added TFA (10.5 kg, 92 mol, 6.0 equiv) slowly over 30 min while maintaining temperature at 0˜5° C. The mixture was then cooled to −45° C. In a separation reactor, crude product 3-3 was dissolved in anhydrous acetonitrile (30 L), which was added slowly to the above solution of NaBH4/TFA while maintaining the internal temperature between −45˜−30° C. The mixture was stirred at −45° C. for 1 h, after which time, HPLC indicated complete consumption of compound 3-3. The mixture was slowly diluted with ice water (50 kg) and the mixture was then warmed to 10° C. The product was extracted with EtOAc (2×40 L) and the combined organic layers were washed with saturated NaHCO3 solution (20 L). pH of the aqueous was ˜8. The organic layers were dried (Na2SO4) and concentrated in vacuo to nearly dryness to afford a residue which was further azeotroped with MeOH (10 L×3) to remove excess EtOAc. In the end, a 10 L solution of crude 3-4 in MeOH was obtained, which was used directly in the subsequent step without further purification. ESI-MS (M+H-1)+: 377.2. 1H NMR (400 MHz, CD3OD) δ: 7.31-7.22 (m, 5H), 4.20 (q, 2H), 4.11-3.86 (m, 3H), 3.15 (s, 1H), 3.00-2.90 (m, 2H), 2.64 (d, 2H), 1.87-1.85 (m, 1H), 1.68 (s, 1H), 1.50-1.25 (m, 15H).

1. temperaturewhile maintaining temperature at 0˜5° C
2. temperaturewhile maintaining the internal temperature between −45˜−30° C
3. customconsumption of compound 3-3
4. additionThe mixture was slowly diluted with ice water (50 kg)
5. temperaturethe mixture was then warmed to 10° C
6. extractionThe product was extracted with EtOAc (2×40 L)
7. washthe combined organic layers were washed with saturated NaHCO3 solution (20 L)
8. dry with materialThe organic layers were dried (Na2SO4)
9. concentrationconcentrated in vacuo to nearly dryness
10. customto afford a residue which
11. customwas further azeotroped with MeOH (10 L×3)
12. customto remove excess EtOAc