反应详情

温度

25 °C

To a stirred solution of Example 1A (1.440 kg, 4.26 mol) in anhydrous THF (7.2 L) under nitrogen was added sodium boronhydride (161 g, 4.26 mol) in one portion at 10˜15° C. After stirring for 30 min, the mixture was cooled to −5˜0° C. and aluminum (III) chloride (1136 g, 8.52 mol) was added carefully portionwise to the reaction mixture over 2 h. The reaction mixture was stirred at 0˜5° C. for 3 h after the addition. The reaction mixture was refluxed (65˜70° C.) for 15 h. The reaction was concentrated and water (5 kg) was added dropwise slowly in 3˜4 h under nitrogen atmosphere so that the internal temperature did not exceed 40° C. The reaction mixture was stirred for 3 h at 0˜5° C. The precipitate was filtered and washed with water (1.5 L). The crude product was then dissolved in 7.2 L absolute ethanol at 50˜55° C. The solution was slowly cooled to 25° C. in 3 h and at 10˜15° C. for 10 h, and 0˜5° C. for 2 h. The slurry was filtered and the solid was washed with chilled ethanol (500 mL) and dried under vacuum at 35° C. to afford the crude product. This product was recrystallized from absolute ethanol (5 L) once more and dried under vacuum at 35° C. to give the desired product (1.310 kg, yield 94%; HPLC purity>99%). 1H NMR (CDCl3, 400 MHz): δ 7.21˜7.29 (m, 3H), 7.11 (d, J=8.8 Hz, 2H,), 6.85 (d, J=8.8 Hz, 2H,), 3.99˜4.07 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).

1. temperaturethe mixture was cooled to −5˜0° C.
2. stirringThe reaction mixture was stirred at 0˜5° C. for 3 h
3. additionafter the addition
4. temperatureThe reaction mixture was refluxed (65˜70° C.) for 15 h
5. concentrationThe reaction was concentrated
6. additionwater (5 kg) was added dropwise slowly in 3˜4 h under nitrogen atmosphere so that the internal temperature
7. customdid not exceed 40° C
8. stirringThe reaction mixture was stirred for 3 h at 0˜5° C
9. filtrationThe precipitate was filtered
10. washwashed with water (1.5 L)
11. dissolutionThe crude product was then dissolved in 7.2 L absolute ethanol at 50˜55° C
12. wait0˜5° C. for 2 h
13. filtrationThe slurry was filtered
14. washthe solid was washed with chilled ethanol (500 mL)
15. customdried under vacuum at 35° C.
16. customto afford the crude product
17. customThis product was recrystallized from absolute ethanol (5 L) once more
18. customdried under vacuum at 35° C.