反应详情

温度

22.5 °C

A solution of tert-butyl 4-(diethoxymethyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-3) (2.80 kg, 7.12 mol) in THF (28.0 L) and water (2.80 L) is stirred at about 20° C. Hydroxylamine hydrochloride (593 g, 8.54 mol) is added while maintaining the reaction temperature between 20-25° C. The reaction mixture is stirred at about 20° C. for 16-20 h then diluted with CH2Cl2 (8.4 L) and 50% brine (11.2 L) and stirred for at least 5 min. The phases are separated then the organic phase is washed with 50% brine (2×2.8 L), dried (Na2SO4) and concentrated. The concentrate is diluted with MeOH (1.4 L) and re-concentrated. The concentrate is diluted with MeOH (14.0 L) and transferred to a reaction vessel. The solution is warmed to about 25° C. then water (14.0 L) is added over about 1-1.5 h; after about 10 L of water is added, the mixture is seeded and a hazy suspension is observed. Additional water (8.4 L) is added over 1.5 h to further precipitate the product. After aging, the solid is collected by filtration. The filter-cake is washed with heptane (5.6 L) and dried to afford tert-butyl 4-((hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4) (1678 g; 71% 71% yield, 91.5 area % purity by HPLC) as an off-white powder. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 4.40 (br s, 3H), 3.96 (dd, J=10.4, 3.6 Hz, 2H), 3.41 (br m, 2H), 1.69-1.61 (m, 4H), 1.39 (br s, 9H).

1. stirringstirred for at least 5 min
2. customThe phases are separated
3. washthe organic phase is washed with 50% brine (2×2.8 L)
4. dry with materialdried (Na2SO4)
5. concentrationconcentrated
6. additionThe concentrate is diluted with MeOH (1.4 L)
7. concentrationre-concentrated
8. additionThe concentrate is diluted with MeOH (14.0 L)
9. customtransferred to a reaction vessel
10. temperatureThe solution is warmed to about 25° C.
11. additionwater (14.0 L) is added over about 1-1.5 h
12. additionafter about 10 L of water is added
13. additionAdditional water (8.4 L) is added over 1.5 h to further precipitate the product
14. filtrationthe solid is collected by filtration
15. washThe filter-cake is washed with heptane (5.6 L)
16. customdried