反应详情

温度

20 °C

Morpholine (43.2 kg, 495.9 mol) was then added over 2 hrs to the solution of methanesulfonic acid 6-methyl-pyridin-3-ylmethyl ester (198 mol; Example 1) in tetrahydrofuran (161 kg) under nitrogen at 15-20° C. and the resulting slurry stirred for 19 hrs. The suspension was filtered through a Silica (15.5 kg) column and the cake washed five times with tetrahydrofuran (43.5 kg). 440 L of the solution was then removed under vacuum distillation and heptane (41.52 kg) added. This was repeated two more times followed by the addition of heptane (48.6 kg) and the solution filtered through a Celite® (4.08 kg) bed at 40° C. and the cake washed twice with heptane (7.2 kg). Then the filtrate cooled to 20° C. over 3 hrs then to −12° C. over 5 hrs and held for 12 hrs at −12° C. The suspension was filtered and the cake washed with cold (0° C.) heptane (8.5 kg) and then dryed at 25° C. under vacuum, which gave 25.44 kg, 67% yield of 4-(6-Methyl-pyridin-3-ylmethyl)-morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.

1. filtrationThe suspension was filtered through a Silica (15.5 kg) column
2. washthe cake washed five times with tetrahydrofuran (43.5 kg)
3. custom440 L of the solution was then removed under vacuum distillation and heptane (41.52 kg)
4. additionadded
5. additionfollowed by the addition of heptane (48.6 kg)
6. filtrationthe solution filtered through a Celite® (4.08 kg) bed at 40° C.
7. washthe cake washed twice with heptane (7.2 kg)
8. waitto −12° C. over 5 hrs
9. waitheld for 12 hrs at −12° C
10. filtrationThe suspension was filtered
11. washthe cake washed with cold (0° C.) heptane (8.5 kg)
12. customdryed at 25° C. under vacuum, which