Sodium hydride → [(3R)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate

Temperature

0 °C

Sodium hydride (0.70 g, 60% dispersion in mineral oil, 17.5 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of (R)-(1-methylpiperidin-3-yl)methanol (0.75 g, 5.83 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (Intermediate 1; 2.19 g, 6.42 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with sat aq NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-25%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 min, filtered and concentrated in vacuo. The residue was further purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give [(3R)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate (619 mg, 32%) as a pale brown solid.

1. customThe heptane was decanted off
2. additionthe flask was charged with THF (20 mL)
3. temperatureto warm to room temperature
4. temperatureThe reaction mixture was then cooled to 0° C.
5. customquenched with the drop-wise addition of sat aq NaHCO3 solution
6. concentrationconcentrated in vacuo
7. dissolutionThe residue was dissolved in ethyl acetate (200 mL)
8. washwashed with sat aq NaHCO3 solution (4×50 mL)
9. dry with materialdried (MgSO4)
10. concentrationconcentrated in vacuo
11. customThe residue was purified by reverse phase chromatography (gradient
12. washeluting with methanol in water, with 1% formic acid in each solvent, 0-25%)
13. dissolutionThe resulting residue was dissolved in DCM (50 mL)
14. stirringstirred with solid K2CO3 for 20 min
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. customThe residue was further purified by normal phase column chromatography (
18. washeluting with DCM
19. additionfollowed by a 90:10 mixture of DCM

ORD record

ord-2aa92dee50874d2a8d41d7695970fa16

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07851471B2