Sodium hydride → 2-(1-Methylpiperidin-4-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate

Temperature

0 °C

NaH (60% dispersion in mineral-oil, 0.81 g, 42.2 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 2-(1-methyl-piperidin-4-yl)-ethanol (1.01 g, 7.03 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (2.89 g, 8.46 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 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 EtOAc (200 mL), washed with a NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) followed by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-20%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give the title compound 2-(1-methylpiperidin-4-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (0.21 g, 7%) as a cream 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 EtOAc (200 mL)
8. washwashed with a NaHCO3 solution (4×50 mL)
9. dry with materialdried (MgSO4)
10. concentrationconcentrated in vacuo
11. customThe residue was purified by normal phase column chromatography (
12. washeluting with DCM
13. additionfollowed by a 90:10 mixture of DCM
14. washeluting with MeOH in water, with 1% formic acid in each solvent, 0-20%)
15. dissolutionThe resulting residue was dissolved in DCM (50 mL)
16. stirringstirred with solid K2CO3 for 20 minutes
17. filtrationfiltered
18. concentrationconcentrated in vacuo

ORD record

ord-75003828979848aa8c631bb2ea8e3ff8

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093248B2