4-Methylmorpholine → [1-(2-Methoxyethyl)piperidin-4-yl]-methyl 4-(4-methylphenyl)piperazine-1-carboxylate

Temperatur

0 °C

(1-(2-methoxyethyl)piperidin-4-yl)methanol (Intermediate 3, step 2; 1.73 g, 10.0 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. NMM (1.21 mL, 11.0 mmol) and 4-nitrophenyl chloroformate (2.02 g, 10.0 mmol) were added. The reaction mixture was stirred at 0° C. for 15 minutes and then added to a solution of 4-(4-methylphenyl)piperazine dihydrochloride (2.62 g, 10.5 mmol) and DIPEA (6.10 mL, 35.0 mmol) in DMF (75 mL). The reaction mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with 1M aq NaOH solution (6×100 mL), brine (100 mL), and then dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [1-(2-methoxyethyl)piperidin-4-yl]-methyl 4-(4-methylphenyl)piperazine-1-carboxylate (0.95 g, 25.4%) as a pale yellow oil.

1. stirringThe reaction mixture was stirred at room temperature for 4 h
2. concentrationconcentrated in vacuo
3. dissolutionThe residue was dissolved in EtOAc (300 mL)
4. washwashed sequentially with 1M aq NaOH solution (6×100 mL), brine (100 mL)
5. dry with materialdried (MgSO4)
6. concentrationconcentrated in vacuo
7. customThe residue was purified by reverse phase chromatography (gradient
8. washeluting with MeOH in water, with 1% formic acid in each solvent, 0-30%)
9. dissolutionThe resulting residue was dissolved in DCM (70 mL)
10. stirringstirred with solid K2CO3 for 20 minutes
11. filtrationfiltered
12. concentrationconcentrated in vacuo

ORD-Eintrag

ord-ded7019769644b098fcc5fdbcb6ff272

Quelldatensatz

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08093248B2