Diisopropylethylamine → (1-Methylpiperidin-4-yl)methyl 4-(3-methylphenyl)piperazine-1-carboxylate

(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.30 g, 14.6 mmol) was dissolved in DMF (50 mL). DIPEA (8.91 mL, 51.1 mmol) and 4-(3-methylphenyl)piperazine dihydrochloride (3.64 g, 14.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and then washed sequentially with 1 M aq NaOH solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and methyl isocyanate resin (1.0 g) was added and the reaction mixture shaken for 14 h, filtered and then 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-methylpiperidin-4-yl)methyl 4-(3-methylphenyl)piperazine-1-carboxylate (0.65 g, 13.3%) as a pale yellow oil.

1. concentrationconcentrated in vacuo
2. dissolutionThe residue was dissolved in EtOAc (500 mL)
3. washwashed sequentially with 1 M aq NaOH solution (6×200 mL), brine (50 mL)
4. dry with materialdried (MgSO4)
5. concentrationconcentrated in vacuo
6. dissolutionThe residue was dissolved in DCM (150 mL)
7. additionmethyl isocyanate resin (1.0 g) was added
8. stirringthe reaction mixture shaken for 14 h
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe residue was purified by reverse phase chromatography (gradient
12. washeluting with MeOH in water, with 1% formic acid in each solvent, 0-30%)
13. dissolutionThe resulting residue was dissolved in DCM (70 mL)
14. stirringstirred with solid K2CO3 for 20 minutes
15. filtrationfiltered
16. concentrationconcentrated in vacuo

ORD-Eintrag

ord-08175fd4836948fc8404c19277fd1eb4

Quelldatensatz

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08093248B2