反应详情

(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.99 g, 16.9 mmol) was dissolved in DMF (40 mL). DIPEA (5.90 mL, 33.9 mmol) and 4-(4-fluoro-phenyl)piperazine (3.21 g, 17.8 mmol) were added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (400 mL) and then washed sequentially with 1 M aq NaOH solution (6×150 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (1.0 g) was added. The reaction mixture was 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-(4-fluorophenyl)piperazine-1-carboxylate (0.67 g, 11.8%) as a pale yellow oil.

1. concentrationconcentrated in vacuo
2. dissolutionThe residue was dissolved in EtOAc (400 mL)
3. washwashed sequentially with 1 M aq NaOH solution (6×150 mL), brine (50 mL)
4. dry with materialdried (MgSO4)
5. concentrationconcentrated in vacuo
6. dissolutionThe residue was dissolved in DCM (100 mL)
7. additionmethyl isocyanate resin (1.0 g) was added
8. stirringThe reaction mixture was 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