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

Participants

Reaction Conditions

Reaction Steps

(1-(2-methoxyethyl)piperidin-4-yl)methanol (Intermediate 3, step 2; 1.34 g, 7.74 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (0.94 mL, 8.51 mmol) and 4-nitrophenyl chloroformate (1.56 g, 7.74 mmol) were added. The reaction mixture was stirred at 0° C. for 20 minutes and then added to a solution of 4-(4-methoxyphenyl)piperazine (1.64 g, 8.51 mmol) and DIPEA (6.10 mL, 35.0 mmol) in DMF (30 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 (5×125 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 the title compound [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (0.637 g, 21.6%) as a pale yellow oil.

Provenance & Evidence