4-Methylmorpholine → [(3S)-1-methylpyrrolidin-3-yl]-4-(4-methylphenyl)-piperazine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

(S)-(+)-3-Hydroxy-N-methylpyrrolidine (1.51 g, 14.9 mmol) was dissolved in DCM (20 mL) and cooled to 0° C. NMM (1.70 mL, 15.5 mmol) and 4-nitrophenyl chloroformate (3.16 g, 15.7 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes and then a solution of 4-(4-methylphenyl)piperazine dihydrochloride (3.71 g, 14.9 mmol) and DIPEA (7.40 mL, 44.7 mmol) in DMF (20 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed with 1 M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (2.0 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. The resulting residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give [(3S)-1-methylpyrrolidin-3-yl]-4-(4-methylphenyl)-piperazine-1-carboxylate (606 mg, 13.0%) as a yellow oil.

Provenance & Evidence