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

Temperature

0 °C

(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.

1. stirringThe reaction mixture was stirred at room temperature for 3 hours
2. concentrationconcentrated in vacuo
3. dissolutionThe residue was dissolved in EtOAc (300 mL)
4. washwashed with 1 M aq Na2CO3 solution (5×200 mL)
5. dry with materialdried (MgSO4)
6. concentrationconcentrated in vacuo
7. dissolutionThe residue was dissolved in DCM (100 mL)
8. additionmethyl isocyanate resin (2.0 g) was added
9. stirringthe reaction mixture was shaken for 14 h
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe residue was purified by reverse phase chromatography (gradient
13. washeluting with MeOH in water, with 1% formic acid in each solvent, 0-30%)
14. dissolutionThe resulting residue was dissolved in DCM (70 mL)
15. stirringstirred with solid K2CO3 for 20 minutes
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customThe resulting residue was purified by normal phase column chromatography (
19. washeluting with DCM
20. additionfollowed by a 90:10 mixture of DCM

ORD record

ord-164dd72074964fa1a28f6df87836e2ae

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093248B2