Formaldehyde → 1,1-Dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate

Temperature

50 °C

1,1-Dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (19.53 g, 0.0639 mol) in dry MeOH (300 mL) under an argon atmosphere at room temperature was treated with paraformaldehyde (5.76 g, 0.1918 mol) and sodium methoxide (17.27 g, 0.3197 mol). The reaction mixture heated at 50° C., stirred overnight then cooled to room temperature. Sodium borohydride (7.26 g, 0.1918 mmol) was added portionwise and the reaction mixture was then re-heated to 50° C. and stirred for 2 days. The reaction mixture was cooled to rt and stirred for a further 24 h, then concentrated and re-dissolved in DCM (200 mL). Saturated aq. NaHCO3 solution (200 mL) was added portionwise with stirring and on completion of addition the mixture was stirred at room temperature for a further 0.5 h. The DCM phase was separated, washed with brine, dried (MgSO4) and concentrated to give a yellow oil which was purified by column chromatography. Elution with 0%, 10% and then 20% EtOAc/hexane yielded the title compound as a yellow oil which crystallised on standing (16.7 g).

1. temperaturethen cooled to room temperature
2. temperaturethe reaction mixture was then re-heated to 50° C.
3. stirringstirred for 2 days
4. temperatureThe reaction mixture was cooled to rt
5. stirringstirred for a further 24 h
6. concentrationconcentrated
7. dissolutionre-dissolved in DCM (200 mL)
8. additionSaturated aq. NaHCO3 solution (200 mL) was added portionwise
9. stirringwith stirring and on completion of addition the mixture
10. stirringwas stirred at room temperature for a further 0.5 h
11. customThe DCM phase was separated
12. washwashed with brine
13. dry with materialdried (MgSO4)
14. concentrationconcentrated
15. customto give a yellow oil which
16. customwas purified by column chromatography
17. washElution with 0%, 10%

ORD record

ord-97fcb50100aa4fa293fd68be3e651f1a

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08853218B2