Isocyanate → (2S,5R)-1-benzyl-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)piperazine

To a mixture of (2S,5R)-1-benzyl-2,5-dimethylpiperazine (11.0 g, 53.8 mmol) and of tetrahydro-4H-pyran-4-one (5.39 g, 53.8 mmol) at 0° C. was added Ti(IV) isopropoxide (19.2 mL, 67.3 mmol). The resulting mixture was stirred at rt overnight and an orange suspension was obtained. To the suspension was added EtOH (25 mL) and NaCNBH3 (4.27 g, 64.6 mmol, 1.20 eq). The resulting mixture was stirred at rt for 24 h. The reaction mixture was then quenched with water (5.0 mL) and a yellow solid was generated. The suspension was diluted with EtOAc (400 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was again diluted with EtOAc (500 mL), dried over Na2SO4, and filtered. The filtrate was collected and concentrated under reduced pressure to afford a yellow oil. The oil was diluted in THF (400 mL) and PS-isocyanate was added to remove secondary amine. The suspension was filtered and the filtrate concentrated. The residue was purified by column chromatography using 50:5:1 CHCl3/MeOH/Et3N to afford the desired compound as yellow oil (13.0 g, 84%)

1. customan orange suspension was obtained
2. stirringThe resulting mixture was stirred at rt for 24 h
3. customThe reaction mixture was then quenched with water (5.0 mL)
4. additionThe suspension was diluted with EtOAc (400 mL)
5. filtrationfiltered
6. concentrationThe filtrate was concentrated under reduced pressure
7. additionThe residue was again diluted with EtOAc (500 mL)
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. customThe filtrate was collected
11. concentrationconcentrated under reduced pressure
12. customto afford a yellow oil
13. customto remove secondary amine
14. filtrationThe suspension was filtered
15. concentrationthe filtrate concentrated
16. customThe residue was purified by column chromatography

ORD record

ord-af74a0ec84fc48c7a86250089c573b26

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08183255B2