Trifluoroacetic acid → HCID 59296025, compound

To a solution of the tert-butyl 4-(3-chloro-4-cyanophenoxy)piperidine-1-carboxylate (2.75 g, 9.09 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (20 ml) and the mixture stirred for 90 min. The solvents were evaporated and the residue azeotroped with toluene (2×20 ml) before dissolving in water (30 ml) and addition of sodium hydroxide to bring the solution to pH 11. The free base was extracted with DCM (5×100 ml). The organics were combined, dried over sodium sulfate and the solvent removed under reduced pressure to give a thick oil which was dissolved in DMF (30 ml) before addition of (2R)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.35 g, 9.09 mmol) and triethylamine (2.54 ml, 18.18 mmol). The mixture was heated at 60° C. for 4 h before addition of sodium azide (1.36 g, 27.27 mmol). Heating was continued at 60° C. for a further 72 h. The reaction mixture was cooled and partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was separated and the solvent removed under reduced pressure. The residue was dissolved in THF (20 ml) and water (2 ml) and triphenylphosphine (5.90 g, 22.72 mmol) added The mixture was heated at 60° C. for 16 h before dilution with ethyl acetate (100 ml). The solution was washed with 1N HCl (50 ml) and the aqueous layer was separated and adjusted to pH 11 with sodium hydroxide. The product was extracted with DCM (4×100 ml). The organics were combined and dried sodium over sulfate and the solvent removed under reduced pressure. The residue was purified by flash chromatography to give the title compound as a pale yellow solid (1.10 g).

1. customThe solvents were evaporated
2. customthe residue azeotroped with toluene (2×20 ml)
3. dissolutionbefore dissolving in water (30 ml)
4. additionaddition of sodium hydroxide
5. extractionThe free base was extracted with DCM (5×100 ml)
6. dry with materialdried over sodium sulfate
7. customthe solvent removed under reduced pressure
8. customto give a thick oil which
9. temperatureHeating
10. waitwas continued at 60° C. for a further 72 h
11. temperatureThe reaction mixture was cooled
12. custompartitioned between water (50 ml) and ethyl acetate (100 ml)
13. customThe organic layer was separated
14. customthe solvent removed under reduced pressure
15. dissolutionThe residue was dissolved in THF (20 ml)
16. washThe solution was washed with 1N HCl (50 ml)
17. customthe aqueous layer was separated
18. extractionThe product was extracted with DCM (4×100 ml)
19. customdried sodium over sulfate and the solvent removed under reduced pressure
20. customThe residue was purified by flash chromatography

ORD record

ord-cb06618d9c0c49c2bf1024ac15f84b35

Source dataset

uspto-grants-2010_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07709500B2