反应详情

To 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D23) (4.255 g, 13.319 mmol) in dry DCM (100 mL) was added saturated aqueous NaHCO3 solution (100 mL) and the mixture was vigorously stirred with cooling in an ice bath for 10 min. The layers were allowed to separate then phosgene solution in toluene (20%, 1.85 M, 12.813 mL, 24.216 mmol) was added directly to the organic layer. The mixture was stirred vigorously for 10 min, then the organic phase was separated and the aqueous layer extracted twice with DCM. The combined organic extracts were dried and concentrated to give a white solid. This material was dissolved in 1,2-dichloroethane (80 mL) and N-(3-fluorophenyl)-4-piperidinamine (D4) (2.352 g, 12.108 mmol) was added, followed by triethylamine (1.685 mL, 12.108 mmol). The reaction mixture was heated at reflux for 2 h, then was allowed to cool to room temperature and was left to stand overnight under argon. The mixture was then treated with PS-trisamine resin (4.16 g) and stirred for 30 min at room temperature. The polymer was removed by filtration and the filtrate concentrated to give the crude product as a yellow gum (10.375 g). This material was combined with the crude product (10.499 g) obtained from a second preparation carried out on the same scale in parallel. The combined crude products were purified by column chromatography eluting with 0-80% EtOAc/petroleum ether to give the title compound as a cream foamy gum (8.281 g). Mass spectral and 1H NMR spectroscopic data consistent with those previously obtained for the product from Description 33.

1. temperaturewith cooling in an ice bath for 10 min
2. customto separate
3. stirringThe mixture was stirred vigorously for 10 min
4. customthe organic phase was separated
5. extractionthe aqueous layer extracted twice with DCM
6. customThe combined organic extracts were dried
7. concentrationconcentrated
8. customto give a white solid
9. temperatureThe reaction mixture was heated
10. temperatureat reflux for 2 h
11. waitwas left
12. stirringstirred for 30 min at room temperature
13. customThe polymer was removed by filtration
14. concentrationthe filtrate concentrated
15. customto give the crude product as a yellow gum (10.375 g)
16. customobtained from a second preparation
17. customwere purified by column chromatography
18. washeluting with 0-80% EtOAc/petroleum ether