反应详情

Degas (bubble nitrogen through the mixture) a suspension of tri-t-butylphosphonium tetrafluoroborate (16.0 g, 54.6 mmol) and allylpalladium(II) chloride dimer (5.07 g, 27.3 mmol) in DMSO (1.40 L) with stirring at room temperature. Add N-tert-butoxycarbonylpiperazine (315 g, 1.64 mol, 97% pure) and N-[(3R,4S)-6-bromo-3-hydroxy-chroman-4-yl]-4-fluoro-benzamide (200.0 g, 546 mmol). Stir the mixture for 15 min under nitrogen and then heat at 80° C. Add sodium tert-butoxide (179 g, 1.80 mol) and heat at 93-98° C. for 45 min. Pour the mixture over a solution of 1 M phosphoric acid (2.73 L, 2.73 mol, adjusted to pH=2.3 with 50% sodium hydroxide) and ethyl acetate (800 mL) and stir for 10 min. Separate the layers and extract the aqueous layer with ethyl acetate (3×300 mL). Wash the combined organic layer with semi-saturated brine (2×500 mL). Treat the organic layer with activated carbon (20 g) and silica gel (200 g) and stir for 30 min. Filter through a pad of diatomaceous earth and concentrate under reduced pressure to obtain a dark oil. Dissolve the oil in methanol (800 mL), add 4 M hydrogen chloride in dioxane (410 mL), and stir the solution at 40° C. for 1 hr. Evaporate the solvent in vacuo, suspend the residue in acetonitrile (1.6 L) and stir at room temperature for 1 hr. Collect the solid by filtration under nitrogen to avoid hydration of the salt. Wash the filtrate with acetonitrile (500 mL) and methyl tert-butyl ether (1 L), and dry under vacuum to obtain the title compound (262 g, 73%). LC-ES/MS m/z 372 [M+H]+.

1. customDegas (
2. custombubble nitrogen through the mixture)
3. stirringStir the mixture for 15 min under nitrogen
4. temperatureheat at 80° C
5. stirringstir for 10 min
6. customSeparate the layers
7. extractionextract the aqueous layer with ethyl acetate (3×300 mL)
8. washWash the combined organic layer with semi-saturated brine (2×500 mL)
9. additionTreat the organic layer with activated carbon (20 g) and silica gel (200 g)
10. stirringstir for 30 min
11. filtrationFilter through a pad of diatomaceous earth
12. concentrationconcentrate under reduced pressure
13. customto obtain a dark oil
14. stirringstir the solution at 40° C. for 1 hr
15. customEvaporate the solvent in vacuo
16. stirringstir at room temperature for 1 hr
17. customCollect the solid
18. filtrationby filtration under nitrogen
19. washWash the filtrate with acetonitrile (500 mL) and methyl tert-butyl ether (1 L)
20. customdry under vacuum