Hydrochloric Acid → 4-(2-Bromo-5-fluorophenoxy)piperidine

Temperature

-78 °C

tert-Butyl 4-(2-bromo-5-fluorophenoxy)piperidine-1-carboxylate from Step 1, Method (i), was dissolved in ethanol (200 mL), cooled to −78° C. and treated with 4 N HCl in dioxane (450 mL). The reaction was warmed and stirred overnight at room temperature. The solvent was removed under reduced pressure and the mixture partitioned between 1 N NaOH (750 mL) and a 1:1 mixture of ether-hexane. After several extractions, the organics layers were combined and evaporated to dryness. The crude material was dissolved in heptane (1 L) and a white precipitate was filtered and discarded. The heptane layer was diluted with ether and treated with 4 N HCl in dioxane (100 mL). The resulting precipitate was collected by filtration and washed three times with a 1:1 mixture of ether-hexane. The salt was partitioned again between 1 N NaOH (500 mL) and a 1:1 mixture of ether-hexane. After several extractions, the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude material was dissolved into heptane (2 L) and washed four times with 1 N NaOH (250 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give the title compound as colorless oil.

1. temperatureThe reaction was warmed
2. customThe solvent was removed under reduced pressure
3. customthe mixture partitioned between 1 N NaOH (750 mL)
4. additiona 1:1 mixture of ether-hexane
5. extractionAfter several extractions
6. customevaporated to dryness
7. dissolutionThe crude material was dissolved in heptane (1 L)
8. filtrationa white precipitate was filtered
9. additionThe heptane layer was diluted with ether
10. additiontreated with 4 N HCl in dioxane (100 mL)
11. filtrationThe resulting precipitate was collected by filtration
12. washwashed three times
13. additionwith a 1:1 mixture of ether-hexane
14. customThe salt was partitioned again between 1 N NaOH (500 mL)
15. additiona 1:1 mixture of ether-hexane
16. extractionAfter several extractions
17. washwashed with brine
18. dry with materialdried over magnesium sulfate
19. filtrationfiltered
20. customevaporated
21. dissolutionThe crude material was dissolved into heptane (2 L)
22. washwashed four times with 1 N NaOH (250 mL)
23. washThe organic layer was washed with brine
24. dry with materialdried over magnesium sulfate
25. filtrationfiltered
26. customevaporated

ORD record

ord-61626f3b11eb4d3e980aa99505badb93

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582633B2