Hydrochloric Acid → 3-Amino-4-fluoro-2,5-dimethylphenol

Temperature

80 °C

A mixture of tert-butyl N-tert-butoxycarbonyl-N-(3-bromo-6-fluoro-2,5-dimethylphenyl)carbamate (0.81 g, 1.94 mmol, 1.0 eq), Pd(dppf)Cl2 (763 mg, 0.19 mmol, 0.1 eq), KOAc (571 mg, 5.82 mmol, 3.0 eq) and bis(pinacolato)diboron (591 mg, 2.33 mmol, 1.2 eq) in DMSO (10 mL) under N2 was stirred at 80° C. overnight. After cooling to room temperature, the reaction was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford a crude residue. The residue obtained was dissolved in THF (10 mL) and the solution cooled to 0° C. H2O2 (30% aqueous solution, 660 mg, 5.82 mmol, 3.0 eq) was added, followed by NaOH (1M aqueous solution, 5.82 mL, 5.82 mmol, 3.0 eq) the mixture was stirred for 10 min and allowed to warm to 10° C. The pH was adjusted to pH 5˜7 by addition of 3M HCl and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was dissolved in MeOH (8 mL) and cooled to 0° C. HCl in dioxane (4M, 12 mL, 48 mmol, 24.7 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was then cooled to 0° C. and the pH adjusted to 5-6 by addition of 1M NaOH. The dioxane was removed in vacuo and the aqueous phase extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a yellow solid (157 mg, 52%).

1. temperatureAfter cooling to room temperature
2. extractionextracted with EtOAc
3. washThe combined organic extracts were washed with water and brine
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. customevaporated in vacuo
7. customto afford a crude residue
8. customThe residue obtained
9. temperaturethe solution cooled to 0° C
10. stirringwas stirred for 10 min
11. temperatureto warm to 10° C
12. extractionthe aqueous layer extracted with EtOAc
13. washThe combined organic extracts were washed with brine
14. dry with materialdried (Na2SO4)
15. filtrationfiltered
16. customevaporated in vacuo
17. customThe residue obtained
18. temperaturecooled to 0° C
19. temperatureto warm to room temperature
20. stirringstirred for 1 h
21. temperatureThe reaction was then cooled to 0° C.
22. customThe dioxane was removed in vacuo
23. extractionthe aqueous phase extracted with EtOAc
24. washThe combined organic extracts were washed with brine
25. dry with materialdried (Na2SO4)
26. filtrationfiltered
27. customevaporated in vacuo
28. customto give a crude residue, which
29. customwas purified by column chromatography (petroleum ether: EtOAc, 10:1)

ORD record

ord-f2ce6e867c4c40bc8fccbc66671cd229

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09249085B2