Hydrochloric Acid → 3-Amino-2,4-difluoro-5-methylphenol

To a solution of 2,6-difluoro-3-methyl-5-triisopropylsilyloxy-benzoic acid (1.08 g, 3.14 mmol, 1.0 eq) in CH2Cl2 (15 mL) was added (COCl)2 (1.19 g, 9.40 mmol, 3.0 eq) dropwise at 0° C. DMF (3 drops) was added and the mixture warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to dryness, and the residue obtained was dissolved in acetone (20 mL) and added dropwise to a cooled solution of NaN3 (815 mg, 12.5 mol, 4 eq) in a mixture of acetone (10 mL) and water (10 mL) at 0° C. The reaction was stirred for 1 h at 0° C., further water (20 mL) was then added and the reaction heated at 70° C. overnight. The reaction was partitioned between EtOAc and water and extracted with EtOAc, the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was dissolved in dioxane (25 mL), aqueous KOH (25% aqueous solution, 12 mL) was added and the reaction heated at reflux overnight. The reaction was then cooled to room temperature and acidified to pH 5-6 with 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with water, brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum Ether: EtOAc, 50:1 to 20:1) to give the title compound as a white solid (270 mg, 87%).

1. concentrationThe reaction mixture was concentrated to dryness
2. customthe residue obtained
3. stirringThe reaction was stirred for 1 h at 0° C.
4. temperaturethe reaction heated at 70° C. overnight
5. customThe reaction was partitioned between EtOAc and water
6. extractionextracted with EtOAc
7. washthe combined organic extracts were washed with water and brine
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe residue obtained
12. temperaturethe reaction heated
13. temperatureat reflux overnight
14. temperatureThe reaction was then cooled to room temperature
15. extractionThe aqueous layer was extracted with EtOAc
16. washthe combined organic extracts washed with water, brine
17. dry with materialdried (Na2SO4)
18. filtrationfiltered
19. customevaporated in vacuo
20. customThe residue obtained
21. customwas purified by column chromatography (petroleum Ether: EtOAc, 50:1 to 20:1)

ORD record

ord-87216deb9a264a6fa2a9938a6acdd0a2

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09249085B2