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

Participants

Reaction Steps

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%).

Provenance & Evidence