4-amino-2-chloro-3-fluorophenol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-amino-2-chloro-3-fluorophenol (11 g, 68.3 mmol) and potassium 2-methylpropan-2-olate (8.4 g, 75.2 mmol) in DMA (120 mL) was stirred at RT under N2 for 0.5 h, treated with 2,4-dichloropyridine (9.1 g, 62.1 mmol), and heated at 80° C. for 8 h. The mixture was concentrated to dryness, the residue treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J=5.6 Hz, 1H), 6.98-6.96 (m, 2 H), 6.88 (dd, J=5.6 Hz, 2.0 Hz, 1 H), 6.80 (t, J=9.2 Hz, 1 H), 5.57 (s, 2H). heated at 80° C. for 8 h The mixture was concentrated to dryness the residue treated with water extracted with EtOAc (3×) the combined organics were washed with brine dried over Na2SO4 concentrated to dryness purified via silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 0° C. solution of 2-chloro-3-fluoro-4-nitrophenol (25 g, 130.9 mmol) in 1:1 MeOH and THF (400 mL) was treated with NH4Cl (70 g, 1.3 mol), followed by the portion-wise addition of zinc (83.2 g, 1.3 mol), then warmed to RT and stirred for 2 h. The solids were removed via filtration, the filtrate concentrated to dryness and the residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to afford 4-amino-2-chloro-3-fluorophenol (16 g, 76%). 1H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1 H), 6.59-6.51 (m, 2 H), 4.65 (s, 2H); MS (ESI): m/z 162.2 [M+H]+. The solids were removed via filtration the filtrate concentrated to dryness the residue was dissolved in EtOAc washed with brine dried over Na2SO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 0° C. solution of 2-chloro-3-fluoro-4-nitrophenol (25 g, 130.9 mmol) in 1:1 MeOH and THF (400 mL) was treated with NH4Cl (70 g, 1.3 mol), followed by the portion-wise addition of zinc (83.2 g, 1.3 mol), then warmed to RT and stirred for 2 h. The solids were removed via filtration, the filtrate concentrated to dryness and the residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to afford 4-amino-2-chloro-3-fluorophenol (16 g, 76%). 1H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1 H), 6.59-6.51 (m, 2 H), 4.65 (s, 2H); MS (ESI): m/z 162.2 [M+H]+. The solids were removed via filtration the filtrate concentrated to dryness the residue was dissolved in EtOAc washed with brine dried over Na2SO4 concentrated