2-amino-5-bromophenol

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

Procedure: 4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.6 g) as a yellow solid. After continuing stirring at rt for 15 mins reaction mass extracted with DCM DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid Solid was triturated with Et2O and Petether mixture (4:1)

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

Procedure: 4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(difluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H). After continuing stirring at rt for 15 mins reaction mass extracted with DCM DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid Solid was triturated with Et2O and Petether mixture (4:1)

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

Procedure: 4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(difluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H). After continuing stirring at rt for 15 mins reaction mass extracted with DCM DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid Solid was triturated with Et2O and Petether mixture (4:1)

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-amino-5-bromophenol (1.72 g, 9.2 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) were dissolved in polyposphoric acid (30 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Solid that formed was filtered and dried to obtain the crude. Crude was purified by combiflash using a gradient mixture of EtOAc and Petether (1:3) as eluent to afford the titled compound (450 mg) as a dark brown solid. Reaction mixture cooled to rt Solid that formed was filtered dried to obtain the crude Crude was purified by combiflash a gradient mixture of EtOAc and Petether (1:3) as eluent

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification. reaction mixture cooled to rt followed by removal of EtOAc

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-amino-5-bromophenol (1.3 g, 6.9 mmol) and isonipecotic acid (893 mg, 6.91 mmol) were dissolved in polyphosphoric acid (39 g). This mixture was heated to 190° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with 10% aqueous NaOH solution to pH 8. Work up (EtOAc/H2O) followed by removal of EtOAc afforded the title compound (500 mg) as a black solid. It was used in the next step without further purification. reaction mixture cooled to rt followed by removal of EtOAc

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-amino-5-bromophenol (51.3 g, 273 mmol) and NaHCO3 (68.8 g, 819 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (46.2 g, 409 mmol) at 0° C. and the reaction mixture was stirred at 15° C. for 0.5 h then heated at 80° C. for 18 h. The reaction mixture was cooled to ambient temperature. The precipitate was collected by suction, washed with water and dried in vacuo to give 7-bromo-4H-benzo[1,4]oxazin-3-one (59.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.17 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.59 (s, 2H). then heated at 80° C. for 18 h The reaction mixture was cooled to ambient temperature The precipitate was collected by suction washed with water dried in vacuo

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,8-Diazabicyclo[5.4.0]undec-7-ene (145.0 μL, 0.975 mmol) was added at room temperature to a solution of 2-amino-5-bromophenol A-1 (200.0 mg, 1.064 mmol) and methyl 2-bromoacetate (115.0 μL, 0.886 mmol) in anhydrous 1-methylpyrrolidin-2-one (4.20 mL) under an atmosphere of argon, in a 10 mL microwave reactor vial. The sealed reaction mixture was heated at 180° C. for 3 mins under microwave irradiation and then diluted with ethyl acetate (25 mL). The organic layer was washed with brine (3×20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one A-2 (217.0 mg, Yield=100%). MS (ESI) [M+1]+ 242, 244. The sealed reaction mixture The organic layer was washed with brine (3×20 mL) dried over anhydrous magnesium sulfate filtered concentrated to dryness under reduced pressure The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient)

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

Procedure: Part 2. A solution of 2-amino-5-bromophenol (2.53 g, 18.2 mmol, 1.0 equiv) in 15 mL of isobutylmethyl ketone and 15 mL of water was cooled to 0° C., NaHCO3 (3.67 g, 2.4 equiv) and then chloroacetyl chloride (2.36 g, 1.67 mL, 1.15 equiv) were added. The mixture was heated to reflux overnight, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated in vacuo. Flash chromatography on silica gel gave 7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one in 77% yield. LRMS found for C9H10NO3 (M+H)+: 180.1. The mixture was heated to reflux overnight washed with water dried over MgSO4 concentrated in vacuo

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

Procedure: 5.0 g 2-Amino-5-bromophenol were dissolved in 100 ml acetone. Then 11.0 g potassium carbonate and 6.74 g ethyl-2-bromoisobutyrate were added. The reaction mixture was stirred at room temperature overnight and refluxed overnight. The cooled reaction mixture was then filtrated and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography on silica gel to obtain 4.6 g 7-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one as a yellow solid. refluxed overnight The cooled reaction mixture was then filtrated the filtrate concentrated in vacuo The resulting residue was purified by chromatography on silica gel

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

Procedure: Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-hydroxybenzoic acid Preparation

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

Procedure: Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-benzyloxybenzoic acid. Preparation