Carbamic acid, N-(3-bromo-5-chloro-2-fluorophenyl)-, 1,1-dimethylethyl ester

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: tert-Butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (1.0 g, 3.1 mmol) was treated with 4.0 M HCl in dioxane (10 mL) and the resulting reaction was maintained at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL). The layers were separated and the organic portion was washed with brine (75 mL), dried (Na2SO4), and concentrated to give 3-bromo-5-chloro-2-fluoroaniline as a colorless oil which was carried forward without further purification: LCMS (m/z) 225.9 (MH+), tR=0.96 minute; 1H NMR (400 MHz, CDCl3) δ 6.88 (m, 1H), 6.70 (d, J=7.0 Hz, 1H). the resulting reaction The reaction mixture was concentrated partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL) The layers were separated the organic portion was washed with brine (75 mL) dried (Na2SO4) concentrated

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

Procedure: A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (3.34 g, 13.2 mmol), DIEA (2.04 g, 15.8 mmol) and diphenyl phosphorazide (DPPA, 4.53 g, 16.5 mmol) in 1:1 dry t-butanol and toluene (35 mL) was heated to and maintained at reflux for 23 hours. The reaction was allowed to cool to room temperature and was then partitioned between CHCl3 (75 mL) and water (75 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and then concentrated under reduced pressure to yield an oily residue. Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane) to yield tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (2.45 g, 7.5 mmol, 57%): LCMS (m/z) not ionized (MH+), tR=1.20 minutes; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 7.16 (m, 1H), 6.72 (br s, 1H), 1.53 (s, 9H). was heated to and maintained at reflux for 23 hours was then partitioned between CHCl3 (75 mL) and water (75 mL) The organic layer was separated washed with brine dried (Na2SO4) concentrated under reduced pressure to yield an oily residue Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane)

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

Procedure: tert-Butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (1.0 g, 3.1 mmol) was treated with 4.0 M HCl in dioxane (10 mL) and the resulting reaction was maintained at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL). The layers were separated and the organic portion was washed with brine (75 mL), dried (Na2SO4), and concentrated to give 3-bromo-5-chloro-2-fluoroaniline as a colorless oil which was carried forward without further purification: LCMS(m/z) 225.9 (MH+), tR=0.96 minute; 1H NMR (400 MHz, CDCl3) δ 6.88 (m, 1H), 6.70 (d, J=7.0 Hz, 1H). the resulting reaction The reaction mixture was concentrated partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL) The layers were separated the organic portion was washed with brine (75 mL) dried (Na2SO4) concentrated

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

Procedure: A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (3.34 g, 13.2 mmol), DIEA (2.04 g, 15.8 mmol) and diphenyl phosphorazide (DPPA, 4.53 g, 16.5 mmol) in 1:1 dry t-butanol and toluene (35 mL) was heated to and maintained at reflux for 23 hours. The reaction was allowed to cool to room temperature and was then partitioned between CHCl3 (75 mL) and water (75 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and then concentrated under reduced pressure to yield an oily residue. Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane) to yield tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (2.45 g, 7.5 mmol, 57%): LCMS(m/z) not ionized (MH+), tR=1.20 minutes; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 7.16 (m, 1H), 6.72 (br s, 1H), 1.53 (s, 9H). was heated to and maintained at reflux for 23 hours was then partitioned between CHCl3 (75 mL) and water (75 mL) The organic layer was separated washed with brine dried (Na2SO4) concentrated under reduced pressure to yield an oily residue Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane)

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

Procedure: A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (3.34 g, 13.2 mmol), DIEA (2.04 g, 15.8 mmol) and diphenyl phosphorazide (DPPA, 4.53 g, 16.5 mmol) in 1:1 dry t-butanol and toluene (35 mL) was heated to and maintained at reflux for 23 hours. The reaction was allowed to cool to room temperature and was then partitioned between CHCl3 (75 mL) and water (75 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and then concentrated under reduced pressure to yield an oily residue. Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane) to yield tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (2.45 g, 7.5 mmol, 57%): LCMS(m/z) not ionized (MH+), tR=1.20 minutes; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 7.16 (m, 1H), 6.72 (br s, 1H), 1.53 (s, 9H). was heated to and maintained at reflux for 23 hours was then partitioned between CHCl3 (75 mL) and water (75 mL) The organic layer was separated washed with brine dried (Na2SO4) concentrated under reduced pressure to yield an oily residue Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane)

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

Procedure: A solution of tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (900 mg, 2.78 mmol) in DCM/TFA (1:1, 20 mL) was stirred at rt for 1 h. The reaction mixture was concentrated, then the residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound (736 mg). MS m/z 223.9 (M+1). The reaction mixture was concentrated washed with aqueous sodium bicarbonate and brine The organic layer was dried over sodium sulfate filtered concentrated

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

Procedure: A solution of tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (900 mg, 2.78 mmol) in DCM/TFA (1:1, 20 mL) was stirred at rt for 1 h. The reaction mixture was concentrated, then the residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound (736 mg). MS m/z 223.9 (M+1). The reaction mixture was concentrated washed with aqueous sodium bicarbonate and brine The organic layer was dried over sodium sulfate filtered concentrated

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

Procedure: A solution of crude Intermediate 3-bromo-5-chloro-2-fluorobenzoic acid (2.03 g, 8 mmol), diphenylphosphoryl azide (2.07 mL, 9.6 mmol, 1.2 eq), and DIPEA (1.67 mL, 9.6 mmol, 1.2 eq) in 1:1 t-butanol/toluene (25 ml) was heated at 110° C. for 36 h. The mixture was concentrated, then partitioned between ethyl acetate and water. The organic layer was washed with brine, and was then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (30:1 to 10:1 hexanes/ethyl acetate eluant) to provide the title compound. MS m/z: 267.8 (M+H)+. (M−tBu). The mixture was concentrated partitioned between ethyl acetate and water The organic layer was washed with brine was then dried over sodium sulfate filtered concentrated The crude product was purified by silica gel chromatography (30:1 to 10:1 hexanes/ethyl acetate eluant)

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

Procedure: tert-Butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (1.0 g, 3.1 mmol) was treated with 4.0 M HCl in dioxane (10 mL) and the resulting reaction was maintained at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL). The layers were separated and the organic portion was washed with brine (75 mL), dried (Na2SO4), and concentrated to give 3-bromo-5-chloro-2-fluoroaniline as a colorless oil which was carried forward without further purification: LCMS (m/z) 225.9 (MH+), tR=0.96 minute; 1H NMR (400 MHz, CDCl3) δ 6.88 (m, 1H), 6.70 (d, J=7.0 Hz, 1H). the resulting reaction The reaction mixture was concentrated partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL) The layers were separated the organic portion was washed with brine (75 mL) dried (Na2SO4) concentrated

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

Procedure: A mixture of 3-bromo-5-chloro-2-fluorobenzoic acid (3.34 g, 13.2 mmol), DIEA (2.04 g, 15.8 mmol) and diphenyl phosphorazide (DPPA, 4.53 g, 16.5 mmol) in 1:1 dry t-butanol and toluene (35 mL) was heated to and maintained at reflux for 23 hours. The reaction was allowed to cool to room temperature and was then partitioned between CHCl3 (75 mL) and water (75 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and then concentrated under reduced pressure to yield an oily residue. Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane) to yield tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (2.45 g, 7.5 mmol, 57%): LCMS (m/z) not ionized (MH+), tR=1.20 minutes; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 7.16 (m, 1H), 6.72 (br s, 1H), 1.53 (s, 9H). was heated to and maintained at reflux for 23 hours was then partitioned between CHCl3 (75 mL) and water (75 mL) The organic layer was separated washed with brine dried (Na2SO4) concentrated under reduced pressure to yield an oily residue Purification by flash chromatography (SiO2, 0-5% EtOAc in heptane)