methyl 3-amino-2-bromo-5-chlorobenzoate

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

Procedure: To a solution of methyl 3-amino-2-bromo-5-chlorobenzoate (1.0 g, 3.8 mmol) in 1,2-dichloroethane (15 ml) at room temperature under nitrogen was added oxan-4-one (0.7 ml, 7.6 mmol) followed by acetic acid (1.3 ml, 23 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.4 g, 11 mmol) at room temperature. After 21 h, additional oxan-4-one (0.7 ml, 7.6 mmol) was added to the reaction mixture, with stirring for 10 minutes before adding sodium triacetoxyborohydride (2.4 g, 11 mmol). After stirring for 20 h, deionized water (30 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×30 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (25 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 903 mg (68%) of the title compound as a white solid. LC-MS 92%, 2.11 min (3 minute LC-MS method), m/z=348.2/350.2/351.9, 1H NMR (500 MHz, Chloroform-d) δ 6.94-7.07 (1H, m), 6.70 (1H, d, J=2.36 Hz), 4.72 (1H, d, J=7.57 Hz), 3.96-4.15 (2H, m), 3.87-3.96 (3H, m), 3.40-3.67 (3H, m), 2.05 (2H, d, J=13.08 Hz), 1.49-1.69 (2H, m). After stirring for 20 h The phases were separated the aqueous layer was extracted with EtOAc (2×30 ml) The combined organic extracts were dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by FCC (25 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 8:2 Heptane:EtOAc)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-5-chloro-3-nitrobenzoate (4.0 g, 14 mmol) in methanol (130 ml) at room temperature was added ammonium chloride (7.13 g, 136 mmol) followed by deionized water (65 ml). The mixture was heated to 70° C. in air before the addition of iron (4.55 g, 81.5 mmol). The reaction was stirred at 70° C. for 3 hours, allowed to cool to room temperature and filtered through Kieselgel. The filter pad was washed with MeOH (65 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (50 ml) and EtOAc (100 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (3×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 1.92 g (48%) of the title compound as a colourless oil. LC-MS 92%, m/z=268.8/265.8/267.6, 1H NMR (500 MHz, Chloroform-d) δ 7.08 (1H, d, J=2.36 Hz), 6.86 (1H, d, J=2.36 Hz), 4.34-4.49 (2H, m), 3.93 (3H, s). to cool to room temperature filtered through Kieselgel The filter pad was washed with MeOH (65 ml) the filtrate concentrated under reduced pressure The residue was dissolved in saturated NaHCO3 (50 ml) The phases were separated the organic phase was washed with saturated NaHCO3(aq) (3×50 ml) before being dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromo-5-chloro-3-nitrobenzoate (4.0 g, 14 mmol) in methanol (130 ml) at room temperature was added ammonium chloride (7.13 g, 136 mmol) followed by deionized water (65 ml). The mixture was heated to 70° C. in air before the addition of iron (4.55 g, 81.5 mmol). The reaction was stirred at 70° C. for 3 hours, allowed to cool to room temperature and filtered through Kieselgel. The filter pad was washed with MeOH (65 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (50 ml) and EtOAc (100 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (3×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 1.92 g (48%) of the title compound as a colourless oil. LC-MS 92%, m/z=268.8/265.8/267.6, 1H NMR (500 MHz, Chloroform-d) δ 7.08 (1H, d, J=2.36 Hz), 6.86 (1H, d, J=2.36 Hz), 4.34-4.49 (2H, m), 3.93 (3H, s). to cool to room temperature filtered through Kieselgel The filter pad was washed with MeOH (65 ml) the filtrate concentrated under reduced pressure The residue was dissolved in saturated NaHCO3 (50 ml) The phases were separated the organic phase was washed with saturated NaHCO3(aq) (3×50 ml) before being dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc)