methyl 4-bromo-3-(bromomethyl)benzoate

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

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromo-3-(bromomethyl)benzoate obtained in step 1 (6.5 g; 21 mmol) in AcOH (32.5 mL) was added sodium acetate (3.46 g; 42 mmol) and the reaction mixture was stirred at 100° C. for 12 hours. After concentration in vacuo, the residue was partitioned between EtOAc and water. The organic layer was washed with 5% aq. NaHCO3 then brine, dried over MgSO4 and concentrated in vacuo. Purification by silica column chromatography (c-hexane/EtOAc, 5/1) afforded the title compound as a white solid (4.78 g, 79%). 1H NMR (DMSO-d6) δ 8.03 (m, 1H), 7.85-7.84 (d, J=1.3 Hz, 1H), 5.18 (s, 2H), 3.87 (s, 3H), 2.11 (s, 3H). HPLC (Method A) Rt 4.37 min (purity 98.1%). After concentration in vacuo the residue was partitioned between EtOAc and water The organic layer was washed with 5% aq. NaHCO3 brine, dried over MgSO4 concentrated in vacuo Purification by silica column chromatography (c-hexane/EtOAc, 5/1)

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

Procedure: To a solution of methyl 4-bromo-3-methylbenzoate (50 g; 218 mmol) in CHCl3 (1 L) were added NBS (46.6 g; 262 mmol) in one portion and α,α′-azoisobutyronitrile (0.72 g; 4.37 mmol). The reaction mixture was stirred at 70° C. for 2 days. It was cooled down to RT and water was added. The organic layer was washed with aq. NaHCO3, then brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with n-pentane to afford the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 8.24 (d, J=1.9 Hz, 1H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A): Rt 4.44 min (purity 97.9%). It was cooled down to RT The organic layer was washed with aq. NaHCO3 brine, dried over MgSO4 concentrated in vacuo The residue was washed with n-pentane

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

Procedure: A solution of methyl 4-bromo-3-(bromomethyl)benzoate obtained in step 1 (37.50 g; 121.77 mmol) in MeOH (1 125 mL) was refluxed for 4 days. After concentration, the mixture was partitioned between EtOAc (500 mL) and water (200 mL). The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (29.8 g, 94%). 1H NMR (DMSO-d6) δ 8.06-8.05 (m, 1H), 7.83 (d, J=1.23 Hz, 2H), 4.54 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 4.42 min (Purity: 93.0%). After concentration the mixture was partitioned between EtOAc (500 mL) and water (200 mL) The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL) dried over MgSO4 concentrated

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

Procedure: Under N2, to a solution of methyl 4-bromo-3-methylbenzoate (50 g; 218.27 mmol) in CHCl3 (1 000 mL) were added NBS (Merck, 46.62 g; 261.93 mmol) in one portion and α,α′-azoisobutyronitrile (0.72 g; 4.37 mmol). The mixture was stirred at 70° C. for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with of a saturated aqueous solution of NaHCO3, water (340 mL), then brine (500 mL), dried over MgSO4 and concentrated affording the title compound as a yellow solid. It was washed with pentane (2×500 mL) affording the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 8.24 (d, J=1.91 Hz, 1H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A) Rt 4.44 min (Purity: 97.9%). The reaction mixture was cooled to RT The organic layer was washed with of a saturated aqueous solution of NaHCO3, water (340 mL) brine (500 mL), dried over MgSO4 concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (6.5 g; 21 mmol; 1 eq.) in AcOH (32.5 mL) was added sodium acetate (3.46 g; 42 mmol; 2 eq.) and the reaction mixture was stirred at 100° C. for 12 hours. After concentration in vacuo, the residue was partitioned between Ethyl acetate and water. The organic layer was washed with 5% aq. NaHCO3 then brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 5/1) afforded the title compound (4.78 g, 79%) as a white solid. After concentration in vacuo the residue was partitioned between Ethyl acetate and water The organic layer was washed with 5% aq. NaHCO3 brine, dried over MgSO4 concentrated in vacuo Purification by column chromatography (c-hexane/ethyl acetate, 5/1)

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

Procedure: To a solution of methyl 4-bromo-3-methylbenzoate (Aldrich 532878, 50 g; 218 mmol; 1 eq.) in CHCl3 (1 L) were added NBS (46.6 g; 262 mmol; 1.2 eq.) in one portion and α,α′-azoisobutyronitrile (0.72 g; 4.37 mmol; 0.02 eq.) and the reaction mixture was stirred at 70° C. for 2 days. The mixture was cooled down to room temperature and water (500 mL) was added. The organic layer was washed with aq. NaHCO3 (400 mL), then brine (500 mL), dried over MgSO4 and concentrated in vacuo. The residue was washed with n-pentane (2×500 mL) to afford the title compound as a yellow solid. The mixture was cooled down to room temperature The organic layer was washed with aq. NaHCO3 (400 mL) brine (500 mL), dried over MgSO4 concentrated in vacuo The residue was washed with n-pentane (2×500 mL)

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

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

Procedure: A solution of methyl 4-bromo-3-(bromomethyl)benzoate (38 g; 122 mmol) in MeOH (1.1 L) was refluxed for 4 days. After concentration, the mixture was partitioned between EtOAc (500 mL) and water (200 mL). The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (30 g, 94%). 1H NMR (DMSO-d6, 300 MHz) δ 8.06-8.05 (m, 1H), 7.83 (m, 2H), 4.54 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 4.42 min (Purity: 93.0%). After concentration the mixture was partitioned between EtOAc (500 mL) and water (200 mL) The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL) dried over MgSO4 concentrated

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

Procedure: Under N2 atmosphere, to a solution of methyl 4-bromo-3-methylbenzoate (Aldrich 532878, 50 g; 218 mmol) in CHCl3 (1 L) were added NBS (47 g; 262 mmol) in one portion and α,α′-azoisobutyronitrile (720 mg; 4.4 mmol). The mixture was stirred at 70° C. for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with 50 mL NaHCO3 saturated solution, water (340 mL), then brine (500 mL), dried over MgSO4 and concentrated affording the title compound as a yellow solid. It was washed with pentane (2×500 mL) affording the title compound as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, J=1.9 Hz, 1H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A) Rt 4.44 min (Purity: 97.9%). The reaction mixture was cooled to RT The organic layer was washed with 50 mL NaHCO3 saturated solution, water (340 mL) brine (500 mL), dried over MgSO4 concentrated