methyl 5-bromo-2-(bromomethyl)benzoate

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-bromo-2-methylbenzoate (1.0 g, 0.45 mol) was dissolved in carbon tetrachloride (15 mL) to which benzoyl peroxide (40 mg) and NBS (1.49 g, 0.83 mol) were added and the reaction mixture was refluxed at 80° C. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to obtain a crude material containing 95% mono bromo and 5% dibromo product. The crude material was used directly for the preparation of compound of example 329 without purification. were added After completion of the reaction the reaction mixture was cooled to room temperature filtered through celite The filtrate was concentrated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H). The mixture was cooled to room temperature the resultant white solid was collected

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

Procedure: To a solution of 5-bromo-2-methylbenzoic acid methyl ester (8.4 g, 37 mmol) in 100 mL CCl4 was added N-bromosuccinimide (7.8 g, 44 mmol) and benzoylperoxide (0.5% as catalyst). The mixture was heated at reflux for 2 h and then was cooled to room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 5-bromo-2-bromomethyl-benzoic acid methyl ester (5.2 g, 46%). 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.60 (d, J=8.0, 1H), 7.32 (d, J=8.0, 1H), 4.89 (s, 2H), 3.94 (s, 3H). The mixture was heated at reflux for 2 h The solvent was removed in vacuo the residue was purified by column chromatography on silica gel (petroleum ether)

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

Procedure: To a solution of 5-bromo-2-methylbenzoic acid methyl ester (8.4 g, 37 mmol) in 100 mL CCl4 was added N-bromosuccinimide (7.8 g, 44 mmol) and benzoylperoxide (0.5% as catalyst). The mixture was heated at reflux for 2 h and then was cooled to room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether) to afford 5-bromo-2-bromomethyl-benzoic acid methyl ester (5.2 g, 46%). 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.60 (d, J=8.0, 1H), 7.32 (d, J=8.0, 1H), 4.89 (s, 2H), 3.94 (s, 3H). The mixture was heated at reflux for 2 h The solvent was removed in vacuo the residue was purified by column chromatography on silica gel (petroleum ether)

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

Procedure: The mixture of 3- and 5-bromo-2-methylbenzoic acid methyl ester (35.79 g; 156 mmol) is dissolved in carbon tetrachloride (200 mL). To the solution is added N-bromosuccinimide (29.5 g; 166 mmol), followed by AIBN (54 mg) and the mixture was heated at reflux temperature for 20 hours. Then the mixture was cooled to room temperature and the succinimide was filtered from solution and rinsed with carbon tetrachloride. The solvent was evaporated to yield a mixture of the title compound and 3-bromo-2-bromomethylbenzoic acid methyl ester (48.1 g; crude mass). the mixture was heated at reflux temperature for 20 hours the succinimide was filtered from solution rinsed with carbon tetrachloride The solvent was evaporated to yield

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

Procedure: The mixture of 3- and 5-bromo-2-methylbenzoic acid methyl ester (35.79 g; 156 mmol) is dissolved in carbon tetrachloride (200 mL). To the solution is added N-bromosuccinimide (29.5 g; 166 mmol), followed by AIBN (54 mg) and the mixture was heated at reflux temperature for 20 hours. Then the mixture was cooled to room temperature and the succinimide was filtered from solution and rinsed with carbon tetrachloride. The solvent was evaporated to yield a mixture of the title compound and 3-bromo-2-bromomethylbenzoic acid methyl ester (48.1 g; crude mass). the mixture was heated at reflux temperature for 20 hours the succinimide was filtered from solution rinsed with carbon tetrachloride The solvent was evaporated to yield

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (0.50 g) in DMF (5.00 mL) were added trans-2-aminocyclohexanol hydrochloride (0.37 g) and N-ethyldiisopropylamine (1.42 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added 5% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.22 g). the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (0.50 g) in DMF (5.00 mL) were added trans-2-aminocyclohexanol hydrochloride (0.37 g) and N-ethyldiisopropylamine (1.42 mL), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture was added 5% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.22 g). the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 5-bromo-2-methylbenzoate (5.27 g) in trifluoromethylbenzene (50.0 mL) were added AIBN (0.04 g) and N-bromosuccinimide (4.50 g), and the mixture was stirred at 90° C. for 4 hr under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.89 g). the mixture was washed with saturated brine The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 5-bromo-2-methylbenzoate (1.0 g, 0.45 mol) was dissolved in carbon tetrachloride (15 mL) to which benzoyl peroxide (40 mg) and NBS (1.49 g, 0.83 mol) were added and the reaction mixture was refluxed at 80° C. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to obtain a crude material containing 95% mono bromo and 5% dibromo product. The crude material was used directly for the preparation of compound of example 329 without purification. were added After completion of the reaction the reaction mixture was cooled to room temperature filtered through celite The filtrate was concentrated