methyl 2-bromo-4-chlorobenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound was prepared using the procedure described in Example 234 and Intermediate C and methyl 2-bromo-4-chlorobenzoate as starting materials. 1H NMR (300 MHz, CD2Cl2) δ 9.33 (s, 1H), 7.84 (d, 1H), 7.20-7.30 (m, 4H), 7.15 (s, 1H), 6.68 (d, 1H), 6.13 (s, 1H), 3.72 (s, 3H), 2.06 (s, 3H), 1.31 (s, 9H). ES-MS m/z 398.3 (MH)+; HPLC RT (min) 4.27. This compound was prepared

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound was prepared using the procedure described in Example 234 and Intermediate C and methyl 2-bromo-4-chlorobenzoate as starting materials. 1H NMR (300 MHz, CD2Cl2) δ 9.33 (s, 1H), 7.84 (d, 1H), 7.20-7.30 (m, 4H), 7.15 (s, 1H), 6.68 (d, 1H), 6.13 (s, 1H), 3.72 (s, 3H), 2.06 (s, 3H), 1.31 (s, 9H). ES-MS m/z 398.3 (MH)+; HPLC RT (min) 4.27. This compound was prepared

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step. The ice water bath was removed The mixture was heated to mild reflux for 12 h After completion of the reaction the reaction mixture was concentrated Crude product was dissolved in dichloromethane (DCM, 250 ml) washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml) dried over sodium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step. The ice water bath was removed The mixture was heated to mild reflux for 12 h After completion of the reaction the reaction mixture was concentrated Crude product was dissolved in dichloromethane (DCM, 250 ml) washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml) dried over sodium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step. The ice water bath was removed The mixture was heated to mild reflux for 12 h After completion of the reaction the reaction mixture was concentrated Crude product was dissolved in dichloromethane (DCM, 250 ml) washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml) dried over sodium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step. The ice water bath was removed The mixture was heated to mild reflux for 12 h After completion of the reaction the reaction mixture was concentrated Crude product was dissolved in dichloromethane (DCM, 250 ml) washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml) dried over sodium sulfate concentrated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1.0 M solution of diisobutylaluminum hydride in toluene (43 mL, 0.043 mol) was added slowly drop-wise to a −78° C. solution of 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 0.042 mol) in toluene (50 mL) and hexanes (425 mL). The reaction mixture was stirred at −78° C. for 1.5 hours. After this time, a white solid had precipitated out of solution. The reaction mixture was quenched at −78° C. with ethyl acetate (100 mL). Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to a clear oil. TLC (30% ethyl acetate/hexanes) and 1H NMR revealed a mixture with unreacted 2-bromo-4-chloro-benzoic acid methyl ester as the major component. The crude material was dissolved in toluene (300 mL), and the resulting solution was cooled to −78° C. A 1.0 M solution of diisobutylaluminum hydride in toluene (55 mL, 0.055 mol) was added slowly drop-wise to the reaction mixture. The reaction mixture was warmed to −45° C. and stirred at this temperature for 35 minutes. At this time, TLC (10% ethyl acetate/hexanes) indicated nearly complete consumption of the starting material. The reaction mixture was quenched at −45° C. with ethyl acetate. Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The organic phase was separated, dried over Na2SO4, and concentrated to a yellow oil. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes-ethyl acetate ramped to 4:1 hexanes-ethyl acetate). (2-Bromo-4-chloro-phenyl)-methanol was isolated as 5.57 g (60% yield) of a white solid. After this time, a white solid had precipitated out of solution The reaction mixture was quenched at −78° C. with ethyl acetate (100 mL) Saturated aqueous sodium potassium tartrate was added the reaction mixture was warmed to room temperature The organic phase was separated dried over Na2SO4 filtered concentrated to a clear oil The crude material was dissolved in toluene (300 mL) the resulting solution was cooled to −78° C The reaction mixture was warmed to −45° C. stirred at this temperature for 35 minutes consumption of the starting material The reaction mixture was quenched at −45° C. with ethyl acetate Saturated aqueous sodium potassium tartrate was added the reaction mixture was warmed to room temperature stirred at room temperature for 1 hour The organic phase was separated dried over Na2SO4 concentrated to a yellow oil A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel an ISCO purification system (95:5 hexanes-ethyl acetate ramped to 4:1 hexanes-ethyl acetate)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Concentrated sulfuric acid (5 mL) was added drop-wise to an ice-cold mixture of 2-bromo-4-chloro-benzoic acid (10.14 g, 0.0431 mol) and methanol (40 mL). The resulting mixture was heated at reflux for 17 hours. After this time, the reaction mixture was cooled to room temperature, and then poured into ice-cold water (150 mL), creating a white suspension. The suspension was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated aqueous NaHCO3 (100 mL), followed by saturated aqueous NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 98% yield) as a clear oil. The resulting mixture was heated at reflux for 17 hours The suspension was extracted with ethyl acetate (150 mL) The organic phase was washed with saturated aqueous NaHCO3 (100 mL) The organic layer was dried over Na2SO4 filtered concentrated