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With sodium chlorite; sodium dihydrogenphosphate dihydrate; 2-methyl-but-2-ene; In water; tert-butyl alcohol; at 23℃; for 2h;
To a solution of 4-bromo-2-fluoro-6-methoxy-benzaldehyde (3.4 g, 14.6 mmol) in tert-butanol (70 ml) and water (35 ml), sodium chlorite (2.64 g, 29.2 mmol), monosodium phosphate dihydrate (11.4 g, 72.9 mmol) and 2-methyl-2-butene (12.4 ml, 116.7 mmol) are added successively at room temperature and the mixture is stirred for 2 h. After completion of the reaction (monitored by TLC), the mixture is concentrated under reduced pressure and the residue is diluted with ice water (50 ml) and acidified to pH 5 by adding 2N hydrochloric acid. The mixture is extracted with methyl tert-butyl ether (2 x 100 ml). The methyl tert-butyl ether layer is extracted again with 10% aqueous sodium hydroxide (100 ml). The aqueous layer is acidified to pH 2 with 5N hydrochloric acid and extracted with dichloromethane (2 x 50 ml). The organic layer is washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to obtain 4-bromo-2-fluoro-6-methoxy-benzoic acid (2.5 g, 10.0 mmol, 68%).
68%
With hydrogenchloride; sodium chlorite; sodium dihydrogenphosphate dihydrate; 2-methyl-but-2-ene; In water; tert-butyl alcohol; at 20℃; for 2h;
c) Synthesis of 4-bromo-2-fluoro-6-methoxy-benzoic acid To a solution of 4-bromo-2-fluoro-6-methoxy-benzaldehyde (3.4 g, 14.6 mmol) in tert-butanol (70 ml) and water (35 ml), sodium chlorite (2.64 g, 29.2 mmol), monosodium phosphate dihydrate (11.4 g, 72.9 mmol) and 2-methyl-2-butene (12.4 ml, 116.7 mmol) are added successively at room temperature and the mixture is stirred for 2 h. After completion of the reaction (monitored by TLC), the mixture is concentrated under reduced pressure and the residue is diluted with ice water (50 ml) and acidified to pH 5 by adding 2N hydrochloric acid. The mixture is extracted with methyl tert-butyl ether (2*100 ml). The methyl tert-butyl ether layer is extracted again with 10% aqueous sodium hydroxide (100 ml). The aqueous layer is acidified to pH 2 with 5N hydrochloric acid and extracted with dichloromethane (2*50 ml). The organic layer is washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to obtain 4-bromo-2-fluoro-6-methoxy-benzoic acid (2.5 g, 10.0 mmol, 68%).
To a solution <strong>[1472104-49-6]4-bromo-2-fluoro-6-methoxy-benzoic acid</strong> (2.5 g, 10.0 mmol) in dichloromethane (30 ml) is added oxalyl chloride (1.04 ml, 12.0 mmol) added drop wise at 0 oC followed by addition of a catalytic amount of dimethylformamide. The mixture is stirred at the same temperature for 2 h. The solution is added via a cannula to a mixture of 4-chloro benzyl amine (1.7 g, 12.0 mmol) and triethyl amine (4.2 ml, 30.0 mmol) in dry tetrahydrofuran (50 ml) at 0 oC. After stirring at room temperature for 16 h the mixture is diluted with dichloromethane (50 ml) and washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]- 2-fluoro-6-methoxy-benzamide (2.8 g, 7.52 mmol, 74%).
74%
d) Synthesis of 4-bromo-N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-benzamide To a solution <strong>[1472104-49-6]4-bromo-2-fluoro-6-methoxy-benzoic acid</strong> (2.5 g, 10.0 mmol) in dichloromethane (30 ml) is added oxalyl chloride (1.04 ml, 12.0 mmol) added drop wise at 0 C. followed by addition of a catalytic amount of dimethylformamide. The mixture is stirred at the same temperature for 2 h. The solution is added via a cannula to a mixture of 4-chloro benzyl amine (1.7 g, 12.0 mmol) and triethyl amine (4.2 ml, 30.0 mmol) in dry tetrahydrofuran (50 ml) at 0 C. After stirring at room temperature for 16 h the mixture is diluted with dichloromethane (50 ml) and washed with water (50 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to obtain 4-bromo-N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-benzamide (2.8 g, 7.52 mmol, 74%).
4-bromo-2-fluoro-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of <strong>[1472104-49-6]4-bromo-2-fluoro-6-methoxy-benzoic acid</strong> (500 mg, 2 mmol, 1 eq.) and HATU (841 mg, 2.2 mmol, 1.1 eq.) in anhydrous DMF (5 mL) is added DIPEA (701 pL, 4 mmol, 2 eq.). The mixture is stirred at RT for 10 min and trifluoroethylamine (189 pL, 2.4 mmol, 1.2 eq.) is added. The resulting mixture is stirred overnight at RT. The reaction mixture is concentrated in vacuo and diluted with DCM and water. The product is extracted with DCM and the organic layers are dried on Na2S04, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluting with DCM) affords the desired compound. LCMS: MW (calcd): 330.1; m/z MW (obsd): 330.1 - 332.1 (M+H)
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