N-(4-bromo-2-fluoro-6-methylphenyl)-2,2-dimethylpropanamide

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(4-bromo-2-fluoro-6-methylphenyl)-2,2-dimethylpropanamide (21.7 g, 79.2 mmol) in anhydrous tetrahydrofuran (500 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and stirred while butyllithium (124 mL of a 1.6M solution in hexanes, 198 mmol) was added dropwise. The resulting mixture was aged at −78° C. for 30 minutes and then treated with N,N-dirnethylhexanamide (28.3 g, 198 mmol). After warming up to 0° C. over 2 hours, the mixture was removed from the cooling bath and treated with aqueous saturated NH4Cl (20 mL). The resulting slurry was diluted with CH2Cl2 (1000 mL), dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 19:1 to 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide N-(2-fluoro-4-hexanoyl-6-methylphenyl)-2,2-dimethylpropanamide (12.7 g, 55%) as a yellow foam. cooled in a dry ice-acetone bath was added dropwise the mixture was removed from the cooling bath treated with aqueous saturated NH4Cl (20 mL) The resulting slurry was diluted with CH2Cl2 (1000 mL) dried over MgSO4 filtered through a pad of silica concentrated under vacuum The residue was purified by flash chromatography on a Biotage 40M KP-Sil column eluting with 19:1 to 9:1 hexanes-EtOAc The product containing fractions were evaporated under vacuum

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

Procedure: Pivaloyl chloride (4 mL, 38.4 mmol) was added slowly (caution—exothermic reaction) to an ice cold solution of the crude 4-bromo-2-fluoro-6-methylaniline from step 4 (about 32 mmol) in pyridine (20 mL). After the addition, the ice bath was removed and the warm reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a water solution of 1 N HCl and extracted with EtOAc. The organic layer was washed with 1N HCl three times, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide N-(4-bromo-2-fluoro-6-methylphenyl)-2,2-dimethylpropanamide (4.3 g, 49% for 3 steps) as a yellow solid. After the addition the ice bath was removed the warm reaction mixture extracted with EtOAc The organic layer was washed with 1N HCl three times dried over MgSO4 filtered concentrated under vacuum The residue was purified by flash chromatography on a Biotage 40M KP-Sil column eluting with 9:1 hexanes-EtOAc The product containing fractions were evaporated under vacuum