Benzoyl Peroxide → 4-(bromomethyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide

Participants

Reaction Steps

To a suspension of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (Preparation 22, 118 g, 0.45 mol) in 1,2-dichloroethane (1.25 L) were added N-bromosuccinimide (91 g, 0.51 mol) and benzoyl peroxide (5 g, 20 mmol) and the mixture was heated at reflux for 18 hours. N-bromosuccinimide (30 g, 0.17 mol) was added and the mixture was heated for further 24 hours. N-bromosuccinimide (20 g, 0.11 mol) was then added and the mixture heated for another 3 hours, then cooled and washed with water (1 L) and aqueous sodium thiosulphate (0.5 M, 200 mL). The organic layer was washed with water (500 mL), dried over sodium sulfate and evaporated. The resulting crude tan solid was dissolved in EtOAc (1 L), diisopropylethylamine (130 mL, 0.75 mol) and diethyl phosphite (27.6 g, 0.2 mol) were added and the mixture was stirred for 5 hours under a nitrogen atmosphere. The reaction mixture was then washed with aqueous hydrochloric acid (2 M, 1 L), dried over magnesium sulfate and evaporated to yield a dark solid, which was triturated with diethyl ether (200 mL) to afford the title compound as a tan solid (68 g). The filtrate was purified by silica gel chromatography eluting with 10% EtOAc and 1% acetic acid in DCM, followed by recrystallization with MeCN (130 mL) to afford a second crop of the title compound.

Provenance & Evidence