Tert-Butyl1-(4-Bromophenyl)cyclobutylcarbamate

1032350-05-2

75-65-0

1032350-06-3

To a 3 L three-neck flask was added 1-(4-bromophenyl)cyclobutane-1-carboxamide (250 g, 0.98 mol, 1.0 eq.) and tert-butanol (1250 mL, 5.0 v/v). The mixture was heated to 65 °C and stirred until all solids were dissolved (about 10 min). Lead tetraacetate (40.1 g, 1.13 mol, 1.15 eq.) was carefully added in batches over 35 minutes while controlling the temperature below 75°C. After addition, the reaction mixture was stirred at 80 °C for 80 min and the completion of the reaction was confirmed by HPLC analysis. Subsequently, the mixture was cooled to 25 °C, sodium carbonate (250 g, 1.0 wt. eq.) was added, followed by methyl tert-butyl ether (1.9 L). After stirring for 30 min, the solids were removed by filtration through a Celite pad. The filtrate was washed sequentially with 10% aqueous sodium bicarbonate (3 x 2.0 L), 10% brine (500 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate [301 g, 94% yield, 89% purity (AUC)] as a lavender-colored solid. The crude product was purified by repurification in 10/90 methyl tert-butyl ether/heptane (5.0 v/v) to afford tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate [270 g, 84% yield, 94% purity (AUC)] as an off-white solid. The resulting product [270 g, 0.83 mol, 94% purity (AUC)] was re-slurried in 1/1 acetonitrile/water (5.0 v/v) for 22 h at room temperature. The solid was filtered and dried to give the compound tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate [240 g, 89% recovery, 95.2% purity (AUC)] as a white solid. This was combined with other batches of product and purified by a silica gel column (packed and eluted with 1/99 methanol/dichloromethane). The product-rich fraction was collected, concentrated to dryness (525 g), and then slurried in methyl tert-butyl ether (2.0 v/v) and heptane (6.0 v/v) at room temperature to obtain a homogeneous batch, which ultimately yielded tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate [513 g, 97.2% purity (AUC)] as a white solid.