Triisopropyl borate → (2-Aminopyrimidin-5-yl)boronic acid

Participants

Reaction Conditions

Reaction Steps

By the alternative synthetic route in Scheme 8, to a 3-L flask under nitrogen was charged tetrahydrofuran (1055 mL), followed by 5-bromopyrimidine-2-amine 9 (70.0 g, 0.40 mol). The mixture was cooled to a temperature between −60° C. and −70° C. and lithium bis(trimethylsilyl)amide (LiHMDS) (1M in tetrahydrofuran, 483 mL, 0.483 mol) was charged over 30 min while maintaining the temperature between −60° C. and −70° C. The mixture was stirred at −60° C. to −70° C. for 1 h. n-Butyllithium (2.5 M in hexanes, 515 mL, 1.29 mol) was charged over 1 h while maintaining the temperature between −60° C. and −70° C., and the reaction mixture was then aged for 2 h. Additional n-butyllithium (2.5 M in hexanes, 48 mL, 0.12 mol) was charged over 15 min while maintaining the temperature between −60° C. and −70° C., and the reaction mixture was stirred for 1 h. To the mixture was added triisopropyl borate (91.0 g, 0.48 mol) over 1 h while maintaining the temperature between −60° C. and −70° C., and the reaction mixture was stirred for 1 h. The mixture was then allowed to warm to 0-5° C. and water (700 mL) was added over 1 h. After being aged at 0-5° C. for 30 min, the resulting layers were separated. To the aqueous layer was added water (420 mL) over 30 min, followed by addition of tert-butyl methyl ether (822 mL). The mixture was allowed to warm to 20-25° C. and was stirred for 30 min. The layers were separated and the aqueous layer was washed with tert-butyl methyl ether (5×700 mL). The aqueous layer was cooled to 0-5° C., and 35% aqueous hydrochloric acid solution (137 mL) was added over 1 h while maintaining the temperature between 0-5° C. The mixture was stirred at 0-5° C. for 1.5 h, filtered, washed with water (14 mL) and the cake was dried under vacuum at 45-50° C. to afford the crude product (26.7 g). The crude product was charged to a 5-L flask, followed by addition of methanol (908 mL), and the mixture was stirred at room temperature (rt) for 20 min. The mixture was warmed to 65° C. and stirred for 1.5 h. To the mixture was added water (2136 mL) over 2 h and the suspension was stirred for 1.5 h. The mixture was cooled to 20° C. and stirred for 14 h. The solid was collected by filtration and the filter cake was washed with water (13 mL), dried under vacuum at 45-50° C. for 12 h to afford 2-aminopyrimidin-5-ylboronic acid III (23.6 g, 42% yield)

Provenance & Evidence