p-Toluenesulfonic acid monohydrate → Flubromazepam Isomer

Participants

Reaction Steps

A solution of 72.7 g (0.199 moles) of (Z)-N-[(2-amino-5-fluorophenyl)(2-bromophenyl)methylene]glycine methyl ester), 1450 mL of toluene, and 42.8 g (0.225 moles) of p-toluenesulfonic acid monohydrate was heated to reflux for 3 hours under nitrogen After cooling, the product crystallized out of the reaction mixture The resultant suspension was filtered and the collected solid was washed twice with 100 mL of toluene, followed by two washes with 100 mL of hexane. The solid was partitioned between 1.0 L of methylene chloride and 1.0 L of saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with 250 mL of methylene chloride. The combined organic layers were washed twice with 250 mL of 1:1 mixture brine/water, dried with Na2SO4, filtered, and concentrated under vacuum. The residue was redissolved in 800 mL of methylene chloride and concentrated to give 55.5 g of 5-(2-bromophenyl)-7-fluoro-1,3-dihydro-1,4-benzodiazepine-2 (2H)-one as a light yellow solid.

Provenance & Evidence