Diisopropylethylamine → tert-butyl 1-[[2-bromo-4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]azetidine-3-carboxylate

Participants

Reaction Conditions

Reaction Steps

A reaction vial containing a stir bar was charged with 3-bromo-4-(bromomethyl)benzonitrile (100 mg, 0.364 mmol), tert-butyl azetidine-3-carboxylate acetic acid salt, Int.1-C (95 mg, 0.436 mmol), DMF (1 mL), and DIPEA (0.381 mL, 2.182 mmol). The vial was flushed with argon, sealed and placed on a reaction block which was heated to 65° C. After 5 hours, the reaction was cooled to RT and directly purified by preparative HPLC (methanol/water plus 0.1% TFA as eluent). To the product fractions was added a solution of sodium bicarbonate (200 mg) in water (4 mL) and then the volatiles were removed in vacuo to afford a white solid which was slurried in methanol (10 mL). Hydroxylamine hydrochloride (37.6 mg, 0.541 mmol) was added and the reaction was heated overnight in an oil bath set to 50° C. Additional hydroxylamine hydrochloride (30 mg) along with sodium bicarbonate (150 mg) were added and heating continued at 50° C. for 8 hours. The volatiles were removed in vacuo and the residue purified by preparative HPLC (methanol/water plus 0.1% TFA as eluent). The pH of the product containing fractions was adjusted to ˜7 using sodium bicarbonate, the solvents were concentrated and the resulting aqueous solution was extracted with DCM. The organics were dried over anhydrous magnesium sulfate then concentrated to afford (Z)-tert-butyl 1-(2-bromo-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (12.6 mg, 0.032 mmol). The compound had an HPLC retention time=0.72 min.−Column: BEH C18 2.1×50 mm 1.7 u (gradient: 2% MeCN/water plus 0.05% to 98% MeCN/water plus 0.05% TFA over 1 min.); LC/MS M+1=384/386.

Provenance & Evidence