Flubromazepam

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Step 1 (21.17 g, 51 mmol) was dissolved in ammonia, 2M in methanol (400 mL, 800 mmol) that was further saturated with anhydrous ammonia. The solution was heated to reflux for 16 hr overnight, and allowed to cool to room temperature. The solution was concentrated and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was washed twice with water, dried with brine, and concentrated to give a yellow solid. The solid was recrystallized from ethyl acetate/hexane to give a white powder that was washed with hexane and air dried (9.65 g, 56.8%). The solution was heated to reflux for 16 hr overnight The solution was concentrated the residue was dissolved in ethyl acetate The ethyl acetate layer was washed twice with water dried with brine concentrated to give a yellow solid The solid was recrystallized from ethyl acetate/hexane to give a white powder that was washed with hexane and air dried (9.65 g, 56.8%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round-bottomed flask was charged with 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (500 mg) and tetrahydrofuran (20 mL). To this mixture was added lithium aluminum hydride (1.8 mL of 1M solution in tetrahydrofuran). The reaction was stirred overnight at room temperature, then quenched with water and 10% sodium hydroxide. The quenched mixture was filtered through Celite and the filter was washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and concentrated to an oil. Silica gel purification provided 7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg) as a yellow powder. H1 NMR (d6-dmso): 7.43-7.50 (m, 1H), 7.40 (dt, 1H), 7.18-7.28 (m, 3H), 6.75-6.81 (m, 2H), 6.71 (d, 1H), 3.95 (m, 2H), 3.49 (m, 2H). Mass (ES+)=319.1 (100%). quenched with water and 10% sodium hydroxide The quenched mixture was filtered through Celite the filter was washed with ethyl acetate The filtrate was dried over magnesium sulfate filtered concentrated to an oil Silica gel purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round-bottomed flask was charged with N1-{4-bromo-2-[(2-fluorophenyl)carbonyl]-phenyl}glycinamide (135 mg), ethanol (3 mL) and acetic acid (0.5 mL). The mixture was heated to reflux for 15 min, then cooled and concentrated to dryness. The residue was treated with a saturated solution of sodium bicarbonate and stirred for 10 min. before extracting with ethyl acetate. The combined organics were dried over magnesium sulfate then filtered and concentrated to dryness. The residue was reconcentrated from diethyl ether to provide 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (100 mg) as a light yellow foam. H1 NMR (d6-dmso): 10.74 (br s, 1H), 7.71 (dd, 1H), 7.52-7.59 (m, 2H), 7.15-7.34 (m, 4H), 4.20 (s, 2H). The mixture was heated to reflux for 15 min cooled concentrated to dryness The residue was treated with a saturated solution of sodium bicarbonate before extracting with ethyl acetate The combined organics were dried over magnesium sulfate then filtered concentrated to dryness