methyl 2-bromo-4-phenylbutanoate

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

Procedure: 2.3 g (53.2 mmol) of sodium hydride in the form of a suspension in mineral oil are placed at 0° in 30 ml of tetrahydrofuran. Then at 0° to 10°, 6.6 g (44.:3 mmol) of thioglycolic acid tert-butyl ester are added dropwise thereto. A viscous suspension is formed which is diluted with 50 ml of tetrahydrofuran. The mixture is then stirred for 20 minutes at 0° and then 12 g (44.3 mmol) of 2-bromo-4-phenyl-butyric acid methyl ester are added dropwise thereto. The mixture is stirred for 2 hours at room temperature, then taken up in 100 ml of ethyl acetate and extracted by shaking in succession with 50 ml of water and 50 ml of saturated sodium chloride solution. The aqueous phases are combined and extracted by shaking with 25 ml of ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica g al with hexane/ethyl acetate (20:1) as eluant yields 5.7 g (38% of theory) of 2-tert-butyloxycabonylmethylthio-4-phenyl-butyric acid ethyl ester in the form of an oil. A viscous suspension is formed which The mixture is stirred for 2 hours at room temperature extracted by shaking in succession with 50 ml of water and 50 ml of saturated sodium chloride solution extracted by shaking with 25 ml of ethyl acetate dried over sodium sulfate filtered concentrated by evaporation

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 1-butylpiperazine-2,3-dione (Intermediate D, 500 mg, 2.9 mmol) in 4 mL DMF, cooled to 0° C., was added sodium hydride (60% dispersion in mineral oil, 128 mg, 3.2 mmol). The reaction was stirred at rt for 30 min, recooled to 0° C. and a solution of methyl 2-bromo-4-phenylbutanoate (Intermediate C, 820 mg, 3.2 mmol) in 1 mL DMF was added dropwise. The mixture was stirred at rt for 1 h, quenched with brine and extracted with EtOAc. Drying, solvent evaporation and flash chromatography (silica gel, 35-90% EtOAc/hexanes) gave methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)-4-phenylbutanoate. 1H NMR (CDCl3) δ 7.29 (m, 2H), 7.18 (m, 3H), 5.27 (X of ABX, 1H, J=10.8 Hz, J=4.6 Hz), 3.72 (s, 3H), 3.63 (m, 1H), 3.54 (m, 1H), 3.47 (m, 2H), 3.38 (m, 1H), 3.28 (m, 1H), 2.67 (m, 2H), 2.36 (m, 1H), 2.03 (m, 2H), 1.57 (m, 2H), 1.35 (m, 2H), 0.95 (t, 3H, J=7.3 Hz). recooled to 0° C. The mixture was stirred at rt for 1 h quenched with brine extracted with EtOAc Drying solvent evaporation and flash chromatography (silica gel, 35-90% EtOAc/hexanes)