4-Nitrobenzoic Acid → Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-{[(4-nitrophenyl)carbonyl]oxy}bicyclo[3.1.0]hexane-2,6-dicarboxylate

Participants

Reaction Conditions

Reaction Steps

To a solution of di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (539.00 g, 751.00 mmol) in tetrahydrofuran (6.76 L) is added triphenylphosphine (393.96 g, 1.50 mol) and 4-nitrobenzoic acid (251.02 g, 1.50 mol). The mixture is cooled to 10° C. whereupon diisopropyl azodicarboxylate (40% v/v in toluene, 744.41 mL, 759.30 g, 1.50 mol) is added dropwise over 15 minutes and allowed to warm to 23° C. After 18 hours, the mixture is diluted with methyl tert-butyl ether (2 L), washed sequentially with aq. sat. NaHCO3 (2×2 L) and brine (1 L), and concentrated in vacuo. The residue is slurried in heptane (5 L) at 40° C. for 30 minutes then cooled to 23° C. The resulting solid is filtered and washed sequentially with heptane (2×500 mL), heptane/methyl tert-butyl ether (3×1 L). The combined filtrates are concentrated in vacuo and residue is purified by chromatography (2.5 kg of SiO2; eluent:hexane/ethyl acetate 95:5 to 75:25) followed by recrystallization in heptane (10 L/kg) to yield the title compound as a white solid (273 g, 49% yield).

Provenance & Evidence