Chloroacetic Acid → rac-tert-butyl (4R,5S)-4-fluoro-5-hydroxyazepane-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (25.00 g, 107.2 mmol) was dissolved in THF (1100 mL). To this solution was added 2-chloroacetic acid (15.19 g, 160.8 mmol) and PPh3 (42.16 g, 160.8 mmol). The solution was cooled to 0° C. and DEAD (25.31 mL, 160.8 mmol) was added as a THF solution (250 mL). The reaction mixture was protected from light and stirred overnight as it slowly increased to ambient temperature. The THF was removed in vacuo and replaced with EtOAc. The solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in dioxane (500 mL), and water was added (250 mL). A 1N NaOH solution was added until the pH reached ˜10 (200 mL). The mixture was stirred for 1 hour and then quenched with 1N KHSO4 (250 mL). The mixture was extracted with EtOAc (3×250 mL) and the combined organic phases were washed with saturated aqueous NaHCO3, dried over Na2CO3, filtered and concentrated to a white paste. The paste was then slurried in 50% Et2O/hexanes (200 mL) and filtered through qualitative paper. The resulting white solid was washed with 50% Et2O/hexanes (3×200 mL) and the filtrate was concentrated. The crude residue was purified by column chromatography (10 to 40% Acetone/hexanes) to provide the product (22.4 g, 89%) as a thick colorless oil.

Provenance & Evidence