Hydrochloric Acid → (2R,4S)-Methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.13 g, 3.06 mmol) was dissolved in MeOH (14 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.128 g, 3.21 mmol) dissolved in water (1.400 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.197 mL, 3.21 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15.80 mL, 94.82 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (423 mg, 41%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.12-2.15 (m, 14H), 2.93-3.04 (m, 1H), 3.10-3.31 (m, 2H), 3.35-3.50 (m, 2H), 3.70 (s, 3H), 3.83-3.94 (m, 1H), 4.05-4.15 (m, 1H), 5.75 (s, 1H). MS m/z 339 (M+H)+

Provenance & Evidence