Hydrochloric Acid → trans-Methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (549 mg, 1.61 mmol) (from example 95, step 1) in MeOH (1.2 mL) was added to a solution of NaOH (70 mg, 1.75 mmol) in MeOH/H2O (1.3 mL/0.08 mL) at −30° C. After 10 min was added hydroxylaminehydrochloride (223 mg, 3.22 mmol) and NaOH (129 mg, 3.22 mmol) in MeOH (1.6 mL) and H2O (1.6 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (2.4 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (194 mg, 39%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.02-1.78 (m, 6H), 1.89-2.03 (m, 2H), 2.83-3.09 (m, 2H), 3.71 (s, 3H), 3.99-4.51 (m, 2H), 5.65 (s, 1H). MS m/z 311 (M+H)+

Provenance & Evidence