Cis-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (5.23 g, 14.16 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. Sodium hydroxide (3.73 mL, 14.16 mmol) dissolved in water (5.00 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (0.868 mL, 14.16 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (73.2 mL, 438.95 mmol) and stirred for 20 min. The solvent was concentrated in vacuo. DCM (200 mL) and water (150 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (150 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.41 g, 71.2%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.81-1.88 (m, 1H), 2.08-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.38 (m, 1H), 3.02-3.11 (m, 1H), 3.32-3.40 (m, 1H), 3.67 (s, 3H), 4.09-4.18 (m, 1H), 5.02-5.08 (m, 1H), 5.56 (s, 1H), 6.86-6.92 (m, 1H), 6.95-7.01 (m, 1H), 7.03-7.10 (m, 1H). MS m/z 339 (M+H)+.
