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

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Reaction Conditions

Reaction Steps

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.95 g, 5.34 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.213 g, 5.34 mmol) dissolved in water (2.000 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.327 mL, 5.34 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.09 g, 61%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.80-2.17 (m, 4H), 2.72-2.87 (m, 2H), 2.91-3.02 (m, 1H), 3.12-3.24 (m, 1H), 3.52 (s, 3H), 3.95-4.05 (m, 1H), 4.29-4.40 (m, 1H), 5.72 (s, 1H), 6.94-7.12 (m, 3H), 7.12-7.20 (m, 1H). MS m/z 335 (M+H)+

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