Hydrochloric Acid → HCID 66742254, compound

Participants

Reaction Conditions

Reaction Steps

Cis-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.66 g, 6.83 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (2.009 mL, 6.83 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.419 mL, 6.83 mmol) was added during 8 min. 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 (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.6 g, 65%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.10-2.12 (m, 15H), 2.96-3.05 (m, 1H), 3.08-3.19 (m, 1H), 3.71 (s, 3H), 3.87-4.00 (m, 1H), 4.14-4.24 (m, 1H), 5.72 (s, 1H). MS m/z 357 (M−H)−

Provenance & Evidence