Hydrochloric Acid → trans-Methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

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Reaction Conditions

Reaction Steps

Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.399 g, 1.04 mmol) (from example 127, step 1) was dissolved in MeOH (3.5 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.306 mL, 1.04 mmol) was added over 5 min. After 45 min with stirring, hydroxylamine (50% by weight in water, 0.064 mL, 1.04 mmol) was added over one minute and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5.36 mL, 32.16 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated to give crude trans-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.331 g, 90%). MS m/z 353 (M+H)+

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