4-Hydroxypiperidine-1-carbonitrile → 1-(3-Isopropyl-1,2,4-oxadiazol-5-YL)piperidin-4-OL

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Reaction Steps

A solution of zinc chloride (1 M in ether; 9.5 mL, 9.5 mmol) was added dropwise over 10 min to a solution of N-hydroxy-isobutyramidine (Intermediate 8; 8.28 g, 81 mmol) and 4-hydroxy-piperidine-1-carbonitrile (from Step 1; 10.0 g, 79 mmol) in ethyl acetate (400 mL). The mixture was stirred at room temperature for 20 min, then the precipitate was filtered off and washed with ether (2×50 mL). A mixture of concentrated HCl (50 mL) and ethanol (100 mL) was added to the precipitate, and the resulting mixture was heated at reflux for 1 h, cooled to room temperature and filtered. The volume of the filtrate was reduced to approximately 50 mL. Water (80 mL) was added and the mixture was made slightly basic by the addition of solid sodium carbonate. Dichloromethane (150 mL) was added. The mixture was filtered and the solids were washed with dichloromethane. The combined organic solutions were dried (magnesium sulfate), filtered, evaporated, and dried under high vacuum to give crude 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (6.7 g, 40%). 1H NMR (CDCl3, 300 MHz) showed that the isolated material contained about 10 mol % of unreacted 4-hydroxy-piperidine-1-carbonitrile and minor solvent related impurities. This material was used directly in the next step without further purification.

Provenance & Evidence