18-Crown-6 → Tert-butyl 4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidine-1-carboxylate

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Reaction Steps

Cool a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (352 g, 1.75 mol) and 18-crown-6 (463 g, 1.75 mol) in THF to between 0° C. and 5° C. Add potassium tert-butoxide (268 g, 2.39 mol) while maintaining the temperature between 0° C. and 10° C. Cool the resulting mixture to −10° C. to −5° C. Add a 40 wt % solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in THF (1.38 kg, 1.59 mol) while maintaining the temperature between −5° C. and 0° C. Allow the mixture to warm to 15° C. to 25° C. and stir for 2 h. Cool to 0° C. to 5° C., and add water dropwise while maintaining the temperature between 0° C. and 10° C. Add ethyl acetate (3.5 L) and brine (5.5 L). Separate the phases and extract the aqueous phase with ethyl acetate (2×2.5 L). Wash the combined organic phases with brine (3×5.5 L). Concentrate the organic phase under vacuum to approximately 1.5 L total volume to afford a solution of crude 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester. Add additional ethyl acetate (3.0 L). Cool the solution to 0° C. to 5° C. Add HCl (gaseous) (319 g, 8.75 mol) while maintaining the temperature between 0° C. and 5° C. Allow to warm to 15° C. to 25° C. and stir for 4 h. Concentrate the mixture under vacuum to approximately 1.2 L total volume. Filter the resulting solid and wash with cold ethyl acetate (2×0.6 L). Dry to afford 506 g (79%) of the title compound as an off-white solid. mp 200-202° C. (by differential scanning calorimetry).

Provenance & Evidence