18-Crown-6 → 4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepane-1-carboxylic acid tert-butyl ester

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Reaction Steps

To a solution of 36.11 g (167.7 mmol) of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester in 300 mL of tetrahydrofuran at 0° C. (ice bath), 18-crown-6 (63.43 g, 237.58 mmol) and potassium tert-butoxide (28.06 g, 250.04 mmol) are added. The resulting mixture is stirred for 20 min at room temperature under nitrogen, followed by addition of a solution of 48.5 g (139.75 mmol) of 4-Bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in 100 mL tetrahydrofuran over a 1 hour period. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 12 hours. Water (200 mL) is added to the reaction mixture and the solvent is removed under reduced pressure. The resulting brown oil is diluted with EtOAc (2×250 mL), and washed with brine (2×150 mL). The organic layer is dried (Na2SO4), filtered and concentrated to afford a crude which is purified on silica gel column chromatography (Eluting with Hexanes/EtOAc 8:2) to obtain 56 g of the title compound as a white/yellow oil. (83%). MS (m/e): 481 (M+1).

Provenance & Evidence