Hexachloroethane → 4-[5-[[3-Fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide

Participants

Reaction Conditions

Reaction Steps

A solution of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide (1.0 g, 3.2 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.12 g, 9.6 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. Butyllithium (6 mL, 1.6 M, 9.6 mmol) was then added to this solution. After 30 min, hexachloroethane (2.27 g, 9.6 mmol) was added to the reaction mixture, the reaction mixture was warmed to −30° C., and then quenched with dilute hydrochloric acid. The reaction mixture was extracted with ethyl acetate (100 mL), washed with brine, dried and concentrated to afford a 1:1 mixture of the desired 5-chloromethyl isoxazole product and the starting material as an inseparable mixture, which was carried to the next stage without further purification. The crude 5-chloromethyl isoxazole (0.25 g, 0.718 mmol) was added to a solution of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol (Example 8, Step 4) (0.324 g) in dioxane (5 mL) and aqueous sodium hydroxide (1N, 2.86 mL), and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water and brine, dried, filtered, and concentrated. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:2 ethyl acetate in hexane, to give 0.130 g (67%) of 4-[5-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)-phenoxy]-methyl]-3-phenylisoxazol-4-yl]benzenesulfonamide as a crystalline solid: 1H NMR (CDCl3/300 MHz) δ 7.93 (d, 2H, J=8.5 Hz), 7.42–7.36 (m, 7H), 6.78–6.54 (m, 3H), 5.15 (s, 2H), 3.79–3.82 (m, 4H), 2.99 (s, 3H), 1.88–1.86 (m, 4H). FABMS m/z=545 (M+Li). HRMS calcd for C28H27N2FO6S 538.1652. Found 539.1652 (M+H).

Provenance & Evidence