Hydrochloric Acid → HCID 67155606, compound

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A solution of methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate (300 mg, 780 μmol) in tetrahydrofuran (2.0 mL) was diluted with methanol (4.0 mL, 780 μmol) and treated at rt with sodium borohydride (30 mg, 780 μmol). After 2.25 h, the solution was poured into water (about 25 mL), treated with 1.0 M aqueous HCl (about 1 mL) and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide crude racemic methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxychroman-3-carboxylate as a white solid (292 mg). Without further purification, this material was dissolved in dichloromethane (9.5 mL) and treated with trifluoroacetic acid (0.5 mL). After standing at rt for 1.5 h, the solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography (silica gel, 2-10% ethyl acetate/hexane) to provide crude racemic methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxylate as a colorless gum (65 mg). Without further purification, a solution of a portion of this gum (60 mg) in methanol (2.0 mL) was treated with 1.0 M aqueous sodium hydroxide (2.0 mL) and heated at reflux for 4.5 h. After this time, the solution was cooled to rt. Once at the prescribed temperature, a white solid formed, which was removed by filtration and washed with water. The combined filtrate and wash were acidified with 1.0 M aqueous HCl, giving a gummy material. A small amount of methanol was added to the gummy material and the resulting mixture was heated briefly, then stirred while cooling to rt, thereby forming a white solid, which was collected by filtration, washed with water and dried under vacuum to provide Example 2-1 (29 mg). 1H NMR (400 MHz, CDCl3) δ ppm 6.26 (s, 1 H) 6.83 (d, J=8.1 Hz, 1 H) 6.96 (t, J=7.1 Hz, 1 H) 7.23 (dd, J=7.6, 1.0 Hz, 1 H) 7.29 (m, 1 H) 7.41 (d, J=8.1 Hz, 1 H) 7.46 (dd, J=8.6, 2.0 Hz, 1 H) 7.72 (d, J=1.5 Hz, 1 H) 7.83 (s, 1 H. Mass spectrum m/z 355.24 (M+H)+, 377.16 (M+Na)+.

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