Acetone → 4-[5-(1-Hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one

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Reaction Steps

To a solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.500 g, 1.852 mmol) (Example 9a) in THF (20 mL) at −78° C. is added 1M methyl magnesium bromide in dibutyl ether (2.41 mL, 2.41 mmol). The reaction mixture is stirred at −78° C. for 3 h, whereupon acetone (2 mL) is added. The mixture is allowed to warm to ambient temperature and then poured into water (50 mL). The mixture is extracted with ethyl acetate. The combined organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient methanol in dichloromethane, 1% to 5%) to give 4-[5-(1-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as a white solid. Resolution of all four stereoisomers of the title compound is achieved by chiral HPLC. Stereoisomer A is separated with a ChiralPak IA column using an 85:15 heptane-isopropanol mobile phase. The remaining three stereoisomers are resolved with a ChiralPak AD using an 85:15 heptane-ethanol mobile phase to give stereoisomer B (tr=61.4 min), stereoisomer C (tr=76.7 min) and stereoisomer D (tr=94.9 min)

Provenance & Evidence