Methyl iodide → 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester

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Reaction Steps

[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.25 mmol) is dissolved in anhydrous tetrahydrofuran (200 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (6.63 mL of 2M soln., 13.25 mmol) is slowly added to the solution at room temperature. This is allowed to stir under nitrogen for 6 hours at room temperature. Hexamethylphosphor-amide (9.2 mL, 53 mmol) is added to the reaction followed by methyl iodide (1.74 mL, 26.5 mmol), added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester (1.6 g, 4.51 mmol) is isolated in 34% yield after column chromatography. The racemic 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester is resolved on a Chiralpak AD column (4.6×150 mm). Eluted with 15% 3A alcohol in heptane with 0.2% dimethy-ethylamine at 0.6 mL per minute with detection at 260 nm and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 98.9% ee; isomer 2, 96.4% ee).

Provenance & Evidence