Sodium Cyanide → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(cyano-hydroxy-methyl)-pyrazin-2-yl]-3-cyclopentyl-propionamide

Participants

Reaction Conditions

Reaction Steps

A solution of 2-(R)-(3-chloro-4-methanesulfonylphenyl)-3-cyclopentyl-N-(5-dimethoxymethylpyrazin-2-yl)-propionamide (prepared as in Example 21, 740 mg, 1.53 mmol) and p-toluenesulfonic acid monohydrate (80 mg, 0.41 mmol) in acetone/water (20 mL, 9:1) was heated at 60° C. for 30 min. The mixture was cooled and then diluted with ethyl acetate (100 mL). The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (1×30 mL), water (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a pale yellow foam. The resulting material was dissolved in a mixture of ethyl acetate/water (1:1, 10 mL), cooled to 0° C., and then treated with sodium bisulfite (69 mg, 1.5 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min. At this time, the reaction was treated with sodium cyanide (73 mg, 1.5 mmol), and the reaction was stirred at 0° C. for 30 min. At this time, the mixture was partitioned between a saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with a saturated ammonium chloride solution (1×30 mL), a saturated aqueous sodium bicarbonate solution (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(cyano-hydroxy-methyl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (230 mg, 32%) as a yellow foam: (ES)+-HRMS m/e calcd for C21H23ClN4O4S (M+H)+ 463.1208, found 463.1202.

Provenance & Evidence