Dimethyl Sulfate → (5-Chloro-2-methoxyphenyl)acetic acid methyl ester

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Reaction Conditions

Reaction Steps

A flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet, thermocouple and reflux condenser, was vacuum/argon purged. The flask was charged with the product obtained in Step A (345.0 g, 1.72 mol), anhydrous potassium carbonate (285 g, 2.06 mol) and anhydrous acetonitrile (1.7 L). To the resultant suspension was added dimethyl sulfate (200 mL, 2.11 mol) over 5 minutes with stirring and then heated to reflux at about 82° C. for 1.5 h to complete the esterification. The reaction mixture was cooled to room temperature and the excess dimethyl sulfate was quenched with triethylamine (70 mL). The resultant precipitate was filtered and washed with ethyl acetate (2 L) and the combined filtrate was concentrated on a rotary evaporator to afford a residue. This residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L). The organic layer was separated, washed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L) and dried over magnesium sulfate. The solution was filtered and the solvent was removed on a rotary evaporator to afford the crude ester as a dark brown oil. This residual oil was distilled under vacuum (170° C. at about 25 mm Hg) to afford 310 g (about 85% yield, 97% by HPLC) of the title compound as a viscous pale yellow oil.

Provenance & Evidence