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

Temperature

82 °C

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.

1. customA flame dried three-necked 3-L round-bottomed flask, equipped with a stopper, mechanical stirrer, argon inlet
2. temperaturethermocouple and reflux condenser
3. custompurged
4. temperatureheated
5. temperatureThe reaction mixture was cooled to room temperature
6. customthe excess dimethyl sulfate was quenched with triethylamine (70 mL)
7. filtrationThe resultant precipitate was filtered
8. washwashed with ethyl acetate (2 L)
9. concentrationthe combined filtrate was concentrated on a rotary evaporator
10. customto afford a residue
11. customThis residue was partitioned between ethyl acetate (2 L) and 0.25N HCl (1 L)
12. customThe organic layer was separated
13. washwashed with saturated sodium bicarbonate (2×2 L), 50% saturated sodium chloride solution (2 L)
14. dry with materialdried over magnesium sulfate
15. filtrationThe solution was filtered
16. customthe solvent was removed on a rotary evaporator
17. customto afford the crude ester as a dark brown oil
18. distillationThis residual oil was distilled under vacuum (170° C. at about 25 mm Hg)

ORD record

ord-308db860bc3c4669b80df35c1af7588d

Source dataset

uspto-grants-1999_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05892106