Trimethyl orthoformate → 3-Chloro-2-dimethoxymethyl-4-fluorophenol

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Reaction Steps

2-Chloro-3-fluoro-6-hydroxybenzaldehyde (79.0 g, 452 mmol) was taken in a single neck flask equipped with a condenser and a nitrogen inlet. To this, trimethylorthoformate (96.0 g, 99.0 mL, 905 mmol) and a solution of ammonium nitrate (3.6 g, 45 mmol) in methanol (40 mL) were added and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium carbonate solution, stirred for few minutes, and extracted with ethyl acetate (300 mL, 200 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give crude product. It was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give 65 g (64% yield) of the title compound. 1HNMR (CDCl3, 300 MHz): δ=8.52 (s, 1H), 7.04 (dd, J=9.0 Hz, 1H), 6.74-6.78 (m, 1H), 5.84 (s, 1H), 3.47 (s, 6H).

Provenance & Evidence