Methyl 2-(hydroxymethyl)isonicotinate

Synthesis

The reaction was performed in 2 separate 1000 mL round-bottomed flasks. To a solution of methyl isonicotinate (70 g, 510.44 mmol) and sulfuric acid (2.340 mL, 43.90 mmol) in MeOH (700 mL) under reflux added a solution of ammonium peroxydisulfate (210 g, 918.80 mmol) in water (350 mL) over 20 min. The reaction was refluxed for 20 min and was then allowed to cool to room temperature. The solid was filtered off and washed with MeOH. After that, MeOH was removed from the filtrate under reduced pressure and then neutralized by cautious stepwise addition of solid Na2CO3 under ice-cooling. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4 and evaporated. The dark-brown residue was treated with cyclohexane (3×300 mL) and the cyclohexane phase was decanted. The remaining dark-brown residue was purified by automated flash chromatography on 2 Biotage KP-SIL 340 g columns. A gradient from 25% to 100% of EtOAc in heptane over 10 CV was used as the mobile phase. Methyl 2-(hydroxymethyl)isonicotinate (27.5 g, 32%) was isolated.