Dimethyl 2,5-pyridine dicarboxylate → 6-Hydroxymethyl-nicotinic acid methyl ester

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Reaction Steps

Calcium chloride (22.7 g, 204.9 mmol) was added to a suspension of dimethylpyridine-2,5-dicarboxylate (10.0 g, 51.2 mmol) in a mixture 1:2 THF: MeOH (300 mL). The mixture was cooled at 0 C, sodium borohydride (4.85 g, 128.1 mmol) was added portion wise. The reaction mixture warmed slowly to room temperature and stirred for 18 h. An additional 2.5 equivalent of sodium borohydride was added and the reaction mixture was stirred at room temperature for 2 days. Additional THF (100 mL) and MeOH (100 mL) was added and the mixture was stirred for ˜15 h. An additional 2.5 equivalent of sodium borohydride (newer batch) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was slowly poured onto ice-water and diluted with EtOAc (˜200 mL). The white solid was filtered and discarded. Phases from the filtrate were separated, the organic phase was washed with water (3×100 mL). The aqueous washes were combined and re-extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound as an off white solid (5.8 g, 73%). Method B HPLC-MS: MH+ requires m/z=168 Found: m/z=168, Rt=0.91 min (100%).

Provenance & Evidence