Ethanol → 2-Hydroxy-3-pyridin-3-yl-acrylic acid ethyl ester

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Reaction Steps

A dry 1 L round bottomed flask was charged with anhydrous Et2O (500 mL) and cooled to 0° C. (ice-water bath). After having been rinsed with hexane, NaH (60% w/w suspension in mineral oil, 16 g, 400 mmol, 2 eq, weight before rinsing) was added followed by absolute EtOH (23.2 mL, 400 moles, 2 eq). After 10 minutes, a mixture of 3-pyridine carboxaldehyde (18.8 mL, 200 mmol, 1 eq) and N,N-dimethyl glycine ethyl ester (84.8 mL, 3 eq) (N,N-dimethyl glycine methyl ester also performs satisfactorily in this preparation) was added during 1 minute. This mixture was as stirred overnight at room temperature, heated at 30° C. for 1 h, and then transferred to a 2 L separation funnel. The mixture was diluted with EtOAc (500 mL) and H20 (500 mL) and the organic phase was transferred to a beaker and stirred with 1N HCl (500 mL) at room temperature for 10 minutes. The mixture was checked to confirm a pH=1 and then the phases were separated. The aqueous layer was retained and slowly neutralized by the addition of solid NaHCO3. This solution was extracted with EtOAc (3×300 mL), the combined extracts dried (Na2SO4), filtered and concentrated to a yellow solid. Crystallization from EtOAc-Hexanes (4:1) provided 20.0 g (52% yield) of pale yellow 8. RP-HPLC Method 2-100% B.

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