Nicotinate → 6-{[(1,1,1-Trifluoropropan-2-yl)oxy]methyl}pyridine-3-carboxylic acid

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Reaction Steps

1,1,1-Trifluoropropan-2-ol (0.406 mL, 4.483 mmol) was added drop wise to a suspension of sodium hydride (60% in mineral oil) (0.239 g, 5.977 mmol) in dry THF (20 mL) at 0 C. The mixture was stirred at 0 C for 15 minutes. A solution of methyl 6-(methanesulfonyloxy)methyl]pyridine-3-carboxylate (Intermediate 189, 0.733 g, 2.989 mmol) in THF (10 mL) was added drop wise. The reaction mixture was stirred at 0 C for 30 minutes and room temperature for 3 days. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (30 mL). The phases were separated, and the organic phase was extracted with a saturated aqueous solution of sodium bicarbonate (3×15 mL). The aqueous extracts were combined, washed with EtOAc (1×10 mL). The organic phase was discarded and the aqueous phase was acidified to pH 4 using 2N HCl and extracted with EtOAc (3×30 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide a brown crude residue. The crude material was purified by flash chromatography (DCM:MeOH 98:2) to afford the title compound as a beige solid (0.345 g, 46%). Method B HPLC-MS: MH+ requires m/z=250 Found: m/z=250, Rt=1.61 min (89%).

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