Sodium Bicarbonate → Benzyl 4-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate

Participants

Reaction Steps

A 500 mL round bottom flask was charged with crude pyridine 33 (8.20 g, 27.7 mmol), acetone (300 mL), and O-methyloxime 30 (6.8 g, 27.7 mmol), and the reaction mixture was allowed to stir at room temperature for 12 hours, after which thin-layer chromatography testing suggested that pyridinyl salt formation was complete. The reaction was then concentrated under reduced pressure in a 500 mL round bottom flask, and charged with methanol (200 mL), additional pyridinyl salt prepared previously (600 mg), and potassium tert-butoxide (3.90 g, 34.6 mmol). The resulting mixture was heated to 65° C. for 4 hours. The reaction mixture was then poured into 400 mL of an aqueous solution saturated with NaHCO3 and extracted with 3×250 mL of methylene chloride. The organic fractions were pooled, dried over Na2SO4, filtered, concentrated under reduced pressure, then dissolved in a minimum volume of CH2Cl2, then loaded onto 3×40 g Isco RediSep normal phase silica cartridges, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, and 1% concentrated ammonium hydroxide. Fractions containing the desired product were pooled and concentrated under reduced pressure; fractions containing impure product were pooled, concentrated under reduced pressure, then dissolved in a minimum volume of CH2Cl2, and loaded onto 2×40 g Isco RediSep normal phase silica cartridges, and purified on an Isco OptiX10 CombiFlash instrument using a gradient which started at 100% heptane and ended at 100% ethyl acetate. This process was repeated once on the remaining impure product. Yield of 34: 3.10 g (26%). 1H NMR (500 MHz, CDCl3) δ 1.50 (m, 2H), 1.76 (m, 2H), 2.55 (m, 1H), 2.77 (bs, 2H), 4.45 (bs, 2H), 5.04 (s, 2H), 6.48 (d, J=5.3 Hz, 1H), 6.96 (t, J=8.8 Hz, 2H), 7.24 (m, 6H), 7.57 (s, 1H), 7.76 (m, 2H), 7.86 (d, J=7.1 Hz, 1H). MS (ESI+) 430.2.

Provenance & Evidence