Chloromethyl Methyl Ether → 4-Bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine

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Reaction Steps

2-Fluoro-6-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol (1.90 g, 9.63 mmol) was dissolved in mixture of HOAc (100 mL) and NaOH (1.0 N, 20 mL, 20.00 mmol). The mixture was cooled in an ice bath and bromine (0.6 mL, 11.65 mmol) was added. It was stirred for 15 min. Sodium sulfite (1.1 g) was added and the mixture stirred for 5 min. Water (300 mL) and EtOAc (400 mL) were added and the phases mixed and separated. The organic was dried with brine (200 mL) then magnesium sulfate before evaporating to dryness under reduced pressure and further dried under high vacuo. The crude was dissolved in ACN (100 mL) and treated with cesium carbonate (0.98 mL, 12.28 mmol). It was cooled in an ice bath and chloromethyl methyl ether (0.90 mL, 11.85 mmol) was added slowly over 2 min. The reaction was stirred for 90 minutes. The mixture was evaporated to dryness under reduced pressure and the crude partitioned between water (300 mL) and ethyl acetate (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 4-bromo-2-fluoro-3-(methoxymethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridine (1.80 g, 5.62 mmol, 58.4% yield) as a pale yellow oil. MS m/z=320.0, 322.0 [M+H]+. Calculated for C12H15BrFNO3: 319.02.

Provenance & Evidence