Sodium hydride → Tert-butyl 3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate

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Reaction Steps

To a solution of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (2.5 g, 14.43 mmol) in anhydrous THF (65 mL) was added NaH (55 w/w % in mineral oil, 381 mg, 15.9 mmol) under N2 atmosphere at 0 to 5° C. The mixture was allowed to warm to room temperature and stirred for 2 hr. Then, this reaction mixture was cooled to −5 to 0° C., and was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (3.28 g, 14.43 mmol) in anhydrous THF (28 mL) at −5 to 0° C. The mixture was stirred at −5 to 0° C. for 2 hr, then allowed to warm to room temperature and stirred for additional 6 h. After this time, the mixture was quenched with water (75 mL) at 0° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel; eluting with 10% ethyl acetate in hexane) to give the title compound (1) (3.35 g, 64%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 5.38-5.46 (m, 1H), 4.38 (dd, J=10.3, 6.5 Hz, 2H), 4.06 (dd, J=10.4, 4.1 Hz, 2H), 1.46 (s, 9H); MS (APCI, M+H+) C12H16BrClN3O3, calcd. 364.0. found 307.9 (M+1-t-butyl), 309.9 (M+3-t-butyl)

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