Trifluoroacetic acid → {(1R,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}methanol

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Reaction Conditions

Reaction Steps

To a cold (0° C.), stirred solution tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (intermediate 4, 5.0 g, 19.58 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (100 mL) slowly over 10 minutes. After being stirred at 0° C. for 1 h, the mixture was concentrated under vacuum. Residual TFA was further removed by stripping twice from dichloromethane followed by drying in vacuum. The resulting residue was dissolved in DMF (40 ml) followed by the addition of cesium carbonate (35.09 g, 107.69 mmol) and 2-chloro-5-ethylpyrimidine (5.6 g, 39.15 mmol). The mixture was stirred at RT for 15 h before being quenched with H2O. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with H2O (2×), brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 2:1→1:1 hexane:ethyl acetate) to yield the title compound. H NMR (500 MHz, CDCl3) δ 8.18 (s, 2H), 4.74-4.65 (m, 2H), 3.74-3.67 (m, 2H), 2.89-2.81 (m, 2H), 2.47 (q, J 7.6 Hz, 2H), 1.91-1.82 (m, 2H), 1.46-1.34 (m, 2H), 1.23-1.16 (M, 4H), 1.16-1.07 (m 1H), 0.77-0.70 (m, 2H), 0.09-0.04 (m, 1H). MS (ESI) m/z 262 [M+H]+.

Provenance & Evidence