Hydrochloric Acid → {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid

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Reaction Steps

To a solution of methyl {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetate (3.15 g, 6.62 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. 5 M sodium hydroxide (4.50 ml, 22.5 mmol) was added and the mixture stirred at RT overnight. 2 M hydrochloric acid (11.3 ml, 22.5 mmol) was added to adjust the pH of the solution to 4. The volatiles were removed under vacuum, and the aqueous phase extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over magnesium sulphate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-60% EtOAc:hexanes (700 ml) to afford the title compound. 1H NMR (CDCl3): δ 8.29 (s, 2H), 6.48 (d, J=9.1 Hz, 2H), 4.67-4.74 (m, 2H), 4.26 (s, 2H), 4.00-4.04 (m, 2H), 3.67 (s, 2H), 3.34 (s, 3H), 2.84-2.91 (m, 2H), 2.12-2.18 (m, 1H), 1.83 (d, J=12.4 Hz, 2H), 1.48-1.55 (m, 1H), 1.33-1.41 (m, 2H), 1.05-1.12 (m, 1H), 0.87-0.94 (m, 1H), 0.64-0.71 (m, 1H), 0.58-0.64 (m, 1H), −0.10 (m, 1H). LC/MS (m/z) 463.4 (M+H)+.

Provenance & Evidence