Diisopropylethylamine → 1-({2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetyl)azetidin-3-ol

Participants

Reaction Steps

To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (1.00 g, 2.17 mmol) in 8 ml anhydrous DMF at RT was added azetidin-3-ol hydrochloride (0.475 g, 4.33 mmol) and N,N-diisopropylethylamine (1.84 ml, 10.8 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.65 g, 4.33 mmol) was added and the mixture stirred at RT overnight. The mixture was filtered and purified by reverse-phase HPLC column chromatography (SunFire Prep C18 OBD Sum 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (CD3OD): δ 8.26 (s, 2H), 6.57 (d, J=9.4 Hz, 2H), 4.69 (t, J=12.5 Hz, 2H), 4.57-4.59 (m, 1H), 4.45-4.49 (m, 1H), 4.27 (s, 2H), 4.18-4.22 (m, 1H), 4.01-4.09 (m, 3H), 3.75-3.78 (m, 1H), 3.47 (s, 2H), 3.34 (s, 3H), 2.86-2.93 (m, 2H), 2.09-2.12 (m, 1H), 1.82-1.88 (m, 2H), 1.56-1.58 (m, 1H), 1.31-1.35 (m, 2H), 1.16-1.18 (m, 1H), 0.95-0.97 (m, 1H), 0.59-0.68 (m, 2H), −0.04 (m, 1H). LC/MS (m/z): 517.5 (M+H)+. Human EC50: 1.6 nM

Provenance & Evidence