Dichloromethane → 2,2-dichloro-N-[(1S,2R)-2-(4-{6-[cyano(fluoro)methyl]pyridin-3-yl}phenyl)-1-(fluoromethyl)-2-hydroxyethyl]acetamide

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Reaction Conditions

Reaction Steps

A stirred mixture of the product of step 1, Example 22 (127 mg, 0.591 mmol), bis(pinacolato)diboron (163 mg, 0.640 mmol), and potassium acetate (193 mg, 1.97 mmol) in dry dimethylformamide (4.9 mL) is sparged with nitrogen for 5 min before [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (40.2 mg, 0.0492 mmol) is added. The mixture is sparged with nitrogen for another 5 min, heated to 80° C. under nitrogen and maintained at this temperature. After 4.5 hours, the mixture is cooled to ambient temperature, solid 2,2-dichloro-N-[(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-(4-iodophenyl)ethyl]acetamide (previously described in WO13057619 Preparation 1 page 16, 200 mg, 0.492 mmol) and cesium carbonate (0.562 g, 1.72 mmol) were added under a stream of nitrogen, and the mixture is sparged with nitrogen for 5 min and heated to 80° C. After 2 hours, the mixture is cooled to ambient temperature, diluted with water (25 mL), and extracted with ethylacetate (2×25 mL). The combined organic phase is washed with water (3×20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel chromatography (40 g, 25-45% ethyl acetate/hexanes) gave the title compound (77 mg): 1H NMR (300 MHz, DMSO-d6) δ 4.28 (m, 1.5H), 4.45 (m, 0.5H), 4.58 (m, 0.5H), 4.72 (m, 0.5H), 4.93 (m, 1H), 6.02 (d, 1H), 6.53 (s, 1H), 6.93 (d, 1H), 7.51 (d, 2H), 7.77 (m, 3H), 8.28 (dd, 1H), 8.62 (bd, 1H), 9.04 (m, 1H). MS (ESI+) m/z 414 [M+H].

Provenance & Evidence