4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine → (2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Participants

Reaction Conditions

Reaction Steps

To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg, 0.21 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I) iodide (3 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol). The reaction mixture was warmed to 66° C. for 2 hr, re-treated with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol) and warming continued at 66° C. for a further 1 hr. Following cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was slurried in diethyl ether (0.5 mL) to which was introduced acetonitrile until a fine cream precipitate resulted. Filtration furnished the title compound as a cream solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d, J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+394.00 (M+H)+.

Provenance & Evidence