3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol → (2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(3,3-difluoro-2-hydroxy-2-methylpropyl)-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 3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol (75 mg, 0.19 mmol) in piperidine (1 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for 1.5 hr under an atmosphere of nitrogen. After cooling to RT, the reaction mixture was re-treated with additional tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol). The reaction mixture was warmed to 65° C. for a further 3 hr. After cooling to RT, the reaction mixture was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, eluent 9:1 DCM/MeOH) furnished a partially purified product. Further purification by reverse phase preparative HPLC gave the title compound as a brown solid: 1H NMR (500 MHz, DMSO) delta 1.17 (3H, s), 1.90 (3H, s), 2.63 (3H, s), 3.09 (1H, d, J 14.2), 3.21 (1H, d, J 14.2), 5.50 (1H, s), 5.92 (1H, t, J 56.1), 6.78 (1H, s), 7.01 (2H, s), 7.08 (1H, d, J 5.5), 7.36 (1H, dd, J 8.3, 1.2), 7.94 (1H, d, J 8.3), 8.29 (1H, d, J 5.5), 8.89 (1H, s); LC-MS: m/z=+470.05 (M+H)+.

Provenance & Evidence