Cesium carbonate → 4-amino-6-[[(1S)-1-[6-fluoro-1-methyl-7-(1H-pyrazol-4-yl)benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrile

Participants

Reaction Conditions

Reaction Steps

A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.065 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 80 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 428 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.23 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 13.10 (1H, s), 8.28 (1H, s), 8.04 (1H, s), 7.83 (1H, s), 7.66-7.64 (1H, m), 7.60 (1H, dd, J=8.74, 4.77 Hz), 7.31 (2H, s), 7.12-7.06 (1H, m), 5.66-5.61 (1H, m), 3.66 (3H, s), 1.57 (3H, d, J=6.73 Hz)

Provenance & Evidence