Cesium carbonate → 4-amino-6-[[(1S)-1-[6-fluoro-1-methyl-7-(4-pyridyl)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-pyridyl boronic acid (0.041 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. 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). The relevant fractions were concentrated to approximately ⅓ volume then partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 429 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.32 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (2H, d, J=5.05 Hz), 8.03 (1H, s), 7.71-7.70 (2H, m), 7.53 (2H, d, J=13.97 Hz), 7.31 (2H, s), 7.18 (1H, dd, J=10.45, 8.79 Hz), 5.64 (1H, m), 3.21 (3H, s), 1.58 (3H, d, J=6.74 Hz)

Provenance & Evidence