Cesium carbonate → 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine

Participants

Reaction Conditions

Reaction Steps

A mixture of CuI (Aldrich, 26.6 mg, 0.27 mmol), cesium carbonate (Aldrich, 351 mg, 1.08 mmol), 1,1′-bis(diphenylphosphino)ferrocene (14.9 mg, 0.03 mmol), palladium(II) acetate (Strem Chemicals, 3.0 mg, 0.01 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (Combi-Phos, 142 mg, 0.54 mmol), and tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e, 150 mg, 0.27 mmol) in a 5 mL conical microwave vial was sealed, evacuated and back-filled with N2 3×. DMF (2.7 mL) was added, and the reaction mixture was stirred at 80° C. for 16 h. The resulting reaction mixture was cooled to RT, filtered, and concentrated to dryness. The crude product was purified by HPLC (5 to 80% 0.1% TFA:Water:0.1% TFA:ACN over 25 min). The fractions were combined, washed with sat. aq. NaHCO3 and extracted with 20% IPA in chloroform. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to a tan oil. The oil was dissolved in MeOH/DCM before adding 6 N HCl in IPA and stirring at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure before resolubilizing with MeOH and passing through a MeOH washed plug of Si-propylsulfonic acid. The compound was released with 2M NH3 in MeOH (30 mL) to afford 1-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine as a dark tan solid. MS (ESI, pos. ion) m/z: 431 (M+1).

Provenance & Evidence