Investigations into the Suzuki–Miyaura coupling aiming at multikilogram synthesis of E2040 using (o-cyanophenyl)boronic esters

The Suzuki–Miyaura cross-coupling reaction between 1-{3-bromo-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine ((R)-1b) and thermally unstable (o-cyanophenyl)boronic ester 6b in the presence of dichlorobis(triphenylphosphine)palladium and potassium phosphate hydrate in boiling toluene was found to afford 1-{3-(2-cyanophenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine ((R)-5), an intermediate for the synthesis of E2040, in excellent yields. The reaction conditions for the cross-coupling were optimized by the design of experiments (DOE) approach and found to be applicable to electron-rich and/or sterically hindered aryl bromides. Safety evaluation for the production of (R)-5 is also described.