Study on the Synthesis Technology of Anticancer Drug Gilteritinib Fumarate

Based on the reported routes, a convergent eight-step approach to Gilteritinib fumarate was designed, which is suitable for industrial implementation. The first key intermediate, 3,5-dichloro-6-ethylpyrazine-2-carboxamide ( 6 ), was obtained from 2,6-dichloropyrazine in 49.3% yield by two subsequent one-pot Minisci reactions. The second key intermediate, 1-methyl-4-(piperidin-4-yl)piperazine ( 3 ), was synthesized from Boc-4-piperidone and N -methylpiperazine in 88.5% overall yield via two step reaction sequence that included reductive amination and the removal of Boc protective group. The target compound, Gilteritinib fumarate, was obtained in five steps from 1-fluoro-2-methoxy-4-nitrobenzene in 46.9% overall yield. Of special interest in this reaction sequence is the Ullmann-type coupling that was performed in the presence of the CuI- l -quebrachitol catalytic system providing an excellent catalytic effect.