Process Development of the Pyrazinecarboxamide Component of Gilteritinib, a FLT3 Inhibitor

Gilteritinib (ASP2215) is an inhibitor of the mutated FMS-like tyrosine kinase 3 (FLT3) for the treatment of relapsed or refractory acute myeloid leukemia. Discovery chemistry identified a key pyrazinecarboxamide intermediate, 3,5-dichloro-6-ethylpyrazine-2-carboxamide, in the synthesis of gilteritinib. However, the four-step route to the intermediate from 2,6-dichloropyrazine required cryogenic conditions and column chromatography and was therefore not appropriate for large-scale synthesis to cover all of the material requirements of the final active pharmaceutical ingredient, gilteritinib, for early stage development thereof. To address these issues urgently and determine a scalable synthetic route to the key compound, a thorough process investigation was undertaken, and the efficient second route starting from methyl 3-oxopentanoate was successfully discovered. Highlights of the newly developed route included (1) higher throughput and overall yield compared to the discovery route, (2) no requirement for cryogenic conditions or column chromatography, (3) avoidance of heavy metals, and (4) minimization of waste generation compared to the discovery route. Furthermore, scale-up studies especially from a safety standpoint were implemented for the second-generation route prior to the first production. These investigations enabled us to produce a single 125 kg batch of the key intermediate in a greatly shortened lead time by the cyclization strategy from readily available methyl 3-oxopentanoate, which contributed to the early stage development and future commercial synthesis of gilteritinib.