Commercial Synthesis of a Pyrrolotriazine–Fluoroindole Intermediate to Brivanib Alaninate: Process Development Directed toward Impurity Control

The development of a practical, commercial process for the preparation of 4-fluoro-2-methyl-indol-5-ol and its subsequent coupling with a pyrrolotriazine to form an advanced intermediate of the oncology therapy brivanib alaninate is described. A key aspect is the multikilogram-scale preparation of the fluoroindole intermediate from trifluoronitrobenzene and the subsequent coupling while achieving impurity minimalization. As brivanib alaninate is a high-dose drug, the synthesis of high-quality API with low levels of impurities is critical.