Control Strategy for the Manufacture of Brivanib Alaninate, a Novel Pyrrolotriazine VEGFR/FGFR Inhibitor

Abstract

This manuscript describes the control strategy for the commercial process to manufacture brivanib alaninate. The active pharmaceutical ingredient is a prodrug which is susceptible to hydrolysis. In addition to controlling hydrolysis, a robust strategy was required in order to control input and process-related impurities. Three significant aspects of control include understanding of the reaction parameters in order to minimize the regioisomer during the alkylation with (R)-propylene oxide, development of a design space through statistical models to control impurity formation, and the use of in situ FT-IR to monitor the hydrogenolysis of the Cbz protecting group.

Aiming for a standardized protocol for preparing a process green synthesis report and for ranking multiple synthesis plans to a common target product

“…We first present and describe the various sections of such a report and then illustrate its use by showing example reports for the industrial manufacture of three pharmaceuticals shown in Figure 1: 5-HT2B and 5-HT7 antagonist [25], brivanib [26][27][28][29], and orexin receptor agonist [30]. The pros and cons of each synthesis are discussed with respect to the three categories of green metrics mentioned above.…”