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

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• 作者：Paul C. Lobben ; Evan Barlow ; James S. Bergum ; Alan Braem ; Shih-Ying Chang ; Frank Gibson ; Nathaniel Kopp ; Chiajen Lai ; Thomas L. LaPorte ; David K. Leahy ; Jale M眉slehiddino臒lu ; Fernando Quiroz ; Dimitri Skliar ; Lori Spangler ; Sushil Srivastava ; Daniel Wasser ; John Wasylyk ; Robert Wethman ; Zhongmin Xu
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：August 21, 2015
• 年：2015
• 卷：19
• 期：8
• 页码：900-907
• 全文大小：439K
• ISSN：1520-586X

文摘

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.