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

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 proce...

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Bibliographic Details
Published in:Organic process research & development 2015-08, Vol.19 (8), p.900-907
Main Authors: Lobben, Paul C, Barlow, Evan, Bergum, James S, Braem, Alan, Chang, Shih-Ying, Gibson, Frank, Kopp, Nathaniel, Lai, Chiajen, LaPorte, Thomas L, Leahy, David K, Müslehiddinoğlu, Jale, Quiroz, Fernando, Skliar, Dimitri, Spangler, Lori, Srivastava, Sushil, Wasser, Daniel, Wasylyk, John, Wethman, Robert, Xu, Zhongmin
Format: Article
Language:English
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/op500126u