Control Strategy for the Manufacture of Brivanib Alaninate, a Novel Pyrrolotriazine VEGFR/FGFR Inhibitor
Organic Process Research & Development2014Vol. 19(8), pp. 900–907
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Paul C. Lobben, Evan Barlow, James Bergum, Alan Braem, Shih‐Ying Chang, Frank S. Gibson, Nathaniel Kopp, Chiajen Lai, Thomas L. LaPorte, David K. Leahy, Jale Müslehiddinoğlu, Fernando Quiroz, Dimitri Skliar, Lori A. Spangler, Sushil Srivastava, Daniel Wasser, John M. Wasylyk, Robert Wethman, Zhongmin Xu
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.
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